%0 Journal Article %J Circ Cardiovasc Genet %D 2009 %T Association of novel genetic Loci with circulating fibrinogen levels: a genome-wide association study in 6 population-based cohorts. %A Dehghan, Abbas %A Yang, Qiong %A Peters, Annette %A Basu, Saonli %A Bis, Joshua C %A Rudnicka, Alicja R %A Kavousi, Maryam %A Chen, Ming-Huei %A Baumert, Jens %A Lowe, Gordon D O %A McKnight, Barbara %A Tang, Weihong %A de Maat, Moniek %A Larson, Martin G %A Eyhermendy, Susana %A McArdle, Wendy L %A Lumley, Thomas %A Pankow, James S %A Hofman, Albert %A Massaro, Joseph M %A Rivadeneira, Fernando %A Kolz, Melanie %A Taylor, Kent D %A van Duijn, Cornelia M %A Kathiresan, Sekar %A Illig, Thomas %A Aulchenko, Yurii S %A Volcik, Kelly A %A Johnson, Andrew D %A Uitterlinden, André G %A Tofler, Geoffrey H %A Gieger, Christian %A Psaty, Bruce M %A Couper, David J %A Boerwinkle, Eric %A Koenig, Wolfgang %A O'Donnell, Christopher J %A Witteman, Jacqueline C %A Strachan, David P %A Smith, Nicholas L %A Folsom, Aaron R %K Adult %K Aged %K Aged, 80 and over %K Cardiovascular Diseases %K Cohort Studies %K European Continental Ancestry Group %K Female %K Fibrinogen %K Genetic Loci %K Genome-Wide Association Study %K Humans %K Male %K Middle Aged %K Pedigree %K Polymorphism, Single Nucleotide %K Young Adult %X

BACKGROUND: Fibrinogen is both central to blood coagulation and an acute-phase reactant. We aimed to identify common variants influencing circulation fibrinogen levels.

METHODS AND RESULTS: We conducted a genome-wide association analysis on 6 population-based studies, the Rotterdam Study, the Framingham Heart Study, the Cardiovascular Health Study, the Atherosclerosis Risk in Communities Study, the Monitoring of Trends and Determinants in Cardiovascular Disease/KORA Augsburg Study, and the British 1958 Birth Cohort Study, including 22 096 participants of European ancestry. Four loci were marked by 1 or more single-nucleotide polymorphisms that demonstrated genome-wide significance (P<5.0 x 10(-8)). These included a single-nucleotide polymorphism located in the fibrinogen beta chain (FGB) gene and 3 single-nucleotide polymorphisms representing newly identified loci. The high-signal single-nucleotide polymorphisms were rs1800789 in exon 7 of FGB (P=1.8 x 10(-30)), rs2522056 downstream from the interferon regulatory factor 1 (IRF1) gene (P=1.3 x 10(-15)), rs511154 within intron 1 of the propionyl coenzyme A carboxylase (PCCB) gene (P=5.9 x 10(-10)), and rs1539019 on the NLR family pyrin domain containing 3 isoforms (NLRP3) gene (P=1.04 x 10(-8)).

CONCLUSIONS: Our findings highlight biological pathways that may be important in regulation of inflammation underlying cardiovascular disease.

%B Circ Cardiovasc Genet %V 2 %P 125-33 %8 2009 Apr %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/20031576?dopt=Abstract %R 10.1161/CIRCGENETICS.108.825224 %0 Journal Article %J Circ Cardiovasc Genet %D 2009 %T Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium: Design of prospective meta-analyses of genome-wide association studies from 5 cohorts. %A Psaty, Bruce M %A O'Donnell, Christopher J %A Gudnason, Vilmundur %A Lunetta, Kathryn L %A Folsom, Aaron R %A Rotter, Jerome I %A Uitterlinden, André G %A Harris, Tamara B %A Witteman, Jacqueline C M %A Boerwinkle, Eric %K Adult %K Aged %K Aging %K Cohort Studies %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genotype %K Heart Diseases %K Humans %K Male %K Meta-Analysis as Topic %K Middle Aged %K Phenotype %K Research Design %K Risk Factors %X

BACKGROUND: The primary aim of genome-wide association studies is to identify novel genetic loci associated with interindividual variation in the levels of risk factors, the degree of subclinical disease, or the risk of clinical disease. The requirement for large sample sizes and the importance of replication have served as powerful incentives for scientific collaboration. Methods- The Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium was formed to facilitate genome-wide association studies meta-analyses and replication opportunities among multiple large population-based cohort studies, which collect data in a standardized fashion and represent the preferred method for estimating disease incidence. The design of the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium includes 5 prospective cohort studies from the United States and Europe: the Age, Gene/Environment Susceptibility-Reykjavik Study, the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Rotterdam Study. With genome-wide data on a total of about 38 000 individuals, these cohort studies have a large number of health-related phenotypes measured in similar ways. For each harmonized trait, within-cohort genome-wide association study analyses are combined by meta-analysis. A prospective meta-analysis of data from all 5 cohorts, with a properly selected level of genome-wide statistical significance, is a powerful approach to finding genuine phenotypic associations with novel genetic loci.

CONCLUSIONS: The Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium and collaborating non-member studies or consortia provide an excellent framework for the identification of the genetic determinants of risk factors, subclinical-disease measures, and clinical events.

%B Circ Cardiovasc Genet %V 2 %P 73-80 %8 2009 Feb %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/20031568?dopt=Abstract %R 10.1161/CIRCGENETICS.108.829747 %0 Journal Article %J JAMA %D 2009 %T Genetic variants associated with cardiac structure and function: a meta-analysis and replication of genome-wide association data. %A Vasan, Ramachandran S %A Glazer, Nicole L %A Felix, Janine F %A Lieb, Wolfgang %A Wild, Philipp S %A Felix, Stephan B %A Watzinger, Norbert %A Larson, Martin G %A Smith, Nicholas L %A Dehghan, Abbas %A Grosshennig, Anika %A Schillert, Arne %A Teumer, Alexander %A Schmidt, Reinhold %A Kathiresan, Sekar %A Lumley, Thomas %A Aulchenko, Yurii S %A König, Inke R %A Zeller, Tanja %A Homuth, Georg %A Struchalin, Maksim %A Aragam, Jayashri %A Bis, Joshua C %A Rivadeneira, Fernando %A Erdmann, Jeanette %A Schnabel, Renate B %A Dörr, Marcus %A Zweiker, Robert %A Lind, Lars %A Rodeheffer, Richard J %A Greiser, Karin Halina %A Levy, Daniel %A Haritunians, Talin %A Deckers, Jaap W %A Stritzke, Jan %A Lackner, Karl J %A Völker, Uwe %A Ingelsson, Erik %A Kullo, Iftikhar %A Haerting, Johannes %A O'Donnell, Christopher J %A Heckbert, Susan R %A Stricker, Bruno H %A Ziegler, Andreas %A Reffelmann, Thorsten %A Redfield, Margaret M %A Werdan, Karl %A Mitchell, Gary F %A Rice, Kenneth %A Arnett, Donna K %A Hofman, Albert %A Gottdiener, John S %A Uitterlinden, André G %A Meitinger, Thomas %A Blettner, Maria %A Friedrich, Nele %A Wang, Thomas J %A Psaty, Bruce M %A van Duijn, Cornelia M %A Wichmann, H-Erich %A Munzel, Thomas F %A Kroemer, Heyo K %A Benjamin, Emelia J %A Rotter, Jerome I %A Witteman, Jacqueline C %A Schunkert, Heribert %A Schmidt, Helena %A Völzke, Henry %A Blankenberg, Stefan %K Adult %K Aged %K Aged, 80 and over %K Aorta %K Cardiovascular Diseases %K Echocardiography %K European Continental Ancestry Group %K Female %K Genome-Wide Association Study %K Genotype %K Heart Atria %K Heart Ventricles %K Humans %K Male %K Middle Aged %K Organ Size %K Phenotype %K Polymorphism, Single Nucleotide %K Risk Factors %K Ventricular Dysfunction, Left %K Ventricular Function, Left %X

CONTEXT: Echocardiographic measures of left ventricular (LV) structure and function are heritable phenotypes of cardiovascular disease.

OBJECTIVE: To identify common genetic variants associated with cardiac structure and function by conducting a meta-analysis of genome-wide association data in 5 population-based cohort studies (stage 1) with replication (stage 2) in 2 other community-based samples.

DESIGN, SETTING, AND PARTICIPANTS: Within each of 5 community-based cohorts comprising the EchoGen consortium (stage 1; n = 12 612 individuals of European ancestry; 55% women, aged 26-95 years; examinations between 1978-2008), we estimated the association between approximately 2.5 million single-nucleotide polymorphisms (SNPs; imputed to the HapMap CEU panel) and echocardiographic traits. In stage 2, SNPs significantly associated with traits in stage 1 were tested for association in 2 other cohorts (n = 4094 people of European ancestry). Using a prespecified P value threshold of 5 x 10(-7) to indicate genome-wide significance, we performed an inverse variance-weighted fixed-effects meta-analysis of genome-wide association data from each cohort.

MAIN OUTCOME MEASURES: Echocardiographic traits: LV mass, internal dimensions, wall thickness, systolic dysfunction, aortic root, and left atrial size.

RESULTS: In stage 1, 16 genetic loci were associated with 5 echocardiographic traits: 1 each with LV internal dimensions and systolic dysfunction, 3 each with LV mass and wall thickness, and 8 with aortic root size. In stage 2, 5 loci replicated (6q22 locus associated with LV diastolic dimensions, explaining <1% of trait variance; 5q23, 12p12, 12q14, and 17p13 associated with aortic root size, explaining 1%-3% of trait variance).

CONCLUSIONS: We identified 5 genetic loci harboring common variants that were associated with variation in LV diastolic dimensions and aortic root size, but such findings explained a very small proportion of variance. Further studies are required to replicate these findings, identify the causal variants at or near these loci, characterize their functional significance, and determine whether they are related to overt cardiovascular disease.

%B JAMA %V 302 %P 168-78 %8 2009 Jul 08 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/19584346?dopt=Abstract %R 10.1001/jama.2009.978-a %0 Journal Article %J J Thromb Haemost %D 2009 %T Genome-wide association studies of cardiovascular risk factors: design, conduct and interpretation. %A Bis, J C %A Glazer, N L %A Psaty, B M %K Cardiovascular Diseases %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Quantitative Trait Loci %K Risk Factors %X

Relying on known biology, candidate-gene studies have been only modestly successful in identifying genetic variants associated with cardiovascular risk factors. Genome-wide association (GWA) studies, in contrast, allow broad scans across millions of loci in search of unsuspected genetic associations with phenotypes. The large numbers of statistical tests in GWA studies and the large sample sizes required to detect modest-sized associations have served as a powerful incentive for the development of large collaborative efforts such as the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. This article uses published data on three phenotypes, fibrinogen, uric acid, and electrocardiographic QT interval duration, from the CHARGE Consortium to describe several methodologic issues in the design, conduct, and interpretation of GWA studies, including the use of imputation and the need for additional genotyping. Even with large studies, novel genetic loci explain only a small proportion of the variance of cardiovascular phenotypes.

%B J Thromb Haemost %V 7 Suppl 1 %P 308-11 %8 2009 Jul %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/19630823?dopt=Abstract %R 10.1111/j.1538-7836.2009.03392.x %0 Journal Article %J N Engl J Med %D 2009 %T Genomewide association studies of stroke. %A Ikram, M Arfan %A Seshadri, Sudha %A Bis, Joshua C %A Fornage, Myriam %A DeStefano, Anita L %A Aulchenko, Yurii S %A Debette, Stephanie %A Lumley, Thomas %A Folsom, Aaron R %A van den Herik, Evita G %A Bos, Michiel J %A Beiser, Alexa %A Cushman, Mary %A Launer, Lenore J %A Shahar, Eyal %A Struchalin, Maksim %A Du, Yangchun %A Glazer, Nicole L %A Rosamond, Wayne D %A Rivadeneira, Fernando %A Kelly-Hayes, Margaret %A Lopez, Oscar L %A Coresh, Josef %A Hofman, Albert %A DeCarli, Charles %A Heckbert, Susan R %A Koudstaal, Peter J %A Yang, Qiong %A Smith, Nicholas L %A Kase, Carlos S %A Rice, Kenneth %A Haritunians, Talin %A Roks, Gerwin %A de Kort, Paul L M %A Taylor, Kent D %A de Lau, Lonneke M %A Oostra, Ben A %A Uitterlinden, André G %A Rotter, Jerome I %A Boerwinkle, Eric %A Psaty, Bruce M %A Mosley, Thomas H %A van Duijn, Cornelia M %A Breteler, Monique M B %A Longstreth, W T %A Wolf, Philip A %K African Continental Ancestry Group %K Aged %K Chromosomes, Human, Pair 12 %K Cohort Studies %K European Continental Ancestry Group %K Female %K Genetic Markers %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genotype %K Humans %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Proportional Hazards Models %K Risk Factors %K Stroke %X

BACKGROUND: The genes underlying the risk of stroke in the general population remain undetermined.

METHODS: We carried out an analysis of genomewide association data generated from four large cohorts composing the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, including 19,602 white persons (mean [+/-SD] age, 63+/-8 years) in whom 1544 incident strokes (1164 ischemic strokes) developed over an average follow-up of 11 years. We tested the markers most strongly associated with stroke in a replication cohort of 2430 black persons with 215 incident strokes (191 ischemic strokes), another cohort of 574 black persons with 85 incident strokes (68 ischemic strokes), and 652 Dutch persons with ischemic stroke and 3613 unaffected persons.

RESULTS: Two intergenic single-nucleotide polymorphisms on chromosome 12p13 and within 11 kb of the gene NINJ2 were associated with stroke (P<5x10(-8)). NINJ2 encodes an adhesion molecule expressed in glia and shows increased expression after nerve injury. Direct genotyping showed that rs12425791 was associated with an increased risk of total (i.e., all types) and ischemic stroke, with hazard ratios of 1.30 (95% confidence interval [CI], 1.19 to 1.42) and 1.33 (95% CI, 1.21 to 1.47), respectively, yielding population attributable risks of 11% and 12% in the discovery cohorts. Corresponding hazard ratios were 1.35 (95% CI, 1.01 to 1.79; P=0.04) and 1.42 (95% CI, 1.06 to 1.91; P=0.02) in the large cohort of black persons and 1.17 (95% CI, 1.01 to 1.37; P=0.03) and 1.19 (95% CI, 1.01 to 1.41; P=0.04) in the Dutch sample; the results of an underpowered analysis of the smaller black cohort were nonsignificant.

CONCLUSIONS: A genetic locus on chromosome 12p13 is associated with an increased risk of stroke.

%B N Engl J Med %V 360 %P 1718-28 %8 2009 Apr 23 %G eng %N 17 %1 https://www.ncbi.nlm.nih.gov/pubmed/19369658?dopt=Abstract %R 10.1056/NEJMoa0900094 %0 Journal Article %J Nat Genet %D 2009 %T Genome-wide association study of blood pressure and hypertension. %A Levy, Daniel %A Ehret, Georg B %A Rice, Kenneth %A Verwoert, Germaine C %A Launer, Lenore J %A Dehghan, Abbas %A Glazer, Nicole L %A Morrison, Alanna C %A Johnson, Andrew D %A Aspelund, Thor %A Aulchenko, Yurii %A Lumley, Thomas %A Köttgen, Anna %A Vasan, Ramachandran S %A Rivadeneira, Fernando %A Eiriksdottir, Gudny %A Guo, Xiuqing %A Arking, Dan E %A Mitchell, Gary F %A Mattace-Raso, Francesco U S %A Smith, Albert V %A Taylor, Kent %A Scharpf, Robert B %A Hwang, Shih-Jen %A Sijbrands, Eric J G %A Bis, Joshua %A Harris, Tamara B %A Ganesh, Santhi K %A O'Donnell, Christopher J %A Hofman, Albert %A Rotter, Jerome I %A Coresh, Josef %A Benjamin, Emelia J %A Uitterlinden, André G %A Heiss, Gerardo %A Fox, Caroline S %A Witteman, Jacqueline C M %A Boerwinkle, Eric %A Wang, Thomas J %A Gudnason, Vilmundur %A Larson, Martin G %A Chakravarti, Aravinda %A Psaty, Bruce M %A van Duijn, Cornelia M %K Blood Pressure %K Cell Line %K Chromosome Mapping %K Chromosomes, Human %K Diastole %K Gene Expression Regulation %K Genetic Association Studies %K Genome-Wide Association Study %K Humans %K Hypertension %K Liver %K Lymphocytes %K Meta-Analysis as Topic %K Odds Ratio %K Phenotype %K Prevalence %K Risk Assessment %K Systole %X

Blood pressure is a major cardiovascular disease risk factor. To date, few variants associated with interindividual blood pressure variation have been identified and replicated. Here we report results of a genome-wide association study of systolic (SBP) and diastolic (DBP) blood pressure and hypertension in the CHARGE Consortium (n = 29,136), identifying 13 SNPs for SBP, 20 for DBP and 10 for hypertension at P < 4 × 10(-7). The top ten loci for SBP and DBP were incorporated into a risk score; mean BP and prevalence of hypertension increased in relation to the number of risk alleles carried. When ten CHARGE SNPs for each trait were included in a joint meta-analysis with the Global BPgen Consortium (n = 34,433), four CHARGE loci attained genome-wide significance (P < 5 × 10(-8)) for SBP (ATP2B1, CYP17A1, PLEKHA7, SH2B3), six for DBP (ATP2B1, CACNB2, CSK-ULK3, SH2B3, TBX3-TBX5, ULK4) and one for hypertension (ATP2B1). Identifying genes associated with blood pressure advances our understanding of blood pressure regulation and highlights potential drug targets for the prevention or treatment of hypertension.

%B Nat Genet %V 41 %P 677-87 %8 2009 Jun %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/19430479?dopt=Abstract %R 10.1038/ng.384 %0 Journal Article %J PLoS One %D 2009 %T Multiple independent genetic factors at NOS1AP modulate the QT interval in a multi-ethnic population. %A Arking, Dan E %A Khera, Amit %A Xing, Chao %A Kao, W H Linda %A Post, Wendy %A Boerwinkle, Eric %A Chakravarti, Aravinda %K Adaptor Proteins, Signal Transducing %K Adolescent %K Adult %K African Americans %K Aged %K Death, Sudden, Cardiac %K Electrocardiography %K Ethnic Groups %K European Continental Ancestry Group %K Female %K Genome-Wide Association Study %K Heart Diseases %K Heart Rate %K Hispanic Americans %K Humans %K Linear Models %K Linkage Disequilibrium %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Sex Factors %K Young Adult %X

Extremes of electrocardiographic QT interval are associated with increased risk for sudden cardiac death (SCD); thus, identification and characterization of genetic variants that modulate QT interval may elucidate the underlying etiology of SCD. Previous studies have revealed an association between a common genetic variant in NOS1AP and QT interval in populations of European ancestry, but this finding has not been extended to other ethnic populations. We sought to characterize the effects of NOS1AP genetic variants on QT interval in the multi-ethnic population-based Dallas Heart Study (DHS, n = 3,072). The SNP most strongly associated with QT interval in previous samples of European ancestry, rs16847548, was the most strongly associated in White (P = 0.005) and Black (P = 3.6 x 10(-5)) participants, with the same direction of effect in Hispanics (P = 0.17), and further showed a significant SNP x sex-interaction (P = 0.03). A second SNP, rs16856785, uncorrelated with rs16847548, was also associated with QT interval in Blacks (P = 0.01), with qualitatively similar results in Whites and Hispanics. In a previously genotyped cohort of 14,107 White individuals drawn from the combined Atherosclerotic Risk in Communities (ARIC) and Cardiovascular Health Study (CHS) cohorts, we validated both the second locus at rs16856785 (P = 7.63 x 10(-8)), as well as the sex-interaction with rs16847548 (P = 8.68 x 10(-6)). These data extend the association of genetic variants in NOS1AP with QT interval to a Black population, with similar trends, though not statistically significant at P<0.05, in Hispanics. In addition, we identify a strong sex-interaction and the presence of a second independent site within NOS1AP associated with the QT interval. These results highlight the consistent and complex role of NOS1AP genetic variants in modulating QT interval.

%B PLoS One %V 4 %P e4333 %8 2009 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/19180230?dopt=Abstract %R 10.1371/journal.pone.0004333 %0 Journal Article %J Nat Genet %D 2009 %T Multiple loci associated with indices of renal function and chronic kidney disease. %A Köttgen, Anna %A Glazer, Nicole L %A Dehghan, Abbas %A Hwang, Shih-Jen %A Katz, Ronit %A Li, Man %A Yang, Qiong %A Gudnason, Vilmundur %A Launer, Lenore J %A Harris, Tamara B %A Smith, Albert V %A Arking, Dan E %A Astor, Brad C %A Boerwinkle, Eric %A Ehret, Georg B %A Ruczinski, Ingo %A Scharpf, Robert B %A Chen, Yii-Der Ida %A de Boer, Ian H %A Haritunians, Talin %A Lumley, Thomas %A Sarnak, Mark %A Siscovick, David %A Benjamin, Emelia J %A Levy, Daniel %A Upadhyay, Ashish %A Aulchenko, Yurii S %A Hofman, Albert %A Rivadeneira, Fernando %A Uitterlinden, André G %A van Duijn, Cornelia M %A Chasman, Daniel I %A Paré, Guillaume %A Ridker, Paul M %A Kao, W H Linda %A Witteman, Jacqueline C %A Coresh, Josef %A Shlipak, Michael G %A Fox, Caroline S %K Chromosome Mapping %K Cohort Studies %K Genetic Variation %K Genome-Wide Association Study %K Glomerular Filtration Rate %K Humans %K Kidney %K Kidney Failure, Chronic %K Meta-Analysis as Topic %K Mucoproteins %K Netherlands %K Polymorphism, Single Nucleotide %K Prevalence %K Uromodulin %X

Chronic kidney disease (CKD) has a heritable component and is an important global public health problem because of its high prevalence and morbidity. We conducted genome-wide association studies (GWAS) to identify susceptibility loci for glomerular filtration rate, estimated by serum creatinine (eGFRcrea) and cystatin C (eGFRcys), and CKD (eGFRcrea < 60 ml/min/1.73 m(2)) in European-ancestry participants of four population-based cohorts (ARIC, CHS, FHS, RS; n = 19,877; 2,388 CKD cases), and tested for replication in 21,466 participants (1,932 CKD cases). We identified significant SNP associations (P < 5 × 10(-8)) with CKD at the UMOD locus, with eGFRcrea at UMOD, SHROOM3 and GATM-SPATA5L1, and with eGFRcys at CST and STC1. UMOD encodes the most common protein in human urine, Tamm-Horsfall protein, and rare mutations in UMOD cause mendelian forms of kidney disease. Our findings provide new insights into CKD pathogenesis and underscore the importance of common genetic variants influencing renal function and disease.

%B Nat Genet %V 41 %P 712-7 %8 2009 Jun %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/19430482?dopt=Abstract %R 10.1038/ng.377 %0 Journal Article %J Nat Genet %D 2009 %T Multiple loci influence erythrocyte phenotypes in the CHARGE Consortium. %A Ganesh, Santhi K %A Zakai, Neil A %A van Rooij, Frank J A %A Soranzo, Nicole %A Smith, Albert V %A Nalls, Michael A %A Chen, Ming-Huei %A Köttgen, Anna %A Glazer, Nicole L %A Dehghan, Abbas %A Kuhnel, Brigitte %A Aspelund, Thor %A Yang, Qiong %A Tanaka, Toshiko %A Jaffe, Andrew %A Bis, Joshua C M %A Verwoert, Germaine C %A Teumer, Alexander %A Fox, Caroline S %A Guralnik, Jack M %A Ehret, Georg B %A Rice, Kenneth %A Felix, Janine F %A Rendon, Augusto %A Eiriksdottir, Gudny %A Levy, Daniel %A Patel, Kushang V %A Boerwinkle, Eric %A Rotter, Jerome I %A Hofman, Albert %A Sambrook, Jennifer G %A Hernandez, Dena G %A Zheng, Gang %A Bandinelli, Stefania %A Singleton, Andrew B %A Coresh, Josef %A Lumley, Thomas %A Uitterlinden, André G %A Vangils, Janine M %A Launer, Lenore J %A Cupples, L Adrienne %A Oostra, Ben A %A Zwaginga, Jaap-Jan %A Ouwehand, Willem H %A Thein, Swee-Lay %A Meisinger, Christa %A Deloukas, Panos %A Nauck, Matthias %A Spector, Tim D %A Gieger, Christian %A Gudnason, Vilmundur %A van Duijn, Cornelia M %A Psaty, Bruce M %A Ferrucci, Luigi %A Chakravarti, Aravinda %A Greinacher, Andreas %A O'Donnell, Christopher J %A Witteman, Jacqueline C M %A Furth, Susan %A Cushman, Mary %A Harris, Tamara B %A Lin, Jing-Ping %K Blood Pressure %K Cell Line %K Cohort Studies %K Endothelial Cells %K Erythrocytes %K Gene Expression %K Genome, Human %K Genome-Wide Association Study %K Humans %K Hypertension %K Phenotype %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %X

Measurements of erythrocytes within the blood are important clinical traits and can indicate various hematological disorders. We report here genome-wide association studies (GWAS) for six erythrocyte traits, including hemoglobin concentration (Hb), hematocrit (Hct), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC) and red blood cell count (RBC). We performed an initial GWAS in cohorts of the CHARGE Consortium totaling 24,167 individuals of European ancestry and replication in additional independent cohorts of the HaemGen Consortium totaling 9,456 individuals. We identified 23 loci significantly associated with these traits in a meta-analysis of the discovery and replication cohorts (combined P values ranging from 5 x 10(-8) to 7 x 10(-86)). Our findings include loci previously associated with these traits (HBS1L-MYB, HFE, TMPRSS6, TFR2, SPTA1) as well as new associations (EPO, TFRC, SH2B3 and 15 other loci). This study has identified new determinants of erythrocyte traits, offering insight into common variants underlying variation in erythrocyte measures.

%B Nat Genet %V 41 %P 1191-8 %8 2009 Nov %G eng %N 11 %1 http://www.ncbi.nlm.nih.gov/pubmed/19862010?dopt=Abstract %R 10.1038/ng.466 %0 Journal Article %J PLoS Genet %D 2009 %T NRXN3 is a novel locus for waist circumference: a genome-wide association study from the CHARGE Consortium. %A Heard-Costa, Nancy L %A Zillikens, M Carola %A Monda, Keri L %A Johansson, Asa %A Harris, Tamara B %A Fu, Mao %A Haritunians, Talin %A Feitosa, Mary F %A Aspelund, Thor %A Eiriksdottir, Gudny %A Garcia, Melissa %A Launer, Lenore J %A Smith, Albert V %A Mitchell, Braxton D %A McArdle, Patrick F %A Shuldiner, Alan R %A Bielinski, Suzette J %A Boerwinkle, Eric %A Brancati, Fred %A Demerath, Ellen W %A Pankow, James S %A Arnold, Alice M %A Chen, Yii-Der Ida %A Glazer, Nicole L %A McKnight, Barbara %A Psaty, Bruce M %A Rotter, Jerome I %A Amin, Najaf %A Campbell, Harry %A Gyllensten, Ulf %A Pattaro, Cristian %A Pramstaller, Peter P %A Rudan, Igor %A Struchalin, Maksim %A Vitart, Veronique %A Gao, Xiaoyi %A Kraja, Aldi %A Province, Michael A %A Zhang, Qunyuan %A Atwood, Larry D %A Dupuis, Josée %A Hirschhorn, Joel N %A Jaquish, Cashell E %A O'Donnell, Christopher J %A Vasan, Ramachandran S %A White, Charles C %A Aulchenko, Yurii S %A Estrada, Karol %A Hofman, Albert %A Rivadeneira, Fernando %A Uitterlinden, André G %A Witteman, Jacqueline C M %A Oostra, Ben A %A Kaplan, Robert C %A Gudnason, Vilmundur %A O'Connell, Jeffrey R %A Borecki, Ingrid B %A van Duijn, Cornelia M %A Cupples, L Adrienne %A Fox, Caroline S %A North, Kari E %K Aged %K Body Mass Index %K Cohort Studies %K European Continental Ancestry Group %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Male %K Middle Aged %K Nerve Tissue Proteins %K Obesity %K Polymorphism, Single Nucleotide %K Waist Circumference %X

Central abdominal fat is a strong risk factor for diabetes and cardiovascular disease. To identify common variants influencing central abdominal fat, we conducted a two-stage genome-wide association analysis for waist circumference (WC). In total, three loci reached genome-wide significance. In stage 1, 31,373 individuals of Caucasian descent from eight cohort studies confirmed the role of FTO and MC4R and identified one novel locus associated with WC in the neurexin 3 gene [NRXN3 (rs10146997, p = 6.4x10(-7))]. The association with NRXN3 was confirmed in stage 2 by combining stage 1 results with those from 38,641 participants in the GIANT consortium (p = 0.009 in GIANT only, p = 5.3x10(-8) for combined analysis, n = 70,014). Mean WC increase per copy of the G allele was 0.0498 z-score units (0.65 cm). This SNP was also associated with body mass index (BMI) [p = 7.4x10(-6), 0.024 z-score units (0.10 kg/m(2)) per copy of the G allele] and the risk of obesity (odds ratio 1.13, 95% CI 1.07-1.19; p = 3.2x10(-5) per copy of the G allele). The NRXN3 gene has been previously implicated in addiction and reward behavior, lending further evidence that common forms of obesity may be a central nervous system-mediated disorder. Our findings establish that common variants in NRXN3 are associated with WC, BMI, and obesity.

%B PLoS Genet %V 5 %P e1000539 %8 2009 Jun %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/19557197?dopt=Abstract %R 10.1371/journal.pgen.1000539 %0 Journal Article %J Nat Genet %D 2009 %T Variants in ZFHX3 are associated with atrial fibrillation in individuals of European ancestry. %A Benjamin, Emelia J %A Rice, Kenneth M %A Arking, Dan E %A Pfeufer, Arne %A van Noord, Charlotte %A Smith, Albert V %A Schnabel, Renate B %A Bis, Joshua C %A Boerwinkle, Eric %A Sinner, Moritz F %A Dehghan, Abbas %A Lubitz, Steven A %A D'Agostino, Ralph B %A Lumley, Thomas %A Ehret, Georg B %A Heeringa, Jan %A Aspelund, Thor %A Newton-Cheh, Christopher %A Larson, Martin G %A Marciante, Kristin D %A Soliman, Elsayed Z %A Rivadeneira, Fernando %A Wang, Thomas J %A Eiriksdottir, Gudny %A Levy, Daniel %A Psaty, Bruce M %A Li, Man %A Chamberlain, Alanna M %A Hofman, Albert %A Vasan, Ramachandran S %A Harris, Tamara B %A Rotter, Jerome I %A Kao, W H Linda %A Agarwal, Sunil K %A Stricker, Bruno H Ch %A Wang, Ke %A Launer, Lenore J %A Smith, Nicholas L %A Chakravarti, Aravinda %A Uitterlinden, André G %A Wolf, Philip A %A Sotoodehnia, Nona %A Köttgen, Anna %A van Duijn, Cornelia M %A Meitinger, Thomas %A Mueller, Martina %A Perz, Siegfried %A Steinbeck, Gerhard %A Wichmann, H-Erich %A Lunetta, Kathryn L %A Heckbert, Susan R %A Gudnason, Vilmundur %A Alonso, Alvaro %A Kääb, Stefan %A Ellinor, Patrick T %A Witteman, Jacqueline C M %K Atrial Fibrillation %K Chromosomes, Human, Pair 16 %K European Continental Ancestry Group %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Homeodomain Proteins %K Humans %K Meta-Analysis as Topic %K Mutation %K Polymorphism, Single Nucleotide %K Reproducibility of Results %X

We conducted meta-analyses of genome-wide association studies for atrial fibrillation (AF) in participants from five community-based cohorts. Meta-analyses of 896 prevalent (15,768 referents) and 2,517 incident (21,337 referents) AF cases identified a new locus for AF (ZFHX3, rs2106261, risk ratio RR = 1.19; P = 2.3 x 10(-7)). We replicated this association in an independent cohort from the German AF Network (odds ratio = 1.44; P = 1.6 x 10(-11); combined RR = 1.25; combined P = 1.8 x 10(-15)).

%B Nat Genet %V 41 %P 879-81 %8 2009 Aug %G eng %N 8 %1 http://www.ncbi.nlm.nih.gov/pubmed/19597492?dopt=Abstract %R 10.1038/ng.416 %0 Journal Article %J Nat Genet %D 2010 %T Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. %A Speliotes, Elizabeth K %A Willer, Cristen J %A Berndt, Sonja I %A Monda, Keri L %A Thorleifsson, Gudmar %A Jackson, Anne U %A Lango Allen, Hana %A Lindgren, Cecilia M %A Luan, Jian'an %A Mägi, Reedik %A Randall, Joshua C %A Vedantam, Sailaja %A Winkler, Thomas W %A Qi, Lu %A Workalemahu, Tsegaselassie %A Heid, Iris M %A Steinthorsdottir, Valgerdur %A Stringham, Heather M %A Weedon, Michael N %A Wheeler, Eleanor %A Wood, Andrew R %A Ferreira, Teresa %A Weyant, Robert J %A Segrè, Ayellet V %A Estrada, Karol %A Liang, Liming %A Nemesh, James %A Park, Ju-Hyun %A Gustafsson, Stefan %A Kilpeläinen, Tuomas O %A Yang, Jian %A Bouatia-Naji, Nabila %A Esko, Tõnu %A Feitosa, Mary F %A Kutalik, Zoltán %A Mangino, Massimo %A Raychaudhuri, Soumya %A Scherag, Andre %A Smith, Albert Vernon %A Welch, Ryan %A Zhao, Jing Hua %A Aben, Katja K %A Absher, Devin M %A Amin, Najaf %A Dixon, Anna L %A Fisher, Eva %A Glazer, Nicole L %A Goddard, Michael E %A Heard-Costa, Nancy L %A Hoesel, Volker %A Hottenga, Jouke-Jan %A Johansson, Asa %A Johnson, Toby %A Ketkar, Shamika %A Lamina, Claudia %A Li, Shengxu %A Moffatt, Miriam F %A Myers, Richard H %A Narisu, Narisu %A Perry, John R B %A Peters, Marjolein J %A Preuss, Michael %A Ripatti, Samuli %A Rivadeneira, Fernando %A Sandholt, Camilla %A Scott, Laura J %A Timpson, Nicholas J %A Tyrer, Jonathan P %A van Wingerden, Sophie %A Watanabe, Richard M %A White, Charles C %A Wiklund, Fredrik %A Barlassina, Christina %A Chasman, Daniel I %A Cooper, Matthew N %A Jansson, John-Olov %A Lawrence, Robert W %A Pellikka, Niina %A Prokopenko, Inga %A Shi, Jianxin %A Thiering, Elisabeth %A Alavere, Helene %A Alibrandi, Maria T S %A Almgren, Peter %A Arnold, Alice M %A Aspelund, Thor %A Atwood, Larry D %A Balkau, Beverley %A Balmforth, Anthony J %A Bennett, Amanda J %A Ben-Shlomo, Yoav %A Bergman, Richard N %A Bergmann, Sven %A Biebermann, Heike %A Blakemore, Alexandra I F %A Boes, Tanja %A Bonnycastle, Lori L %A Bornstein, Stefan R %A Brown, Morris J %A Buchanan, Thomas A %A Busonero, Fabio %A Campbell, Harry %A Cappuccio, Francesco P %A Cavalcanti-Proença, Christine %A Chen, Yii-Der Ida %A Chen, Chih-Mei %A Chines, Peter S %A Clarke, Robert %A Coin, Lachlan %A Connell, John %A Day, Ian N M %A den Heijer, Martin %A Duan, Jubao %A Ebrahim, Shah %A Elliott, Paul %A Elosua, Roberto %A Eiriksdottir, Gudny %A Erdos, Michael R %A Eriksson, Johan G %A Facheris, Maurizio F %A Felix, Stephan B %A Fischer-Posovszky, Pamela %A Folsom, Aaron R %A Friedrich, Nele %A Freimer, Nelson B %A Fu, Mao %A Gaget, Stefan %A Gejman, Pablo V %A Geus, Eco J C %A Gieger, Christian %A Gjesing, Anette P %A Goel, Anuj %A Goyette, Philippe %A Grallert, Harald %A Grässler, Jürgen %A Greenawalt, Danielle M %A Groves, Christopher J %A Gudnason, Vilmundur %A Guiducci, Candace %A Hartikainen, Anna-Liisa %A Hassanali, Neelam %A Hall, Alistair S %A Havulinna, Aki S %A Hayward, Caroline %A Heath, Andrew C %A Hengstenberg, Christian %A Hicks, Andrew A %A Hinney, Anke %A Hofman, Albert %A Homuth, Georg %A Hui, Jennie %A Igl, Wilmar %A Iribarren, Carlos %A Isomaa, Bo %A Jacobs, Kevin B %A Jarick, Ivonne %A Jewell, Elizabeth %A John, Ulrich %A Jørgensen, Torben %A Jousilahti, Pekka %A Jula, Antti %A Kaakinen, Marika %A Kajantie, Eero %A Kaplan, Lee M %A Kathiresan, Sekar %A Kettunen, Johannes %A Kinnunen, Leena %A Knowles, Joshua W %A Kolcic, Ivana %A König, Inke R %A Koskinen, Seppo %A Kovacs, Peter %A Kuusisto, Johanna %A Kraft, Peter %A Kvaløy, Kirsti %A Laitinen, Jaana %A Lantieri, Olivier %A Lanzani, Chiara %A Launer, Lenore J %A Lecoeur, Cécile %A Lehtimäki, Terho %A Lettre, Guillaume %A Liu, Jianjun %A Lokki, Marja-Liisa %A Lorentzon, Mattias %A Luben, Robert N %A Ludwig, Barbara %A Manunta, Paolo %A Marek, Diana %A Marre, Michel %A Martin, Nicholas G %A McArdle, Wendy L %A McCarthy, Anne %A McKnight, Barbara %A Meitinger, Thomas %A Melander, Olle %A Meyre, David %A Midthjell, Kristian %A Montgomery, Grant W %A Morken, Mario A %A Morris, Andrew P %A Mulic, Rosanda %A Ngwa, Julius S %A Nelis, Mari %A Neville, Matt J %A Nyholt, Dale R %A O'Donnell, Christopher J %A O'Rahilly, Stephen %A Ong, Ken K %A Oostra, Ben %A Paré, Guillaume %A Parker, Alex N %A Perola, Markus %A Pichler, Irene %A Pietiläinen, Kirsi H %A Platou, Carl G P %A Polasek, Ozren %A Pouta, Anneli %A Rafelt, Suzanne %A Raitakari, Olli %A Rayner, Nigel W %A Ridderstråle, Martin %A Rief, Winfried %A Ruokonen, Aimo %A Robertson, Neil R %A Rzehak, Peter %A Salomaa, Veikko %A Sanders, Alan R %A Sandhu, Manjinder S %A Sanna, Serena %A Saramies, Jouko %A Savolainen, Markku J %A Scherag, Susann %A Schipf, Sabine %A Schreiber, Stefan %A Schunkert, Heribert %A Silander, Kaisa %A Sinisalo, Juha %A Siscovick, David S %A Smit, Jan H %A Soranzo, Nicole %A Sovio, Ulla %A Stephens, Jonathan %A Surakka, Ida %A Swift, Amy J %A Tammesoo, Mari-Liis %A Tardif, Jean-Claude %A Teder-Laving, Maris %A Teslovich, Tanya M %A Thompson, John R %A Thomson, Brian %A Tönjes, Anke %A Tuomi, Tiinamaija %A van Meurs, Joyce B J %A van Ommen, Gert-Jan %A Vatin, Vincent %A Viikari, Jorma %A Visvikis-Siest, Sophie %A Vitart, Veronique %A Vogel, Carla I G %A Voight, Benjamin F %A Waite, Lindsay L %A Wallaschofski, Henri %A Walters, G Bragi %A Widen, Elisabeth %A Wiegand, Susanna %A Wild, Sarah H %A Willemsen, Gonneke %A Witte, Daniel R %A Witteman, Jacqueline C %A Xu, Jianfeng %A Zhang, Qunyuan %A Zgaga, Lina %A Ziegler, Andreas %A Zitting, Paavo %A Beilby, John P %A Farooqi, I Sadaf %A Hebebrand, Johannes %A Huikuri, Heikki V %A James, Alan L %A Kähönen, Mika %A Levinson, Douglas F %A Macciardi, Fabio %A Nieminen, Markku S %A Ohlsson, Claes %A Palmer, Lyle J %A Ridker, Paul M %A Stumvoll, Michael %A Beckmann, Jacques S %A Boeing, Heiner %A Boerwinkle, Eric %A Boomsma, Dorret I %A Caulfield, Mark J %A Chanock, Stephen J %A Collins, Francis S %A Cupples, L Adrienne %A Smith, George Davey %A Erdmann, Jeanette %A Froguel, Philippe %A Grönberg, Henrik %A Gyllensten, Ulf %A Hall, Per %A Hansen, Torben %A Harris, Tamara B %A Hattersley, Andrew T %A Hayes, Richard B %A Heinrich, Joachim %A Hu, Frank B %A Hveem, Kristian %A Illig, Thomas %A Jarvelin, Marjo-Riitta %A Kaprio, Jaakko %A Karpe, Fredrik %A Khaw, Kay-Tee %A Kiemeney, Lambertus A %A Krude, Heiko %A Laakso, Markku %A Lawlor, Debbie A %A Metspalu, Andres %A Munroe, Patricia B %A Ouwehand, Willem H %A Pedersen, Oluf %A Penninx, Brenda W %A Peters, Annette %A Pramstaller, Peter P %A Quertermous, Thomas %A Reinehr, Thomas %A Rissanen, Aila %A Rudan, Igor %A Samani, Nilesh J %A Schwarz, Peter E H %A Shuldiner, Alan R %A Spector, Timothy D %A Tuomilehto, Jaakko %A Uda, Manuela %A Uitterlinden, Andre %A Valle, Timo T %A Wabitsch, Martin %A Waeber, Gérard %A Wareham, Nicholas J %A Watkins, Hugh %A Wilson, James F %A Wright, Alan F %A Zillikens, M Carola %A Chatterjee, Nilanjan %A McCarroll, Steven A %A Purcell, Shaun %A Schadt, Eric E %A Visscher, Peter M %A Assimes, Themistocles L %A Borecki, Ingrid B %A Deloukas, Panos %A Fox, Caroline S %A Groop, Leif C %A Haritunians, Talin %A Hunter, David J %A Kaplan, Robert C %A Mohlke, Karen L %A O'Connell, Jeffrey R %A Peltonen, Leena %A Schlessinger, David %A Strachan, David P %A van Duijn, Cornelia M %A Wichmann, H-Erich %A Frayling, Timothy M %A Thorsteinsdottir, Unnur %A Abecasis, Goncalo R %A Barroso, Inês %A Boehnke, Michael %A Stefansson, Kari %A North, Kari E %A McCarthy, Mark I %A Hirschhorn, Joel N %A Ingelsson, Erik %A Loos, Ruth J F %K Body Height %K Body Mass Index %K Body Size %K Body Weight %K Chromosome Mapping %K European Continental Ancestry Group %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Obesity %K Polymorphism, Single Nucleotide %X

Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ∼ 2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 × 10⁻⁸), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.

%B Nat Genet %V 42 %P 937-48 %8 2010 Nov %G eng %N 11 %1 http://www.ncbi.nlm.nih.gov/pubmed/20935630?dopt=Abstract %R 10.1038/ng.686 %0 Journal Article %J Circ Cardiovasc Genet %D 2010 %T Association of genome-wide variation with the risk of incident heart failure in adults of European and African ancestry: a prospective meta-analysis from the cohorts for heart and aging research in genomic epidemiology (CHARGE) consortium. %A Smith, Nicholas L %A Felix, Janine F %A Morrison, Alanna C %A Demissie, Serkalem %A Glazer, Nicole L %A Loehr, Laura R %A Cupples, L Adrienne %A Dehghan, Abbas %A Lumley, Thomas %A Rosamond, Wayne D %A Lieb, Wolfgang %A Rivadeneira, Fernando %A Bis, Joshua C %A Folsom, Aaron R %A Benjamin, Emelia %A Aulchenko, Yurii S %A Haritunians, Talin %A Couper, David %A Murabito, Joanne %A Wang, Ying A %A Stricker, Bruno H %A Gottdiener, John S %A Chang, Patricia P %A Wang, Thomas J %A Rice, Kenneth M %A Hofman, Albert %A Heckbert, Susan R %A Fox, Ervin R %A O'Donnell, Christopher J %A Uitterlinden, André G %A Rotter, Jerome I %A Willerson, James T %A Levy, Daniel %A van Duijn, Cornelia M %A Psaty, Bruce M %A Witteman, Jacqueline C M %A Boerwinkle, Eric %A Vasan, Ramachandran S %K African Americans %K Aged %K Aged, 80 and over %K Cohort Studies %K Endopeptidases %K European Continental Ancestry Group %K Female %K Genome-Wide Association Study %K Heart Failure %K Humans %K Incidence %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Risk %K Ubiquitin-Specific Proteases %X

BACKGROUND: Although genetic factors contribute to the onset of heart failure (HF), no large-scale genome-wide investigation of HF risk has been published to date. We have investigated the association of 2,478,304 single-nucleotide polymorphisms with incident HF by meta-analyzing data from 4 community-based prospective cohorts: the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Rotterdam Study.

METHODS AND RESULTS: Eligible participants for these analyses were of European or African ancestry and free of clinical HF at baseline. Each study independently conducted genome-wide scans and imputed data to the approximately 2.5 million single-nucleotide polymorphisms in HapMap. Within each study, Cox proportional hazards regression models provided age- and sex-adjusted estimates of the association between each variant and time to incident HF. Fixed-effect meta-analyses combined results for each single-nucleotide polymorphism from the 4 cohorts to produce an overall association estimate and P value. A genome-wide significance P value threshold was set a priori at 5.0x10(-7). During a mean follow-up of 11.5 years, 2526 incident HF events (12%) occurred in 20 926 European-ancestry participants. The meta-analysis identified a genome-wide significant locus at chromosomal position 15q22 (1.4x10(-8)), which was 58.8 kb from USP3. Among 2895 African-ancestry participants, 466 incident HF events (16%) occurred during a mean follow-up of 13.7 years. One genome-wide significant locus was identified at 12q14 (6.7x10(-8)), which was 6.3 kb from LRIG3.

CONCLUSIONS: We identified 2 loci that were associated with incident HF and exceeded genome-wide significance. The findings merit replication in other community-based settings of incident HF.

%B Circ Cardiovasc Genet %V 3 %P 256-66 %8 2010 Jun %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/20445134?dopt=Abstract %R 10.1161/CIRCGENETICS.109.895763 %0 Journal Article %J Nature %D 2010 %T Biological, clinical and population relevance of 95 loci for blood lipids. %A Teslovich, Tanya M %A Musunuru, Kiran %A Smith, Albert V %A Edmondson, Andrew C %A Stylianou, Ioannis M %A Koseki, Masahiro %A Pirruccello, James P %A Ripatti, Samuli %A Chasman, Daniel I %A Willer, Cristen J %A Johansen, Christopher T %A Fouchier, Sigrid W %A Isaacs, Aaron %A Peloso, Gina M %A Barbalic, Maja %A Ricketts, Sally L %A Bis, Joshua C %A Aulchenko, Yurii S %A Thorleifsson, Gudmar %A Feitosa, Mary F %A Chambers, John %A Orho-Melander, Marju %A Melander, Olle %A Johnson, Toby %A Li, Xiaohui %A Guo, Xiuqing %A Li, Mingyao %A Shin Cho, Yoon %A Jin Go, Min %A Jin Kim, Young %A Lee, Jong-Young %A Park, Taesung %A Kim, Kyunga %A Sim, Xueling %A Twee-Hee Ong, Rick %A Croteau-Chonka, Damien C %A Lange, Leslie A %A Smith, Joshua D %A Song, Kijoung %A Hua Zhao, Jing %A Yuan, Xin %A Luan, Jian'an %A Lamina, Claudia %A Ziegler, Andreas %A Zhang, Weihua %A Zee, Robert Y L %A Wright, Alan F %A Witteman, Jacqueline C M %A Wilson, James F %A Willemsen, Gonneke %A Wichmann, H-Erich %A Whitfield, John B %A Waterworth, Dawn M %A Wareham, Nicholas J %A Waeber, Gérard %A Vollenweider, Peter %A Voight, Benjamin F %A Vitart, Veronique %A Uitterlinden, André G %A Uda, Manuela %A Tuomilehto, Jaakko %A Thompson, John R %A Tanaka, Toshiko %A Surakka, Ida %A Stringham, Heather M %A Spector, Tim D %A Soranzo, Nicole %A Smit, Johannes H %A Sinisalo, Juha %A Silander, Kaisa %A Sijbrands, Eric J G %A Scuteri, Angelo %A Scott, James %A Schlessinger, David %A Sanna, Serena %A Salomaa, Veikko %A Saharinen, Juha %A Sabatti, Chiara %A Ruokonen, Aimo %A Rudan, Igor %A Rose, Lynda M %A Roberts, Robert %A Rieder, Mark %A Psaty, Bruce M %A Pramstaller, Peter P %A Pichler, Irene %A Perola, Markus %A Penninx, Brenda W J H %A Pedersen, Nancy L %A Pattaro, Cristian %A Parker, Alex N %A Paré, Guillaume %A Oostra, Ben A %A O'Donnell, Christopher J %A Nieminen, Markku S %A Nickerson, Deborah A %A Montgomery, Grant W %A Meitinger, Thomas %A McPherson, Ruth %A McCarthy, Mark I %A McArdle, Wendy %A Masson, David %A Martin, Nicholas G %A Marroni, Fabio %A Mangino, Massimo %A Magnusson, Patrik K E %A Lucas, Gavin %A Luben, Robert %A Loos, Ruth J F %A Lokki, Marja-Liisa %A Lettre, Guillaume %A Langenberg, Claudia %A Launer, Lenore J %A Lakatta, Edward G %A Laaksonen, Reijo %A Kyvik, Kirsten O %A Kronenberg, Florian %A König, Inke R %A Khaw, Kay-Tee %A Kaprio, Jaakko %A Kaplan, Lee M %A Johansson, Asa %A Jarvelin, Marjo-Riitta %A Janssens, A Cecile J W %A Ingelsson, Erik %A Igl, Wilmar %A Kees Hovingh, G %A Hottenga, Jouke-Jan %A Hofman, Albert %A Hicks, Andrew A %A Hengstenberg, Christian %A Heid, Iris M %A Hayward, Caroline %A Havulinna, Aki S %A Hastie, Nicholas D %A Harris, Tamara B %A Haritunians, Talin %A Hall, Alistair S %A Gyllensten, Ulf %A Guiducci, Candace %A Groop, Leif C %A Gonzalez, Elena %A Gieger, Christian %A Freimer, Nelson B %A Ferrucci, Luigi %A Erdmann, Jeanette %A Elliott, Paul %A Ejebe, Kenechi G %A Döring, Angela %A Dominiczak, Anna F %A Demissie, Serkalem %A Deloukas, Panagiotis %A de Geus, Eco J C %A de Faire, Ulf %A Crawford, Gabriel %A Collins, Francis S %A Chen, Yii-der I %A Caulfield, Mark J %A Campbell, Harry %A Burtt, Noel P %A Bonnycastle, Lori L %A Boomsma, Dorret I %A Boekholdt, S Matthijs %A Bergman, Richard N %A Barroso, Inês %A Bandinelli, Stefania %A Ballantyne, Christie M %A Assimes, Themistocles L %A Quertermous, Thomas %A Altshuler, David %A Seielstad, Mark %A Wong, Tien Y %A Tai, E-Shyong %A Feranil, Alan B %A Kuzawa, Christopher W %A Adair, Linda S %A Taylor, Herman A %A Borecki, Ingrid B %A Gabriel, Stacey B %A Wilson, James G %A Holm, Hilma %A Thorsteinsdottir, Unnur %A Gudnason, Vilmundur %A Krauss, Ronald M %A Mohlke, Karen L %A Ordovas, Jose M %A Munroe, Patricia B %A Kooner, Jaspal S %A Tall, Alan R %A Hegele, Robert A %A Kastelein, John J P %A Schadt, Eric E %A Rotter, Jerome I %A Boerwinkle, Eric %A Strachan, David P %A Mooser, Vincent %A Stefansson, Kari %A Reilly, Muredach P %A Samani, Nilesh J %A Schunkert, Heribert %A Cupples, L Adrienne %A Sandhu, Manjinder S %A Ridker, Paul M %A Rader, Daniel J %A van Duijn, Cornelia M %A Peltonen, Leena %A Abecasis, Goncalo R %A Boehnke, Michael %A Kathiresan, Sekar %K African Americans %K Animals %K Asian Continental Ancestry Group %K Cholesterol, HDL %K Cholesterol, LDL %K Coronary Artery Disease %K Europe %K European Continental Ancestry Group %K Female %K Genetic Loci %K Genome-Wide Association Study %K Genotype %K Humans %K Lipid Metabolism %K Lipids %K Liver %K Male %K Mice %K N-Acetylgalactosaminyltransferases %K Phenotype %K Polymorphism, Single Nucleotide %K Protein Phosphatase 1 %K Reproducibility of Results %K Triglycerides %X

Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P < 5 x 10(-8)), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.

%B Nature %V 466 %P 707-13 %8 2010 Aug 05 %G eng %N 7307 %1 http://www.ncbi.nlm.nih.gov/pubmed/20686565?dopt=Abstract %R 10.1038/nature09270 %0 Journal Article %J Lancet %D 2010 %T Common genetic determinants of vitamin D insufficiency: a genome-wide association study. %A Wang, Thomas J %A Zhang, Feng %A Richards, J Brent %A Kestenbaum, Bryan %A van Meurs, Joyce B %A Berry, Diane %A Kiel, Douglas P %A Streeten, Elizabeth A %A Ohlsson, Claes %A Koller, Daniel L %A Peltonen, Leena %A Cooper, Jason D %A O'Reilly, Paul F %A Houston, Denise K %A Glazer, Nicole L %A Vandenput, Liesbeth %A Peacock, Munro %A Shi, Julia %A Rivadeneira, Fernando %A McCarthy, Mark I %A Anneli, Pouta %A de Boer, Ian H %A Mangino, Massimo %A Kato, Bernet %A Smyth, Deborah J %A Booth, Sarah L %A Jacques, Paul F %A Burke, Greg L %A Goodarzi, Mark %A Cheung, Ching-Lung %A Wolf, Myles %A Rice, Kenneth %A Goltzman, David %A Hidiroglou, Nick %A Ladouceur, Martin %A Wareham, Nicholas J %A Hocking, Lynne J %A Hart, Deborah %A Arden, Nigel K %A Cooper, Cyrus %A Malik, Suneil %A Fraser, William D %A Hartikainen, Anna-Liisa %A Zhai, Guangju %A Macdonald, Helen M %A Forouhi, Nita G %A Loos, Ruth J F %A Reid, David M %A Hakim, Alan %A Dennison, Elaine %A Liu, Yongmei %A Power, Chris %A Stevens, Helen E %A Jaana, Laitinen %A Vasan, Ramachandran S %A Soranzo, Nicole %A Bojunga, Jörg %A Psaty, Bruce M %A Lorentzon, Mattias %A Foroud, Tatiana %A Harris, Tamara B %A Hofman, Albert %A Jansson, John-Olov %A Cauley, Jane A %A Uitterlinden, André G %A Gibson, Quince %A Jarvelin, Marjo-Riitta %A Karasik, David %A Siscovick, David S %A Econs, Michael J %A Kritchevsky, Stephen B %A Florez, Jose C %A Todd, John A %A Dupuis, Josée %A Hyppönen, Elina %A Spector, Timothy D %K Canada %K Chromosomes, Human, Pair 11 %K Chromosomes, Human, Pair 4 %K Cohort Studies %K Dietary Supplements %K Europe %K European Continental Ancestry Group %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Heterozygote %K Homozygote %K Humans %K Immunoassay %K International Cooperation %K Linkage Disequilibrium %K Polymorphism, Single Nucleotide %K Seasons %K United States %K Vitamin D %K Vitamin D Deficiency %X

BACKGROUND: Vitamin D is crucial for maintenance of musculoskeletal health, and might also have a role in extraskeletal tissues. Determinants of circulating 25-hydroxyvitamin D concentrations include sun exposure and diet, but high heritability suggests that genetic factors could also play a part. We aimed to identify common genetic variants affecting vitamin D concentrations and risk of insufficiency.

METHODS: We undertook a genome-wide association study of 25-hydroxyvitamin D concentrations in 33 996 individuals of European descent from 15 cohorts. Five epidemiological cohorts were designated as discovery cohorts (n=16 125), five as in-silico replication cohorts (n=9367), and five as de-novo replication cohorts (n=8504). 25-hydroxyvitamin D concentrations were measured by radioimmunoassay, chemiluminescent assay, ELISA, or mass spectrometry. Vitamin D insufficiency was defined as concentrations lower than 75 nmol/L or 50 nmol/L. We combined results of genome-wide analyses across cohorts using Z-score-weighted meta-analysis. Genotype scores were constructed for confirmed variants.

FINDINGS: Variants at three loci reached genome-wide significance in discovery cohorts for association with 25-hydroxyvitamin D concentrations, and were confirmed in replication cohorts: 4p12 (overall p=1.9x10(-109) for rs2282679, in GC); 11q12 (p=2.1x10(-27) for rs12785878, near DHCR7); and 11p15 (p=3.3x10(-20) for rs10741657, near CYP2R1). Variants at an additional locus (20q13, CYP24A1) were genome-wide significant in the pooled sample (p=6.0x10(-10) for rs6013897). Participants with a genotype score (combining the three confirmed variants) in the highest quartile were at increased risk of having 25-hydroxyvitamin D concentrations lower than 75 nmol/L (OR 2.47, 95% CI 2.20-2.78, p=2.3x10(-48)) or lower than 50 nmol/L (1.92, 1.70-2.16, p=1.0x10(-26)) compared with those in the lowest quartile.

INTERPRETATION: Variants near genes involved in cholesterol synthesis, hydroxylation, and vitamin D transport affect vitamin D status. Genetic variation at these loci identifies individuals who have substantially raised risk of vitamin D insufficiency.

FUNDING: Full funding sources listed at end of paper (see Acknowledgments).

%B Lancet %V 376 %P 180-8 %8 2010 Jul 17 %G eng %N 9736 %1 http://www.ncbi.nlm.nih.gov/pubmed/20541252?dopt=Abstract %R 10.1016/S0140-6736(10)60588-0 %0 Journal Article %J J Am Soc Nephrol %D 2010 %T Common genetic variants associate with serum phosphorus concentration. %A Kestenbaum, Bryan %A Glazer, Nicole L %A Köttgen, Anna %A Felix, Janine F %A Hwang, Shih-Jen %A Liu, Yongmei %A Lohman, Kurt %A Kritchevsky, Stephen B %A Hausman, Dorothy B %A Petersen, Ann-Kristin %A Gieger, Christian %A Ried, Janina S %A Meitinger, Thomas %A Strom, Tim M %A Wichmann, H Erich %A Campbell, Harry %A Hayward, Caroline %A Rudan, Igor %A de Boer, Ian H %A Psaty, Bruce M %A Rice, Kenneth M %A Chen, Yii-Der Ida %A Li, Man %A Arking, Dan E %A Boerwinkle, Eric %A Coresh, Josef %A Yang, Qiong %A Levy, Daniel %A van Rooij, Frank J A %A Dehghan, Abbas %A Rivadeneira, Fernando %A Uitterlinden, André G %A Hofman, Albert %A van Duijn, Cornelia M %A Shlipak, Michael G %A Kao, W H Linda %A Witteman, Jacqueline C M %A Siscovick, David S %A Fox, Caroline S %K Adult %K Aged %K European Continental Ancestry Group %K Female %K Fibroblast Growth Factors %K Gene Frequency %K Genetic Loci %K Genetic Variation %K Genome-Wide Association Study %K Humans %K Kidney %K Male %K Middle Aged %K Phosphorus %K Polymorphism, Single Nucleotide %K Receptors, Calcium-Sensing %K Sex Factors %K Sodium-Phosphate Cotransporter Proteins, Type IIa %X

Phosphorus is an essential mineral that maintains cellular energy and mineralizes the skeleton. Because complex actions of ion transporters and regulatory hormones regulate serum phosphorus concentrations, genetic variation may determine interindividual variation in phosphorus metabolism. Here, we report a comprehensive genome-wide association study of serum phosphorus concentration. We evaluated 16,264 participants of European ancestry from the Cardiovascular Heath Study, Atherosclerosis Risk in Communities Study, Framingham Offspring Study, and the Rotterdam Study. We excluded participants with an estimated GFR <45 ml/min per 1.73 m(2) to focus on phosphorus metabolism under normal conditions. We imputed genotypes to approximately 2.5 million single-nucleotide polymorphisms in the HapMap and combined study-specific findings using meta-analysis. We tested top polymorphisms from discovery cohorts in a 5444-person replication sample. Polymorphisms in seven loci with minor allele frequencies 0.08 to 0.49 associate with serum phosphorus concentration (P = 3.5 x 10(-16) to 3.6 x 10(-7)). Three loci were near genes encoding the kidney-specific type IIa sodium phosphate co-transporter (SLC34A1), the calcium-sensing receptor (CASR), and fibroblast growth factor 23 (FGF23), proteins that contribute to phosphorus metabolism. We also identified genes encoding phosphatases, kinases, and phosphodiesterases that have yet-undetermined roles in phosphorus homeostasis. In the replication sample, five of seven top polymorphisms associate with serum phosphorous concentrations (P < 0.05 for each). In conclusion, common genetic variants associate with serum phosphorus in the general population. Further study of the loci identified in this study may help elucidate mechanisms of phosphorus regulation.

%B J Am Soc Nephrol %V 21 %P 1223-32 %8 2010 Jul %G eng %N 7 %1 http://www.ncbi.nlm.nih.gov/pubmed/20558539?dopt=Abstract %R 10.1681/ASN.2009111104 %0 Journal Article %J Nat Genet %D 2010 %T Common variants in 22 loci are associated with QRS duration and cardiac ventricular conduction. %A Sotoodehnia, Nona %A Isaacs, Aaron %A de Bakker, Paul I W %A Dörr, Marcus %A Newton-Cheh, Christopher %A Nolte, Ilja M %A van der Harst, Pim %A Müller, Martina %A Eijgelsheim, Mark %A Alonso, Alvaro %A Hicks, Andrew A %A Padmanabhan, Sandosh %A Hayward, Caroline %A Smith, Albert Vernon %A Polasek, Ozren %A Giovannone, Steven %A Fu, Jingyuan %A Magnani, Jared W %A Marciante, Kristin D %A Pfeufer, Arne %A Gharib, Sina A %A Teumer, Alexander %A Li, Man %A Bis, Joshua C %A Rivadeneira, Fernando %A Aspelund, Thor %A Köttgen, Anna %A Johnson, Toby %A Rice, Kenneth %A Sie, Mark P S %A Wang, Ying A %A Klopp, Norman %A Fuchsberger, Christian %A Wild, Sarah H %A Mateo Leach, Irene %A Estrada, Karol %A Völker, Uwe %A Wright, Alan F %A Asselbergs, Folkert W %A Qu, Jiaxiang %A Chakravarti, Aravinda %A Sinner, Moritz F %A Kors, Jan A %A Petersmann, Astrid %A Harris, Tamara B %A Soliman, Elsayed Z %A Munroe, Patricia B %A Psaty, Bruce M %A Oostra, Ben A %A Cupples, L Adrienne %A Perz, Siegfried %A de Boer, Rudolf A %A Uitterlinden, André G %A Völzke, Henry %A Spector, Timothy D %A Liu, Fang-Yu %A Boerwinkle, Eric %A Dominiczak, Anna F %A Rotter, Jerome I %A van Herpen, Gé %A Levy, Daniel %A Wichmann, H-Erich %A van Gilst, Wiek H %A Witteman, Jacqueline C M %A Kroemer, Heyo K %A Kao, W H Linda %A Heckbert, Susan R %A Meitinger, Thomas %A Hofman, Albert %A Campbell, Harry %A Folsom, Aaron R %A van Veldhuisen, Dirk J %A Schwienbacher, Christine %A O'Donnell, Christopher J %A Volpato, Claudia Beu %A Caulfield, Mark J %A Connell, John M %A Launer, Lenore %A Lu, Xiaowen %A Franke, Lude %A Fehrmann, Rudolf S N %A te Meerman, Gerard %A Groen, Harry J M %A Weersma, Rinse K %A van den Berg, Leonard H %A Wijmenga, Cisca %A Ophoff, Roel A %A Navis, Gerjan %A Rudan, Igor %A Snieder, Harold %A Wilson, James F %A Pramstaller, Peter P %A Siscovick, David S %A Wang, Thomas J %A Gudnason, Vilmundur %A van Duijn, Cornelia M %A Felix, Stephan B %A Fishman, Glenn I %A Jamshidi, Yalda %A Stricker, Bruno H Ch %A Samani, Nilesh J %A Kääb, Stefan %A Arking, Dan E %K Animals %K Animals, Newborn %K Chromosomes, Human %K Computational Biology %K Electrocardiography %K Genetic Loci %K Genome-Wide Association Study %K Heart Conduction System %K Humans %K Mice %K Mice, Transgenic %K Models, Animal %K Myocytes, Cardiac %K NAV1.8 Voltage-Gated Sodium Channel %K Polymorphism, Single Nucleotide %K Sodium Channels %X

The QRS interval, from the beginning of the Q wave to the end of the S wave on an electrocardiogram, reflects ventricular depolarization and conduction time and is a risk factor for mortality, sudden death and heart failure. We performed a genome-wide association meta-analysis in 40,407 individuals of European descent from 14 studies, with further genotyping in 7,170 additional Europeans, and we identified 22 loci associated with QRS duration (P < 5 × 10(-8)). These loci map in or near genes in pathways with established roles in ventricular conduction such as sodium channels, transcription factors and calcium-handling proteins, but also point to previously unidentified biologic processes, such as kinase inhibitors and genes related to tumorigenesis. We demonstrate that SCN10A, a candidate gene at the most significantly associated locus in this study, is expressed in the mouse ventricular conduction system, and treatment with a selective SCN10A blocker prolongs QRS duration. These findings extend our current knowledge of ventricular depolarization and conduction.

%B Nat Genet %V 42 %P 1068-76 %8 2010 Dec %G eng %N 12 %1 http://www.ncbi.nlm.nih.gov/pubmed/21076409?dopt=Abstract %R 10.1038/ng.716 %0 Journal Article %J Nat Genet %D 2010 %T Common variants in KCNN3 are associated with lone atrial fibrillation. %A Ellinor, Patrick T %A Lunetta, Kathryn L %A Glazer, Nicole L %A Pfeufer, Arne %A Alonso, Alvaro %A Chung, Mina K %A Sinner, Moritz F %A de Bakker, Paul I W %A Mueller, Martina %A Lubitz, Steven A %A Fox, Ervin %A Darbar, Dawood %A Smith, Nicholas L %A Smith, Jonathan D %A Schnabel, Renate B %A Soliman, Elsayed Z %A Rice, Kenneth M %A Van Wagoner, David R %A Beckmann, Britt-M %A van Noord, Charlotte %A Wang, Ke %A Ehret, Georg B %A Rotter, Jerome I %A Hazen, Stanley L %A Steinbeck, Gerhard %A Smith, Albert V %A Launer, Lenore J %A Harris, Tamara B %A Makino, Seiko %A Nelis, Mari %A Milan, David J %A Perz, Siegfried %A Esko, Tõnu %A Köttgen, Anna %A Moebus, Susanne %A Newton-Cheh, Christopher %A Li, Man %A Möhlenkamp, Stefan %A Wang, Thomas J %A Kao, W H Linda %A Vasan, Ramachandran S %A Nöthen, Markus M %A MacRae, Calum A %A Stricker, Bruno H Ch %A Hofman, Albert %A Uitterlinden, André G %A Levy, Daniel %A Boerwinkle, Eric %A Metspalu, Andres %A Topol, Eric J %A Chakravarti, Aravinda %A Gudnason, Vilmundur %A Psaty, Bruce M %A Roden, Dan M %A Meitinger, Thomas %A Wichmann, H-Erich %A Witteman, Jacqueline C M %A Barnard, John %A Arking, Dan E %A Benjamin, Emelia J %A Heckbert, Susan R %A Kääb, Stefan %K Adolescent %K Adult %K Aged %K Atrial Fibrillation %K Case-Control Studies %K Cohort Studies %K Female %K Genome-Wide Association Study %K Humans %K Introns %K Male %K Meta-Analysis as Topic %K Middle Aged %K Polymorphism, Single Nucleotide %K Small-Conductance Calcium-Activated Potassium Channels %K Young Adult %X

Atrial fibrillation (AF) is the most common sustained arrhythmia. Previous studies have identified several genetic loci associated with typical AF. We sought to identify common genetic variants underlying lone AF. This condition affects a subset of individuals without overt heart disease and with an increased heritability of AF. We report a meta-analysis of genome-wide association studies conducted using 1,335 individuals with lone AF (cases) and 12,844 unaffected individuals (referents). Cases were obtained from the German AF Network, Heart and Vascular Health Study, the Atherosclerosis Risk in Communities Study, the Cleveland Clinic and Massachusetts General Hospital. We identified an association on chromosome 1q21 to lone AF (rs13376333, adjusted odds ratio = 1.56; P = 6.3 x 10(-12)), and we replicated this association in two independent cohorts with lone AF (overall combined odds ratio = 1.52, 95% CI 1.40-1.64; P = 1.83 x 10(-21)). rs13376333 is intronic to KCNN3, which encodes a potassium channel protein involved in atrial repolarization.

%B Nat Genet %V 42 %P 240-4 %8 2010 Mar %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/20173747?dopt=Abstract %R 10.1038/ng.537 %0 Journal Article %J Circulation %D 2010 %T European ancestry as a risk factor for atrial fibrillation in African Americans. %A Marcus, Gregory M %A Alonso, Alvaro %A Peralta, Carmen A %A Lettre, Guillaume %A Vittinghoff, Eric %A Lubitz, Steven A %A Fox, Ervin R %A Levitzky, Yamini S %A Mehra, Reena %A Kerr, Kathleen F %A Deo, Rajat %A Sotoodehnia, Nona %A Akylbekova, Meggie %A Ellinor, Patrick T %A Paltoo, Dina N %A Soliman, Elsayed Z %A Benjamin, Emelia J %A Heckbert, Susan R %K African Americans %K Aged %K Atrial Fibrillation %K European Continental Ancestry Group %K Female %K Genome-Wide Association Study %K Humans %K Male %K Middle Aged %K Risk Factors %X

BACKGROUND: Despite a higher burden of standard atrial fibrillation (AF) risk factors, African Americans have a lower risk of AF than whites. It is unknown whether the higher risk is due to genetic or environmental factors. Because African Americans have varying degrees of European ancestry, we sought to test the hypothesis that European ancestry is an independent risk factor for AF.

METHODS AND RESULTS: We studied whites (n=4543) and African Americans (n=822) in the Cardiovascular Health Study (CHS) and whites (n=10 902) and African Americans (n=3517) in the Atherosclerosis Risk in Communities (ARIC) Study (n=3517). Percent European ancestry in African Americans was estimated with 1747 ancestry informative markers from the Illumina custom ITMAT-Broad-CARe array. Among African Americans without baseline AF, 120 of 804 CHS participants and 181 of 3517 ARIC participants developed incident AF. A meta-analysis from the 2 studies revealed that every 10% increase in European ancestry increased the risk of AF by 13% (hazard ratio, 1.13; 95% confidence interval, 1.03 to 1.23; P=0.007). After adjustment for potential confounders, European ancestry remained a predictor of incident AF in each cohort alone, with a combined estimated hazard ratio for each 10% increase in European ancestry of 1.17 (95% confidence interval, 1.07 to 1.29; P=0.001). A second analysis using 3192 ancestry informative markers from a genome-wide Affymetrix 6.0 array in ARIC African Americans yielded similar results.

CONCLUSIONS: European ancestry predicted risk of incident AF. Our study suggests that investigating genetic variants contributing to differential AF risk in individuals of African versus European ancestry will be informative.

%B Circulation %V 122 %P 2009-15 %8 2010 Nov 16 %G eng %N 20 %1 http://www.ncbi.nlm.nih.gov/pubmed/21098467?dopt=Abstract %R 10.1161/CIRCULATIONAHA.110.958306 %0 Journal Article %J PLoS Genet %D 2010 %T Four novel Loci (19q13, 6q24, 12q24, and 5q14) influence the microcirculation in vivo. %A Ikram, M Kamran %A Sim, Xueling %A Xueling, Sim %A Jensen, Richard A %A Cotch, Mary Frances %A Hewitt, Alex W %A Ikram, M Arfan %A Wang, Jie Jin %A Klein, Ronald %A Klein, Barbara E K %A Breteler, Monique M B %A Cheung, Ning %A Liew, Gerald %A Mitchell, Paul %A Uitterlinden, André G %A Rivadeneira, Fernando %A Hofman, Albert %A de Jong, Paulus T V M %A van Duijn, Cornelia M %A Kao, Linda %A Cheng, Ching-Yu %A Smith, Albert Vernon %A Glazer, Nicole L %A Lumley, Thomas %A McKnight, Barbara %A Psaty, Bruce M %A Jonasson, Fridbert %A Eiriksdottir, Gudny %A Aspelund, Thor %A Harris, Tamara B %A Launer, Lenore J %A Taylor, Kent D %A Li, Xiaohui %A Iyengar, Sudha K %A Xi, Quansheng %A Sivakumaran, Theru A %A Mackey, David A %A Macgregor, Stuart %A Martin, Nicholas G %A Young, Terri L %A Bis, Josh C %A Wiggins, Kerri L %A Heckbert, Susan R %A Hammond, Christopher J %A Andrew, Toby %A Fahy, Samantha %A Attia, John %A Holliday, Elizabeth G %A Scott, Rodney J %A Islam, F M Amirul %A Rotter, Jerome I %A McAuley, Annie K %A Boerwinkle, Eric %A Tai, E Shyong %A Gudnason, Vilmundur %A Siscovick, David S %A Vingerling, Johannes R %A Wong, Tien Y %K Adolescent %K Adult %K Aged %K Aged, 80 and over %K Cardiovascular Diseases %K Child %K Child, Preschool %K Chromosomes, Human, Pair 12 %K Chromosomes, Human, Pair 19 %K Chromosomes, Human, Pair 5 %K Chromosomes, Human, Pair 6 %K Cohort Studies %K European Continental Ancestry Group %K Female %K Genetic Loci %K Genome-Wide Association Study %K Humans %K Male %K Meta-Analysis as Topic %K Microcirculation %K Middle Aged %K Polymorphism, Single Nucleotide %K Retinal Vessels %K Young Adult %X

There is increasing evidence that the microcirculation plays an important role in the pathogenesis of cardiovascular diseases. Changes in retinal vascular caliber reflect early microvascular disease and predict incident cardiovascular events. We performed a genome-wide association study to identify genetic variants associated with retinal vascular caliber. We analyzed data from four population-based discovery cohorts with 15,358 unrelated Caucasian individuals, who are members of the Cohort for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and replicated findings in four independent Caucasian cohorts (n  =  6,652). All participants had retinal photography and retinal arteriolar and venular caliber measured from computer software. In the discovery cohorts, 179 single nucleotide polymorphisms (SNP) spread across five loci were significantly associated (p<5.0×10(-8)) with retinal venular caliber, but none showed association with arteriolar caliber. Collectively, these five loci explain 1.0%-3.2% of the variation in retinal venular caliber. Four out of these five loci were confirmed in independent replication samples. In the combined analyses, the top SNPs at each locus were: rs2287921 (19q13; p  =  1.61×10(-25), within the RASIP1 locus), rs225717 (6q24; p = 1.25×10(-16), adjacent to the VTA1 and NMBR loci), rs10774625 (12q24; p  =  2.15×10(-13), in the region of ATXN2,SH2B3 and PTPN11 loci), and rs17421627 (5q14; p = 7.32×10(-16), adjacent to the MEF2C locus). In two independent samples, locus 12q24 was also associated with coronary heart disease and hypertension. Our population-based genome-wide association study demonstrates four novel loci associated with retinal venular caliber, an endophenotype of the microcirculation associated with clinical cardiovascular disease. These data provide further insights into the contribution and biological mechanisms of microcirculatory changes that underlie cardiovascular disease.

%B PLoS Genet %V 6 %P e1001184 %8 2010 Oct 28 %G eng %N 10 %1 http://www.ncbi.nlm.nih.gov/pubmed/21060863?dopt=Abstract %R 10.1371/journal.pgen.1001184 %0 Journal Article %J Hum Mol Genet %D 2010 %T Fucosyltransferase 2 (FUT2) non-secretor status is associated with Crohn's disease. %A McGovern, Dermot P B %A Jones, Michelle R %A Taylor, Kent D %A Marciante, Kristin %A Yan, Xiaofei %A Dubinsky, Marla %A Ippoliti, Andy %A Vasiliauskas, Eric %A Berel, Dror %A Derkowski, Carrie %A Dutridge, Deb %A Fleshner, Phil %A Shih, David Q %A Melmed, Gil %A Mengesha, Emebet %A King, Lily %A Pressman, Sheila %A Haritunians, Talin %A Guo, Xiuqing %A Targan, Stephan R %A Rotter, Jerome I %K Adolescent %K Adult %K Aged %K Child %K Child, Preschool %K Cohort Studies %K Crohn Disease %K Female %K Fucosyltransferases %K Genome-Wide Association Study %K Humans %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Young Adult %X

Genetic variation in both innate and adaptive immune systems is associated with Crohn's disease (CD) susceptibility, but much of the heritability to CD remains unknown. We performed a genome-wide association study (GWAS) in 896 CD cases and 3204 healthy controls all of Caucasian origin as defined by multidimensional scaling. We found supportive evidence for 21 out of 40 CD loci identified in a recent CD GWAS meta-analysis, including two loci which had only nominally achieved replication (rs4807569, 19p13; rs991804, CCL2/CCL7). In addition, we identified associations with genes involved in tight junctions/epithelial integrity (ASHL, ARPC1A), innate immunity (EXOC2), dendritic cell biology [CADM1 (IGSF4)], macrophage development (MMD2), TGF-beta signaling (MAP3K7IP1) and FUT2 (a physiological trait that regulates gastrointestinal mucosal expression of blood group A and B antigens) (rs602662, P=3.4x10(-5)). Twenty percent of Caucasians are 'non-secretors' who do not express ABO antigens in saliva as a result of the FUT2 W134X allele. We demonstrated replication in an independent cohort of 1174 CD cases and 357 controls between the four primary FUT2 single nucleotide polymorphisms (SNPs) and CD (rs602662, combined P-value 4.90x10(-8)) and also association with FUT2 W143X (P=2.6x10(-5)). Further evidence of the relevance of this locus to CD pathogenesis was demonstrated by the association of the original four SNPs and CD in the recently published CD GWAS meta-analysis (rs602662, P=0.001). These findings strongly implicate this locus in CD susceptibility and highlight the role of the mucus layer in the development of CD.

%B Hum Mol Genet %V 19 %P 3468-76 %8 2010 Sep 01 %G eng %N 17 %1 http://www.ncbi.nlm.nih.gov/pubmed/20570966?dopt=Abstract %R 10.1093/hmg/ddq248 %0 Journal Article %J Inflamm Bowel Dis %D 2010 %T Genetic predictors of medically refractory ulcerative colitis. %A Haritunians, Talin %A Taylor, Kent D %A Targan, Stephan R %A Dubinsky, Marla %A Ippoliti, Andrew %A Kwon, Soonil %A Guo, Xiuqing %A Melmed, Gil Y %A Berel, Dror %A Mengesha, Emebet %A Psaty, Bruce M %A Glazer, Nicole L %A Vasiliauskas, Eric A %A Rotter, Jerome I %A Fleshner, Phillip R %A McGovern, Dermot P B %K Acute Disease %K Adolescent %K Adult %K Cohort Studies %K Colectomy %K Colitis, Ulcerative %K Female %K Genetic Loci %K Genome-Wide Association Study %K Humans %K Major Histocompatibility Complex %K Male %K Polymorphism, Single Nucleotide %K Risk Factors %K Severity of Illness Index %K Tumor Necrosis Factor Ligand Superfamily Member 15 %K Young Adult %X

BACKGROUND: Acute severe ulcerative colitis (UC) remains a significant clinical challenge and the ability to predict, at an early stage, those individuals at risk of colectomy for medically refractory UC (MR-UC) would be a major clinical advance. The aim of this study was to use a genome-wide association study (GWAS) in a well-characterized cohort of UC patients to identify genetic variation that contributes to MR-UC.

METHODS: A GWAS comparing 324 MR-UC patients with 537 non-MR-UC patients was analyzed using logistic regression and Cox proportional hazards methods. In addition, the MR-UC patients were compared with 2601 healthy controls.

RESULTS: MR-UC was associated with more extensive disease (P = 2.7 × 10(-6)) and a positive family history of UC (P = 0.004). A risk score based on the combination of 46 single nucleotide polymorphisms (SNPs) associated with MR-UC explained 48% of the variance for colectomy risk in our cohort. Risk scores divided into quarters showed the risk of colectomy to be 0%, 17%, 74%, and 100% in the four groups. Comparison of the MR-UC subjects with healthy controls confirmed the contribution of the major histocompatibility complex to severe UC (peak association: rs17207986, P = 1.4 × 10(-16)) and provided genome-wide suggestive association at the TNFSF15 (TL1A) locus (peak association: rs11554257, P = 1.4 × 10(-6)).

CONCLUSIONS: A SNP-based risk scoring system, identified here by GWAS analyses, may provide a useful adjunct to clinical parameters for predicting the natural history of UC. Furthermore, discovery of genetic processes underlying disease severity may help to identify pathways for novel therapeutic intervention in severe UC.

%B Inflamm Bowel Dis %V 16 %P 1830-40 %8 2010 Nov %G eng %N 11 %1 http://www.ncbi.nlm.nih.gov/pubmed/20848476?dopt=Abstract %R 10.1002/ibd.21293 %0 Journal Article %J JAMA %D 2010 %T Genome-wide analysis of genetic loci associated with Alzheimer disease. %A Seshadri, Sudha %A Fitzpatrick, Annette L %A Ikram, M Arfan %A DeStefano, Anita L %A Gudnason, Vilmundur %A Boada, Merce %A Bis, Joshua C %A Smith, Albert V %A Carassquillo, Minerva M %A Lambert, Jean Charles %A Harold, Denise %A Schrijvers, Elisabeth M C %A Ramirez-Lorca, Reposo %A Debette, Stephanie %A Longstreth, W T %A Janssens, A Cecile J W %A Pankratz, V Shane %A Dartigues, Jean François %A Hollingworth, Paul %A Aspelund, Thor %A Hernandez, Isabel %A Beiser, Alexa %A Kuller, Lewis H %A Koudstaal, Peter J %A Dickson, Dennis W %A Tzourio, Christophe %A Abraham, Richard %A Antunez, Carmen %A Du, Yangchun %A Rotter, Jerome I %A Aulchenko, Yurii S %A Harris, Tamara B %A Petersen, Ronald C %A Berr, Claudine %A Owen, Michael J %A Lopez-Arrieta, Jesus %A Varadarajan, Badri N %A Becker, James T %A Rivadeneira, Fernando %A Nalls, Michael A %A Graff-Radford, Neill R %A Campion, Dominique %A Auerbach, Sanford %A Rice, Kenneth %A Hofman, Albert %A Jonsson, Palmi V %A Schmidt, Helena %A Lathrop, Mark %A Mosley, Thomas H %A Au, Rhoda %A Psaty, Bruce M %A Uitterlinden, André G %A Farrer, Lindsay A %A Lumley, Thomas %A Ruiz, Agustin %A Williams, Julie %A Amouyel, Philippe %A Younkin, Steve G %A Wolf, Philip A %A Launer, Lenore J %A Lopez, Oscar L %A van Duijn, Cornelia M %A Breteler, Monique M B %K Age of Onset %K Aged %K Alzheimer Disease %K Case-Control Studies %K Genetic Loci %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Odds Ratio %K Polymorphism, Single Nucleotide %X

CONTEXT: Genome-wide association studies (GWAS) have recently identified CLU, PICALM, and CR1 as novel genes for late-onset Alzheimer disease (AD).

OBJECTIVES: To identify and strengthen additional loci associated with AD and confirm these in an independent sample and to examine the contribution of recently identified genes to AD risk prediction in a 3-stage analysis of new and previously published GWAS on more than 35,000 persons (8371 AD cases).

DESIGN, SETTING, AND PARTICIPANTS: In stage 1, we identified strong genetic associations (P < 10(-3)) in a sample of 3006 AD cases and 14,642 controls by combining new data from the population-based Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (1367 AD cases [973 incident]) with previously reported results from the Translational Genomics Research Institute and the Mayo AD GWAS. We identified 2708 single-nucleotide polymorphisms (SNPs) with P < 10(-3). In stage 2, we pooled results for these SNPs with the European AD Initiative (2032 cases and 5328 controls) to identify 38 SNPs (10 loci) with P < 10(-5). In stage 3, we combined data for these 10 loci with data from the Genetic and Environmental Risk in AD consortium (3333 cases and 6995 controls) to identify 4 SNPs with P < 1.7x10(-8). These 4 SNPs were replicated in an independent Spanish sample (1140 AD cases and 1209 controls). Genome-wide association analyses were completed in 2007-2008 and the meta-analyses and replication in 2009.

MAIN OUTCOME MEASURE: Presence of Alzheimer disease.

RESULTS: Two loci were identified to have genome-wide significance for the first time: rs744373 near BIN1 (odds ratio [OR],1.13; 95% confidence interval [CI],1.06-1.21 per copy of the minor allele; P = 1.59x10(-11)) and rs597668 near EXOC3L2/BLOC1S3/MARK4 (OR, 1.18; 95% CI, 1.07-1.29; P = 6.45x10(-9)). Associations of these 2 loci plus the previously identified loci CLU and PICALM with AD were confirmed in the Spanish sample (P < .05). However, although CLU and PICALM were confirmed to be associated with AD in this independent sample, they did not improve the ability of a model that included age, sex, and APOE to predict incident AD (improvement in area under the receiver operating characteristic curve from 0.847 to 0.849 in the Rotterdam Study and 0.702 to 0.705 in the Cardiovascular Health Study).

CONCLUSIONS: Two genetic loci for AD were found for the first time to reach genome-wide statistical significance. These findings were replicated in an independent population. Two recently reported associations were also confirmed. These loci did not improve AD risk prediction. While not clinically useful, they may implicate biological pathways useful for future research.

%B JAMA %V 303 %P 1832-40 %8 2010 May 12 %G eng %N 18 %1 http://www.ncbi.nlm.nih.gov/pubmed/20460622?dopt=Abstract %R 10.1001/jama.2010.574 %0 Journal Article %J Hum Mol Genet %D 2010 %T Genome-wide association analysis identifies multiple loci related to resting heart rate. %A Eijgelsheim, Mark %A Newton-Cheh, Christopher %A Sotoodehnia, Nona %A de Bakker, Paul I W %A Müller, Martina %A Morrison, Alanna C %A Smith, Albert V %A Isaacs, Aaron %A Sanna, Serena %A Dörr, Marcus %A Navarro, Pau %A Fuchsberger, Christian %A Nolte, Ilja M %A de Geus, Eco J C %A Estrada, Karol %A Hwang, Shih-Jen %A Bis, Joshua C %A Rückert, Ina-Maria %A Alonso, Alvaro %A Launer, Lenore J %A Hottenga, Jouke Jan %A Rivadeneira, Fernando %A Noseworthy, Peter A %A Rice, Kenneth M %A Perz, Siegfried %A Arking, Dan E %A Spector, Tim D %A Kors, Jan A %A Aulchenko, Yurii S %A Tarasov, Kirill V %A Homuth, Georg %A Wild, Sarah H %A Marroni, Fabio %A Gieger, Christian %A Licht, Carmilla M %A Prineas, Ronald J %A Hofman, Albert %A Rotter, Jerome I %A Hicks, Andrew A %A Ernst, Florian %A Najjar, Samer S %A Wright, Alan F %A Peters, Annette %A Fox, Ervin R %A Oostra, Ben A %A Kroemer, Heyo K %A Couper, David %A Völzke, Henry %A Campbell, Harry %A Meitinger, Thomas %A Uda, Manuela %A Witteman, Jacqueline C M %A Psaty, Bruce M %A Wichmann, H-Erich %A Harris, Tamara B %A Kääb, Stefan %A Siscovick, David S %A Jamshidi, Yalda %A Uitterlinden, André G %A Folsom, Aaron R %A Larson, Martin G %A Wilson, James F %A Penninx, Brenda W %A Snieder, Harold %A Pramstaller, Peter P %A van Duijn, Cornelia M %A Lakatta, Edward G %A Felix, Stephan B %A Gudnason, Vilmundur %A Pfeufer, Arne %A Heckbert, Susan R %A Stricker, Bruno H Ch %A Boerwinkle, Eric %A O'Donnell, Christopher J %K Adult %K Aged %K Base Pairing %K Cohort Studies %K Female %K Genetic Loci %K Genome, Human %K Genome-Wide Association Study %K Heart Rate %K Humans %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Rest %X

Higher resting heart rate is associated with increased cardiovascular disease and mortality risk. Though heritable factors play a substantial role in population variation, little is known about specific genetic determinants. This knowledge can impact clinical care by identifying novel factors that influence pathologic heart rate states, modulate heart rate through cardiac structure and function or by improving our understanding of the physiology of heart rate regulation. To identify common genetic variants associated with heart rate, we performed a meta-analysis of 15 genome-wide association studies (GWAS), including 38,991 subjects of European ancestry, estimating the association between age-, sex- and body mass-adjusted RR interval (inverse heart rate) and approximately 2.5 million markers. Results with P < 5 × 10(-8) were considered genome-wide significant. We constructed regression models with multiple markers to assess whether results at less stringent thresholds were likely to be truly associated with RR interval. We identified six novel associations with resting heart rate at six loci: 6q22 near GJA1; 14q12 near MYH7; 12p12 near SOX5, c12orf67, BCAT1, LRMP and CASC1; 6q22 near SLC35F1, PLN and c6orf204; 7q22 near SLC12A9 and UfSp1; and 11q12 near FADS1. Associations at 6q22 400 kb away from GJA1, at 14q12 MYH6 and at 1q32 near CD34 identified in previously published GWAS were confirmed. In aggregate, these variants explain approximately 0.7% of RR interval variance. A multivariant regression model including 20 variants with P < 10(-5) increased the explained variance to 1.6%, suggesting that some loci falling short of genome-wide significance are likely truly associated. Future research is warranted to elucidate underlying mechanisms that may impact clinical care.

%B Hum Mol Genet %V 19 %P 3885-94 %8 2010 Oct 01 %G eng %N 19 %1 http://www.ncbi.nlm.nih.gov/pubmed/20639392?dopt=Abstract %R 10.1093/hmg/ddq303 %0 Journal Article %J Nat Genet %D 2010 %T Genome-wide association identifies multiple ulcerative colitis susceptibility loci. %A McGovern, Dermot P B %A Gardet, Agnès %A Törkvist, Leif %A Goyette, Philippe %A Essers, Jonah %A Taylor, Kent D %A Neale, Benjamin M %A Ong, Rick T H %A Lagacé, Caroline %A Li, Chun %A Green, Todd %A Stevens, Christine R %A Beauchamp, Claudine %A Fleshner, Phillip R %A Carlson, Marie %A D'Amato, Mauro %A Halfvarson, Jonas %A Hibberd, Martin L %A Lördal, Mikael %A Padyukov, Leonid %A Andriulli, Angelo %A Colombo, Elisabetta %A Latiano, Anna %A Palmieri, Orazio %A Bernard, Edmond-Jean %A Deslandres, Colette %A Hommes, Daan W %A de Jong, Dirk J %A Stokkers, Pieter C %A Weersma, Rinse K %A Sharma, Yashoda %A Silverberg, Mark S %A Cho, Judy H %A Wu, Jing %A Roeder, Kathryn %A Brant, Steven R %A Schumm, L Phillip %A Duerr, Richard H %A Dubinsky, Marla C %A Glazer, Nicole L %A Haritunians, Talin %A Ippoliti, Andy %A Melmed, Gil Y %A Siscovick, David S %A Vasiliauskas, Eric A %A Targan, Stephan R %A Annese, Vito %A Wijmenga, Cisca %A Pettersson, Sven %A Rotter, Jerome I %A Xavier, Ramnik J %A Daly, Mark J %A Rioux, John D %A Seielstad, Mark %K Colitis, Ulcerative %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Membrane Proteins %K Meta-Analysis as Topic %K Polymorphism, Single Nucleotide %K Receptors, IgG %X

Ulcerative colitis is a chronic, relapsing inflammatory condition of the gastrointestinal tract with a complex genetic and environmental etiology. In an effort to identify genetic variation underlying ulcerative colitis risk, we present two distinct genome-wide association studies of ulcerative colitis and their joint analysis with a previously published scan, comprising, in aggregate, 2,693 individuals with ulcerative colitis and 6,791 control subjects. Fifty-nine SNPs from 14 independent loci attained an association significance of P < 10(-5). Seven of these loci exceeded genome-wide significance (P < 5 x 10(-8)). After testing an independent cohort of 2,009 cases of ulcerative colitis and 1,580 controls, we identified 13 loci that were significantly associated with ulcerative colitis (P < 5 x 10(-8)), including the immunoglobulin receptor gene FCGR2A, 5p15, 2p16 and ORMDL3 (orosomucoid1-like 3). We confirmed association with 14 previously identified ulcerative colitis susceptibility loci, and an analysis of acknowledged Crohn's disease loci showed that roughly half of the known Crohn's disease associations are shared with ulcerative colitis. These data implicate approximately 30 loci in ulcerative colitis, thereby providing insight into disease pathogenesis.

%B Nat Genet %V 42 %P 332-7 %8 2010 Apr %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/20228799?dopt=Abstract %R 10.1038/ng.549 %0 Journal Article %J Proc Natl Acad Sci U S A %D 2010 %T Genome-wide association identifies OBFC1 as a locus involved in human leukocyte telomere biology. %A Levy, Daniel %A Neuhausen, Susan L %A Hunt, Steven C %A Kimura, Masayuki %A Hwang, Shih-Jen %A Chen, Wei %A Bis, Joshua C %A Fitzpatrick, Annette L %A Smith, Erin %A Johnson, Andrew D %A Gardner, Jeffrey P %A Srinivasan, Sathanur R %A Schork, Nicholas %A Rotter, Jerome I %A Herbig, Utz %A Psaty, Bruce M %A Sastrasinh, Malinee %A Murray, Sarah S %A Vasan, Ramachandran S %A Province, Michael A %A Glazer, Nicole L %A Lu, Xiaobin %A Cao, Xiaojian %A Kronmal, Richard %A Mangino, Massimo %A Soranzo, Nicole %A Spector, Tim D %A Berenson, Gerald S %A Aviv, Abraham %K Cohort Studies %K Genome-Wide Association Study %K Genotype %K Humans %K Leukocytes %K Polymorphism, Single Nucleotide %K Receptors, CXCR4 %K Telomere %K Telomere-Binding Proteins %X

Telomeres are engaged in a host of cellular functions, and their length is regulated by multiple genes. Telomere shortening, in the course of somatic cell replication, ultimately leads to replicative senescence. In humans, rare mutations in genes that regulate telomere length have been identified in monogenic diseases such as dyskeratosis congenita and idiopathic pulmonary fibrosis, which are associated with shortened leukocyte telomere length (LTL) and increased risk for aplastic anemia. Shortened LTL is observed in a host of aging-related complex genetic diseases and is associated with diminished survival in the elderly. We report results of a genome-wide association study of LTL in a consortium of four observational studies (n = 3,417 participants with LTL and genome-wide genotyping). SNPs in the regions of the oligonucleotide/oligosaccharide-binding folds containing one gene (OBFC1; rs4387287; P = 3.9 x 10(-9)) and chemokine (C-X-C motif) receptor 4 gene (CXCR4; rs4452212; P = 2.9 x 10(-8)) were associated with LTL at a genome-wide significance level (P < 5 x 10(-8)). We attempted replication of the top SNPs at these loci through de novo genotyping of 1,893 additional individuals and in silico lookup in another observational study (n = 2,876), and we confirmed the association findings for OBFC1 but not CXCR4. In addition, we confirmed the telomerase RNA component (TERC) as a gene associated with LTL (P = 1.1 x 10(-5)). The identification of OBFC1 through genome-wide association as a locus for interindividual variation in LTL in the general population advances the understanding of telomere biology in humans and may provide insights into aging-related disorders linked to altered LTL dynamics.

%B Proc Natl Acad Sci U S A %V 107 %P 9293-8 %8 2010 May 18 %G eng %N 20 %1 http://www.ncbi.nlm.nih.gov/pubmed/20421499?dopt=Abstract %R 10.1073/pnas.0911494107 %0 Journal Article %J Stroke %D 2010 %T Genome-wide association studies of MRI-defined brain infarcts: meta-analysis from the CHARGE Consortium. %A Debette, Stephanie %A Bis, Joshua C %A Fornage, Myriam %A Schmidt, Helena %A Ikram, M Arfan %A Sigurdsson, Sigurdur %A Heiss, Gerardo %A Struchalin, Maksim %A Smith, Albert V %A van der Lugt, Aad %A DeCarli, Charles %A Lumley, Thomas %A Knopman, David S %A Enzinger, Christian %A Eiriksdottir, Gudny %A Koudstaal, Peter J %A DeStefano, Anita L %A Psaty, Bruce M %A Dufouil, Carole %A Catellier, Diane J %A Fazekas, Franz %A Aspelund, Thor %A Aulchenko, Yurii S %A Beiser, Alexa %A Rotter, Jerome I %A Tzourio, Christophe %A Shibata, Dean K %A Tscherner, Maria %A Harris, Tamara B %A Rivadeneira, Fernando %A Atwood, Larry D %A Rice, Kenneth %A Gottesman, Rebecca F %A van Buchem, Mark A %A Uitterlinden, André G %A Kelly-Hayes, Margaret %A Cushman, Mary %A Zhu, Yicheng %A Boerwinkle, Eric %A Gudnason, Vilmundur %A Hofman, Albert %A Romero, Jose R %A Lopez, Oscar %A van Duijn, Cornelia M %A Au, Rhoda %A Heckbert, Susan R %A Wolf, Philip A %A Mosley, Thomas H %A Seshadri, Sudha %A Breteler, Monique M B %A Schmidt, Reinhold %A Launer, Lenore J %A Longstreth, W T %K African Americans %K Aged %K Brain %K Brain Infarction %K Cohort Studies %K DNA Mutational Analysis %K Female %K Gene Frequency %K Genetic Markers %K Genetic Predisposition to Disease %K Genetic Testing %K Genetic Variation %K Genome-Wide Association Study %K Humans %K Linkage Disequilibrium %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Prospective Studies %X

BACKGROUND AND PURPOSE: Previous studies examining genetic associations with MRI-defined brain infarct have yielded inconsistent findings. We investigated genetic variation underlying covert MRI infarct in persons without histories of transient ischemic attack or stroke. We performed meta-analysis of genome-wide association studies of white participants in 6 studies comprising the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium.

METHODS: Using 2.2 million genotyped and imputed single nucleotide polymorphisms, each study performed cross-sectional genome-wide association analysis of MRI infarct using age- and sex-adjusted logistic regression models. Study-specific findings were combined in an inverse-variance-weighted meta-analysis, including 9401 participants with mean age 69.7 (19.4% of whom had >or=1 MRI infarct).

RESULTS: The most significant association was found with rs2208454 (minor allele frequency, 20%), located in intron 3 of MACRO domain containing 2 gene and in the downstream region of fibronectin leucine-rich transmembrane protein 3 gene. Each copy of the minor allele was associated with lower risk of MRI infarcts (odds ratio, 0.76; 95% confidence interval, 0.68-0.84; P=4.64x10(-7)). Highly suggestive associations (P<1.0x10(-5)) were also found for 22 other single nucleotide polymorphisms in linkage disequilibrium (r(2)>0.64) with rs2208454. The association with rs2208454 did not replicate in independent samples of 1822 white and 644 black participants, although 4 single nucleotide polymorphisms within 200 kb from rs2208454 were associated with MRI infarcts in the black population sample.

CONCLUSIONS: This first community-based, genome-wide association study on covert MRI infarcts uncovered novel associations. Although replication of the association with top single nucleotide polymorphisms failed, possibly because of insufficient power, results in the black population sample are encouraging, and further efforts at replication are needed.

%B Stroke %V 41 %P 210-7 %8 2010 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/20044523?dopt=Abstract %R 10.1161/STROKEAHA.109.569194 %0 Journal Article %J PLoS Genet %D 2010 %T Genome-wide association studies of serum magnesium, potassium, and sodium concentrations identify six Loci influencing serum magnesium levels. %A Meyer, Tamra E %A Verwoert, Germaine C %A Hwang, Shih-Jen %A Glazer, Nicole L %A Smith, Albert V %A van Rooij, Frank J A %A Ehret, Georg B %A Boerwinkle, Eric %A Felix, Janine F %A Leak, Tennille S %A Harris, Tamara B %A Yang, Qiong %A Dehghan, Abbas %A Aspelund, Thor %A Katz, Ronit %A Homuth, Georg %A Kocher, Thomas %A Rettig, Rainer %A Ried, Janina S %A Gieger, Christian %A Prucha, Hanna %A Pfeufer, Arne %A Meitinger, Thomas %A Coresh, Josef %A Hofman, Albert %A Sarnak, Mark J %A Chen, Yii-Der Ida %A Uitterlinden, André G %A Chakravarti, Aravinda %A Psaty, Bruce M %A van Duijn, Cornelia M %A Kao, W H Linda %A Witteman, Jacqueline C M %A Gudnason, Vilmundur %A Siscovick, David S %A Fox, Caroline S %A Köttgen, Anna %K Adult %K Aged %K European Continental Ancestry Group %K Female %K Genome-Wide Association Study %K Humans %K Magnesium %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Potassium %K Sodium %X

Magnesium, potassium, and sodium, cations commonly measured in serum, are involved in many physiological processes including energy metabolism, nerve and muscle function, signal transduction, and fluid and blood pressure regulation. To evaluate the contribution of common genetic variation to normal physiologic variation in serum concentrations of these cations, we conducted genome-wide association studies of serum magnesium, potassium, and sodium concentrations using approximately 2.5 million genotyped and imputed common single nucleotide polymorphisms (SNPs) in 15,366 participants of European descent from the international CHARGE Consortium. Study-specific results were combined using fixed-effects inverse-variance weighted meta-analysis. SNPs demonstrating genome-wide significant (p<5 x 10(-8)) or suggestive associations (p<4 x 10(-7)) were evaluated for replication in an additional 8,463 subjects of European descent. The association of common variants at six genomic regions (in or near MUC1, ATP2B1, DCDC5, TRPM6, SHROOM3, and MDS1) with serum magnesium levels was genome-wide significant when meta-analyzed with the replication dataset. All initially significant SNPs from the CHARGE Consortium showed nominal association with clinically defined hypomagnesemia, two showed association with kidney function, two with bone mineral density, and one of these also associated with fasting glucose levels. Common variants in CNNM2, a magnesium transporter studied only in model systems to date, as well as in CNNM3 and CNNM4, were also associated with magnesium concentrations in this study. We observed no associations with serum sodium or potassium levels exceeding p<4 x 10(-7). Follow-up studies of newly implicated genomic loci may provide additional insights into the regulation and homeostasis of human serum magnesium levels.

%B PLoS Genet %V 6 %8 2010 Aug 05 %G eng %N 8 %1 http://www.ncbi.nlm.nih.gov/pubmed/20700443?dopt=Abstract %R 10.1371/journal.pgen.1001045 %0 Journal Article %J PLoS One %D 2010 %T Genome-wide association study identifies GPC5 as a novel genetic locus protective against sudden cardiac arrest. %A Arking, Dan E %A Reinier, Kyndaron %A Post, Wendy %A Jui, Jonathan %A Hilton, Gina %A O'Connor, Ashley %A Prineas, Ronald J %A Boerwinkle, Eric %A Psaty, Bruce M %A Tomaselli, Gordon F %A Rea, Thomas %A Sotoodehnia, Nona %A Siscovick, David S %A Burke, Gregory L %A Marbán, Eduardo %A Spooner, Peter M %A Chakravarti, Aravinda %A Chugh, Sumeet S %K Aged %K Alleles %K Case-Control Studies %K Cohort Studies %K Death, Sudden, Cardiac %K Ethnic Groups %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Glypicans %K Heart Diseases %K Humans %K Male %K Middle Aged %K Models, Genetic %K Oligonucleotide Array Sequence Analysis %K Oregon %K Polymorphism, Single Nucleotide %X

BACKGROUND: Existing studies indicate a significant genetic component for sudden cardiac arrest (SCA) and genome-wide association studies (GWAS) provide an unbiased approach for identification of novel genes. We performed a GWAS to identify genetic determinants of SCA.

METHODOLOGY/PRINCIPAL FINDINGS: We used a case-control design within the ongoing Oregon Sudden Unexpected Death Study (Oregon-SUDS). Cases (n = 424) were SCAs with coronary artery disease (CAD) among residents of Portland, OR (2002-07, population approximately 1,000,000) and controls (n = 226) were residents with CAD, but no history of SCA. All subjects were of White-European ancestry and GWAS was performed using Affymetrix 500K/5.0 and 6.0 arrays. High signal markers were genotyped in SCA cases (n = 521) identified from the Atherosclerosis Risk in Communities Study (ARIC) and the Cardiovascular Health Study (CHS) (combined n = 19,611). No SNPs reached genome-wide significance (p<5x10(-8)). SNPs at 6 loci were prioritized for follow-up primarily based on significance of p<10(-4) and proximity to a known gene (CSMD2, GPR37L1, LIN9, B4GALNT3, GPC5, and ZNF592). The minor allele of GPC5 (GLYPICAN 5, rs3864180) was associated with a lower risk of SCA in Oregon-SUDS, an effect that was also observed in ARIC/CHS whites (p<0.05) and blacks (p<0.04). In a combined Cox proportional hazards model analysis that adjusted for race, the minor allele exhibited a hazard ratio of 0.85 (95% CI 0.74 to 0.98; p<0.01).

CONCLUSIONS/SIGNIFICANCE: A novel genetic locus for SCA, GPC5, was identified from Oregon-SUDS and successfully validated in the ARIC and CHS cohorts. Three other members of the Glypican family have been previously implicated in human disease, including cardiac conditions. The mechanism of this specific association requires further study.

%B PLoS One %V 5 %P e9879 %8 2010 Mar 25 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/20360844?dopt=Abstract %R 10.1371/journal.pone.0009879 %0 Journal Article %J Nat Genet %D 2010 %T Genome-wide association study of PR interval. %A Pfeufer, Arne %A van Noord, Charlotte %A Marciante, Kristin D %A Arking, Dan E %A Larson, Martin G %A Smith, Albert Vernon %A Tarasov, Kirill V %A Müller, Martina %A Sotoodehnia, Nona %A Sinner, Moritz F %A Verwoert, Germaine C %A Li, Man %A Kao, W H Linda %A Köttgen, Anna %A Coresh, Josef %A Bis, Joshua C %A Psaty, Bruce M %A Rice, Kenneth %A Rotter, Jerome I %A Rivadeneira, Fernando %A Hofman, Albert %A Kors, Jan A %A Stricker, Bruno H C %A Uitterlinden, André G %A van Duijn, Cornelia M %A Beckmann, Britt M %A Sauter, Wiebke %A Gieger, Christian %A Lubitz, Steven A %A Newton-Cheh, Christopher %A Wang, Thomas J %A Magnani, Jared W %A Schnabel, Renate B %A Chung, Mina K %A Barnard, John %A Smith, Jonathan D %A Van Wagoner, David R %A Vasan, Ramachandran S %A Aspelund, Thor %A Eiriksdottir, Gudny %A Harris, Tamara B %A Launer, Lenore J %A Najjar, Samer S %A Lakatta, Edward %A Schlessinger, David %A Uda, Manuela %A Abecasis, Goncalo R %A Müller-Myhsok, Bertram %A Ehret, Georg B %A Boerwinkle, Eric %A Chakravarti, Aravinda %A Soliman, Elsayed Z %A Lunetta, Kathryn L %A Perz, Siegfried %A Wichmann, H-Erich %A Meitinger, Thomas %A Levy, Daniel %A Gudnason, Vilmundur %A Ellinor, Patrick T %A Sanna, Serena %A Kääb, Stefan %A Witteman, Jacqueline C M %A Alonso, Alvaro %A Benjamin, Emelia J %A Heckbert, Susan R %K Aged %K Atrial Fibrillation %K Cohort Studies %K Electrocardiography %K Female %K Genetic Loci %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Heart Conduction System %K Humans %K Male %K Meta-Analysis as Topic %X

The electrocardiographic PR interval (or PQ interval) reflects atrial and atrioventricular nodal conduction, disturbances of which increase risk of atrial fibrillation. We report a meta-analysis of genome-wide association studies for PR interval from seven population-based European studies in the CHARGE Consortium: AGES, ARIC, CHS, FHS, KORA, Rotterdam Study, and SardiNIA (N = 28,517). We identified nine loci associated with PR interval at P < 5 x 10(-8). At the 3p22.2 locus, we observed two independent associations in voltage-gated sodium channel genes, SCN10A and SCN5A. Six of the loci were near cardiac developmental genes, including CAV1-CAV2, NKX2-5 (CSX1), SOX5, WNT11, MEIS1, and TBX5-TBX3, providing pathophysiologically interesting candidate genes. Five of the loci, SCN5A, SCN10A, NKX2-5, CAV1-CAV2, and SOX5, were also associated with atrial fibrillation (N = 5,741 cases, P < 0.0056). This suggests a role for common variation in ion channel and developmental genes in atrial and atrioventricular conduction as well as in susceptibility to atrial fibrillation.

%B Nat Genet %V 42 %P 153-9 %8 2010 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/20062060?dopt=Abstract %R 10.1038/ng.517 %0 Journal Article %J Nat Genet %D 2010 %T Genome-wide meta-analyses identify multiple loci associated with smoking behavior. %K Age Factors %K Alleles %K Chromosome Mapping %K Female %K Genome %K Genome-Wide Association Study %K Genotype %K Humans %K Male %K Molecular Epidemiology %K Odds Ratio %K Phenotype %K Polymorphism, Single Nucleotide %K Receptors, Nicotinic %K Smoking %X

Consistent but indirect evidence has implicated genetic factors in smoking behavior. We report meta-analyses of several smoking phenotypes within cohorts of the Tobacco and Genetics Consortium (n = 74,053). We also partnered with the European Network of Genetic and Genomic Epidemiology (ENGAGE) and Oxford-GlaxoSmithKline (Ox-GSK) consortia to follow up the 15 most significant regions (n > 140,000). We identified three loci associated with number of cigarettes smoked per day. The strongest association was a synonymous 15q25 SNP in the nicotinic receptor gene CHRNA3 (rs1051730[A], beta = 1.03, standard error (s.e.) = 0.053, P = 2.8 x 10(-73)). Two 10q25 SNPs (rs1329650[G], beta = 0.367, s.e. = 0.059, P = 5.7 x 10(-10); and rs1028936[A], beta = 0.446, s.e. = 0.074, P = 1.3 x 10(-9)) and one 9q13 SNP in EGLN2 (rs3733829[G], beta = 0.333, s.e. = 0.058, P = 1.0 x 10(-8)) also exceeded genome-wide significance for cigarettes per day. For smoking initiation, eight SNPs exceeded genome-wide significance, with the strongest association at a nonsynonymous SNP in BDNF on chromosome 11 (rs6265[C], odds ratio (OR) = 1.06, 95% confidence interval (Cl) 1.04-1.08, P = 1.8 x 10(-8)). One SNP located near DBH on chromosome 9 (rs3025343[G], OR = 1.12, 95% Cl 1.08-1.18, P = 3.6 x 10(-8)) was significantly associated with smoking cessation.

%B Nat Genet %V 42 %P 441-7 %8 2010 May %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/20418890?dopt=Abstract %R 10.1038/ng.571 %0 Journal Article %J Nat Genet %D 2010 %T Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci. %A Franke, Andre %A McGovern, Dermot P B %A Barrett, Jeffrey C %A Wang, Kai %A Radford-Smith, Graham L %A Ahmad, Tariq %A Lees, Charlie W %A Balschun, Tobias %A Lee, James %A Roberts, Rebecca %A Anderson, Carl A %A Bis, Joshua C %A Bumpstead, Suzanne %A Ellinghaus, David %A Festen, Eleonora M %A Georges, Michel %A Green, Todd %A Haritunians, Talin %A Jostins, Luke %A Latiano, Anna %A Mathew, Christopher G %A Montgomery, Grant W %A Prescott, Natalie J %A Raychaudhuri, Soumya %A Rotter, Jerome I %A Schumm, Philip %A Sharma, Yashoda %A Simms, Lisa A %A Taylor, Kent D %A Whiteman, David %A Wijmenga, Cisca %A Baldassano, Robert N %A Barclay, Murray %A Bayless, Theodore M %A Brand, Stephan %A Büning, Carsten %A Cohen, Albert %A Colombel, Jean-Frederick %A Cottone, Mario %A Stronati, Laura %A Denson, Ted %A De Vos, Martine %A D'Inca, Renata %A Dubinsky, Marla %A Edwards, Cathryn %A Florin, Tim %A Franchimont, Denis %A Gearry, Richard %A Glas, Jürgen %A Van Gossum, Andre %A Guthery, Stephen L %A Halfvarson, Jonas %A Verspaget, Hein W %A Hugot, Jean-Pierre %A Karban, Amir %A Laukens, Debby %A Lawrance, Ian %A Lemann, Marc %A Levine, Arie %A Libioulle, Cecile %A Louis, Edouard %A Mowat, Craig %A Newman, William %A Panés, Julián %A Phillips, Anne %A Proctor, Deborah D %A Regueiro, Miguel %A Russell, Richard %A Rutgeerts, Paul %A Sanderson, Jeremy %A Sans, Miquel %A Seibold, Frank %A Steinhart, A Hillary %A Stokkers, Pieter C F %A Törkvist, Leif %A Kullak-Ublick, Gerd %A Wilson, David %A Walters, Thomas %A Targan, Stephan R %A Brant, Steven R %A Rioux, John D %A D'Amato, Mauro %A Weersma, Rinse K %A Kugathasan, Subra %A Griffiths, Anne M %A Mansfield, John C %A Vermeire, Severine %A Duerr, Richard H %A Silverberg, Mark S %A Satsangi, Jack %A Schreiber, Stefan %A Cho, Judy H %A Annese, Vito %A Hakonarson, Hakon %A Daly, Mark J %A Parkes, Miles %K Computational Biology %K Crohn Disease %K Genetic Linkage %K Genetic Loci %K Genetic Predisposition to Disease %K Genetic Variation %K Genome, Human %K Genome-Wide Association Study %K Humans %K Reproducibility of Results %X

We undertook a meta-analysis of six Crohn's disease genome-wide association studies (GWAS) comprising 6,333 affected individuals (cases) and 15,056 controls and followed up the top association signals in 15,694 cases, 14,026 controls and 414 parent-offspring trios. We identified 30 new susceptibility loci meeting genome-wide significance (P < 5 × 10⁻⁸). A series of in silico analyses highlighted particular genes within these loci and, together with manual curation, implicated functionally interesting candidate genes including SMAD3, ERAP2, IL10, IL2RA, TYK2, FUT2, DNMT3A, DENND1B, BACH2 and TAGAP. Combined with previously confirmed loci, these results identify 71 distinct loci with genome-wide significant evidence for association with Crohn's disease.

%B Nat Genet %V 42 %P 1118-25 %8 2010 Dec %G eng %N 12 %1 http://www.ncbi.nlm.nih.gov/pubmed/21102463?dopt=Abstract %R 10.1038/ng.717 %0 Journal Article %J Circ Cardiovasc Genet %D 2010 %T Genomic variation associated with mortality among adults of European and African ancestry with heart failure: the cohorts for heart and aging research in genomic epidemiology consortium. %A Morrison, Alanna C %A Felix, Janine F %A Cupples, L Adrienne %A Glazer, Nicole L %A Loehr, Laura R %A Dehghan, Abbas %A Demissie, Serkalem %A Bis, Joshua C %A Rosamond, Wayne D %A Aulchenko, Yurii S %A Wang, Ying A %A Haritunians, Talin %A Folsom, Aaron R %A Rivadeneira, Fernando %A Benjamin, Emelia J %A Lumley, Thomas %A Couper, David %A Stricker, Bruno H %A O'Donnell, Christopher J %A Rice, Kenneth M %A Chang, Patricia P %A Hofman, Albert %A Levy, Daniel %A Rotter, Jerome I %A Fox, Ervin R %A Uitterlinden, André G %A Wang, Thomas J %A Psaty, Bruce M %A Willerson, James T %A van Duijn, Cornelia M %A Boerwinkle, Eric %A Witteman, Jacqueline C M %A Vasan, Ramachandran S %A Smith, Nicholas L %K African Americans %K Aged %K Aged, 80 and over %K Chemokines %K Cohort Studies %K European Continental Ancestry Group %K Female %K Genome-Wide Association Study %K Genotype %K Heart Failure %K Humans %K Introns %K Male %K MARVEL Domain-Containing Proteins %K Membrane Proteins %K Middle Aged %K Polymorphism, Single Nucleotide %K Risk Factors %X

BACKGROUND: Prognosis and survival are significant concerns for individuals with heart failure (HF). To better understand the pathophysiology of HF prognosis, the association between 2,366,858 single-nucleotide polymorphisms (SNPs) and all-cause mortality was evaluated among individuals with incident HF from 4 community-based prospective cohorts: the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Rotterdam Study.

METHODS AND RESULTS: Participants were 2526 individuals of European ancestry and 466 individuals of African ancestry who experienced an incident HF event during follow-up in the respective cohorts. Within each study, the association between genetic variants and time to mortality among individuals with HF was assessed by Cox proportional hazards models that included adjustment for sex and age at the time of the HF event. Prospective fixed-effect meta-analyses were conducted for the 4 study populations of European ancestry (N=1645 deaths) and for the 2 populations of African ancestry (N=281 deaths). Genome-wide significance was set at P=5.0x10(-7). Meta-analytic findings among individuals of European ancestry revealed 1 genome-wide significant locus on chromosome 3p22 in an intron of CKLF-like MARVEL transmembrane domain containing 7 (CMTM7, P=3.2x10(-7)). Eight additional loci in individuals of European ancestry and 4 loci in individuals of African ancestry were identified by high-signal SNPs (P<1.0x10(-5)) but did not meet genome-wide significance.

CONCLUSIONS: This study identified a novel locus associated with all-cause mortality among individuals of European ancestry with HF. This finding warrants additional investigation, including replication, in other studies of HF.

%B Circ Cardiovasc Genet %V 3 %P 248-55 %8 2010 Jun %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/20400778?dopt=Abstract %R 10.1161/CIRCGENETICS.109.895995 %0 Journal Article %J Nature %D 2010 %T Hundreds of variants clustered in genomic loci and biological pathways affect human height. %A Lango Allen, Hana %A Estrada, Karol %A Lettre, Guillaume %A Berndt, Sonja I %A Weedon, Michael N %A Rivadeneira, Fernando %A Willer, Cristen J %A Jackson, Anne U %A Vedantam, Sailaja %A Raychaudhuri, Soumya %A Ferreira, Teresa %A Wood, Andrew R %A Weyant, Robert J %A Segrè, Ayellet V %A Speliotes, Elizabeth K %A Wheeler, Eleanor %A Soranzo, Nicole %A Park, Ju-Hyun %A Yang, Jian %A Gudbjartsson, Daniel %A Heard-Costa, Nancy L %A Randall, Joshua C %A Qi, Lu %A Vernon Smith, Albert %A Mägi, Reedik %A Pastinen, Tomi %A Liang, Liming %A Heid, Iris M %A Luan, Jian'an %A Thorleifsson, Gudmar %A Winkler, Thomas W %A Goddard, Michael E %A Sin Lo, Ken %A Palmer, Cameron %A Workalemahu, Tsegaselassie %A Aulchenko, Yurii S %A Johansson, Asa %A Zillikens, M Carola %A Feitosa, Mary F %A Esko, Tõnu %A Johnson, Toby %A Ketkar, Shamika %A Kraft, Peter %A Mangino, Massimo %A Prokopenko, Inga %A Absher, Devin %A Albrecht, Eva %A Ernst, Florian %A Glazer, Nicole L %A Hayward, Caroline %A Hottenga, Jouke-Jan %A Jacobs, Kevin B %A Knowles, Joshua W %A Kutalik, Zoltán %A Monda, Keri L %A Polasek, Ozren %A Preuss, Michael %A Rayner, Nigel W %A Robertson, Neil R %A Steinthorsdottir, Valgerdur %A Tyrer, Jonathan P %A Voight, Benjamin F %A Wiklund, Fredrik %A Xu, Jianfeng %A Zhao, Jing Hua %A Nyholt, Dale R %A Pellikka, Niina %A Perola, Markus %A Perry, John R B %A Surakka, Ida %A Tammesoo, Mari-Liis %A Altmaier, Elizabeth L %A Amin, Najaf %A Aspelund, Thor %A Bhangale, Tushar %A Boucher, Gabrielle %A Chasman, Daniel I %A Chen, Constance %A Coin, Lachlan %A Cooper, Matthew N %A Dixon, Anna L %A Gibson, Quince %A Grundberg, Elin %A Hao, Ke %A Juhani Junttila, M %A Kaplan, Lee M %A Kettunen, Johannes %A König, Inke R %A Kwan, Tony %A Lawrence, Robert W %A Levinson, Douglas F %A Lorentzon, Mattias %A McKnight, Barbara %A Morris, Andrew P %A Müller, Martina %A Suh Ngwa, Julius %A Purcell, Shaun %A Rafelt, Suzanne %A Salem, Rany M %A Salvi, Erika %A Sanna, Serena %A Shi, Jianxin %A Sovio, Ulla %A Thompson, John R %A Turchin, Michael C %A Vandenput, Liesbeth %A Verlaan, Dominique J %A Vitart, Veronique %A White, Charles C %A Ziegler, Andreas %A Almgren, Peter %A Balmforth, Anthony J %A Campbell, Harry %A Citterio, Lorena %A De Grandi, Alessandro %A Dominiczak, Anna %A Duan, Jubao %A Elliott, Paul %A Elosua, Roberto %A Eriksson, Johan G %A Freimer, Nelson B %A Geus, Eco J C %A Glorioso, Nicola %A Haiqing, Shen %A Hartikainen, Anna-Liisa %A Havulinna, Aki S %A Hicks, Andrew A %A Hui, Jennie %A Igl, Wilmar %A Illig, Thomas %A Jula, Antti %A Kajantie, Eero %A Kilpeläinen, Tuomas O %A Koiranen, Markku %A Kolcic, Ivana %A Koskinen, Seppo %A Kovacs, Peter %A Laitinen, Jaana %A Liu, Jianjun %A Lokki, Marja-Liisa %A Marusic, Ana %A Maschio, Andrea %A Meitinger, Thomas %A Mulas, Antonella %A Paré, Guillaume %A Parker, Alex N %A Peden, John F %A Petersmann, Astrid %A Pichler, Irene %A Pietiläinen, Kirsi H %A Pouta, Anneli %A Ridderstråle, Martin %A Rotter, Jerome I %A Sambrook, Jennifer G %A Sanders, Alan R %A Schmidt, Carsten Oliver %A Sinisalo, Juha %A Smit, Jan H %A Stringham, Heather M %A Bragi Walters, G %A Widen, Elisabeth %A Wild, Sarah H %A Willemsen, Gonneke %A Zagato, Laura %A Zgaga, Lina %A Zitting, Paavo %A Alavere, Helene %A Farrall, Martin %A McArdle, Wendy L %A Nelis, Mari %A Peters, Marjolein J %A Ripatti, Samuli %A van Meurs, Joyce B J %A Aben, Katja K %A Ardlie, Kristin G %A Beckmann, Jacques S %A Beilby, John P %A Bergman, Richard N %A Bergmann, Sven %A Collins, Francis S %A Cusi, Daniele %A den Heijer, Martin %A Eiriksdottir, Gudny %A Gejman, Pablo V %A Hall, Alistair S %A Hamsten, Anders %A Huikuri, Heikki V %A Iribarren, Carlos %A Kähönen, Mika %A Kaprio, Jaakko %A Kathiresan, Sekar %A Kiemeney, Lambertus %A Kocher, Thomas %A Launer, Lenore J %A Lehtimäki, Terho %A Melander, Olle %A Mosley, Tom H %A Musk, Arthur W %A Nieminen, Markku S %A O'Donnell, Christopher J %A Ohlsson, Claes %A Oostra, Ben %A Palmer, Lyle J %A Raitakari, Olli %A Ridker, Paul M %A Rioux, John D %A Rissanen, Aila %A Rivolta, Carlo %A Schunkert, Heribert %A Shuldiner, Alan R %A Siscovick, David S %A Stumvoll, Michael %A Tönjes, Anke %A Tuomilehto, Jaakko %A van Ommen, Gert-Jan %A Viikari, Jorma %A Heath, Andrew C %A Martin, Nicholas G %A Montgomery, Grant W %A Province, Michael A %A Kayser, Manfred %A Arnold, Alice M %A Atwood, Larry D %A Boerwinkle, Eric %A Chanock, Stephen J %A Deloukas, Panos %A Gieger, Christian %A Grönberg, Henrik %A Hall, Per %A Hattersley, Andrew T %A Hengstenberg, Christian %A Hoffman, Wolfgang %A Lathrop, G Mark %A Salomaa, Veikko %A Schreiber, Stefan %A Uda, Manuela %A Waterworth, Dawn %A Wright, Alan F %A Assimes, Themistocles L %A Barroso, Inês %A Hofman, Albert %A Mohlke, Karen L %A Boomsma, Dorret I %A Caulfield, Mark J %A Cupples, L Adrienne %A Erdmann, Jeanette %A Fox, Caroline S %A Gudnason, Vilmundur %A Gyllensten, Ulf %A Harris, Tamara B %A Hayes, Richard B %A Jarvelin, Marjo-Riitta %A Mooser, Vincent %A Munroe, Patricia B %A Ouwehand, Willem H %A Penninx, Brenda W %A Pramstaller, Peter P %A Quertermous, Thomas %A Rudan, Igor %A Samani, Nilesh J %A Spector, Timothy D %A Völzke, Henry %A Watkins, Hugh %A Wilson, James F %A Groop, Leif C %A Haritunians, Talin %A Hu, Frank B %A Kaplan, Robert C %A Metspalu, Andres %A North, Kari E %A Schlessinger, David %A Wareham, Nicholas J %A Hunter, David J %A O'Connell, Jeffrey R %A Strachan, David P %A Wichmann, H-Erich %A Borecki, Ingrid B %A van Duijn, Cornelia M %A Schadt, Eric E %A Thorsteinsdottir, Unnur %A Peltonen, Leena %A Uitterlinden, André G %A Visscher, Peter M %A Chatterjee, Nilanjan %A Loos, Ruth J F %A Boehnke, Michael %A McCarthy, Mark I %A Ingelsson, Erik %A Lindgren, Cecilia M %A Abecasis, Goncalo R %A Stefansson, Kari %A Frayling, Timothy M %A Hirschhorn, Joel N %K Body Height %K Chromosomes, Human, Pair 3 %K Genetic Loci %K Genetic Predisposition to Disease %K Genome, Human %K Genome-Wide Association Study %K Humans %K Metabolic Networks and Pathways %K Multifactorial Inheritance %K Phenotype %K Polymorphism, Single Nucleotide %X

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.

%B Nature %V 467 %P 832-8 %8 2010 Oct 14 %G eng %N 7317 %1 http://www.ncbi.nlm.nih.gov/pubmed/20881960?dopt=Abstract %R 10.1038/nature09410 %0 Journal Article %J Diabetes Care %D 2010 %T Interactions of dietary whole-grain intake with fasting glucose- and insulin-related genetic loci in individuals of European descent: a meta-analysis of 14 cohort studies. %A Nettleton, Jennifer A %A McKeown, Nicola M %A Kanoni, Stavroula %A Lemaitre, Rozenn N %A Hivert, Marie-France %A Ngwa, Julius %A van Rooij, Frank J A %A Sonestedt, Emily %A Wojczynski, Mary K %A Ye, Zheng %A Tanaka, Tosh %A Garcia, Melissa %A Anderson, Jennifer S %A Follis, Jack L %A Djoussé, Luc %A Mukamal, Kenneth %A Papoutsakis, Constantina %A Mozaffarian, Dariush %A Zillikens, M Carola %A Bandinelli, Stefania %A Bennett, Amanda J %A Borecki, Ingrid B %A Feitosa, Mary F %A Ferrucci, Luigi %A Forouhi, Nita G %A Groves, Christopher J %A Hallmans, Göran %A Harris, Tamara %A Hofman, Albert %A Houston, Denise K %A Hu, Frank B %A Johansson, Ingegerd %A Kritchevsky, Stephen B %A Langenberg, Claudia %A Launer, Lenore %A Liu, Yongmei %A Loos, Ruth J %A Nalls, Michael %A Orho-Melander, Marju %A Renstrom, Frida %A Rice, Kenneth %A Riserus, Ulf %A Rolandsson, Olov %A Rotter, Jerome I %A Saylor, Georgia %A Sijbrands, Eric J G %A Sjogren, Per %A Smith, Albert %A Steingrímsdóttir, Laufey %A Uitterlinden, André G %A Wareham, Nicholas J %A Prokopenko, Inga %A Pankow, James S %A van Duijn, Cornelia M %A Florez, Jose C %A Witteman, Jacqueline C M %A Dupuis, Josée %A Dedoussis, George V %A Ordovas, Jose M %A Ingelsson, Erik %A Cupples, L Adrienne %A Siscovick, David S %A Franks, Paul W %A Meigs, James B %K Adult %K Aged %K Blood Glucose %K Edible Grain %K European Continental Ancestry Group %K Fasting %K Female %K Genetic Loci %K Genome-Wide Association Study %K Genotype %K Humans %K Insulin %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %X

OBJECTIVE: Whole-grain foods are touted for multiple health benefits, including enhancing insulin sensitivity and reducing type 2 diabetes risk. Recent genome-wide association studies (GWAS) have identified several single nucleotide polymorphisms (SNPs) associated with fasting glucose and insulin concentrations in individuals free of diabetes. We tested the hypothesis that whole-grain food intake and genetic variation interact to influence concentrations of fasting glucose and insulin.

RESEARCH DESIGN AND METHODS: Via meta-analysis of data from 14 cohorts comprising ∼ 48,000 participants of European descent, we studied interactions of whole-grain intake with loci previously associated in GWAS with fasting glucose (16 loci) and/or insulin (2 loci) concentrations. For tests of interaction, we considered a P value <0.0028 (0.05 of 18 tests) as statistically significant.

RESULTS: Greater whole-grain food intake was associated with lower fasting glucose and insulin concentrations independent of demographics, other dietary and lifestyle factors, and BMI (β [95% CI] per 1-serving-greater whole-grain intake: -0.009 mmol/l glucose [-0.013 to -0.005], P < 0.0001 and -0.011 pmol/l [ln] insulin [-0.015 to -0.007], P = 0.0003). No interactions met our multiple testing-adjusted statistical significance threshold. The strongest SNP interaction with whole-grain intake was rs780094 (GCKR) for fasting insulin (P = 0.006), where greater whole-grain intake was associated with a smaller reduction in fasting insulin concentrations in those with the insulin-raising allele.

CONCLUSIONS: Our results support the favorable association of whole-grain intake with fasting glucose and insulin and suggest a potential interaction between variation in GCKR and whole-grain intake in influencing fasting insulin concentrations.

%B Diabetes Care %V 33 %P 2684-91 %8 2010 Dec %G eng %N 12 %1 http://www.ncbi.nlm.nih.gov/pubmed/20693352?dopt=Abstract %R 10.2337/dc10-1150 %0 Journal Article %J Hum Mol Genet %D 2010 %T Large-scale genomic studies reveal central role of ABO in sP-selectin and sICAM-1 levels. %A Barbalic, Maja %A Dupuis, Josée %A Dehghan, Abbas %A Bis, Joshua C %A Hoogeveen, Ron C %A Schnabel, Renate B %A Nambi, Vijay %A Bretler, Monique %A Smith, Nicholas L %A Peters, Annette %A Lu, Chen %A Tracy, Russell P %A Aleksic, Nena %A Heeriga, Jan %A Keaney, John F %A Rice, Kenneth %A Lip, Gregory Y H %A Vasan, Ramachandran S %A Glazer, Nicole L %A Larson, Martin G %A Uitterlinden, André G %A Yamamoto, Jennifer %A Durda, Peter %A Haritunians, Talin %A Psaty, Bruce M %A Boerwinkle, Eric %A Hofman, Albert %A Koenig, Wolfgang %A Jenny, Nancy S %A Witteman, Jacqueline C %A Ballantyne, Christie %A Benjamin, Emelia J %K ABO Blood-Group System %K Blood Platelets %K Enzyme-Linked Immunosorbent Assay %K European Continental Ancestry Group %K Fluorescence %K Genome-Wide Association Study %K Humans %K Intercellular Adhesion Molecule-1 %K P-Selectin %X

P-selectin and intercellular adhesion molecule-1 (ICAM-1) participate in inflammatory processes by promoting adhesion of leukocytes to vascular wall endothelium. Their soluble levels have been associated with adverse cardiovascular events. To identify loci affecting soluble levels of P-selectin (sP-selectin) and ICAM-1 (sICAM-1), we performed a genome-wide association study in a sample of 4115 (sP-selectin) and 9813 (sICAM-1) individuals of European ancestry as a part of The Cohorts for Heart and Aging Research in Genome Epidemiology consortium. The most significant SNP association for sP-selectin was within the SELP gene (rs6136, P = 4.05 x 10(-61)) and for sICAM-1 levels within the ICAM-1 gene (rs3093030, P = 3.53 x 10(-23)). Both sP-selectin and sICAM-1 were associated with ABO gene variants (rs579459, P = 1.86 x 10(-41) and rs649129, P = 1.22 x 10(-15), respectively) and in both cases the observed associations could be accounted for by the A1 allele of the ABO blood group. The absence of an association between ABO blood group and platelet-bound P-selectin levels in an independent subsample (N = 1088) from the ARIC study, suggests that the ABO blood group may influence cleavage of the P-selectin protein from the cell surface or clearance from the circulation, rather than its production and cellular presentation. These results provide new insights into adhesion molecule biology.

%B Hum Mol Genet %V 19 %P 1863-72 %8 2010 May 01 %G eng %N 9 %1 http://www.ncbi.nlm.nih.gov/pubmed/20167578?dopt=Abstract %R 10.1093/hmg/ddq061 %0 Journal Article %J Nat Genet %D 2010 %T Meta-analyses of genome-wide association studies identify multiple loci associated with pulmonary function. %A Hancock, Dana B %A Eijgelsheim, Mark %A Wilk, Jemma B %A Gharib, Sina A %A Loehr, Laura R %A Marciante, Kristin D %A Franceschini, Nora %A van Durme, Yannick M T A %A Chen, Ting-Hsu %A Barr, R Graham %A Schabath, Matthew B %A Couper, David J %A Brusselle, Guy G %A Psaty, Bruce M %A van Duijn, Cornelia M %A Rotter, Jerome I %A Uitterlinden, André G %A Hofman, Albert %A Punjabi, Naresh M %A Rivadeneira, Fernando %A Morrison, Alanna C %A Enright, Paul L %A North, Kari E %A Heckbert, Susan R %A Lumley, Thomas %A Stricker, Bruno H C %A O'Connor, George T %A London, Stephanie J %K Databases, Genetic %K Female %K Forced Expiratory Volume %K Genetic Predisposition to Disease %K Genome, Human %K Genome-Wide Association Study %K Humans %K Lung %K Lung Diseases %K Male %K Meta-Analysis as Topic %K Polymorphism, Single Nucleotide %K Spirometry %K Vital Capacity %X

Spirometric measures of lung function are heritable traits that reflect respiratory health and predict morbidity and mortality. We meta-analyzed genome-wide association studies for two clinically important lung-function measures: forced expiratory volume in the first second (FEV(1)) and its ratio to forced vital capacity (FEV(1)/FVC), an indicator of airflow obstruction. This meta-analysis included 20,890 participants of European ancestry from four CHARGE Consortium studies: Atherosclerosis Risk in Communities, Cardiovascular Health Study, Framingham Heart Study and Rotterdam Study. We identified eight loci associated with FEV(1)/FVC (HHIP, GPR126, ADAM19, AGER-PPT2, FAM13A, PTCH1, PID1 and HTR4) and one locus associated with FEV(1) (INTS12-GSTCD-NPNT) at or near genome-wide significance (P < 5 x 10(-8)) in the CHARGE Consortium dataset. Our findings may offer insights into pulmonary function and pathogenesis of chronic lung disease.

%B Nat Genet %V 42 %P 45-52 %8 2010 Jan %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/20010835?dopt=Abstract %R 10.1038/ng.500 %0 Journal Article %J Nat Genet %D 2010 %T Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution. %A Heid, Iris M %A Jackson, Anne U %A Randall, Joshua C %A Winkler, Thomas W %A Qi, Lu %A Steinthorsdottir, Valgerdur %A Thorleifsson, Gudmar %A Zillikens, M Carola %A Speliotes, Elizabeth K %A Mägi, Reedik %A Workalemahu, Tsegaselassie %A White, Charles C %A Bouatia-Naji, Nabila %A Harris, Tamara B %A Berndt, Sonja I %A Ingelsson, Erik %A Willer, Cristen J %A Weedon, Michael N %A Luan, Jian'an %A Vedantam, Sailaja %A Esko, Tõnu %A Kilpeläinen, Tuomas O %A Kutalik, Zoltán %A Li, Shengxu %A Monda, Keri L %A Dixon, Anna L %A Holmes, Christopher C %A Kaplan, Lee M %A Liang, Liming %A Min, Josine L %A Moffatt, Miriam F %A Molony, Cliona %A Nicholson, George %A Schadt, Eric E %A Zondervan, Krina T %A Feitosa, Mary F %A Ferreira, Teresa %A Lango Allen, Hana %A Weyant, Robert J %A Wheeler, Eleanor %A Wood, Andrew R %A Estrada, Karol %A Goddard, Michael E %A Lettre, Guillaume %A Mangino, Massimo %A Nyholt, Dale R %A Purcell, Shaun %A Smith, Albert Vernon %A Visscher, Peter M %A Yang, Jian %A McCarroll, Steven A %A Nemesh, James %A Voight, Benjamin F %A Absher, Devin %A Amin, Najaf %A Aspelund, Thor %A Coin, Lachlan %A Glazer, Nicole L %A Hayward, Caroline %A Heard-Costa, Nancy L %A Hottenga, Jouke-Jan %A Johansson, Asa %A Johnson, Toby %A Kaakinen, Marika %A Kapur, Karen %A Ketkar, Shamika %A Knowles, Joshua W %A Kraft, Peter %A Kraja, Aldi T %A Lamina, Claudia %A Leitzmann, Michael F %A McKnight, Barbara %A Morris, Andrew P %A Ong, Ken K %A Perry, John R B %A Peters, Marjolein J %A Polasek, Ozren %A Prokopenko, Inga %A Rayner, Nigel W %A Ripatti, Samuli %A Rivadeneira, Fernando %A Robertson, Neil R %A Sanna, Serena %A Sovio, Ulla %A Surakka, Ida %A Teumer, Alexander %A van Wingerden, Sophie %A Vitart, Veronique %A Zhao, Jing Hua %A Cavalcanti-Proença, Christine %A Chines, Peter S %A Fisher, Eva %A Kulzer, Jennifer R %A Lecoeur, Cécile %A Narisu, Narisu %A Sandholt, Camilla %A Scott, Laura J %A Silander, Kaisa %A Stark, Klaus %A Tammesoo, Mari-Liis %A Teslovich, Tanya M %A Timpson, Nicholas John %A Watanabe, Richard M %A Welch, Ryan %A Chasman, Daniel I %A Cooper, Matthew N %A Jansson, John-Olov %A Kettunen, Johannes %A Lawrence, Robert W %A Pellikka, Niina %A Perola, Markus %A Vandenput, Liesbeth %A Alavere, Helene %A Almgren, Peter %A Atwood, Larry D %A Bennett, Amanda J %A Biffar, Reiner %A Bonnycastle, Lori L %A Bornstein, Stefan R %A Buchanan, Thomas A %A Campbell, Harry %A Day, Ian N M %A Dei, Mariano %A Dörr, Marcus %A Elliott, Paul %A Erdos, Michael R %A Eriksson, Johan G %A Freimer, Nelson B %A Fu, Mao %A Gaget, Stefan %A Geus, Eco J C %A Gjesing, Anette P %A Grallert, Harald %A Grässler, Jürgen %A Groves, Christopher J %A Guiducci, Candace %A Hartikainen, Anna-Liisa %A Hassanali, Neelam %A Havulinna, Aki S %A Herzig, Karl-Heinz %A Hicks, Andrew A %A Hui, Jennie %A Igl, Wilmar %A Jousilahti, Pekka %A Jula, Antti %A Kajantie, Eero %A Kinnunen, Leena %A Kolcic, Ivana %A Koskinen, Seppo %A Kovacs, Peter %A Kroemer, Heyo K %A Krzelj, Vjekoslav %A Kuusisto, Johanna %A Kvaloy, Kirsti %A Laitinen, Jaana %A Lantieri, Olivier %A Lathrop, G Mark %A Lokki, Marja-Liisa %A Luben, Robert N %A Ludwig, Barbara %A McArdle, Wendy L %A McCarthy, Anne %A Morken, Mario A %A Nelis, Mari %A Neville, Matt J %A Paré, Guillaume %A Parker, Alex N %A Peden, John F %A Pichler, Irene %A Pietiläinen, Kirsi H %A Platou, Carl G P %A Pouta, Anneli %A Ridderstråle, Martin %A Samani, Nilesh J %A Saramies, Jouko %A Sinisalo, Juha %A Smit, Jan H %A Strawbridge, Rona J %A Stringham, Heather M %A Swift, Amy J %A Teder-Laving, Maris %A Thomson, Brian %A Usala, Gianluca %A van Meurs, Joyce B J %A van Ommen, Gert-Jan %A Vatin, Vincent %A Volpato, Claudia B %A Wallaschofski, Henri %A Walters, G Bragi %A Widen, Elisabeth %A Wild, Sarah H %A Willemsen, Gonneke %A Witte, Daniel R %A Zgaga, Lina %A Zitting, Paavo %A Beilby, John P %A James, Alan L %A Kähönen, Mika %A Lehtimäki, Terho %A Nieminen, Markku S %A Ohlsson, Claes %A Palmer, Lyle J %A Raitakari, Olli %A Ridker, Paul M %A Stumvoll, Michael %A Tönjes, Anke %A Viikari, Jorma %A Balkau, Beverley %A Ben-Shlomo, Yoav %A Bergman, Richard N %A Boeing, Heiner %A Smith, George Davey %A Ebrahim, Shah %A Froguel, Philippe %A Hansen, Torben %A Hengstenberg, Christian %A Hveem, Kristian %A Isomaa, Bo %A Jørgensen, Torben %A Karpe, Fredrik %A Khaw, Kay-Tee %A Laakso, Markku %A Lawlor, Debbie A %A Marre, Michel %A Meitinger, Thomas %A Metspalu, Andres %A Midthjell, Kristian %A Pedersen, Oluf %A Salomaa, Veikko %A Schwarz, Peter E H %A Tuomi, Tiinamaija %A Tuomilehto, Jaakko %A Valle, Timo T %A Wareham, Nicholas J %A Arnold, Alice M %A Beckmann, Jacques S %A Bergmann, Sven %A Boerwinkle, Eric %A Boomsma, Dorret I %A Caulfield, Mark J %A Collins, Francis S %A Eiriksdottir, Gudny %A Gudnason, Vilmundur %A Gyllensten, Ulf %A Hamsten, Anders %A Hattersley, Andrew T %A Hofman, Albert %A Hu, Frank B %A Illig, Thomas %A Iribarren, Carlos %A Jarvelin, Marjo-Riitta %A Kao, W H Linda %A Kaprio, Jaakko %A Launer, Lenore J %A Munroe, Patricia B %A Oostra, Ben %A Penninx, Brenda W %A Pramstaller, Peter P %A Psaty, Bruce M %A Quertermous, Thomas %A Rissanen, Aila %A Rudan, Igor %A Shuldiner, Alan R %A Soranzo, Nicole %A Spector, Timothy D %A Syvänen, Ann-Christine %A Uda, Manuela %A Uitterlinden, Andre %A Völzke, Henry %A Vollenweider, Peter %A Wilson, James F %A Witteman, Jacqueline C %A Wright, Alan F %A Abecasis, Goncalo R %A Boehnke, Michael %A Borecki, Ingrid B %A Deloukas, Panos %A Frayling, Timothy M %A Groop, Leif C %A Haritunians, Talin %A Hunter, David J %A Kaplan, Robert C %A North, Kari E %A O'Connell, Jeffrey R %A Peltonen, Leena %A Schlessinger, David %A Strachan, David P %A Hirschhorn, Joel N %A Assimes, Themistocles L %A Wichmann, H-Erich %A Thorsteinsdottir, Unnur %A van Duijn, Cornelia M %A Stefansson, Kari %A Cupples, L Adrienne %A Loos, Ruth J F %A Barroso, Inês %A McCarthy, Mark I %A Fox, Caroline S %A Mohlke, Karen L %A Lindgren, Cecilia M %K Adipose Tissue %K Age Factors %K Chromosome Mapping %K Female %K Genome, Human %K Genome-Wide Association Study %K Humans %K Male %K Meta-Analysis as Topic %K Polymorphism, Single Nucleotide %K Sex Characteristics %K Waist-Hip Ratio %X

Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 × 10⁻⁹ to P = 1.8 × 10⁻⁴⁰) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 × 10⁻³ to P = 1.2 × 10⁻¹³). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions.

%B Nat Genet %V 42 %P 949-60 %8 2010 Nov %G eng %N 11 %1 http://www.ncbi.nlm.nih.gov/pubmed/20935629?dopt=Abstract %R 10.1038/ng.685 %0 Journal Article %J J Gerontol A Biol Sci Med Sci %D 2010 %T A meta-analysis of four genome-wide association studies of survival to age 90 years or older: the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium. %A Newman, Anne B %A Walter, Stefan %A Lunetta, Kathryn L %A Garcia, Melissa E %A Slagboom, P Eline %A Christensen, Kaare %A Arnold, Alice M %A Aspelund, Thor %A Aulchenko, Yurii S %A Benjamin, Emelia J %A Christiansen, Lene %A D'Agostino, Ralph B %A Fitzpatrick, Annette L %A Franceschini, Nora %A Glazer, Nicole L %A Gudnason, Vilmundur %A Hofman, Albert %A Kaplan, Robert %A Karasik, David %A Kelly-Hayes, Margaret %A Kiel, Douglas P %A Launer, Lenore J %A Marciante, Kristin D %A Massaro, Joseph M %A Miljkovic, Iva %A Nalls, Michael A %A Hernandez, Dena %A Psaty, Bruce M %A Rivadeneira, Fernando %A Rotter, Jerome %A Seshadri, Sudha %A Smith, Albert V %A Taylor, Kent D %A Tiemeier, Henning %A Uh, Hae-Won %A Uitterlinden, André G %A Vaupel, James W %A Walston, Jeremy %A Westendorp, Rudi G J %A Harris, Tamara B %A Lumley, Thomas %A van Duijn, Cornelia M %A Murabito, Joanne M %K Adult %K Age Factors %K Aged %K Aged, 80 and over %K Alleles %K Cohort Studies %K Confidence Intervals %K Female %K Genome-Wide Association Study %K Genotype %K Humans %K Longevity %K Male %K Middle Aged %K Odds Ratio %K Polymorphism, Single Nucleotide %X

BACKGROUND: Genome-wide association studies (GWAS) may yield insights into longevity.

METHODS: We performed a meta-analysis of GWAS in Caucasians from four prospective cohort studies: the Age, Gene/Environment Susceptibility-Reykjavik Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Rotterdam Study participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Longevity was defined as survival to age 90 years or older (n = 1,836); the comparison group comprised cohort members who died between the ages of 55 and 80 years (n = 1,955). In a second discovery stage, additional genotyping was conducted in the Leiden Longevity Study cohort and the Danish 1905 cohort.

RESULTS: There were 273 single-nucleotide polymorphism (SNP) associations with p < .0001, but none reached the prespecified significance level of 5 x 10(-8). Of the most significant SNPs, 24 were independent signals, and 16 of these SNPs were successfully genotyped in the second discovery stage, with one association for rs9664222, reaching 6.77 x 10(-7) for the combined meta-analysis of CHARGE and the stage 2 cohorts. The SNP lies in a region near MINPP1 (chromosome 10), a well-conserved gene involved in regulation of cellular proliferation. The minor allele was associated with lower odds of survival past age 90 (odds ratio = 0.82). Associations of interest in a homologue of the longevity assurance gene (LASS3) and PAPPA2 were not strengthened in the second stage.

CONCLUSION: Survival studies of larger size or more extreme or specific phenotypes may support or refine these initial findings.

%B J Gerontol A Biol Sci Med Sci %V 65 %P 478-87 %8 2010 May %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/20304771?dopt=Abstract %R 10.1093/gerona/glq028 %0 Journal Article %J Circ Cardiovasc Genet %D 2010 %T Multiple genetic loci influence serum urate levels and their relationship with gout and cardiovascular disease risk factors. %A Yang, Qiong %A Köttgen, Anna %A Dehghan, Abbas %A Smith, Albert V %A Glazer, Nicole L %A Chen, Ming-Huei %A Chasman, Daniel I %A Aspelund, Thor %A Eiriksdottir, Gudny %A Harris, Tamara B %A Launer, Lenore %A Nalls, Michael %A Hernandez, Dena %A Arking, Dan E %A Boerwinkle, Eric %A Grove, Megan L %A Li, Man %A Linda Kao, W H %A Chonchol, Michel %A Haritunians, Talin %A Li, Guo %A Lumley, Thomas %A Psaty, Bruce M %A Shlipak, Michael %A Hwang, Shih-Jen %A Larson, Martin G %A O'Donnell, Christopher J %A Upadhyay, Ashish %A van Duijn, Cornelia M %A Hofman, Albert %A Rivadeneira, Fernando %A Stricker, Bruno %A Uitterlinden, André G %A Paré, Guillaume %A Parker, Alex N %A Ridker, Paul M %A Siscovick, David S %A Gudnason, Vilmundur %A Witteman, Jacqueline C %A Fox, Caroline S %A Coresh, Josef %K Cardiovascular Diseases %K Coronary Disease %K Female %K Genetic Loci %K Genome-Wide Association Study %K Gout %K Humans %K Male %K Risk Factors %K Uric Acid %X

BACKGROUND: Elevated serum urate levels can lead to gout and are associated with cardiovascular risk factors. We performed a genome-wide association study to search for genetic susceptibility loci for serum urate and gout and investigated the causal nature of the associations of serum urate with gout and selected cardiovascular risk factors and coronary heart disease (CHD).

METHODS AND RESULTS: Meta-analyses of genome-wide association studies (GWAS) were performed in 5 population-based cohorts of the Cohorts for Heart and Aging Research in Genome Epidemiology consortium for serum urate and gout in 28 283 white participants. The effect of the most significant single-nucleotide polymorphism at all genome-wide significant loci on serum urate was added to create a genetic urate score. Findings were replicated in the Women's Genome Health Study (n=22 054). Single-nucleotide polymorphisms at 8 genetic loci achieved genome-wide significance with serum urate levels (P=4×10(-8) to 2×10(-242) in SLC22A11, GCKR, R3HDM2-INHBC region, RREB1, PDZK1, SLC2A9, ABCG2, and SLC17A1). Only 2 loci (SLC2A9, ABCG2) showed genome-wide significant association with gout. The genetic urate score was strongly associated with serum urate and gout (odds ratio, 12.4 per 100 μmol/L; P=3×10(-39)) but not with blood pressure, glucose, estimated glomerular filtration rate, chronic kidney disease, or CHD. The lack of association between the genetic score and the latter phenotypes also was observed in the Women's Genome Health Study.

CONCLUSIONS: The genetic urate score analysis suggested a causal relationship between serum urate and gout but did not provide evidence for one between serum urate and cardiovascular risk factors and CHD.

%B Circ Cardiovasc Genet %V 3 %P 523-30 %8 2010 Dec %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/20884846?dopt=Abstract %R 10.1161/CIRCGENETICS.109.934455 %0 Journal Article %J Nat Genet %D 2010 %T New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. %A Dupuis, Josée %A Langenberg, Claudia %A Prokopenko, Inga %A Saxena, Richa %A Soranzo, Nicole %A Jackson, Anne U %A Wheeler, Eleanor %A Glazer, Nicole L %A Bouatia-Naji, Nabila %A Gloyn, Anna L %A Lindgren, Cecilia M %A Mägi, Reedik %A Morris, Andrew P %A Randall, Joshua %A Johnson, Toby %A Elliott, Paul %A Rybin, Denis %A Thorleifsson, Gudmar %A Steinthorsdottir, Valgerdur %A Henneman, Peter %A Grallert, Harald %A Dehghan, Abbas %A Hottenga, Jouke Jan %A Franklin, Christopher S %A Navarro, Pau %A Song, Kijoung %A Goel, Anuj %A Perry, John R B %A Egan, Josephine M %A Lajunen, Taina %A Grarup, Niels %A Sparsø, Thomas %A Doney, Alex %A Voight, Benjamin F %A Stringham, Heather M %A Li, Man %A Kanoni, Stavroula %A Shrader, Peter %A Cavalcanti-Proença, Christine %A Kumari, Meena %A Qi, Lu %A Timpson, Nicholas J %A Gieger, Christian %A Zabena, Carina %A Rocheleau, Ghislain %A Ingelsson, Erik %A An, Ping %A O'Connell, Jeffrey %A Luan, Jian'an %A Elliott, Amanda %A McCarroll, Steven A %A Payne, Felicity %A Roccasecca, Rosa Maria %A Pattou, François %A Sethupathy, Praveen %A Ardlie, Kristin %A Ariyurek, Yavuz %A Balkau, Beverley %A Barter, Philip %A Beilby, John P %A Ben-Shlomo, Yoav %A Benediktsson, Rafn %A Bennett, Amanda J %A Bergmann, Sven %A Bochud, Murielle %A Boerwinkle, Eric %A Bonnefond, Amélie %A Bonnycastle, Lori L %A Borch-Johnsen, Knut %A Böttcher, Yvonne %A Brunner, Eric %A Bumpstead, Suzannah J %A Charpentier, Guillaume %A Chen, Yii-Der Ida %A Chines, Peter %A Clarke, Robert %A Coin, Lachlan J M %A Cooper, Matthew N %A Cornelis, Marilyn %A Crawford, Gabe %A Crisponi, Laura %A Day, Ian N M %A de Geus, Eco J C %A Delplanque, Jerome %A Dina, Christian %A Erdos, Michael R %A Fedson, Annette C %A Fischer-Rosinsky, Antje %A Forouhi, Nita G %A Fox, Caroline S %A Frants, Rune %A Franzosi, Maria Grazia %A Galan, Pilar %A Goodarzi, Mark O %A Graessler, Jürgen %A Groves, Christopher J %A Grundy, Scott %A Gwilliam, Rhian %A Gyllensten, Ulf %A Hadjadj, Samy %A Hallmans, Göran %A Hammond, Naomi %A Han, Xijing %A Hartikainen, Anna-Liisa %A Hassanali, Neelam %A Hayward, Caroline %A Heath, Simon C %A Hercberg, Serge %A Herder, Christian %A Hicks, Andrew A %A Hillman, David R %A Hingorani, Aroon D %A Hofman, Albert %A Hui, Jennie %A Hung, Joe %A Isomaa, Bo %A Johnson, Paul R V %A Jørgensen, Torben %A Jula, Antti %A Kaakinen, Marika %A Kaprio, Jaakko %A Kesaniemi, Y Antero %A Kivimaki, Mika %A Knight, Beatrice %A Koskinen, Seppo %A Kovacs, Peter %A Kyvik, Kirsten Ohm %A Lathrop, G Mark %A Lawlor, Debbie A %A Le Bacquer, Olivier %A Lecoeur, Cécile %A Li, Yun %A Lyssenko, Valeriya %A Mahley, Robert %A Mangino, Massimo %A Manning, Alisa K %A Martínez-Larrad, María Teresa %A McAteer, Jarred B %A McCulloch, Laura J %A McPherson, Ruth %A Meisinger, Christa %A Melzer, David %A Meyre, David %A Mitchell, Braxton D %A Morken, Mario A %A Mukherjee, Sutapa %A Naitza, Silvia %A Narisu, Narisu %A Neville, Matthew J %A Oostra, Ben A %A Orrù, Marco %A Pakyz, Ruth %A Palmer, Colin N A %A Paolisso, Giuseppe %A Pattaro, Cristian %A Pearson, Daniel %A Peden, John F %A Pedersen, Nancy L %A Perola, Markus %A Pfeiffer, Andreas F H %A Pichler, Irene %A Polasek, Ozren %A Posthuma, Danielle %A Potter, Simon C %A Pouta, Anneli %A Province, Michael A %A Psaty, Bruce M %A Rathmann, Wolfgang %A Rayner, Nigel W %A Rice, Kenneth %A Ripatti, Samuli %A Rivadeneira, Fernando %A Roden, Michael %A Rolandsson, Olov %A Sandbaek, Annelli %A Sandhu, Manjinder %A Sanna, Serena %A Sayer, Avan Aihie %A Scheet, Paul %A Scott, Laura J %A Seedorf, Udo %A Sharp, Stephen J %A Shields, Beverley %A Sigurethsson, Gunnar %A Sijbrands, Eric J G %A Silveira, Angela %A Simpson, Laila %A Singleton, Andrew %A Smith, Nicholas L %A Sovio, Ulla %A Swift, Amy %A Syddall, Holly %A Syvänen, Ann-Christine %A Tanaka, Toshiko %A Thorand, Barbara %A Tichet, Jean %A Tönjes, Anke %A Tuomi, Tiinamaija %A Uitterlinden, André G %A van Dijk, Ko Willems %A van Hoek, Mandy %A Varma, Dhiraj %A Visvikis-Siest, Sophie %A Vitart, Veronique %A Vogelzangs, Nicole %A Waeber, Gérard %A Wagner, Peter J %A Walley, Andrew %A Walters, G Bragi %A Ward, Kim L %A Watkins, Hugh %A Weedon, Michael N %A Wild, Sarah H %A Willemsen, Gonneke %A Witteman, Jaqueline C M %A Yarnell, John W G %A Zeggini, Eleftheria %A Zelenika, Diana %A Zethelius, Björn %A Zhai, Guangju %A Zhao, Jing Hua %A Zillikens, M Carola %A Borecki, Ingrid B %A Loos, Ruth J F %A Meneton, Pierre %A Magnusson, Patrik K E %A Nathan, David M %A Williams, Gordon H %A Hattersley, Andrew T %A Silander, Kaisa %A Salomaa, Veikko %A Smith, George Davey %A Bornstein, Stefan R %A Schwarz, Peter %A Spranger, Joachim %A Karpe, Fredrik %A Shuldiner, Alan R %A Cooper, Cyrus %A Dedoussis, George V %A Serrano-Ríos, Manuel %A Morris, Andrew D %A Lind, Lars %A Palmer, Lyle J %A Hu, Frank B %A Franks, Paul W %A Ebrahim, Shah %A Marmot, Michael %A Kao, W H Linda %A Pankow, James S %A Sampson, Michael J %A Kuusisto, Johanna %A Laakso, Markku %A Hansen, Torben %A Pedersen, Oluf %A Pramstaller, Peter Paul %A Wichmann, H Erich %A Illig, Thomas %A Rudan, Igor %A Wright, Alan F %A Stumvoll, Michael %A Campbell, Harry %A Wilson, James F %A Bergman, Richard N %A Buchanan, Thomas A %A Collins, Francis S %A Mohlke, Karen L %A Tuomilehto, Jaakko %A Valle, Timo T %A Altshuler, David %A Rotter, Jerome I %A Siscovick, David S %A Penninx, Brenda W J H %A Boomsma, Dorret I %A Deloukas, Panos %A Spector, Timothy D %A Frayling, Timothy M %A Ferrucci, Luigi %A Kong, Augustine %A Thorsteinsdottir, Unnur %A Stefansson, Kari %A van Duijn, Cornelia M %A Aulchenko, Yurii S %A Cao, Antonio %A Scuteri, Angelo %A Schlessinger, David %A Uda, Manuela %A Ruokonen, Aimo %A Jarvelin, Marjo-Riitta %A Waterworth, Dawn M %A Vollenweider, Peter %A Peltonen, Leena %A Mooser, Vincent %A Abecasis, Goncalo R %A Wareham, Nicholas J %A Sladek, Robert %A Froguel, Philippe %A Watanabe, Richard M %A Meigs, James B %A Groop, Leif %A Boehnke, Michael %A McCarthy, Mark I %A Florez, Jose C %A Barroso, Inês %K Adolescent %K Adult %K Alleles %K Blood Glucose %K Child %K Databases, Genetic %K Diabetes Mellitus, Type 2 %K DNA Copy Number Variations %K Fasting %K Gene Expression Regulation %K Genetic Loci %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Homeostasis %K Humans %K Meta-Analysis as Topic %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %K Quantitative Trait, Heritable %K Reproducibility of Results %X

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes.

%B Nat Genet %V 42 %P 105-16 %8 2010 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/20081858?dopt=Abstract %R 10.1038/ng.520 %0 Journal Article %J Nat Genet %D 2010 %T New loci associated with kidney function and chronic kidney disease. %A Köttgen, Anna %A Pattaro, Cristian %A Böger, Carsten A %A Fuchsberger, Christian %A Olden, Matthias %A Glazer, Nicole L %A Parsa, Afshin %A Gao, Xiaoyi %A Yang, Qiong %A Smith, Albert V %A O'Connell, Jeffrey R %A Li, Man %A Schmidt, Helena %A Tanaka, Toshiko %A Isaacs, Aaron %A Ketkar, Shamika %A Hwang, Shih-Jen %A Johnson, Andrew D %A Dehghan, Abbas %A Teumer, Alexander %A Paré, Guillaume %A Atkinson, Elizabeth J %A Zeller, Tanja %A Lohman, Kurt %A Cornelis, Marilyn C %A Probst-Hensch, Nicole M %A Kronenberg, Florian %A Tönjes, Anke %A Hayward, Caroline %A Aspelund, Thor %A Eiriksdottir, Gudny %A Launer, Lenore J %A Harris, Tamara B %A Rampersaud, Evadnie %A Mitchell, Braxton D %A Arking, Dan E %A Boerwinkle, Eric %A Struchalin, Maksim %A Cavalieri, Margherita %A Singleton, Andrew %A Giallauria, Francesco %A Metter, Jeffrey %A de Boer, Ian H %A Haritunians, Talin %A Lumley, Thomas %A Siscovick, David %A Psaty, Bruce M %A Zillikens, M Carola %A Oostra, Ben A %A Feitosa, Mary %A Province, Michael %A de Andrade, Mariza %A Turner, Stephen T %A Schillert, Arne %A Ziegler, Andreas %A Wild, Philipp S %A Schnabel, Renate B %A Wilde, Sandra %A Munzel, Thomas F %A Leak, Tennille S %A Illig, Thomas %A Klopp, Norman %A Meisinger, Christa %A Wichmann, H-Erich %A Koenig, Wolfgang %A Zgaga, Lina %A Zemunik, Tatijana %A Kolcic, Ivana %A Minelli, Cosetta %A Hu, Frank B %A Johansson, Asa %A Igl, Wilmar %A Zaboli, Ghazal %A Wild, Sarah H %A Wright, Alan F %A Campbell, Harry %A Ellinghaus, David %A Schreiber, Stefan %A Aulchenko, Yurii S %A Felix, Janine F %A Rivadeneira, Fernando %A Uitterlinden, André G %A Hofman, Albert %A Imboden, Medea %A Nitsch, Dorothea %A Brandstätter, Anita %A Kollerits, Barbara %A Kedenko, Lyudmyla %A Mägi, Reedik %A Stumvoll, Michael %A Kovacs, Peter %A Boban, Mladen %A Campbell, Susan %A Endlich, Karlhans %A Völzke, Henry %A Kroemer, Heyo K %A Nauck, Matthias %A Völker, Uwe %A Polasek, Ozren %A Vitart, Veronique %A Badola, Sunita %A Parker, Alexander N %A Ridker, Paul M %A Kardia, Sharon L R %A Blankenberg, Stefan %A Liu, Yongmei %A Curhan, Gary C %A Franke, Andre %A Rochat, Thierry %A Paulweber, Bernhard %A Prokopenko, Inga %A Wang, Wei %A Gudnason, Vilmundur %A Shuldiner, Alan R %A Coresh, Josef %A Schmidt, Reinhold %A Ferrucci, Luigi %A Shlipak, Michael G %A van Duijn, Cornelia M %A Borecki, Ingrid %A Krämer, Bernhard K %A Rudan, Igor %A Gyllensten, Ulf %A Wilson, James F %A Witteman, Jacqueline C %A Pramstaller, Peter P %A Rettig, Rainer %A Hastie, Nick %A Chasman, Daniel I %A Kao, W H %A Heid, Iris M %A Fox, Caroline S %K Cohort Studies %K Creatinine %K Cystatin C %K Diet %K Europe %K Genetic Markers %K Genome-Wide Association Study %K Glomerular Filtration Rate %K Humans %K Kidney %K Kidney Failure, Chronic %K Models, Genetic %K Risk Factors %X

Chronic kidney disease (CKD) is a significant public health problem, and recent genetic studies have identified common CKD susceptibility variants. The CKDGen consortium performed a meta-analysis of genome-wide association data in 67,093 individuals of European ancestry from 20 predominantly population-based studies in order to identify new susceptibility loci for reduced renal function as estimated by serum creatinine (eGFRcrea), serum cystatin c (eGFRcys) and CKD (eGFRcrea < 60 ml/min/1.73 m(2); n = 5,807 individuals with CKD (cases)). Follow-up of the 23 new genome-wide-significant loci (P < 5 x 10(-8)) in 22,982 replication samples identified 13 new loci affecting renal function and CKD (in or near LASS2, GCKR, ALMS1, TFDP2, DAB2, SLC34A1, VEGFA, PRKAG2, PIP5K1B, ATXN2, DACH1, UBE2Q2 and SLC7A9) and 7 loci suspected to affect creatinine production and secretion (CPS1, SLC22A2, TMEM60, WDR37, SLC6A13, WDR72 and BCAS3). These results further our understanding of the biologic mechanisms of kidney function by identifying loci that potentially influence nephrogenesis, podocyte function, angiogenesis, solute transport and metabolic functions of the kidney.

%B Nat Genet %V 42 %P 376-84 %8 2010 May %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/20383146?dopt=Abstract %R 10.1038/ng.568 %0 Journal Article %J Circulation %D 2010 %T Novel associations of multiple genetic loci with plasma levels of factor VII, factor VIII, and von Willebrand factor: The CHARGE (Cohorts for Heart and Aging Research in Genome Epidemiology) Consortium. %A Smith, Nicholas L %A Chen, Ming-Huei %A Dehghan, Abbas %A Strachan, David P %A Basu, Saonli %A Soranzo, Nicole %A Hayward, Caroline %A Rudan, Igor %A Sabater-Lleal, Maria %A Bis, Joshua C %A de Maat, Moniek P M %A Rumley, Ann %A Kong, Xiaoxiao %A Yang, Qiong %A Williams, Frances M K %A Vitart, Veronique %A Campbell, Harry %A Mälarstig, Anders %A Wiggins, Kerri L %A van Duijn, Cornelia M %A McArdle, Wendy L %A Pankow, James S %A Johnson, Andrew D %A Silveira, Angela %A McKnight, Barbara %A Uitterlinden, André G %A Aleksic, Nena %A Meigs, James B %A Peters, Annette %A Koenig, Wolfgang %A Cushman, Mary %A Kathiresan, Sekar %A Rotter, Jerome I %A Bovill, Edwin G %A Hofman, Albert %A Boerwinkle, Eric %A Tofler, Geoffrey H %A Peden, John F %A Psaty, Bruce M %A Leebeek, Frank %A Folsom, Aaron R %A Larson, Martin G %A Spector, Timothy D %A Wright, Alan F %A Wilson, James F %A Hamsten, Anders %A Lumley, Thomas %A Witteman, Jacqueline C M %A Tang, Weihong %A O'Donnell, Christopher J %K Adult %K Factor VII %K Factor VIII %K Female %K Genome-Wide Association Study %K Hemostasis %K Humans %K Male %K Middle Aged %K Phenotype %K Polymorphism, Single Nucleotide %K Thrombosis %K von Willebrand Factor %X

BACKGROUND: Plasma levels of coagulation factors VII (FVII), VIII (FVIII), and von Willebrand factor (vWF) influence risk of hemorrhage and thrombosis. We conducted genome-wide association studies to identify new loci associated with plasma levels.

METHODS AND RESULTS: The setting of the study included 5 community-based studies for discovery comprising 23 608 European-ancestry participants: Atherosclerosis Risk In Communities Study, Cardiovascular Health Study, British 1958 Birth Cohort, Framingham Heart Study, and Rotterdam Study. All subjects had genome-wide single-nucleotide polymorphism (SNP) scans and at least 1 phenotype measured: FVII activity/antigen, FVIII activity, and vWF antigen. Each study used its genotype data to impute to HapMap SNPs and independently conducted association analyses of hemostasis measures using an additive genetic model. Study findings were combined by meta-analysis. Replication was conducted in 7604 participants not in the discovery cohort. For FVII, 305 SNPs exceeded the genome-wide significance threshold of 5.0x10(-8) and comprised 5 loci on 5 chromosomes: 2p23 (smallest P value 6.2x10(-24)), 4q25 (3.6x10(-12)), 11q12 (2.0x10(-10)), 13q34 (9.0x10(-259)), and 20q11.2 (5.7x10(-37)). Loci were within or near genes, including 4 new candidate genes and F7 (13q34). For vWF, 400 SNPs exceeded the threshold and marked 8 loci on 6 chromosomes: 6q24 (1.2x10(-22)), 8p21 (1.3x10(-16)), 9q34 (<5.0x10(-324)), 12p13 (1.7x10(-32)), 12q23 (7.3x10(-10)), 12q24.3 (3.8x10(-11)), 14q32 (2.3x10(-10)), and 19p13.2 (1.3x10(-9)). All loci were within genes, including 6 new candidate genes, as well as ABO (9q34) and VWF (12p13). For FVIII, 5 loci were identified and overlapped vWF findings. Nine of the 10 new findings were replicated.

CONCLUSIONS: New genetic associations were discovered outside previously known biological pathways and may point to novel prevention and treatment targets of hemostasis disorders.

%B Circulation %V 121 %P 1382-92 %8 2010 Mar 30 %G eng %N 12 %1 http://www.ncbi.nlm.nih.gov/pubmed/20231535?dopt=Abstract %R 10.1161/CIRCULATIONAHA.109.869156 %0 Journal Article %J Circ Cardiovasc Genet %D 2011 %T Association of genetic variants and incident coronary heart disease in multiethnic cohorts: the PAGE study. %A Franceschini, Nora %A Carty, Cara %A Bůzková, Petra %A Reiner, Alex P %A Garrett, Tiana %A Lin, Yi %A Vöckler, Jens-S %A Hindorff, Lucia A %A Cole, Shelley A %A Boerwinkle, Eric %A Lin, Dan-Yu %A Bookman, Ebony %A Best, Lyle G %A Bella, Jonathan N %A Eaton, Charles %A Greenland, Philip %A Jenny, Nancy %A North, Kari E %A Taverna, Darin %A Young, Alicia M %A Deelman, Ewa %A Kooperberg, Charles %A Psaty, Bruce %A Heiss, Gerardo %K Aged %K Aged, 80 and over %K Continental Population Groups %K Coronary Disease %K Female %K Genome-Wide Association Study %K Humans %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Prospective Studies %X

BACKGROUND: Genome-wide association studies identified several single nucleotide polymorphisms (SNP) associated with prevalent coronary heart disease (CHD), but less is known of associations with incident CHD. The association of 13 published CHD SNPs was examined in 5 ancestry groups of 4 large US prospective cohorts.

METHODS AND RESULTS: The analyses included incident coronary events over an average 9.1 to 15.7 follow-up person-years in up to 26 617 white individuals (6626 events), 8018 black individuals (914 events), 1903 Hispanic individuals (113 events), 3669 American Indian individuals (595 events), and 885 Asian/Pacific Islander individuals (66 events). We used Cox proportional hazards models (with additive mode of inheritance) adjusted for age, sex, and ancestry (as needed). Nine loci were statistically associated with incident CHD events in white participants: 9p21 (rs10757278; P=4.7 × 10(-41)), 16q23.1 (rs2549513; P=0.0004), 6p24.1 (rs499818; P=0.0002), 2q36.3 (rs2943634; P=6.7 × 10(-6)), MTHFD1L (rs6922269, P=5.1 × 10(-10)), APOE (rs429358; P=2.7×10(-18)), ZNF627 (rs4804611; P=5.0 × 10(-8)), CXCL12 (rs501120; P=1.4 × 10(-6)) and LPL (rs268; P=2.7 × 10(-17)). The 9p21 region showed significant between-study heterogeneity, with larger effects in individuals age 55 years or younger and in women. Inclusion of coronary revascularization procedures among the incident CHD events introduced heterogeneity. The SNPs were not associated with CHD in black participants, and associations varied in other US minorities.

CONCLUSIONS: Prospective analyses of white participants replicated several reported cross-sectional CHD-SNP associations.

%B Circ Cardiovasc Genet %V 4 %P 661-72 %8 2011 Dec %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/22042884?dopt=Abstract %R 10.1161/CIRCGENETICS.111.960096 %0 Journal Article %J Hum Mol Genet %D 2011 %T Association of genetic variation with systolic and diastolic blood pressure among African Americans: the Candidate Gene Association Resource study. %A Fox, Ervin R %A Young, J Hunter %A Li, Yali %A Dreisbach, Albert W %A Keating, Brendan J %A Musani, Solomon K %A Liu, Kiang %A Morrison, Alanna C %A Ganesh, Santhi %A Kutlar, Abdullah %A Ramachandran, Vasan S %A Polak, Josef F %A Fabsitz, Richard R %A Dries, Daniel L %A Farlow, Deborah N %A Redline, Susan %A Adeyemo, Adebowale %A Hirschorn, Joel N %A Sun, Yan V %A Wyatt, Sharon B %A Penman, Alan D %A Palmas, Walter %A Rotter, Jerome I %A Townsend, Raymond R %A Doumatey, Ayo P %A Tayo, Bamidele O %A Mosley, Thomas H %A Lyon, Helen N %A Kang, Sun J %A Rotimi, Charles N %A Cooper, Richard S %A Franceschini, Nora %A Curb, J David %A Martin, Lisa W %A Eaton, Charles B %A Kardia, Sharon L R %A Taylor, Herman A %A Caulfield, Mark J %A Ehret, Georg B %A Johnson, Toby %A Chakravarti, Aravinda %A Zhu, Xiaofeng %A Levy, Daniel %K Adult %K African Americans %K Aged %K Blood Pressure %K Cohort Studies %K Diastole %K European Continental Ancestry Group %K Female %K Genetic Loci %K Genome-Wide Association Study %K Genotype %K Humans %K Hypertension %K Male %K Middle Aged %K Phenotype %K Polymorphism, Single Nucleotide %K Systole %X

The prevalence of hypertension in African Americans (AAs) is higher than in other US groups; yet, few have performed genome-wide association studies (GWASs) in AA. Among people of European descent, GWASs have identified genetic variants at 13 loci that are associated with blood pressure. It is unknown if these variants confer susceptibility in people of African ancestry. Here, we examined genome-wide and candidate gene associations with systolic blood pressure (SBP) and diastolic blood pressure (DBP) using the Candidate Gene Association Resource (CARe) consortium consisting of 8591 AAs. Genotypes included genome-wide single-nucleotide polymorphism (SNP) data utilizing the Affymetrix 6.0 array with imputation to 2.5 million HapMap SNPs and candidate gene SNP data utilizing a 50K cardiovascular gene-centric array (ITMAT-Broad-CARe [IBC] array). For Affymetrix data, the strongest signal for DBP was rs10474346 (P= 3.6 × 10(-8)) located near GPR98 and ARRDC3. For SBP, the strongest signal was rs2258119 in C21orf91 (P= 4.7 × 10(-8)). The top IBC association for SBP was rs2012318 (P= 6.4 × 10(-6)) near SLC25A42 and for DBP was rs2523586 (P= 1.3 × 10(-6)) near HLA-B. None of the top variants replicated in additional AA (n = 11 882) or European-American (n = 69 899) cohorts. We replicated previously reported European-American blood pressure SNPs in our AA samples (SH2B3, P= 0.009; TBX3-TBX5, P= 0.03; and CSK-ULK3, P= 0.0004). These genetic loci represent the best evidence of genetic influences on SBP and DBP in AAs to date. More broadly, this work supports that notion that blood pressure among AAs is a trait with genetic underpinnings but also with significant complexity.

%B Hum Mol Genet %V 20 %P 2273-84 %8 2011 Jun 01 %G eng %N 11 %1 http://www.ncbi.nlm.nih.gov/pubmed/21378095?dopt=Abstract %R 10.1093/hmg/ddr092 %0 Journal Article %J Invest Ophthalmol Vis Sci %D 2011 %T Association of polymorphisms in the hepatocyte growth factor gene promoter with keratoconus. %A Burdon, Kathryn P %A Macgregor, Stuart %A Bykhovskaya, Yelena %A Javadiyan, Sharhbanou %A Li, Xiaohui %A Laurie, Kate J %A Muszynska, Dorota %A Lindsay, Richard %A Lechner, Judith %A Haritunians, Talin %A Henders, Anjali K %A Dash, Durga %A Siscovick, David %A Anand, Seema %A Aldave, Anthony %A Coster, Douglas J %A Szczotka-Flynn, Loretta %A Mills, Richard A %A Iyengar, Sudha K %A Taylor, Kent D %A Phillips, Tony %A Montgomery, Grant W %A Rotter, Jerome I %A Hewitt, Alex W %A Sharma, Shiwani %A Rabinowitz, Yaron S %A Willoughby, Colin %A Craig, Jamie E %K Adult %K Aged %K Chromosomes, Human, Pair 7 %K Corneal Topography %K Enzyme-Linked Immunosorbent Assay %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genotype %K Hepatocyte Growth Factor %K Humans %K Keratoconus %K Middle Aged %K Nucleic Acid Hybridization %K Polymorphism, Single Nucleotide %K Promoter Regions, Genetic %K Sequence Tagged Sites %X

PURPOSE: Keratoconus is a progressive disorder of the cornea that can lead to severe visual impairment or blindness. Although several genomic regions have been linked to rare familial forms of keratoconus, no genes have yet been definitively identified for common forms of the disease.

METHODS: Two genome-wide association scans were undertaken in parallel. The first used pooled DNA from an Australian cohort, followed by typing of top-ranked single-nucleotide polymorphisms (SNPs) in individual DNA samples. The second was conducted in individually genotyped patients, and controls from the USA. Tag SNPs around the hepatocyte growth factor (HGF) gene were typed in three additional replication cohorts. Serum levels of HGF protein in normal individuals were assessed with ELISA and correlated with genotype.

RESULTS: The only SNP observed to be associated in both the pooled discovery and primary replication cohort was rs1014091, located upstream of the HGF gene. The nearby SNP rs3735520 was found to be associated in the individually typed discovery cohort (P = 6.1 × 10(-7)). Genotyping of tag SNPs around HGF revealed association at rs3735520 and rs17501108/rs1014091 in four of the five cohorts. Meta-analysis of all five datasets together yielded suggestive P values for rs3735520 (P = 9.9 × 10(-7)) and rs17501108 (P = 9.9 × 10(-5)). In addition, SNP rs3735520 was found to be associated with serum HGF level in normal individuals (P = 0.036).

CONCLUSIONS: Taken together, these results implicate genetic variation at the HGF locus with keratoconus susceptibility.

%B Invest Ophthalmol Vis Sci %V 52 %P 8514-9 %8 2011 Oct 31 %G eng %N 11 %1 http://www.ncbi.nlm.nih.gov/pubmed/22003120?dopt=Abstract %R 10.1167/iovs.11-8261 %0 Journal Article %J Diabetes %D 2011 %T A bivariate genome-wide approach to metabolic syndrome: STAMPEED consortium. %A Kraja, Aldi T %A Vaidya, Dhananjay %A Pankow, James S %A Goodarzi, Mark O %A Assimes, Themistocles L %A Kullo, Iftikhar J %A Sovio, Ulla %A Mathias, Rasika A %A Sun, Yan V %A Franceschini, Nora %A Absher, Devin %A Li, Guo %A Zhang, Qunyuan %A Feitosa, Mary F %A Glazer, Nicole L %A Haritunians, Talin %A Hartikainen, Anna-Liisa %A Knowles, Joshua W %A North, Kari E %A Iribarren, Carlos %A Kral, Brian %A Yanek, Lisa %A O'Reilly, Paul F %A McCarthy, Mark I %A Jaquish, Cashell %A Couper, David J %A Chakravarti, Aravinda %A Psaty, Bruce M %A Becker, Lewis C %A Province, Michael A %A Boerwinkle, Eric %A Quertermous, Thomas %A Palotie, Leena %A Jarvelin, Marjo-Riitta %A Becker, Diane M %A Kardia, Sharon L R %A Rotter, Jerome I %A Chen, Yii-Der Ida %A Borecki, Ingrid B %K Adult %K Aged %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genotype %K Humans %K Male %K Meta-Analysis as Topic %K Metabolic Syndrome %K Middle Aged %K Phenotype %K Polymorphism, Single Nucleotide %X

OBJECTIVE The metabolic syndrome (MetS) is defined as concomitant disorders of lipid and glucose metabolism, central obesity, and high blood pressure, with an increased risk of type 2 diabetes and cardiovascular disease. This study tests whether common genetic variants with pleiotropic effects account for some of the correlated architecture among five metabolic phenotypes that define MetS. RESEARCH DESIGN AND METHODS Seven studies of the STAMPEED consortium, comprising 22,161 participants of European ancestry, underwent genome-wide association analyses of metabolic traits using a panel of ∼2.5 million imputed single nucleotide polymorphisms (SNPs). Phenotypes were defined by the National Cholesterol Education Program (NCEP) criteria for MetS in pairwise combinations. Individuals exceeding the NCEP thresholds for both traits of a pair were considered affected. RESULTS Twenty-nine common variants were associated with MetS or a pair of traits. Variants in the genes LPL, CETP, APOA5 (and its cluster), GCKR (and its cluster), LIPC, TRIB1, LOC100128354/MTNR1B, ABCB11, and LOC100129150 were further tested for their association with individual qualitative and quantitative traits. None of the 16 top SNPs (one per gene) associated simultaneously with more than two individual traits. Of them 11 variants showed nominal associations with MetS per se. The effects of 16 top SNPs on the quantitative traits were relatively small, together explaining from ∼9% of the variance in triglycerides, 5.8% of high-density lipoprotein cholesterol, 3.6% of fasting glucose, and 1.4% of systolic blood pressure. CONCLUSIONS Qualitative and quantitative pleiotropic tests on pairs of traits indicate that a small portion of the covariation in these traits can be explained by the reported common genetic variants.

%B Diabetes %V 60 %P 1329-39 %8 2011 Apr %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/21386085?dopt=Abstract %R 10.2337/db10-1011 %0 Journal Article %J Invest Ophthalmol Vis Sci %D 2011 %T Candidate gene association study for diabetic retinopathy in persons with type 2 diabetes: the Candidate gene Association Resource (CARe). %A Sobrin, Lucia %A Green, Todd %A Sim, Xueling %A Jensen, Richard A %A Tai, E Shyong %A Tay, Wan Ting %A Wang, Jie Jin %A Mitchell, Paul %A Sandholm, Niina %A Liu, Yiyuan %A Hietala, Kustaa %A Iyengar, Sudha K %A Brooks, Matthew %A Buraczynska, Monika %A Van Zuydam, Natalie %A Smith, Albert V %A Gudnason, Vilmundur %A Doney, Alex S F %A Morris, Andrew D %A Leese, Graham P %A Palmer, Colin N A %A Swaroop, Anand %A Taylor, Herman A %A Wilson, James G %A Penman, Alan %A Chen, Ching J %A Groop, Per-Henrik %A Saw, Seang-Mei %A Aung, Tin %A Klein, Barbara E %A Rotter, Jerome I %A Siscovick, David S %A Cotch, Mary Frances %A Klein, Ronald %A Daly, Mark J %A Wong, Tien Y %K Cardiovascular Diseases %K Diabetes Mellitus, Type 2 %K Diabetic Nephropathies %K Diabetic Retinopathy %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genotype %K Humans %K Iduronidase %K Odds Ratio %K P-Selectin %K Polymorphism, Single Nucleotide %K Risk Factors %X

PURPOSE: To investigate whether variants in cardiovascular candidate genes, some of which have been previously associated with type 2 diabetes (T2D), diabetic retinopathy (DR), and diabetic nephropathy (DN), are associated with DR in the Candidate gene Association Resource (CARe).

METHODS: Persons with T2D who were enrolled in the study (n = 2691) had fundus photography and genotyping of single nucleotide polymorphisms (SNPs) in 2000 candidate genes. Two case definitions were investigated: Early Treatment Diabetic Retinopathy Study (ETDRS) grades ≥ 14 and ≥ 30. The χ² analyses for each CARe cohort were combined by Cochran-Mantel-Haenszel (CMH) pooling of odds ratios (ORs) and corrected for multiple hypothesis testing. Logistic regression was performed with adjustment for other DR risk factors. Results from replication in independent cohorts were analyzed with CMH meta-analysis methods.

RESULTS: Among 39 genes previously associated with DR, DN, or T2D, three SNPs in P-selectin (SELP) were associated with DR. The strongest association was to rs6128 (OR = 0.43, P = 0.0001, after Bonferroni correction). These associations remained significant after adjustment for DR risk factors. Among other genes examined, several variants were associated with DR with significant P values, including rs6856425 tagging α-l-iduronidase (IDUA) (P = 2.1 × 10(-5), after Bonferroni correction). However, replication in independent cohorts did not reveal study-wide significant effects. The P values after replication were 0.55 and 0.10 for rs6128 and rs6856425, respectively.

CONCLUSIONS: Genes associated with DN, T2D, and vascular diseases do not appear to be consistently associated with DR. A few genetic variants associated with DR, particularly those in SELP and near IDUA, should be investigated in additional DR cohorts.

%B Invest Ophthalmol Vis Sci %V 52 %P 7593-602 %8 2011 Sep 29 %G eng %N 10 %1 http://www.ncbi.nlm.nih.gov/pubmed/21873659?dopt=Abstract %R 10.1167/iovs.11-7510 %0 Journal Article %J Pharmacogenet Genomics %D 2011 %T Cerivastatin, genetic variants, and the risk of rhabdomyolysis. %A Marciante, Kristin D %A Durda, Jon P %A Heckbert, Susan R %A Lumley, Thomas %A Rice, Ken %A McKnight, Barbara %A Totah, Rheem A %A Tamraz, Bani %A Kroetz, Deanna L %A Fukushima, Hisayo %A Kaspera, Rüdiger %A Bis, Joshua C %A Glazer, Nicole L %A Li, Guo %A Austin, Thomas R %A Taylor, Kent D %A Rotter, Jerome I %A Jaquish, Cashell E %A Kwok, Pui-Yan %A Tracy, Russell P %A Psaty, Bruce M %K Adult %K Aged %K Aged, 80 and over %K Aryl Hydrocarbon Hydroxylases %K Case-Control Studies %K Cytochrome P-450 CYP2C8 %K Female %K Genetic Variation %K Genome-Wide Association Study %K Glucuronosyltransferase %K Humans %K Hydroxymethylglutaryl-CoA Reductase Inhibitors %K Male %K Middle Aged %K Organic Anion Transporters %K Polymorphism, Single Nucleotide %K Pyridines %K Rhabdomyolysis %K Risk %K Ryanodine Receptor Calcium Release Channel %K Solute Carrier Organic Anion Transporter Family Member 1b1 %X

OBJECTIVE: The withdrawal of cerivastatin involved an uncommon but serious adverse reaction, rhabdomyolysis. The bimodal response, rhabdomyolysis in a small proportion of users, points to genetic factors as a potential cause. We conducted a case-control study to evaluate genetic markers for cerivastatin-associated rhabdomyolysis.

METHODS: This study had two components: a candidate gene study to evaluate variants in CYP2C8, UGT1A1, UGT1A3, and SLCO1B1; and a genome-wide association study to identify risk factors in other regions of the genome. A total of 185 rhabdomyolysis cases were frequency matched to statin-using controls from the Cardiovascular Health Study (n=374) and the Heart and Vascular Health Study (n=358). Validation relied on functional studies.

RESULTS: Permutation test results suggested an association between cerivastatin-associated rhabdomyolysis and variants in SLCO1B1 (P=0.002), but not variants in CYP2C8 (P=0.073) or UGTs (P=0.523). An additional copy of the minor allele of SLCO1B1 rs4149056 (p.Val174Ala) was associated with the risk of rhabdomyolysis (odds ratio: 1.89; 95% confidence interval: 1.40-2.56). In transfected cells, this variant reduced cerivastatin transport by 40% compared with the reference transporter (P<0.001). The genome-wide association study identified an intronic variant (rs2819742) in the ryanodine receptor 2 gene (RYR2) as significant (P=1.74E-07). An additional copy of the minor allele of the RYR2 variant was associated with a reduced risk of rhabdomyolysis (odds ratio: 0.48; 95% confidence interval: 0.36-0.63).

CONCLUSION: We identified modest genetic risk factors for an extreme response to cerivastatin. Disabling genetic variants in the candidate genes were not responsible for the bimodal response to cerivastatin.

%B Pharmacogenet Genomics %V 21 %P 280-8 %8 2011 May %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/21386754?dopt=Abstract %R 10.1097/FPC.0b013e328343dd7d %0 Journal Article %J PLoS Genet %D 2011 %T Enhanced statistical tests for GWAS in admixed populations: assessment using African Americans from CARe and a Breast Cancer Consortium. %A Pasaniuc, Bogdan %A Zaitlen, Noah %A Lettre, Guillaume %A Chen, Gary K %A Tandon, Arti %A Kao, W H Linda %A Ruczinski, Ingo %A Fornage, Myriam %A Siscovick, David S %A Zhu, Xiaofeng %A Larkin, Emma %A Lange, Leslie A %A Cupples, L Adrienne %A Yang, Qiong %A Akylbekova, Ermeg L %A Musani, Solomon K %A Divers, Jasmin %A Mychaleckyj, Joe %A Li, Mingyao %A Papanicolaou, George J %A Millikan, Robert C %A Ambrosone, Christine B %A John, Esther M %A Bernstein, Leslie %A Zheng, Wei %A Hu, Jennifer J %A Ziegler, Regina G %A Nyante, Sarah J %A Bandera, Elisa V %A Ingles, Sue A %A Press, Michael F %A Chanock, Stephen J %A Deming, Sandra L %A Rodriguez-Gil, Jorge L %A Palmer, Cameron D %A Buxbaum, Sarah %A Ekunwe, Lynette %A Hirschhorn, Joel N %A Henderson, Brian E %A Myers, Simon %A Haiman, Christopher A %A Reich, David %A Patterson, Nick %A Wilson, James G %A Price, Alkes L %K African Americans %K Algorithms %K Breast Neoplasms %K Chromosome Mapping %K Coronary Disease %K Diabetes Mellitus, Type 2 %K Female %K Gene Frequency %K Genetic Variation %K Genetics, Population %K Genome, Human %K Genome-Wide Association Study %K Genotype %K Humans %K Linkage Disequilibrium %K Male %K Odds Ratio %K Phenotype %K Polymorphism, Single Nucleotide %K Principal Component Analysis %K Receptor, Fibroblast Growth Factor, Type 2 %K Software %X

While genome-wide association studies (GWAS) have primarily examined populations of European ancestry, more recent studies often involve additional populations, including admixed populations such as African Americans and Latinos. In admixed populations, linkage disequilibrium (LD) exists both at a fine scale in ancestral populations and at a coarse scale (admixture-LD) due to chromosomal segments of distinct ancestry. Disease association statistics in admixed populations have previously considered SNP association (LD mapping) or admixture association (mapping by admixture-LD), but not both. Here, we introduce a new statistical framework for combining SNP and admixture association in case-control studies, as well as methods for local ancestry-aware imputation. We illustrate the gain in statistical power achieved by these methods by analyzing data of 6,209 unrelated African Americans from the CARe project genotyped on the Affymetrix 6.0 chip, in conjunction with both simulated and real phenotypes, as well as by analyzing the FGFR2 locus using breast cancer GWAS data from 5,761 African-American women. We show that, at typed SNPs, our method yields an 8% increase in statistical power for finding disease risk loci compared to the power achieved by standard methods in case-control studies. At imputed SNPs, we observe an 11% increase in statistical power for mapping disease loci when our local ancestry-aware imputation framework and the new scoring statistic are jointly employed. Finally, we show that our method increases statistical power in regions harboring the causal SNP in the case when the causal SNP is untyped and cannot be imputed. Our methods and our publicly available software are broadly applicable to GWAS in admixed populations.

%B PLoS Genet %V 7 %P e1001371 %8 2011 Apr %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/21541012?dopt=Abstract %R 10.1371/journal.pgen.1001371 %0 Journal Article %J PLoS Genet %D 2011 %T Genetic association for renal traits among participants of African ancestry reveals new loci for renal function. %A Liu, Ching-Ti %A Garnaas, Maija K %A Tin, Adrienne %A Köttgen, Anna %A Franceschini, Nora %A Peralta, Carmen A %A de Boer, Ian H %A Lu, Xiaoning %A Atkinson, Elizabeth %A Ding, Jingzhong %A Nalls, Michael %A Shriner, Daniel %A Coresh, Josef %A Kutlar, Abdullah %A Bibbins-Domingo, Kirsten %A Siscovick, David %A Akylbekova, Ermeg %A Wyatt, Sharon %A Astor, Brad %A Mychaleckjy, Josef %A Li, Man %A Reilly, Muredach P %A Townsend, Raymond R %A Adeyemo, Adebowale %A Zonderman, Alan B %A de Andrade, Mariza %A Turner, Stephen T %A Mosley, Thomas H %A Harris, Tamara B %A Rotimi, Charles N %A Liu, Yongmei %A Kardia, Sharon L R %A Evans, Michele K %A Shlipak, Michael G %A Kramer, Holly %A Flessner, Michael F %A Dreisbach, Albert W %A Goessling, Wolfram %A Cupples, L Adrienne %A Kao, W Linda %A Fox, Caroline S %K Adaptor Proteins, Vesicular Transport %K Adult %K African Continental Ancestry Group %K Aged %K Animals %K Female %K Gene Knockdown Techniques %K Genetic Association Studies %K Genetic Loci %K Genome-Wide Association Study %K Glomerular Filtration Rate %K Humans %K KCNQ1 Potassium Channel %K Kidney %K Kidney Failure, Chronic %K Male %K Middle Aged %K Neoplasm Proteins %K Phenotype %K Polymorphism, Single Nucleotide %K Zebrafish %X

Chronic kidney disease (CKD) is an increasing global public health concern, particularly among populations of African ancestry. We performed an interrogation of known renal loci, genome-wide association (GWA), and IBC candidate-gene SNP association analyses in African Americans from the CARe Renal Consortium. In up to 8,110 participants, we performed meta-analyses of GWA and IBC array data for estimated glomerular filtration rate (eGFR), CKD (eGFR <60 mL/min/1.73 m(2)), urinary albumin-to-creatinine ratio (UACR), and microalbuminuria (UACR >30 mg/g) and interrogated the 250 kb flanking region around 24 SNPs previously identified in European Ancestry renal GWAS analyses. Findings were replicated in up to 4,358 African Americans. To assess function, individually identified genes were knocked down in zebrafish embryos by morpholino antisense oligonucleotides. Expression of kidney-specific genes was assessed by in situ hybridization, and glomerular filtration was evaluated by dextran clearance. Overall, 23 of 24 previously identified SNPs had direction-consistent associations with eGFR in African Americans, 2 of which achieved nominal significance (UMOD, PIP5K1B). Interrogation of the flanking regions uncovered 24 new index SNPs in African Americans, 12 of which were replicated (UMOD, ANXA9, GCKR, TFDP2, DAB2, VEGFA, ATXN2, GATM, SLC22A2, TMEM60, SLC6A13, and BCAS3). In addition, we identified 3 suggestive loci at DOK6 (p-value = 5.3×10(-7)) and FNDC1 (p-value = 3.0×10(-7)) for UACR, and KCNQ1 with eGFR (p = 3.6×10(-6)). Morpholino knockdown of kcnq1 in the zebrafish resulted in abnormal kidney development and filtration capacity. We identified several SNPs in association with eGFR in African Ancestry individuals, as well as 3 suggestive loci for UACR and eGFR. Functional genetic studies support a role for kcnq1 in glomerular development in zebrafish.

%B PLoS Genet %V 7 %P e1002264 %8 2011 Sep %G eng %N 9 %1 http://www.ncbi.nlm.nih.gov/pubmed/21931561?dopt=Abstract %R 10.1371/journal.pgen.1002264 %0 Journal Article %J PLoS Genet %D 2011 %T Genetic determinants of lipid traits in diverse populations from the population architecture using genomics and epidemiology (PAGE) study. %A Dumitrescu, Logan %A Carty, Cara L %A Taylor, Kira %A Schumacher, Fredrick R %A Hindorff, Lucia A %A Ambite, José L %A Anderson, Garnet %A Best, Lyle G %A Brown-Gentry, Kristin %A Bůzková, Petra %A Carlson, Christopher S %A Cochran, Barbara %A Cole, Shelley A %A Devereux, Richard B %A Duggan, Dave %A Eaton, Charles B %A Fornage, Myriam %A Franceschini, Nora %A Haessler, Jeff %A Howard, Barbara V %A Johnson, Karen C %A Laston, Sandra %A Kolonel, Laurence N %A Lee, Elisa T %A MacCluer, Jean W %A Manolio, Teri A %A Pendergrass, Sarah A %A Quibrera, Miguel %A Shohet, Ralph V %A Wilkens, Lynne R %A Haiman, Christopher A %A Le Marchand, Loïc %A Buyske, Steven %A Kooperberg, Charles %A North, Kari E %A Crawford, Dana C %K Adolescent %K Adult %K Aged %K Aged, 80 and over %K Continental Population Groups %K Female %K Gene Frequency %K Genetics, Population %K Genome-Wide Association Study %K Humans %K Linkage Disequilibrium %K Lipid Metabolism %K Lipoproteins, HDL %K Lipoproteins, LDL %K Male %K Middle Aged %K Molecular Epidemiology %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %K Risk Factors %K Triglycerides %K Young Adult %X

For the past five years, genome-wide association studies (GWAS) have identified hundreds of common variants associated with human diseases and traits, including high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) levels. Approximately 95 loci associated with lipid levels have been identified primarily among populations of European ancestry. The Population Architecture using Genomics and Epidemiology (PAGE) study was established in 2008 to characterize GWAS-identified variants in diverse population-based studies. We genotyped 49 GWAS-identified SNPs associated with one or more lipid traits in at least two PAGE studies and across six racial/ethnic groups. We performed a meta-analysis testing for SNP associations with fasting HDL-C, LDL-C, and ln(TG) levels in self-identified European American (~20,000), African American (~9,000), American Indian (~6,000), Mexican American/Hispanic (~2,500), Japanese/East Asian (~690), and Pacific Islander/Native Hawaiian (~175) adults, regardless of lipid-lowering medication use. We replicated 55 of 60 (92%) SNP associations tested in European Americans at p<0.05. Despite sufficient power, we were unable to replicate ABCA1 rs4149268 and rs1883025, CETP rs1864163, and TTC39B rs471364 previously associated with HDL-C and MAFB rs6102059 previously associated with LDL-C. Based on significance (p<0.05) and consistent direction of effect, a majority of replicated genotype-phentoype associations for HDL-C, LDL-C, and ln(TG) in European Americans generalized to African Americans (48%, 61%, and 57%), American Indians (45%, 64%, and 77%), and Mexican Americans/Hispanics (57%, 56%, and 86%). Overall, 16 associations generalized across all three populations. For the associations that did not generalize, differences in effect sizes, allele frequencies, and linkage disequilibrium offer clues to the next generation of association studies for these traits.

%B PLoS Genet %V 7 %P e1002138 %8 2011 Jun %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/21738485?dopt=Abstract %R 10.1371/journal.pgen.1002138 %0 Journal Article %J PLoS Genet %D 2011 %T Genetic loci associated with plasma phospholipid n-3 fatty acids: a meta-analysis of genome-wide association studies from the CHARGE Consortium. %A Lemaitre, Rozenn N %A Tanaka, Toshiko %A Tang, Weihong %A Manichaikul, Ani %A Foy, Millennia %A Kabagambe, Edmond K %A Nettleton, Jennifer A %A King, Irena B %A Weng, Lu-Chen %A Bhattacharya, Sayanti %A Bandinelli, Stefania %A Bis, Joshua C %A Rich, Stephen S %A Jacobs, David R %A Cherubini, Antonio %A McKnight, Barbara %A Liang, Shuang %A Gu, Xiangjun %A Rice, Kenneth %A Laurie, Cathy C %A Lumley, Thomas %A Browning, Brian L %A Psaty, Bruce M %A Chen, Yii-der I %A Friedlander, Yechiel %A Djoussé, Luc %A Wu, Jason H Y %A Siscovick, David S %A Uitterlinden, André G %A Arnett, Donna K %A Ferrucci, Luigi %A Fornage, Myriam %A Tsai, Michael Y %A Mozaffarian, Dariush %A Steffen, Lyn M %K Alleles %K Continental Population Groups %K Fatty Acids, Omega-3 %K Female %K Genetic Loci %K Genome-Wide Association Study %K Humans %K Male %K Metabolic Networks and Pathways %K Polymorphism, Single Nucleotide %X

Long-chain n-3 polyunsaturated fatty acids (PUFAs) can derive from diet or from α-linolenic acid (ALA) by elongation and desaturation. We investigated the association of common genetic variation with plasma phospholipid levels of the four major n-3 PUFAs by performing genome-wide association studies in five population-based cohorts comprising 8,866 subjects of European ancestry. Minor alleles of SNPs in FADS1 and FADS2 (desaturases) were associated with higher levels of ALA (p = 3 x 10⁻⁶⁴) and lower levels of eicosapentaenoic acid (EPA, p = 5 x 10⁻⁵⁸) and docosapentaenoic acid (DPA, p = 4 x 10⁻¹⁵⁴). Minor alleles of SNPs in ELOVL2 (elongase) were associated with higher EPA (p = 2 x 10⁻¹²) and DPA (p = 1 x 10⁻⁴³) and lower docosahexaenoic acid (DHA, p = 1 x 10⁻¹⁵). In addition to genes in the n-3 pathway, we identified a novel association of DPA with several SNPs in GCKR (glucokinase regulator, p = 1 x 10⁻⁸). We observed a weaker association between ALA and EPA among carriers of the minor allele of a representative SNP in FADS2 (rs1535), suggesting a lower rate of ALA-to-EPA conversion in these subjects. In samples of African, Chinese, and Hispanic ancestry, associations of n-3 PUFAs were similar with a representative SNP in FADS1 but less consistent with a representative SNP in ELOVL2. Our findings show that common variation in n-3 metabolic pathway genes and in GCKR influences plasma phospholipid levels of n-3 PUFAs in populations of European ancestry and, for FADS1, in other ancestries.

%B PLoS Genet %V 7 %P e1002193 %8 2011 Jul %G eng %N 7 %1 http://www.ncbi.nlm.nih.gov/pubmed/21829377?dopt=Abstract %R 10.1371/journal.pgen.1002193 %0 Journal Article %J Circulation %D 2011 %T Genetic predictors of fibrin D-dimer levels in healthy adults. %A Smith, Nicholas L %A Huffman, Jennifer E %A Strachan, David P %A Huang, Jie %A Dehghan, Abbas %A Trompet, Stella %A Lopez, Lorna M %A Shin, So-Youn %A Baumert, Jens %A Vitart, Veronique %A Bis, Joshua C %A Wild, Sarah H %A Rumley, Ann %A Yang, Qiong %A Uitterlinden, André G %A Stott, David J %A Davies, Gail %A Carter, Angela M %A Thorand, Barbara %A Polasek, Ozren %A McKnight, Barbara %A Campbell, Harry %A Rudnicka, Alicja R %A Chen, Ming-Huei %A Buckley, Brendan M %A Harris, Sarah E %A Peters, Annette %A Pulanic, Drazen %A Lumley, Thomas %A de Craen, Anton J M %A Liewald, David C %A Gieger, Christian %A Campbell, Susan %A Ford, Ian %A Gow, Alan J %A Luciano, Michelle %A Porteous, David J %A Guo, Xiuqing %A Sattar, Naveed %A Tenesa, Albert %A Cushman, Mary %A Slagboom, P Eline %A Visscher, Peter M %A Spector, Tim D %A Illig, Thomas %A Rudan, Igor %A Bovill, Edwin G %A Wright, Alan F %A McArdle, Wendy L %A Tofler, Geoffrey %A Hofman, Albert %A Westendorp, Rudi G J %A Starr, John M %A Grant, Peter J %A Karakas, Mahir %A Hastie, Nicholas D %A Psaty, Bruce M %A Wilson, James F %A Lowe, Gordon D O %A O'Donnell, Christopher J %A Witteman, Jacqueline C M %A Jukema, J Wouter %A Deary, Ian J %A Soranzo, Nicole %A Koenig, Wolfgang %A Hayward, Caroline %K Adult %K Aged %K Blood Coagulation %K European Continental Ancestry Group %K Factor V %K Female %K Fibrin Fibrinogen Degradation Products %K Fibrinogen %K Genetic Testing %K Genome-Wide Association Study %K Humans %K Male %K Middle Aged %K Reference Values %K Thromboplastin %X

BACKGROUND: Fibrin fragment D-dimer, one of several peptides produced when crosslinked fibrin is degraded by plasmin, is the most widely used clinical marker of activated blood coagulation. To identity genetic loci influencing D-dimer levels, we performed the first large-scale, genome-wide association search.

METHODS AND RESULTS: A genome-wide investigation of the genomic correlates of plasma D-dimer levels was conducted among 21 052 European-ancestry adults. Plasma levels of D-dimer were measured independently in each of 13 cohorts. Each study analyzed the association between ≈2.6 million genotyped and imputed variants across the 22 autosomal chromosomes and natural-log–transformed D-dimer levels using linear regression in additive genetic models adjusted for age and sex. Among all variants, 74 exceeded the genome-wide significance threshold and marked 3 regions. At 1p22, rs12029080 (P=6.4×10(-52)) was 46.0 kb upstream from F3, coagulation factor III (tissue factor). At 1q24, rs6687813 (P=2.4×10(-14)) was 79.7 kb downstream of F5, coagulation factor V. At 4q32, rs13109457 (P=2.9×10(-18)) was located between 2 fibrinogen genes: 10.4 kb downstream from FGG and 3.0 kb upstream from FGA. Variants were associated with a 0.099-, 0.096-, and 0.061-unit difference, respectively, in natural-log–transformed D-dimer and together accounted for 1.8% of the total variance. When adjusted for nonsynonymous substitutions in F5 and FGA loci known to be associated with D-dimer levels, there was no evidence of an additional association at either locus.

CONCLUSIONS: Three genes were associated with fibrin D-dimer levels. Of these 3, the F3 association was the strongest, and has not been previously reported.

%B Circulation %V 123 %P 1864-72 %8 2011 May 03 %G eng %N 17 %1 http://www.ncbi.nlm.nih.gov/pubmed/21502573?dopt=Abstract %R 10.1161/CIRCULATIONAHA.110.009480 %0 Journal Article %J Nature %D 2011 %T Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk. %A Ehret, Georg B %A Munroe, Patricia B %A Rice, Kenneth M %A Bochud, Murielle %A Johnson, Andrew D %A Chasman, Daniel I %A Smith, Albert V %A Tobin, Martin D %A Verwoert, Germaine C %A Hwang, Shih-Jen %A Pihur, Vasyl %A Vollenweider, Peter %A O'Reilly, Paul F %A Amin, Najaf %A Bragg-Gresham, Jennifer L %A Teumer, Alexander %A Glazer, Nicole L %A Launer, Lenore %A Zhao, Jing Hua %A Aulchenko, Yurii %A Heath, Simon %A Sõber, Siim %A Parsa, Afshin %A Luan, Jian'an %A Arora, Pankaj %A Dehghan, Abbas %A Zhang, Feng %A Lucas, Gavin %A Hicks, Andrew A %A Jackson, Anne U %A Peden, John F %A Tanaka, Toshiko %A Wild, Sarah H %A Rudan, Igor %A Igl, Wilmar %A Milaneschi, Yuri %A Parker, Alex N %A Fava, Cristiano %A Chambers, John C %A Fox, Ervin R %A Kumari, Meena %A Go, Min Jin %A van der Harst, Pim %A Kao, Wen Hong Linda %A Sjögren, Marketa %A Vinay, D G %A Alexander, Myriam %A Tabara, Yasuharu %A Shaw-Hawkins, Sue %A Whincup, Peter H %A Liu, Yongmei %A Shi, Gang %A Kuusisto, Johanna %A Tayo, Bamidele %A Seielstad, Mark %A Sim, Xueling %A Nguyen, Khanh-Dung Hoang %A Lehtimäki, Terho %A Matullo, Giuseppe %A Wu, Ying %A Gaunt, Tom R %A Onland-Moret, N Charlotte %A Cooper, Matthew N %A Platou, Carl G P %A Org, Elin %A Hardy, Rebecca %A Dahgam, Santosh %A Palmen, Jutta %A Vitart, Veronique %A Braund, Peter S %A Kuznetsova, Tatiana %A Uiterwaal, Cuno S P M %A Adeyemo, Adebowale %A Palmas, Walter %A Campbell, Harry %A Ludwig, Barbara %A Tomaszewski, Maciej %A Tzoulaki, Ioanna %A Palmer, Nicholette D %A Aspelund, Thor %A Garcia, Melissa %A Chang, Yen-Pei C %A O'Connell, Jeffrey R %A Steinle, Nanette I %A Grobbee, Diederick E %A Arking, Dan E %A Kardia, Sharon L %A Morrison, Alanna C %A Hernandez, Dena %A Najjar, Samer %A McArdle, Wendy L %A Hadley, David %A Brown, Morris J %A Connell, John M %A Hingorani, Aroon D %A Day, Ian N M %A Lawlor, Debbie A %A Beilby, John P %A Lawrence, Robert W %A Clarke, Robert %A Hopewell, Jemma C %A Ongen, Halit %A Dreisbach, Albert W %A Li, Yali %A Young, J Hunter %A Bis, Joshua C %A Kähönen, Mika %A Viikari, Jorma %A Adair, Linda S %A Lee, Nanette R %A Chen, Ming-Huei %A Olden, Matthias %A Pattaro, Cristian %A Bolton, Judith A Hoffman %A Köttgen, Anna %A Bergmann, Sven %A Mooser, Vincent %A Chaturvedi, Nish %A Frayling, Timothy M %A Islam, Muhammad %A Jafar, Tazeen H %A Erdmann, Jeanette %A Kulkarni, Smita R %A Bornstein, Stefan R %A Grässler, Jürgen %A Groop, Leif %A Voight, Benjamin F %A Kettunen, Johannes %A Howard, Philip %A Taylor, Andrew %A Guarrera, Simonetta %A Ricceri, Fulvio %A Emilsson, Valur %A Plump, Andrew %A Barroso, Inês %A Khaw, Kay-Tee %A Weder, Alan B %A Hunt, Steven C %A Sun, Yan V %A Bergman, Richard N %A Collins, Francis S %A Bonnycastle, Lori L %A Scott, Laura J %A Stringham, Heather M %A Peltonen, Leena %A Perola, Markus %A Vartiainen, Erkki %A Brand, Stefan-Martin %A Staessen, Jan A %A Wang, Thomas J %A Burton, Paul R %A Soler Artigas, Maria %A Dong, Yanbin %A Snieder, Harold %A Wang, Xiaoling %A Zhu, Haidong %A Lohman, Kurt K %A Rudock, Megan E %A Heckbert, Susan R %A Smith, Nicholas L %A Wiggins, Kerri L %A Doumatey, Ayo %A Shriner, Daniel %A Veldre, Gudrun %A Viigimaa, Margus %A Kinra, Sanjay %A Prabhakaran, Dorairaj %A Tripathy, Vikal %A Langefeld, Carl D %A Rosengren, Annika %A Thelle, Dag S %A Corsi, Anna Maria %A Singleton, Andrew %A Forrester, Terrence %A Hilton, Gina %A McKenzie, Colin A %A Salako, Tunde %A Iwai, Naoharu %A Kita, Yoshikuni %A Ogihara, Toshio %A Ohkubo, Takayoshi %A Okamura, Tomonori %A Ueshima, Hirotsugu %A Umemura, Satoshi %A Eyheramendy, Susana %A Meitinger, Thomas %A Wichmann, H-Erich %A Cho, Yoon Shin %A Kim, Hyung-Lae %A Lee, Jong-Young %A Scott, James %A Sehmi, Joban S %A Zhang, Weihua %A Hedblad, Bo %A Nilsson, Peter %A Smith, George Davey %A Wong, Andrew %A Narisu, Narisu %A Stančáková, Alena %A Raffel, Leslie J %A Yao, Jie %A Kathiresan, Sekar %A O'Donnell, Christopher J %A Schwartz, Stephen M %A Ikram, M Arfan %A Longstreth, W T %A Mosley, Thomas H %A Seshadri, Sudha %A Shrine, Nick R G %A Wain, Louise V %A Morken, Mario A %A Swift, Amy J %A Laitinen, Jaana %A Prokopenko, Inga %A Zitting, Paavo %A Cooper, Jackie A %A Humphries, Steve E %A Danesh, John %A Rasheed, Asif %A Goel, Anuj %A Hamsten, Anders %A Watkins, Hugh %A Bakker, Stephan J L %A van Gilst, Wiek H %A Janipalli, Charles S %A Mani, K Radha %A Yajnik, Chittaranjan S %A Hofman, Albert %A Mattace-Raso, Francesco U S %A Oostra, Ben A %A Demirkan, Ayse %A Isaacs, Aaron %A Rivadeneira, Fernando %A Lakatta, Edward G %A Orrù, Marco %A Scuteri, Angelo %A Ala-Korpela, Mika %A Kangas, Antti J %A Lyytikäinen, Leo-Pekka %A Soininen, Pasi %A Tukiainen, Taru %A Würtz, Peter %A Ong, Rick Twee-Hee %A Dörr, Marcus %A Kroemer, Heyo K %A Völker, Uwe %A Völzke, Henry %A Galan, Pilar %A Hercberg, Serge %A Lathrop, Mark %A Zelenika, Diana %A Deloukas, Panos %A Mangino, Massimo %A Spector, Tim D %A Zhai, Guangju %A Meschia, James F %A Nalls, Michael A %A Sharma, Pankaj %A Terzic, Janos %A Kumar, M V Kranthi %A Denniff, Matthew %A Zukowska-Szczechowska, Ewa %A Wagenknecht, Lynne E %A Fowkes, F Gerald R %A Charchar, Fadi J %A Schwarz, Peter E H %A Hayward, Caroline %A Guo, Xiuqing %A Rotimi, Charles %A Bots, Michiel L %A Brand, Eva %A Samani, Nilesh J %A Polasek, Ozren %A Talmud, Philippa J %A Nyberg, Fredrik %A Kuh, Diana %A Laan, Maris %A Hveem, Kristian %A Palmer, Lyle J %A van der Schouw, Yvonne T %A Casas, Juan P %A Mohlke, Karen L %A Vineis, Paolo %A Raitakari, Olli %A Ganesh, Santhi K %A Wong, Tien Y %A Tai, E Shyong %A Cooper, Richard S %A Laakso, Markku %A Rao, Dabeeru C %A Harris, Tamara B %A Morris, Richard W %A Dominiczak, Anna F %A Kivimaki, Mika %A Marmot, Michael G %A Miki, Tetsuro %A Saleheen, Danish %A Chandak, Giriraj R %A Coresh, Josef %A Navis, Gerjan %A Salomaa, Veikko %A Han, Bok-Ghee %A Zhu, Xiaofeng %A Kooner, Jaspal S %A Melander, Olle %A Ridker, Paul M %A Bandinelli, Stefania %A Gyllensten, Ulf B %A Wright, Alan F %A Wilson, James F %A Ferrucci, Luigi %A Farrall, Martin %A Tuomilehto, Jaakko %A Pramstaller, Peter P %A Elosua, Roberto %A Soranzo, Nicole %A Sijbrands, Eric J G %A Altshuler, David %A Loos, Ruth J F %A Shuldiner, Alan R %A Gieger, Christian %A Meneton, Pierre %A Uitterlinden, André G %A Wareham, Nicholas J %A Gudnason, Vilmundur %A Rotter, Jerome I %A Rettig, Rainer %A Uda, Manuela %A Strachan, David P %A Witteman, Jacqueline C M %A Hartikainen, Anna-Liisa %A Beckmann, Jacques S %A Boerwinkle, Eric %A Vasan, Ramachandran S %A Boehnke, Michael %A Larson, Martin G %A Jarvelin, Marjo-Riitta %A Psaty, Bruce M %A Abecasis, Goncalo R %A Chakravarti, Aravinda %A Elliott, Paul %A van Duijn, Cornelia M %A Newton-Cheh, Christopher %A Levy, Daniel %A Caulfield, Mark J %A Johnson, Toby %K Africa %K Asia %K Blood Pressure %K Cardiovascular Diseases %K Coronary Artery Disease %K Europe %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Hypertension %K Kidney Diseases %K Polymorphism, Single Nucleotide %K Stroke %X

Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or  ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention.

%B Nature %V 478 %P 103-9 %8 2011 Sep 11 %G eng %N 7367 %1 http://www.ncbi.nlm.nih.gov/pubmed/21909115?dopt=Abstract %R 10.1038/nature10405 %0 Journal Article %J Nat Genet %D 2011 %T Genetic variation near IRS1 associates with reduced adiposity and an impaired metabolic profile. %A Kilpeläinen, Tuomas O %A Zillikens, M Carola %A Stančáková, Alena %A Finucane, Francis M %A Ried, Janina S %A Langenberg, Claudia %A Zhang, Weihua %A Beckmann, Jacques S %A Luan, Jian'an %A Vandenput, Liesbeth %A Styrkarsdottir, Unnur %A Zhou, Yanhua %A Smith, Albert Vernon %A Zhao, Jing-Hua %A Amin, Najaf %A Vedantam, Sailaja %A Shin, So-Youn %A Haritunians, Talin %A Fu, Mao %A Feitosa, Mary F %A Kumari, Meena %A Halldorsson, Bjarni V %A Tikkanen, Emmi %A Mangino, Massimo %A Hayward, Caroline %A Song, Ci %A Arnold, Alice M %A Aulchenko, Yurii S %A Oostra, Ben A %A Campbell, Harry %A Cupples, L Adrienne %A Davis, Kathryn E %A Döring, Angela %A Eiriksdottir, Gudny %A Estrada, Karol %A Fernández-Real, José Manuel %A Garcia, Melissa %A Gieger, Christian %A Glazer, Nicole L %A Guiducci, Candace %A Hofman, Albert %A Humphries, Steve E %A Isomaa, Bo %A Jacobs, Leonie C %A Jula, Antti %A Karasik, David %A Karlsson, Magnus K %A Khaw, Kay-Tee %A Kim, Lauren J %A Kivimaki, Mika %A Klopp, Norman %A Kuhnel, Brigitte %A Kuusisto, Johanna %A Liu, Yongmei %A Ljunggren, Osten %A Lorentzon, Mattias %A Luben, Robert N %A McKnight, Barbara %A Mellström, Dan %A Mitchell, Braxton D %A Mooser, Vincent %A Moreno, José Maria %A Männistö, Satu %A O'Connell, Jeffery R %A Pascoe, Laura %A Peltonen, Leena %A Peral, Belén %A Perola, Markus %A Psaty, Bruce M %A Salomaa, Veikko %A Savage, David B %A Semple, Robert K %A Skaric-Juric, Tatjana %A Sigurdsson, Gunnar %A Song, Kijoung S %A Spector, Timothy D %A Syvänen, Ann-Christine %A Talmud, Philippa J %A Thorleifsson, Gudmar %A Thorsteinsdottir, Unnur %A Uitterlinden, André G %A van Duijn, Cornelia M %A Vidal-Puig, Antonio %A Wild, Sarah H %A Wright, Alan F %A Clegg, Deborah J %A Schadt, Eric %A Wilson, James F %A Rudan, Igor %A Ripatti, Samuli %A Borecki, Ingrid B %A Shuldiner, Alan R %A Ingelsson, Erik %A Jansson, John-Olov %A Kaplan, Robert C %A Gudnason, Vilmundur %A Harris, Tamara B %A Groop, Leif %A Kiel, Douglas P %A Rivadeneira, Fernando %A Walker, Mark %A Barroso, Inês %A Vollenweider, Peter %A Waeber, Gérard %A Chambers, John C %A Kooner, Jaspal S %A Soranzo, Nicole %A Hirschhorn, Joel N %A Stefansson, Kari %A Wichmann, H-Erich %A Ohlsson, Claes %A O'Rahilly, Stephen %A Wareham, Nicholas J %A Speliotes, Elizabeth K %A Fox, Caroline S %A Laakso, Markku %A Loos, Ruth J F %K Adiponectin %K Adiposity %K Alleles %K Body Fat Distribution %K Body Mass Index %K Body Weight %K Female %K Genetic Variation %K Genome-Wide Association Study %K Humans %K Insulin Receptor Substrate Proteins %K Intracellular Signaling Peptides and Proteins %K Male %K Membrane Proteins %K Meta-Analysis as Topic %K Metabolome %K Obesity %K Polymorphism, Single Nucleotide %K Subcutaneous Fat %X

Genome-wide association studies have identified 32 loci influencing body mass index, but this measure does not distinguish lean from fat mass. To identify adiposity loci, we meta-analyzed associations between ∼2.5 million SNPs and body fat percentage from 36,626 individuals and followed up the 14 most significant (P < 10(-6)) independent loci in 39,576 individuals. We confirmed a previously established adiposity locus in FTO (P = 3 × 10(-26)) and identified two new loci associated with body fat percentage, one near IRS1 (P = 4 × 10(-11)) and one near SPRY2 (P = 3 × 10(-8)). Both loci contain genes with potential links to adipocyte physiology. Notably, the body-fat-decreasing allele near IRS1 is associated with decreased IRS1 expression and with an impaired metabolic profile, including an increased visceral to subcutaneous fat ratio, insulin resistance, dyslipidemia, risk of diabetes and coronary artery disease and decreased adiponectin levels. Our findings provide new insights into adiposity and insulin resistance.

%B Nat Genet %V 43 %P 753-60 %8 2011 Jun 26 %G eng %N 8 %1 http://www.ncbi.nlm.nih.gov/pubmed/21706003?dopt=Abstract %R 10.1038/ng.866 %0 Journal Article %J PLoS Genet %D 2011 %T Genome-wide association analysis of soluble ICAM-1 concentration reveals novel associations at the NFKBIK, PNPLA3, RELA, and SH2B3 loci. %A Paré, Guillaume %A Ridker, Paul M %A Rose, Lynda %A Barbalic, Maja %A Dupuis, Josée %A Dehghan, Abbas %A Bis, Joshua C %A Benjamin, Emelia J %A Shiffman, Dov %A Parker, Alexander N %A Chasman, Daniel I %K ABO Blood-Group System %K Cohort Studies %K Female %K Gene Frequency %K Genetic Loci %K Genome, Human %K Genome-Wide Association Study %K Genotype %K Humans %K I-kappa B Kinase %K Intercellular Adhesion Molecule-1 %K Lipase %K Membrane Proteins %K Models, Genetic %K Multifactorial Inheritance %K Polymorphism, Single Nucleotide %K Proteins %K Transcription Factor RelA %X

Soluble ICAM-1 (sICAM-1) is an endothelium-derived inflammatory marker that has been associated with diverse conditions such as myocardial infarction, diabetes, stroke, and malaria. Despite evidence for a heritable component to sICAM-1 levels, few genetic loci have been identified so far. To comprehensively address this issue, we performed a genome-wide association analysis of sICAM-1 concentration in 22,435 apparently healthy women from the Women's Genome Health Study. While our results confirm the previously reported associations at the ABO and ICAM1 loci, four novel associations were identified in the vicinity of NFKBIK (rs3136642, P = 5.4 × 10(-9)), PNPLA3 (rs738409, P  =  5.8 × 10(-9)), RELA (rs1049728, P =  2.7 × 10(-16)), and SH2B3 (rs3184504, P =  2.9 × 10(-17)). Two loci, NFKBIB and RELA, are involved in NFKB signaling pathway; PNPLA3 is known for its association with fatty liver disease; and SH3B2 has been associated with a multitude of traits and disease including myocardial infarction. These associations provide insights into the genetic regulation of sICAM-1 levels and implicate these loci in the regulation of endothelial function.

%B PLoS Genet %V 7 %P e1001374 %8 2011 Apr %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/21533024?dopt=Abstract %R 10.1371/journal.pgen.1001374 %0 Journal Article %J Nat Genet %D 2011 %T Genome-wide association and large-scale follow up identifies 16 new loci influencing lung function. %A Soler Artigas, Maria %A Loth, Daan W %A Wain, Louise V %A Gharib, Sina A %A Obeidat, Ma'en %A Tang, Wenbo %A Zhai, Guangju %A Zhao, Jing Hua %A Smith, Albert Vernon %A Huffman, Jennifer E %A Albrecht, Eva %A Jackson, Catherine M %A Evans, David M %A Cadby, Gemma %A Fornage, Myriam %A Manichaikul, Ani %A Lopez, Lorna M %A Johnson, Toby %A Aldrich, Melinda C %A Aspelund, Thor %A Barroso, Inês %A Campbell, Harry %A Cassano, Patricia A %A Couper, David J %A Eiriksdottir, Gudny %A Franceschini, Nora %A Garcia, Melissa %A Gieger, Christian %A Gislason, Gauti Kjartan %A Grkovic, Ivica %A Hammond, Christopher J %A Hancock, Dana B %A Harris, Tamara B %A Ramasamy, Adaikalavan %A Heckbert, Susan R %A Heliövaara, Markku %A Homuth, Georg %A Hysi, Pirro G %A James, Alan L %A Jankovic, Stipan %A Joubert, Bonnie R %A Karrasch, Stefan %A Klopp, Norman %A Koch, Beate %A Kritchevsky, Stephen B %A Launer, Lenore J %A Liu, Yongmei %A Loehr, Laura R %A Lohman, Kurt %A Loos, Ruth J F %A Lumley, Thomas %A Al Balushi, Khalid A %A Ang, Wei Q %A Barr, R Graham %A Beilby, John %A Blakey, John D %A Boban, Mladen %A Boraska, Vesna %A Brisman, Jonas %A Britton, John R %A Brusselle, Guy G %A Cooper, Cyrus %A Curjuric, Ivan %A Dahgam, Santosh %A Deary, Ian J %A Ebrahim, Shah %A Eijgelsheim, Mark %A Francks, Clyde %A Gaysina, Darya %A Granell, Raquel %A Gu, Xiangjun %A Hankinson, John L %A Hardy, Rebecca %A Harris, Sarah E %A Henderson, John %A Henry, Amanda %A Hingorani, Aroon D %A Hofman, Albert %A Holt, Patrick G %A Hui, Jennie %A Hunter, Michael L %A Imboden, Medea %A Jameson, Karen A %A Kerr, Shona M %A Kolcic, Ivana %A Kronenberg, Florian %A Liu, Jason Z %A Marchini, Jonathan %A McKeever, Tricia %A Morris, Andrew D %A Olin, Anna-Carin %A Porteous, David J %A Postma, Dirkje S %A Rich, Stephen S %A Ring, Susan M %A Rivadeneira, Fernando %A Rochat, Thierry %A Sayer, Avan Aihie %A Sayers, Ian %A Sly, Peter D %A Smith, George Davey %A Sood, Akshay %A Starr, John M %A Uitterlinden, André G %A Vonk, Judith M %A Wannamethee, S Goya %A Whincup, Peter H %A Wijmenga, Cisca %A Williams, O Dale %A Wong, Andrew %A Mangino, Massimo %A Marciante, Kristin D %A McArdle, Wendy L %A Meibohm, Bernd %A Morrison, Alanna C %A North, Kari E %A Omenaas, Ernst %A Palmer, Lyle J %A Pietiläinen, Kirsi H %A Pin, Isabelle %A Pola Sbreve Ek, Ozren %A Pouta, Anneli %A Psaty, Bruce M %A Hartikainen, Anna-Liisa %A Rantanen, Taina %A Ripatti, Samuli %A Rotter, Jerome I %A Rudan, Igor %A Rudnicka, Alicja R %A Schulz, Holger %A Shin, So-Youn %A Spector, Tim D %A Surakka, Ida %A Vitart, Veronique %A Völzke, Henry %A Wareham, Nicholas J %A Warrington, Nicole M %A Wichmann, H-Erich %A Wild, Sarah H %A Wilk, Jemma B %A Wjst, Matthias %A Wright, Alan F %A Zgaga, Lina %A Zemunik, Tatijana %A Pennell, Craig E %A Nyberg, Fredrik %A Kuh, Diana %A Holloway, John W %A Boezen, H Marike %A Lawlor, Debbie A %A Morris, Richard W %A Probst-Hensch, Nicole %A Kaprio, Jaakko %A Wilson, James F %A Hayward, Caroline %A Kähönen, Mika %A Heinrich, Joachim %A Musk, Arthur W %A Jarvis, Deborah L %A Gläser, Sven %A Jarvelin, Marjo-Riitta %A Ch Stricker, Bruno H %A Elliott, Paul %A O'Connor, George T %A Strachan, David P %A London, Stephanie J %A Hall, Ian P %A Gudnason, Vilmundur %A Tobin, Martin D %K Child %K European Continental Ancestry Group %K Genome-Wide Association Study %K Humans %K Pulmonary Disease, Chronic Obstructive %K Respiratory Function Tests %X

Pulmonary function measures reflect respiratory health and are used in the diagnosis of chronic obstructive pulmonary disease. We tested genome-wide association with forced expiratory volume in 1 second and the ratio of forced expiratory volume in 1 second to forced vital capacity in 48,201 individuals of European ancestry with follow up of the top associations in up to an additional 46,411 individuals. We identified new regions showing association (combined P < 5 × 10(-8)) with pulmonary function in or near MFAP2, TGFB2, HDAC4, RARB, MECOM (also known as EVI1), SPATA9, ARMC2, NCR3, ZKSCAN3, CDC123, C10orf11, LRP1, CCDC38, MMP15, CFDP1 and KCNE2. Identification of these 16 new loci may provide insight into the molecular mechanisms regulating pulmonary function and into molecular targets for future therapy to alleviate reduced lung function.

%B Nat Genet %V 43 %P 1082-90 %8 2011 Sep 25 %G eng %N 11 %1 http://www.ncbi.nlm.nih.gov/pubmed/21946350?dopt=Abstract %R 10.1038/ng.941 %0 Journal Article %J Ann Neurol %D 2011 %T Genome-wide association studies of cerebral white matter lesion burden: the CHARGE consortium. %A Fornage, Myriam %A Debette, Stephanie %A Bis, Joshua C %A Schmidt, Helena %A Ikram, M Arfan %A Dufouil, Carole %A Sigurdsson, Sigurdur %A Lumley, Thomas %A DeStefano, Anita L %A Fazekas, Franz %A Vrooman, Henri A %A Shibata, Dean K %A Maillard, Pauline %A Zijdenbos, Alex %A Smith, Albert V %A Gudnason, Haukur %A de Boer, Renske %A Cushman, Mary %A Mazoyer, Bernard %A Heiss, Gerardo %A Vernooij, Meike W %A Enzinger, Christian %A Glazer, Nicole L %A Beiser, Alexa %A Knopman, David S %A Cavalieri, Margherita %A Niessen, Wiro J %A Harris, Tamara B %A Petrovic, Katja %A Lopez, Oscar L %A Au, Rhoda %A Lambert, Jean-Charles %A Hofman, Albert %A Gottesman, Rebecca F %A Garcia, Melissa %A Heckbert, Susan R %A Atwood, Larry D %A Catellier, Diane J %A Uitterlinden, André G %A Yang, Qiong %A Smith, Nicholas L %A Aspelund, Thor %A Romero, Jose R %A Rice, Kenneth %A Taylor, Kent D %A Nalls, Michael A %A Rotter, Jerome I %A Sharrett, Richey %A van Duijn, Cornelia M %A Amouyel, Philippe %A Wolf, Philip A %A Gudnason, Vilmundur %A van der Lugt, Aad %A Boerwinkle, Eric %A Psaty, Bruce M %A Seshadri, Sudha %A Tzourio, Christophe %A Breteler, Monique M B %A Mosley, Thomas H %A Schmidt, Reinhold %A Longstreth, W T %A DeCarli, Charles %A Launer, Lenore J %K Aged %K Aged, 80 and over %K Cerebral Cortex %K Chromosomes, Human, Pair 17 %K Cognition Disorders %K Cohort Studies %K European Continental Ancestry Group %K Female %K Gene Frequency %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genotype %K Humans %K Leukoencephalopathies %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Movement Disorders %K Nerve Fibers, Myelinated %K Polymorphism, Single Nucleotide %K Residence Characteristics %K RNA, Messenger %X

OBJECTIVE: White matter hyperintensities (WMHs) detectable by magnetic resonance imaging are part of the spectrum of vascular injury associated with aging of the brain and are thought to reflect ischemic damage to the small deep cerebral vessels. WMHs are associated with an increased risk of cognitive and motor dysfunction, dementia, depression, and stroke. Despite a significant heritability, few genetic loci influencing WMH burden have been identified.

METHODS: We performed a meta-analysis of genome-wide association studies (GWASs) for WMH burden in 9,361 stroke-free individuals of European descent from 7 community-based cohorts. Significant findings were tested for replication in 3,024 individuals from 2 additional cohorts.

RESULTS: We identified 6 novel risk-associated single nucleotide polymorphisms (SNPs) in 1 locus on chromosome 17q25 encompassing 6 known genes including WBP2, TRIM65, TRIM47, MRPL38, FBF1, and ACOX1. The most significant association was for rs3744028 (p(discovery) = 4.0 × 10(-9) ; p(replication) = 1.3 × 10(-7) ; p(combined) = 4.0 × 10(-15) ). Other SNPs in this region also reaching genome-wide significance were rs9894383 (p = 5.3 × 10(-9) ), rs11869977 (p = 5.7 × 10(-9) ), rs936393 (p = 6.8 × 10(-9) ), rs3744017 (p = 7.3 × 10(-9) ), and rs1055129 (p = 4.1 × 10(-8) ). Variant alleles at these loci conferred a small increase in WMH burden (4-8% of the overall mean WMH burden in the sample).

INTERPRETATION: This large GWAS of WMH burden in community-based cohorts of individuals of European descent identifies a novel locus on chromosome 17. Further characterization of this locus may provide novel insights into the pathogenesis of cerebral WMH.

%B Ann Neurol %V 69 %P 928-39 %8 2011 Jun %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/21681796?dopt=Abstract %R 10.1002/ana.22403 %0 Journal Article %J Hum Mol Genet %D 2011 %T Genome-wide association study for serum urate concentrations and gout among African Americans identifies genomic risk loci and a novel URAT1 loss-of-function allele. %A Tin, Adrienne %A Woodward, Owen M %A Kao, Wen Hong Linda %A Liu, Ching-Ti %A Lu, Xiaoning %A Nalls, Michael A %A Shriner, Daniel %A Semmo, Mariam %A Akylbekova, Ermeg L %A Wyatt, Sharon B %A Hwang, Shih-Jen %A Yang, Qiong %A Zonderman, Alan B %A Adeyemo, Adebowale A %A Palmer, Cameron %A Meng, Yan %A Reilly, Muredach %A Shlipak, Michael G %A Siscovick, David %A Evans, Michele K %A Rotimi, Charles N %A Flessner, Michael F %A Köttgen, Michael %A Cupples, L Adrienne %A Fox, Caroline S %A Köttgen, Anna %K Adult %K African Americans %K Aged %K Animals %K CHO Cells %K Cricetinae %K European Continental Ancestry Group %K Female %K Genetic Loci %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genotype %K Gout %K Humans %K Loss of Heterozygosity %K Male %K Middle Aged %K Organic Anion Transporters %K Organic Cation Transport Proteins %K Polymorphism, Single Nucleotide %K Uric Acid %K Young Adult %X

Serum urate concentrations are highly heritable and elevated serum urate is a key risk factor for gout. Genome-wide association studies (GWAS) of serum urate in African American (AA) populations are lacking. We conducted a meta-analysis of GWAS of serum urate levels and gout among 5820 AA and a large candidate gene study among 6890 AA and 21 708 participants of European ancestry (EA) within the Candidate Gene Association Resource Consortium. Findings were tested for replication among 1996 independent AA individuals, and evaluated for their association among 28 283 EA participants of the CHARGE Consortium. Functional studies were conducted using (14)C-urate transport assays in mammalian Chinese hamster ovary cells. In the discovery GWAS of serum urate, three loci achieved genome-wide significance (P< 5.0 × 10(-8)): a novel locus near SGK1/SLC2A12 on chromosome 6 (rs9321453, P= 1.0 × 10(-9)), and two loci previously identified in EA participants, SLC2A9 (P= 3.8 × 10(-32)) and SLC22A12 (P= 2.1 × 10(-10)). A novel rare non-synonymous variant of large effect size in SLC22A12, rs12800450 (minor allele frequency 0.01, G65W), was identified and replicated (beta -1.19 mg/dl, P= 2.7 × 10(-16)). (14)C-urate transport assays showed reduced urate transport for the G65W URAT1 mutant. Finally, in analyses of 11 loci previously associated with serum urate in EA individuals, 10 of 11 lead single-nucleotide polymorphisms showed direction-consistent association with urate among AA. In summary, we identified and replicated one novel locus in association with serum urate levels and experimentally characterize the novel G65W variant in URAT1 as a functional allele. Our data support the importance of multi-ethnic GWAS in the identification of novel risk loci as well as functional variants.

%B Hum Mol Genet %V 20 %P 4056-68 %8 2011 Oct 15 %G eng %N 20 %1 http://www.ncbi.nlm.nih.gov/pubmed/21768215?dopt=Abstract %R 10.1093/hmg/ddr307 %0 Journal Article %J Hum Mol Genet %D 2011 %T A genome-wide association study identifies novel loci associated with circulating IGF-I and IGFBP-3. %A Kaplan, Robert C %A Petersen, Ann-Kristin %A Chen, Ming-Huei %A Teumer, Alexander %A Glazer, Nicole L %A Döring, Angela %A Lam, Carolyn S P %A Friedrich, Nele %A Newman, Anne %A Müller, Martina %A Yang, Qiong %A Homuth, Georg %A Cappola, Anne %A Klopp, Norman %A Smith, Holly %A Ernst, Florian %A Psaty, Bruce M %A Wichmann, H-Erich %A Sawyer, Douglas B %A Biffar, Reiner %A Rotter, Jerome I %A Gieger, Christian %A Sullivan, Lisa S %A Völzke, Henry %A Rice, Kenneth %A Spyroglou, Ariadni %A Kroemer, Heyo K %A Ida Chen, Y-D %A Manolopoulou, Jenny %A Nauck, Matthias %A Strickler, Howard D %A Goodarzi, Mark O %A Reincke, Martin %A Pollak, Michael N %A Bidlingmaier, Martin %A Vasan, Ramachandran S %A Wallaschofski, Henri %K Aged %K Chromosomes, Human, Pair 7 %K Cohort Studies %K European Continental Ancestry Group %K Female %K Genome-Wide Association Study %K Humans %K Insulin-Like Growth Factor Binding Protein 3 %K Insulin-Like Growth Factor I %K Male %K Polymorphism, Single Nucleotide %X

Insulin-like growth factor-I (IGF-I) and insulin-like growth factor-binding protein-3 (IGFBP-3) are involved in cell replication, proliferation, differentiation, protein synthesis, carbohydrate homeostasis and bone metabolism. Circulating IGF-I and IGFBP-3 concentrations predict anthropometric traits and risk of cancer and cardiovascular disease. In a genome-wide association study of 10 280 middle-aged and older men and women from four community-based cohort studies, we confirmed a known association of single nucleotide polymorphisms in the IGFBP3 gene region on chromosome 7p12.3 with IGFBP-3 concentrations using a significance threshold of P < 5 × 10(-8) (P = 3.3 × 10(-101)). Furthermore, the same IGFBP3 gene locus (e.g. rs11977526) that was associated with IGFBP-3 concentrations was also associated with the opposite direction of effect, with IGF-I concentration after adjustment for IGFBP-3 concentration (P = 1.9 × 10(-26)). A novel and independent locus on chromosome 7p12.3 (rs700752) had genome-wide significant associations with higher IGFBP-3 (P = 4.4 × 10(-21)) and higher IGF-I (P = 4.9 × 10(-9)) concentrations; when the two measurements were adjusted for one another, the IGF-I association was attenuated but the IGFBP-3 association was not. Two additional loci demonstrated genome-wide significant associations with IGFBP-3 concentration (rs1065656, chromosome 16p13.3, P = 1.2 × 10(-11), IGFALS, a confirmatory finding; and rs4234798, chromosome 4p16.1, P = 4.5 × 10(-10), SORCS2, a novel finding). Together, the four genome-wide significant loci explained 6.5% of the population variation in IGFBP-3 concentration. Furthermore, we observed a borderline statistically significant association between IGF-I concentration and FOXO3 (rs2153960, chromosome 6q21, P = 5.1 × 10(-7)), a locus associated with longevity. These genetic loci deserve further investigation to elucidate the biological basis for the observed associations and clarify their possible role in IGF-mediated regulation of cell growth and metabolism.

%B Hum Mol Genet %V 20 %P 1241-51 %8 2011 Mar 15 %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/21216879?dopt=Abstract %R 10.1093/hmg/ddq560 %0 Journal Article %J Nat Genet %D 2011 %T Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure. %A Wain, Louise V %A Verwoert, Germaine C %A O'Reilly, Paul F %A Shi, Gang %A Johnson, Toby %A Johnson, Andrew D %A Bochud, Murielle %A Rice, Kenneth M %A Henneman, Peter %A Smith, Albert V %A Ehret, Georg B %A Amin, Najaf %A Larson, Martin G %A Mooser, Vincent %A Hadley, David %A Dörr, Marcus %A Bis, Joshua C %A Aspelund, Thor %A Esko, Tõnu %A Janssens, A Cecile J W %A Zhao, Jing Hua %A Heath, Simon %A Laan, Maris %A Fu, Jingyuan %A Pistis, Giorgio %A Luan, Jian'an %A Arora, Pankaj %A Lucas, Gavin %A Pirastu, Nicola %A Pichler, Irene %A Jackson, Anne U %A Webster, Rebecca J %A Zhang, Feng %A Peden, John F %A Schmidt, Helena %A Tanaka, Toshiko %A Campbell, Harry %A Igl, Wilmar %A Milaneschi, Yuri %A Hottenga, Jouke-Jan %A Vitart, Veronique %A Chasman, Daniel I %A Trompet, Stella %A Bragg-Gresham, Jennifer L %A Alizadeh, Behrooz Z %A Chambers, John C %A Guo, Xiuqing %A Lehtimäki, Terho %A Kuhnel, Brigitte %A Lopez, Lorna M %A Polasek, Ozren %A Boban, Mladen %A Nelson, Christopher P %A Morrison, Alanna C %A Pihur, Vasyl %A Ganesh, Santhi K %A Hofman, Albert %A Kundu, Suman %A Mattace-Raso, Francesco U S %A Rivadeneira, Fernando %A Sijbrands, Eric J G %A Uitterlinden, André G %A Hwang, Shih-Jen %A Vasan, Ramachandran S %A Wang, Thomas J %A Bergmann, Sven %A Vollenweider, Peter %A Waeber, Gérard %A Laitinen, Jaana %A Pouta, Anneli %A Zitting, Paavo %A McArdle, Wendy L %A Kroemer, Heyo K %A Völker, Uwe %A Völzke, Henry %A Glazer, Nicole L %A Taylor, Kent D %A Harris, Tamara B %A Alavere, Helene %A Haller, Toomas %A Keis, Aime %A Tammesoo, Mari-Liis %A Aulchenko, Yurii %A Barroso, Inês %A Khaw, Kay-Tee %A Galan, Pilar %A Hercberg, Serge %A Lathrop, Mark %A Eyheramendy, Susana %A Org, Elin %A Sõber, Siim %A Lu, Xiaowen %A Nolte, Ilja M %A Penninx, Brenda W %A Corre, Tanguy %A Masciullo, Corrado %A Sala, Cinzia %A Groop, Leif %A Voight, Benjamin F %A Melander, Olle %A O'Donnell, Christopher J %A Salomaa, Veikko %A d'Adamo, Adamo Pio %A Fabretto, Antonella %A Faletra, Flavio %A Ulivi, Sheila %A Del Greco, Fabiola M %A Facheris, Maurizio %A Collins, Francis S %A Bergman, Richard N %A Beilby, John P %A Hung, Joseph %A Musk, A William %A Mangino, Massimo %A Shin, So-Youn %A Soranzo, Nicole %A Watkins, Hugh %A Goel, Anuj %A Hamsten, Anders %A Gider, Pierre %A Loitfelder, Marisa %A Zeginigg, Marion %A Hernandez, Dena %A Najjar, Samer S %A Navarro, Pau %A Wild, Sarah H %A Corsi, Anna Maria %A Singleton, Andrew %A de Geus, Eco J C %A Willemsen, Gonneke %A Parker, Alex N %A Rose, Lynda M %A Buckley, Brendan %A Stott, David %A Orrù, Marco %A Uda, Manuela %A van der Klauw, Melanie M %A Zhang, Weihua %A Li, Xinzhong %A Scott, James %A Chen, Yii-Der Ida %A Burke, Gregory L %A Kähönen, Mika %A Viikari, Jorma %A Döring, Angela %A Meitinger, Thomas %A Davies, Gail %A Starr, John M %A Emilsson, Valur %A Plump, Andrew %A Lindeman, Jan H %A Hoen, Peter A C 't %A König, Inke R %A Felix, Janine F %A Clarke, Robert %A Hopewell, Jemma C %A Ongen, Halit %A Breteler, Monique %A Debette, Stephanie %A DeStefano, Anita L %A Fornage, Myriam %A Mitchell, Gary F %A Smith, Nicholas L %A Holm, Hilma %A Stefansson, Kari %A Thorleifsson, Gudmar %A Thorsteinsdottir, Unnur %A Samani, Nilesh J %A Preuss, Michael %A Rudan, Igor %A Hayward, Caroline %A Deary, Ian J %A Wichmann, H-Erich %A Raitakari, Olli T %A Palmas, Walter %A Kooner, Jaspal S %A Stolk, Ronald P %A Jukema, J Wouter %A Wright, Alan F %A Boomsma, Dorret I %A Bandinelli, Stefania %A Gyllensten, Ulf B %A Wilson, James F %A Ferrucci, Luigi %A Schmidt, Reinhold %A Farrall, Martin %A Spector, Tim D %A Palmer, Lyle J %A Tuomilehto, Jaakko %A Pfeufer, Arne %A Gasparini, Paolo %A Siscovick, David %A Altshuler, David %A Loos, Ruth J F %A Toniolo, Daniela %A Snieder, Harold %A Gieger, Christian %A Meneton, Pierre %A Wareham, Nicholas J %A Oostra, Ben A %A Metspalu, Andres %A Launer, Lenore %A Rettig, Rainer %A Strachan, David P %A Beckmann, Jacques S %A Witteman, Jacqueline C M %A Erdmann, Jeanette %A van Dijk, Ko Willems %A Boerwinkle, Eric %A Boehnke, Michael %A Ridker, Paul M %A Jarvelin, Marjo-Riitta %A Chakravarti, Aravinda %A Abecasis, Goncalo R %A Gudnason, Vilmundur %A Newton-Cheh, Christopher %A Levy, Daniel %A Munroe, Patricia B %A Psaty, Bruce M %A Caulfield, Mark J %A Rao, Dabeeru C %A Tobin, Martin D %A Elliott, Paul %A van Duijn, Cornelia M %K Arteries %K Blood Pressure %K Case-Control Studies %K Follow-Up Studies %K Genetic Loci %K Genome-Wide Association Study %K Humans %K Hypertension %K Linkage Disequilibrium %K Polymorphism, Single Nucleotide %X

Numerous genetic loci have been associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans. We now report genome-wide association studies of pulse pressure (PP) and mean arterial pressure (MAP). In discovery (N = 74,064) and follow-up studies (N = 48,607), we identified at genome-wide significance (P = 2.7 × 10(-8) to P = 2.3 × 10(-13)) four new PP loci (at 4q12 near CHIC2, 7q22.3 near PIK3CG, 8q24.12 in NOV and 11q24.3 near ADAMTS8), two new MAP loci (3p21.31 in MAP4 and 10q25.3 near ADRB1) and one locus associated with both of these traits (2q24.3 near FIGN) that has also recently been associated with SBP in east Asians. For three of the new PP loci, the estimated effect for SBP was opposite of that for DBP, in contrast to the majority of common SBP- and DBP-associated variants, which show concordant effects on both traits. These findings suggest new genetic pathways underlying blood pressure variation, some of which may differentially influence SBP and DBP.

%B Nat Genet %V 43 %P 1005-11 %8 2011 Sep 11 %G eng %N 10 %1 http://www.ncbi.nlm.nih.gov/pubmed/21909110?dopt=Abstract %R 10.1038/ng.922 %0 Journal Article %J Neurobiol Aging %D 2011 %T A genome-wide association study of aging. %A Walter, Stefan %A Atzmon, Gil %A Demerath, Ellen W %A Garcia, Melissa E %A Kaplan, Robert C %A Kumari, Meena %A Lunetta, Kathryn L %A Milaneschi, Yuri %A Tanaka, Toshiko %A Tranah, Gregory J %A Völker, Uwe %A Yu, Lei %A Arnold, Alice %A Benjamin, Emelia J %A Biffar, Reiner %A Buchman, Aron S %A Boerwinkle, Eric %A Couper, David %A De Jager, Philip L %A Evans, Denis A %A Harris, Tamara B %A Hoffmann, Wolfgang %A Hofman, Albert %A Karasik, David %A Kiel, Douglas P %A Kocher, Thomas %A Kuningas, Maris %A Launer, Lenore J %A Lohman, Kurt K %A Lutsey, Pamela L %A Mackenbach, Johan %A Marciante, Kristin %A Psaty, Bruce M %A Reiman, Eric M %A Rotter, Jerome I %A Seshadri, Sudha %A Shardell, Michelle D %A Smith, Albert V %A van Duijn, Cornelia %A Walston, Jeremy %A Zillikens, M Carola %A Bandinelli, Stefania %A Baumeister, Sebastian E %A Bennett, David A %A Ferrucci, Luigi %A Gudnason, Vilmundur %A Kivimaki, Mika %A Liu, Yongmei %A Murabito, Joanne M %A Newman, Anne B %A Tiemeier, Henning %A Franceschini, Nora %K Aging %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genotype %K Humans %K Longevity %X

Human longevity and healthy aging show moderate heritability (20%-50%). We conducted a meta-analysis of genome-wide association studies from 9 studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium for 2 outcomes: (1) all-cause mortality, and (2) survival free of major disease or death. No single nucleotide polymorphism (SNP) was a genome-wide significant predictor of either outcome (p < 5 × 10(-8)). We found 14 independent SNPs that predicted risk of death, and 8 SNPs that predicted event-free survival (p < 10(-5)). These SNPs are in or near genes that are highly expressed in the brain (HECW2, HIP1, BIN2, GRIA1), genes involved in neural development and function (KCNQ4, LMO4, GRIA1, NETO1) and autophagy (ATG4C), and genes that are associated with risk of various diseases including cancer and Alzheimer's disease. In addition to considerable overlap between the traits, pathway and network analysis corroborated these findings. These findings indicate that variation in genes involved in neurological processes may be an important factor in regulating aging free of major disease and achieving longevity.

%B Neurobiol Aging %V 32 %P 2109.e15-28 %8 2011 Nov %G eng %N 11 %1 http://www.ncbi.nlm.nih.gov/pubmed/21782286?dopt=Abstract %R 10.1016/j.neurobiolaging.2011.05.026 %0 Journal Article %J PLoS Genet %D 2011 %T Identification of a sudden cardiac death susceptibility locus at 2q24.2 through genome-wide association in European ancestry individuals. %A Arking, Dan E %A Junttila, M Juhani %A Goyette, Philippe %A Huertas-Vazquez, Adriana %A Eijgelsheim, Mark %A Blom, Marieke T %A Newton-Cheh, Christopher %A Reinier, Kyndaron %A Teodorescu, Carmen %A Uy-Evanado, Audrey %A Carter-Monroe, Naima %A Kaikkonen, Kari S %A Kortelainen, Marja-Leena %A Boucher, Gabrielle %A Lagacé, Caroline %A Moes, Anna %A Zhao, XiaoQing %A Kolodgie, Frank %A Rivadeneira, Fernando %A Hofman, Albert %A Witteman, Jacqueline C M %A Uitterlinden, André G %A Marsman, Roos F %A Pazoki, Raha %A Bardai, Abdennasser %A Koster, Rudolph W %A Dehghan, Abbas %A Hwang, Shih-Jen %A Bhatnagar, Pallav %A Post, Wendy %A Hilton, Gina %A Prineas, Ronald J %A Li, Man %A Köttgen, Anna %A Ehret, Georg %A Boerwinkle, Eric %A Coresh, Josef %A Kao, W H Linda %A Psaty, Bruce M %A Tomaselli, Gordon F %A Sotoodehnia, Nona %A Siscovick, David S %A Burke, Greg L %A Marbán, Eduardo %A Spooner, Peter M %A Cupples, L Adrienne %A Jui, Jonathan %A Gunson, Karen %A Kesaniemi, Y Antero %A Wilde, Arthur A M %A Tardif, Jean-Claude %A O'Donnell, Christopher J %A Bezzina, Connie R %A Virmani, Renu %A Stricker, Bruno H C H %A Tan, Hanno L %A Albert, Christine M %A Chakravarti, Aravinda %A Rioux, John D %A Huikuri, Heikki V %A Chugh, Sumeet S %K Adult %K Aged %K Alleles %K Chromosomes, Human, Pair 2 %K Death, Sudden, Cardiac %K European Continental Ancestry Group %K Female %K Genetic Loci %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Male %K Middle Aged %K Myocardial Contraction %K Polymorphism, Single Nucleotide %X

Sudden cardiac death (SCD) continues to be one of the leading causes of mortality worldwide, with an annual incidence estimated at 250,000-300,000 in the United States and with the vast majority occurring in the setting of coronary disease. We performed a genome-wide association meta-analysis in 1,283 SCD cases and >20,000 control individuals of European ancestry from 5 studies, with follow-up genotyping in up to 3,119 SCD cases and 11,146 controls from 11 European ancestry studies, and identify the BAZ2B locus as associated with SCD (P = 1.8×10(-10)). The risk allele, while ancestral, has a frequency of ~1.4%, suggesting strong negative selection and increases risk for SCD by 1.92-fold per allele (95% CI 1.57-2.34). We also tested the role of 49 SNPs previously implicated in modulating electrocardiographic traits (QRS, QT, and RR intervals). Consistent with epidemiological studies showing increased risk of SCD with prolonged QRS/QT intervals, the interval-prolonging alleles are in aggregate associated with increased risk for SCD (P = 0.006).

%B PLoS Genet %V 7 %P e1002158 %8 2011 Jun %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/21738491?dopt=Abstract %R 10.1371/journal.pgen.1002158 %0 Journal Article %J Genet Epidemiol %D 2011 %T Meta-analysis of gene-environment interaction: joint estimation of SNP and SNP × environment regression coefficients. %A Manning, Alisa K %A LaValley, Michael %A Liu, Ching-Ti %A Rice, Kenneth %A An, Ping %A Liu, Yongmei %A Miljkovic, Iva %A Rasmussen-Torvik, Laura %A Harris, Tamara B %A Province, Michael A %A Borecki, Ingrid B %A Florez, Jose C %A Meigs, James B %A Cupples, L Adrienne %A Dupuis, Josée %K Adult %K Aged %K Body Mass Index %K Confidence Intervals %K Diabetes Mellitus, Type 2 %K Environment %K Fasting %K Female %K Genome, Human %K Genome-Wide Association Study %K Genotype %K Humans %K Insulin %K Least-Squares Analysis %K Male %K Mathematical Computing %K Meta-Analysis as Topic %K Middle Aged %K Polymorphism, Single Nucleotide %K PPAR gamma %X

INTRODUCTION: Genetic discoveries are validated through the meta-analysis of genome-wide association scans in large international consortia. Because environmental variables may interact with genetic factors, investigation of differing genetic effects for distinct levels of an environmental exposure in these large consortia may yield additional susceptibility loci undetected by main effects analysis. We describe a method of joint meta-analysis (JMA) of SNP and SNP by Environment (SNP × E) regression coefficients for use in gene-environment interaction studies.

METHODS: In testing SNP × E interactions, one approach uses a two degree of freedom test to identify genetic variants that influence the trait of interest. This approach detects both main and interaction effects between the trait and the SNP. We propose a method to jointly meta-analyze the SNP and SNP × E coefficients using multivariate generalized least squares. This approach provides confidence intervals of the two estimates, a joint significance test for SNP and SNP × E terms, and a test of homogeneity across samples.

RESULTS: We present a simulation study comparing this method to four other methods of meta-analysis and demonstrate that the JMA performs better than the others when both main and interaction effects are present. Additionally, we implemented our methods in a meta-analysis of the association between SNPs from the type 2 diabetes-associated gene PPARG and log-transformed fasting insulin levels and interaction by body mass index in a combined sample of 19,466 individuals from five cohorts.

%B Genet Epidemiol %V 35 %P 11-8 %8 2011 Jan %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/21181894?dopt=Abstract %R 10.1002/gepi.20546 %0 Journal Article %J Nat Genet %D 2011 %T Meta-analysis of genome-wide association studies from the CHARGE consortium identifies common variants associated with carotid intima media thickness and plaque. %A Bis, Joshua C %A Kavousi, Maryam %A Franceschini, Nora %A Isaacs, Aaron %A Abecasis, Goncalo R %A Schminke, Ulf %A Post, Wendy S %A Smith, Albert V %A Cupples, L Adrienne %A Markus, Hugh S %A Schmidt, Reinhold %A Huffman, Jennifer E %A Lehtimäki, Terho %A Baumert, Jens %A Münzel, Thomas %A Heckbert, Susan R %A Dehghan, Abbas %A North, Kari %A Oostra, Ben %A Bevan, Steve %A Stoegerer, Eva-Maria %A Hayward, Caroline %A Raitakari, Olli %A Meisinger, Christa %A Schillert, Arne %A Sanna, Serena %A Völzke, Henry %A Cheng, Yu-Ching %A Thorsson, Bolli %A Fox, Caroline S %A Rice, Kenneth %A Rivadeneira, Fernando %A Nambi, Vijay %A Halperin, Eran %A Petrovic, Katja E %A Peltonen, Leena %A Wichmann, H Erich %A Schnabel, Renate B %A Dörr, Marcus %A Parsa, Afshin %A Aspelund, Thor %A Demissie, Serkalem %A Kathiresan, Sekar %A Reilly, Muredach P %A Taylor, Kent %A Uitterlinden, Andre %A Couper, David J %A Sitzer, Matthias %A Kähönen, Mika %A Illig, Thomas %A Wild, Philipp S %A Orrù, Marco %A Lüdemann, Jan %A Shuldiner, Alan R %A Eiriksdottir, Gudny %A White, Charles C %A Rotter, Jerome I %A Hofman, Albert %A Seissler, Jochen %A Zeller, Tanja %A Usala, Gianluca %A Ernst, Florian %A Launer, Lenore J %A D'Agostino, Ralph B %A O'Leary, Daniel H %A Ballantyne, Christie %A Thiery, Joachim %A Ziegler, Andreas %A Lakatta, Edward G %A Chilukoti, Ravi Kumar %A Harris, Tamara B %A Wolf, Philip A %A Psaty, Bruce M %A Polak, Joseph F %A Li, Xia %A Rathmann, Wolfgang %A Uda, Manuela %A Boerwinkle, Eric %A Klopp, Norman %A Schmidt, Helena %A Wilson, James F %A Viikari, Jorma %A Koenig, Wolfgang %A Blankenberg, Stefan %A Newman, Anne B %A Witteman, Jacqueline %A Heiss, Gerardo %A Duijn, Cornelia van %A Scuteri, Angelo %A Homuth, Georg %A Mitchell, Braxton D %A Gudnason, Vilmundur %A O'Donnell, Christopher J %K Adult %K Aged %K Aging %K Atherosclerosis %K Carotid Intima-Media Thickness %K Cohort Studies %K Coronary Artery Disease %K European Continental Ancestry Group %K Genetic Loci %K Genetic Predisposition to Disease %K Genome, Human %K Genome-Wide Association Study %K Genotype %K Heart %K Humans %K Middle Aged %K Phenotype %K Plaque, Atherosclerotic %K Polymorphism, Single Nucleotide %K Risk Factors %X

Carotid intima media thickness (cIMT) and plaque determined by ultrasonography are established measures of subclinical atherosclerosis that each predicts future cardiovascular disease events. We conducted a meta-analysis of genome-wide association data in 31,211 participants of European ancestry from nine large studies in the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. We then sought additional evidence to support our findings among 11,273 individuals using data from seven additional studies. In the combined meta-analysis, we identified three genomic regions associated with common carotid intima media thickness and two different regions associated with the presence of carotid plaque (P < 5 × 10(-8)). The associated SNPs mapped in or near genes related to cellular signaling, lipid metabolism and blood pressure homeostasis, and two of the regions were associated with coronary artery disease (P < 0.006) in the Coronary Artery Disease Genome-Wide Replication and Meta-Analysis (CARDIoGRAM) consortium. Our findings may provide new insight into pathways leading to subclinical atherosclerosis and subsequent cardiovascular events.

%B Nat Genet %V 43 %P 940-7 %8 2011 Sep 11 %G eng %N 10 %1 http://www.ncbi.nlm.nih.gov/pubmed/21909108?dopt=Abstract %R 10.1038/ng.920 %0 Journal Article %J Circulation %D 2011 %T Meta-analysis of genome-wide association studies in >80 000 subjects identifies multiple loci for C-reactive protein levels. %A Dehghan, Abbas %A Dupuis, Josée %A Barbalic, Maja %A Bis, Joshua C %A Eiriksdottir, Gudny %A Lu, Chen %A Pellikka, Niina %A Wallaschofski, Henri %A Kettunen, Johannes %A Henneman, Peter %A Baumert, Jens %A Strachan, David P %A Fuchsberger, Christian %A Vitart, Veronique %A Wilson, James F %A Paré, Guillaume %A Naitza, Silvia %A Rudock, Megan E %A Surakka, Ida %A de Geus, Eco J C %A Alizadeh, Behrooz Z %A Guralnik, Jack %A Shuldiner, Alan %A Tanaka, Toshiko %A Zee, Robert Y L %A Schnabel, Renate B %A Nambi, Vijay %A Kavousi, Maryam %A Ripatti, Samuli %A Nauck, Matthias %A Smith, Nicholas L %A Smith, Albert V %A Sundvall, Jouko %A Scheet, Paul %A Liu, Yongmei %A Ruokonen, Aimo %A Rose, Lynda M %A Larson, Martin G %A Hoogeveen, Ron C %A Freimer, Nelson B %A Teumer, Alexander %A Tracy, Russell P %A Launer, Lenore J %A Buring, Julie E %A Yamamoto, Jennifer F %A Folsom, Aaron R %A Sijbrands, Eric J G %A Pankow, James %A Elliott, Paul %A Keaney, John F %A Sun, Wei %A Sarin, Antti-Pekka %A Fontes, João D %A Badola, Sunita %A Astor, Brad C %A Hofman, Albert %A Pouta, Anneli %A Werdan, Karl %A Greiser, Karin H %A Kuss, Oliver %A Meyer zu Schwabedissen, Henriette E %A Thiery, Joachim %A Jamshidi, Yalda %A Nolte, Ilja M %A Soranzo, Nicole %A Spector, Timothy D %A Völzke, Henry %A Parker, Alexander N %A Aspelund, Thor %A Bates, David %A Young, Lauren %A Tsui, Kim %A Siscovick, David S %A Guo, Xiuqing %A Rotter, Jerome I %A Uda, Manuela %A Schlessinger, David %A Rudan, Igor %A Hicks, Andrew A %A Penninx, Brenda W %A Thorand, Barbara %A Gieger, Christian %A Coresh, Joe %A Willemsen, Gonneke %A Harris, Tamara B %A Uitterlinden, André G %A Jarvelin, Marjo-Riitta %A Rice, Kenneth %A Radke, Dörte %A Salomaa, Veikko %A Willems van Dijk, Ko %A Boerwinkle, Eric %A Vasan, Ramachandran S %A Ferrucci, Luigi %A Gibson, Quince D %A Bandinelli, Stefania %A Snieder, Harold %A Boomsma, Dorret I %A Xiao, Xiangjun %A Campbell, Harry %A Hayward, Caroline %A Pramstaller, Peter P %A van Duijn, Cornelia M %A Peltonen, Leena %A Psaty, Bruce M %A Gudnason, Vilmundur %A Ridker, Paul M %A Homuth, Georg %A Koenig, Wolfgang %A Ballantyne, Christie M %A Witteman, Jacqueline C M %A Benjamin, Emelia J %A Perola, Markus %A Chasman, Daniel I %K Biomarkers %K C-Reactive Protein %K Cardiovascular Diseases %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Risk Factors %K Vasculitis %X

BACKGROUND: C-reactive protein (CRP) is a heritable marker of chronic inflammation that is strongly associated with cardiovascular disease. We sought to identify genetic variants that are associated with CRP levels.

METHODS AND RESULTS: We performed a genome-wide association analysis of CRP in 66 185 participants from 15 population-based studies. We sought replication for the genome-wide significant and suggestive loci in a replication panel comprising 16 540 individuals from 10 independent studies. We found 18 genome-wide significant loci, and we provided evidence of replication for 8 of them. Our results confirm 7 previously known loci and introduce 11 novel loci that are implicated in pathways related to the metabolic syndrome (APOC1, HNF1A, LEPR, GCKR, HNF4A, and PTPN2) or the immune system (CRP, IL6R, NLRP3, IL1F10, and IRF1) or that reside in regions previously not known to play a role in chronic inflammation (PPP1R3B, SALL1, PABPC4, ASCL1, RORA, and BCL7B). We found a significant interaction of body mass index with LEPR (P<2.9×10(-6)). A weighted genetic risk score that was developed to summarize the effect of risk alleles was strongly associated with CRP levels and explained ≈5% of the trait variance; however, there was no evidence for these genetic variants explaining the association of CRP with coronary heart disease.

CONCLUSIONS: We identified 18 loci that were associated with CRP levels. Our study highlights immune response and metabolic regulatory pathways involved in the regulation of chronic inflammation.

%B Circulation %V 123 %P 731-8 %8 2011 Feb 22 %G eng %N 7 %1 http://www.ncbi.nlm.nih.gov/pubmed/21300955?dopt=Abstract %R 10.1161/CIRCULATIONAHA.110.948570 %0 Journal Article %J Nature %D 2011 %T New gene functions in megakaryopoiesis and platelet formation. %A Gieger, Christian %A Radhakrishnan, Aparna %A Cvejic, Ana %A Tang, Weihong %A Porcu, Eleonora %A Pistis, Giorgio %A Serbanovic-Canic, Jovana %A Elling, Ulrich %A Goodall, Alison H %A Labrune, Yann %A Lopez, Lorna M %A Mägi, Reedik %A Meacham, Stuart %A Okada, Yukinori %A Pirastu, Nicola %A Sorice, Rossella %A Teumer, Alexander %A Voss, Katrin %A Zhang, Weihua %A Ramirez-Solis, Ramiro %A Bis, Joshua C %A Ellinghaus, David %A Gögele, Martin %A Hottenga, Jouke-Jan %A Langenberg, Claudia %A Kovacs, Peter %A O'Reilly, Paul F %A Shin, So-Youn %A Esko, Tõnu %A Hartiala, Jaana %A Kanoni, Stavroula %A Murgia, Federico %A Parsa, Afshin %A Stephens, Jonathan %A van der Harst, Pim %A Ellen van der Schoot, C %A Allayee, Hooman %A Attwood, Antony %A Balkau, Beverley %A Bastardot, François %A Basu, Saonli %A Baumeister, Sebastian E %A Biino, Ginevra %A Bomba, Lorenzo %A Bonnefond, Amélie %A Cambien, Francois %A Chambers, John C %A Cucca, Francesco %A D'Adamo, Pio %A Davies, Gail %A de Boer, Rudolf A %A de Geus, Eco J C %A Döring, Angela %A Elliott, Paul %A Erdmann, Jeanette %A Evans, David M %A Falchi, Mario %A Feng, Wei %A Folsom, Aaron R %A Frazer, Ian H %A Gibson, Quince D %A Glazer, Nicole L %A Hammond, Chris %A Hartikainen, Anna-Liisa %A Heckbert, Susan R %A Hengstenberg, Christian %A Hersch, Micha %A Illig, Thomas %A Loos, Ruth J F %A Jolley, Jennifer %A Khaw, Kay Tee %A Kuhnel, Brigitte %A Kyrtsonis, Marie-Christine %A Lagou, Vasiliki %A Lloyd-Jones, Heather %A Lumley, Thomas %A Mangino, Massimo %A Maschio, Andrea %A Mateo Leach, Irene %A McKnight, Barbara %A Memari, Yasin %A Mitchell, Braxton D %A Montgomery, Grant W %A Nakamura, Yusuke %A Nauck, Matthias %A Navis, Gerjan %A Nöthlings, Ute %A Nolte, Ilja M %A Porteous, David J %A Pouta, Anneli %A Pramstaller, Peter P %A Pullat, Janne %A Ring, Susan M %A Rotter, Jerome I %A Ruggiero, Daniela %A Ruokonen, Aimo %A Sala, Cinzia %A Samani, Nilesh J %A Sambrook, Jennifer %A Schlessinger, David %A Schreiber, Stefan %A Schunkert, Heribert %A Scott, James %A Smith, Nicholas L %A Snieder, Harold %A Starr, John M %A Stumvoll, Michael %A Takahashi, Atsushi %A Tang, W H Wilson %A Taylor, Kent %A Tenesa, Albert %A Lay Thein, Swee %A Tönjes, Anke %A Uda, Manuela %A Ulivi, Sheila %A van Veldhuisen, Dirk J %A Visscher, Peter M %A Völker, Uwe %A Wichmann, H-Erich %A Wiggins, Kerri L %A Willemsen, Gonneke %A Yang, Tsun-Po %A Hua Zhao, Jing %A Zitting, Paavo %A Bradley, John R %A Dedoussis, George V %A Gasparini, Paolo %A Hazen, Stanley L %A Metspalu, Andres %A Pirastu, Mario %A Shuldiner, Alan R %A Joost van Pelt, L %A Zwaginga, Jaap-Jan %A Boomsma, Dorret I %A Deary, Ian J %A Franke, Andre %A Froguel, Philippe %A Ganesh, Santhi K %A Jarvelin, Marjo-Riitta %A Martin, Nicholas G %A Meisinger, Christa %A Psaty, Bruce M %A Spector, Timothy D %A Wareham, Nicholas J %A Akkerman, Jan-Willem N %A Ciullo, Marina %A Deloukas, Panos %A Greinacher, Andreas %A Jupe, Steve %A Kamatani, Naoyuki %A Khadake, Jyoti %A Kooner, Jaspal S %A Penninger, Josef %A Prokopenko, Inga %A Stemple, Derek %A Toniolo, Daniela %A Wernisch, Lorenz %A Sanna, Serena %A Hicks, Andrew A %A Rendon, Augusto %A Ferreira, Manuel A %A Ouwehand, Willem H %A Soranzo, Nicole %K Animals %K Blood Platelets %K Cell Size %K Drosophila melanogaster %K Drosophila Proteins %K Europe %K Gene Expression Profiling %K Gene Silencing %K Genome, Human %K Genome-Wide Association Study %K Hematopoiesis %K Humans %K Megakaryocytes %K Platelet Count %K Protein Interaction Maps %K Transcription, Genetic %K Zebrafish %K Zebrafish Proteins %X

Platelets are the second most abundant cell type in blood and are essential for maintaining haemostasis. Their count and volume are tightly controlled within narrow physiological ranges, but there is only limited understanding of the molecular processes controlling both traits. Here we carried out a high-powered meta-analysis of genome-wide association studies (GWAS) in up to 66,867 individuals of European ancestry, followed by extensive biological and functional assessment. We identified 68 genomic loci reliably associated with platelet count and volume mapping to established and putative novel regulators of megakaryopoiesis and platelet formation. These genes show megakaryocyte-specific gene expression patterns and extensive network connectivity. Using gene silencing in Danio rerio and Drosophila melanogaster, we identified 11 of the genes as novel regulators of blood cell formation. Taken together, our findings advance understanding of novel gene functions controlling fate-determining events during megakaryopoiesis and platelet formation, providing a new example of successful translation of GWAS to function.

%B Nature %V 480 %P 201-8 %8 2011 Nov 30 %G eng %N 7376 %1 http://www.ncbi.nlm.nih.gov/pubmed/22139419?dopt=Abstract %R 10.1038/nature10659 %0 Journal Article %J Am J Epidemiol %D 2011 %T The Next PAGE in understanding complex traits: design for the analysis of Population Architecture Using Genetics and Epidemiology (PAGE) Study. %A Matise, Tara C %A Ambite, Jose Luis %A Buyske, Steven %A Carlson, Christopher S %A Cole, Shelley A %A Crawford, Dana C %A Haiman, Christopher A %A Heiss, Gerardo %A Kooperberg, Charles %A Marchand, Loic Le %A Manolio, Teri A %A North, Kari E %A Peters, Ulrike %A Ritchie, Marylyn D %A Hindorff, Lucia A %A Haines, Jonathan L %K Epidemiologic Methods %K Epidemiologic Research Design %K Ethnic Groups %K Genetic Association Studies %K Genetics, Population %K Genome-Wide Association Study %K Humans %K Interinstitutional Relations %K Multifactorial Inheritance %K National Human Genome Research Institute (U.S.) %K Phenotype %K Pilot Projects %K Research Design %K Risk Factors %K United States %X

Genetic studies have identified thousands of variants associated with complex traits. However, most association studies are limited to populations of European descent and a single phenotype. The Population Architecture using Genomics and Epidemiology (PAGE) Study was initiated in 2008 by the National Human Genome Research Institute to investigate the epidemiologic architecture of well-replicated genetic variants associated with complex diseases in several large, ethnically diverse population-based studies. Combining DNA samples and hundreds of phenotypes from multiple cohorts, PAGE is well-suited to address generalization of associations and variability of effects in diverse populations; identify genetic and environmental modifiers; evaluate disease subtypes, intermediate phenotypes, and biomarkers; and investigate associations with novel phenotypes. PAGE investigators harmonize phenotypes across studies where possible and perform coordinated cohort-specific analyses and meta-analyses. PAGE researchers are genotyping thousands of genetic variants in up to 121,000 DNA samples from African-American, white, Hispanic/Latino, Asian/Pacific Islander, and American Indian participants. Initial analyses will focus on single nucleotide polymorphisms (SNPs) associated with obesity, lipids, cardiovascular disease, type 2 diabetes, inflammation, various cancers, and related biomarkers. PAGE SNPs are also assessed for pleiotropy using the "phenome-wide association study" approach, testing each SNP for associations with hundreds of phenotypes. PAGE data will be deposited into the National Center for Biotechnology Information's Database of Genotypes and Phenotypes and made available via a custom browser.

%B Am J Epidemiol %V 174 %P 849-59 %8 2011 Oct 01 %G eng %N 7 %1 http://www.ncbi.nlm.nih.gov/pubmed/21836165?dopt=Abstract %R 10.1093/aje/kwr160 %0 Journal Article %J J Bone Miner Res %D 2012 %T Assessment of gene-by-sex interaction effect on bone mineral density. %A Liu, Ching-Ti %A Estrada, Karol %A Yerges-Armstrong, Laura M %A Amin, Najaf %A Evangelou, Evangelos %A Li, Guo %A Minster, Ryan L %A Carless, Melanie A %A Kammerer, Candace M %A Oei, Ling %A Zhou, Yanhua %A Alonso, Nerea %A Dailiana, Zoe %A Eriksson, Joel %A García-Giralt, Natalia %A Giroux, Sylvie %A Husted, Lise Bjerre %A Khusainova, Rita I %A Koromila, Theodora %A Kung, Annie Waichee %A Lewis, Joshua R %A Masi, Laura %A Mencej-Bedrac, Simona %A Nogues, Xavier %A Patel, Millan S %A Prezelj, Janez %A Richards, J Brent %A Sham, Pak Chung %A Spector, Timothy %A Vandenput, Liesbeth %A Xiao, Su-Mei %A Zheng, Hou-Feng %A Zhu, Kun %A Balcells, Susana %A Brandi, Maria Luisa %A Frost, Morten %A Goltzman, David %A González-Macías, Jesús %A Karlsson, Magnus %A Khusnutdinova, Elza K %A Kollia, Panagoula %A Langdahl, Bente Lomholt %A Ljunggren, Osten %A Lorentzon, Mattias %A Marc, Janja %A Mellström, Dan %A Ohlsson, Claes %A Olmos, José M %A Ralston, Stuart H %A Riancho, José A %A Rousseau, François %A Urreizti, Roser %A Van Hul, Wim %A Zarrabeitia, María T %A Castano-Betancourt, Martha %A Demissie, Serkalem %A Grundberg, Elin %A Herrera, Lizbeth %A Kwan, Tony %A Medina-Gómez, Carolina %A Pastinen, Tomi %A Sigurdsson, Gunnar %A Thorleifsson, Gudmar %A Vanmeurs, Joyce Bj %A Blangero, John %A Hofman, Albert %A Liu, Yongmei %A Mitchell, Braxton D %A O'Connell, Jeffrey R %A Oostra, Ben A %A Rotter, Jerome I %A Stefansson, Kari %A Streeten, Elizabeth A %A Styrkarsdottir, Unnur %A Thorsteinsdottir, Unnur %A Tylavsky, Frances A %A Uitterlinden, Andre %A Cauley, Jane A %A Harris, Tamara B %A Ioannidis, John Pa %A Psaty, Bruce M %A Robbins, John A %A Zillikens, M Carola %A Vanduijn, Cornelia M %A Prince, Richard L %A Karasik, David %A Rivadeneira, Fernando %A Kiel, Douglas P %A Cupples, L Adrienne %A Hsu, Yi-Hsiang %K Bone Density %K Cohort Studies %K Female %K Genes %K Genome-Wide Association Study %K Humans %K Male %K Meta-Analysis as Topic %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %K Reproducibility of Results %K Sex Characteristics %X

Sexual dimorphism in various bone phenotypes, including bone mineral density (BMD), is widely observed; however, the extent to which genes explain these sex differences is unclear. To identify variants with different effects by sex, we examined gene-by-sex autosomal interactions genome-wide, and performed expression quantitative trait loci (eQTL) analysis and bioinformatics network analysis. We conducted an autosomal genome-wide meta-analysis of gene-by-sex interaction on lumbar spine (LS) and femoral neck (FN) BMD in 25,353 individuals from 8 cohorts. In a second stage, we followed up the 12 top single-nucleotide polymorphisms (SNPs; p < 1 × 10(-5) ) in an additional set of 24,763 individuals. Gene-by-sex interaction and sex-specific effects were examined in these 12 SNPs. We detected one novel genome-wide significant interaction associated with LS-BMD at the Chr3p26.1-p25.1 locus, near the GRM7 gene (male effect = 0.02 and p = 3.0 × 10(-5) ; female effect = -0.007 and p = 3.3 × 10(-2) ), and 11 suggestive loci associated with either FN- or LS-BMD in discovery cohorts. However, there was no evidence for genome-wide significant (p < 5 × 10(-8) ) gene-by-sex interaction in the joint analysis of discovery and replication cohorts. Despite the large collaborative effort, no genome-wide significant evidence for gene-by-sex interaction was found to influence BMD variation in this screen of autosomal markers. If they exist, gene-by-sex interactions for BMD probably have weak effects, accounting for less than 0.08% of the variation in these traits per implicated SNP. © 2012 American Society for Bone and Mineral Research.

%B J Bone Miner Res %V 27 %P 2051-64 %8 2012 Oct %G eng %N 10 %1 http://www.ncbi.nlm.nih.gov/pubmed/22692763?dopt=Abstract %R 10.1002/jbmr.1679 %0 Journal Article %J Circ Cardiovasc Genet %D 2012 %T Association between chromosome 9p21 variants and the ankle-brachial index identified by a meta-analysis of 21 genome-wide association studies. %A Murabito, Joanne M %A White, Charles C %A Kavousi, Maryam %A Sun, Yan V %A Feitosa, Mary F %A Nambi, Vijay %A Lamina, Claudia %A Schillert, Arne %A Coassin, Stefan %A Bis, Joshua C %A Broer, Linda %A Crawford, Dana C %A Franceschini, Nora %A Frikke-Schmidt, Ruth %A Haun, Margot %A Holewijn, Suzanne %A Huffman, Jennifer E %A Hwang, Shih-Jen %A Kiechl, Stefan %A Kollerits, Barbara %A Montasser, May E %A Nolte, Ilja M %A Rudock, Megan E %A Senft, Andrea %A Teumer, Alexander %A van der Harst, Pim %A Vitart, Veronique %A Waite, Lindsay L %A Wood, Andrew R %A Wassel, Christina L %A Absher, Devin M %A Allison, Matthew A %A Amin, Najaf %A Arnold, Alice %A Asselbergs, Folkert W %A Aulchenko, Yurii %A Bandinelli, Stefania %A Barbalic, Maja %A Boban, Mladen %A Brown-Gentry, Kristin %A Couper, David J %A Criqui, Michael H %A Dehghan, Abbas %A den Heijer, Martin %A Dieplinger, Benjamin %A Ding, Jingzhong %A Dörr, Marcus %A Espinola-Klein, Christine %A Felix, Stephan B %A Ferrucci, Luigi %A Folsom, Aaron R %A Fraedrich, Gustav %A Gibson, Quince %A Goodloe, Robert %A Gunjaca, Grgo %A Haltmayer, Meinhard %A Heiss, Gerardo %A Hofman, Albert %A Kieback, Arne %A Kiemeney, Lambertus A %A Kolcic, Ivana %A Kullo, Iftikhar J %A Kritchevsky, Stephen B %A Lackner, Karl J %A Li, Xiaohui %A Lieb, Wolfgang %A Lohman, Kurt %A Meisinger, Christa %A Melzer, David %A Mohler, Emile R %A Mudnic, Ivana %A Mueller, Thomas %A Navis, Gerjan %A Oberhollenzer, Friedrich %A Olin, Jeffrey W %A O'Connell, Jeff %A O'Donnell, Christopher J %A Palmas, Walter %A Penninx, Brenda W %A Petersmann, Astrid %A Polasek, Ozren %A Psaty, Bruce M %A Rantner, Barbara %A Rice, Ken %A Rivadeneira, Fernando %A Rotter, Jerome I %A Seldenrijk, Adrie %A Stadler, Marietta %A Summerer, Monika %A Tanaka, Toshiko %A Tybjaerg-Hansen, Anne %A Uitterlinden, André G %A van Gilst, Wiek H %A Vermeulen, Sita H %A Wild, Sarah H %A Wild, Philipp S %A Willeit, Johann %A Zeller, Tanja %A Zemunik, Tatijana %A Zgaga, Lina %A Assimes, Themistocles L %A Blankenberg, Stefan %A Boerwinkle, Eric %A Campbell, Harry %A Cooke, John P %A de Graaf, Jacqueline %A Herrington, David %A Kardia, Sharon L R %A Mitchell, Braxton D %A Murray, Anna %A Münzel, Thomas %A Newman, Anne B %A Oostra, Ben A %A Rudan, Igor %A Shuldiner, Alan R %A Snieder, Harold %A van Duijn, Cornelia M %A Völker, Uwe %A Wright, Alan F %A Wichmann, H-Erich %A Wilson, James F %A Witteman, Jacqueline C M %A Liu, Yongmei %A Hayward, Caroline %A Borecki, Ingrid B %A Ziegler, Andreas %A North, Kari E %A Cupples, L Adrienne %A Kronenberg, Florian %K Adult %K Age Factors %K Aged %K Aged, 80 and over %K Alleles %K Ankle Brachial Index %K Chromosomes, Human, Pair 9 %K Cohort Studies %K Cyclin-Dependent Kinase Inhibitor p15 %K Female %K Genome-Wide Association Study %K Genotype %K HapMap Project %K Humans %K Logistic Models %K Male %K Middle Aged %K Peripheral Vascular Diseases %K Phenotype %K Polymorphism, Single Nucleotide %K Risk Factors %K Sex Factors %X

BACKGROUND: Genetic determinants of peripheral arterial disease (PAD) remain largely unknown. To identify genetic variants associated with the ankle-brachial index (ABI), a noninvasive measure of PAD, we conducted a meta-analysis of genome-wide association study data from 21 population-based cohorts.

METHODS AND RESULTS: Continuous ABI and PAD (ABI ≤0.9) phenotypes adjusted for age and sex were examined. Each study conducted genotyping and imputed data to the ≈2.5 million single nucleotide polymorphisms (SNPs) in HapMap. Linear and logistic regression models were used to test each SNP for association with ABI and PAD using additive genetic models. Study-specific data were combined using fixed effects inverse variance weighted meta-analyses. There were a total of 41 692 participants of European ancestry (≈60% women, mean ABI 1.02 to 1.19), including 3409 participants with PAD and with genome-wide association study data available. In the discovery meta-analysis, rs10757269 on chromosome 9 near CDKN2B had the strongest association with ABI (β=-0.006, P=2.46×10(-8)). We sought replication of the 6 strongest SNP associations in 5 population-based studies and 3 clinical samples (n=16 717). The association for rs10757269 strengthened in the combined discovery and replication analysis (P=2.65×10(-9)). No other SNP associations for ABI or PAD achieved genome-wide significance. However, 2 previously reported candidate genes for PAD and 1 SNP associated with coronary artery disease were associated with ABI: DAB21P (rs13290547, P=3.6×10(-5)), CYBA (rs3794624, P=6.3×10(-5)), and rs1122608 (LDLR, P=0.0026).

CONCLUSIONS: Genome-wide association studies in more than 40 000 individuals identified 1 genome wide significant association on chromosome 9p21 with ABI. Two candidate genes for PAD and 1 SNP for coronary artery disease are associated with ABI.

%B Circ Cardiovasc Genet %V 5 %P 100-12 %8 2012 Feb 01 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/22199011?dopt=Abstract %R 10.1161/CIRCGENETICS.111.961292 %0 Journal Article %J Circ Cardiovasc Genet %D 2012 %T Associations between incident ischemic stroke events and stroke and cardiovascular disease-related genome-wide association studies single nucleotide polymorphisms in the Population Architecture Using Genomics and Epidemiology study. %A Carty, Cara L %A Bůzková, Petra %A Fornage, Myriam %A Franceschini, Nora %A Cole, Shelley %A Heiss, Gerardo %A Hindorff, Lucia A %A Howard, Barbara V %A Mann, Sue %A Martin, Lisa W %A Zhang, Ying %A Matise, Tara C %A Prentice, Ross %A Reiner, Alexander P %A Kooperberg, Charles %K Aged %K Aged, 80 and over %K Cardiovascular Diseases %K Cholesterol, HDL %K Cholesterol, LDL %K European Continental Ancestry Group %K Female %K Genetics, Population %K Genome-Wide Association Study %K Genomics %K Humans %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Risk Factors %K Stroke %K Triglycerides %X

BACKGROUND: Genome-wide association studies (GWAS) have identified loci associated with ischemic stroke (IS) and cardiovascular disease (CVD) in European-descent individuals, but their replication in different populations has been largely unexplored.

METHODS AND RESULTS: Nine single nucleotide polymorphisms (SNPs) selected from GWAS and meta-analyses of stroke, and 86 SNPs previously associated with myocardial infarction and CVD risk factors, including blood lipids (high density lipoprotein [HDL], low density lipoprotein [LDL], and triglycerides), type 2 diabetes, and body mass index (BMI), were investigated for associations with incident IS in European Americans (EA) N=26 276, African-Americans (AA) N=8970, and American Indians (AI) N=3570 from the Population Architecture using Genomics and Epidemiology Study. Ancestry-specific fixed effects meta-analysis with inverse variance weighting was used to combine study-specific log hazard ratios from Cox proportional hazards models. Two of 9 stroke SNPs (rs783396 and rs1804689) were significantly associated with [corrected] IS hazard in AA; none were significant in this large EA cohort. Of 73 CVD risk factor SNPs tested in EA, 2 (HDL and triglycerides SNPs) were associated with IS. In AA, SNPs associated with LDL, HDL, and BMI were significantly associated with IS (3 of 86 SNPs tested). Out of 58 SNPs tested in AI, 1 LDL SNP was significantly associated with IS.

CONCLUSIONS: Our analyses showing lack of replication in spite of reasonable power for many stroke SNPs and differing results by ancestry highlight the need to follow up on GWAS findings and conduct genetic association studies in diverse populations. We found modest IS associations with BMI and lipids SNPs, though these findings require confirmation.

%B Circ Cardiovasc Genet %V 5 %P 210-6 %8 2012 Apr 01 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/22403240?dopt=Abstract %R 10.1161/CIRCGENETICS.111.962191 %0 Journal Article %J Diabetes %D 2012 %T Consistent directions of effect for established type 2 diabetes risk variants across populations: the population architecture using Genomics and Epidemiology (PAGE) Consortium. %A Haiman, Christopher A %A Fesinmeyer, Megan D %A Spencer, Kylee L %A Bůzková, Petra %A Voruganti, V Saroja %A Wan, Peggy %A Haessler, Jeff %A Franceschini, Nora %A Monroe, Kristine R %A Howard, Barbara V %A Jackson, Rebecca D %A Florez, Jose C %A Kolonel, Laurence N %A Buyske, Steven %A Goodloe, Robert J %A Liu, Simin %A Manson, JoAnn E %A Meigs, James B %A Waters, Kevin %A Mukamal, Kenneth J %A Pendergrass, Sarah A %A Shrader, Peter %A Wilkens, Lynne R %A Hindorff, Lucia A %A Ambite, Jose Luis %A North, Kari E %A Peters, Ulrike %A Crawford, Dana C %A Le Marchand, Loïc %A Pankow, James S %K Adult %K Aged %K Aged, 80 and over %K Alleles %K Diabetes Mellitus, Type 2 %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genotype %K Humans %K Male %K Metagenomics %K Middle Aged %K Population Groups %K Risk %K Risk Factors %X

Common genetic risk variants for type 2 diabetes (T2D) have primarily been identified in populations of European and Asian ancestry. We tested whether the direction of association with 20 T2D risk variants generalizes across six major racial/ethnic groups in the U.S. as part of the Population Architecture using Genomics and Epidemiology Consortium (16,235 diabetes case and 46,122 control subjects of European American, African American, Hispanic, East Asian, American Indian, and Native Hawaiian ancestry). The percentage of positive (odds ratio [OR] >1 for putative risk allele) associations ranged from 69% in American Indians to 100% in European Americans. Of the nine variants where we observed significant heterogeneity of effect by racial/ethnic group (P(heterogeneity) < 0.05), eight were positively associated with risk (OR >1) in at least five groups. The marked directional consistency of association observed for most genetic variants across populations implies a shared functional common variant in each region. Fine-mapping of all loci will be required to reveal markers of risk that are important within and across populations.

%B Diabetes %V 61 %P 1642-7 %8 2012 Jun %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/22474029?dopt=Abstract %R 10.2337/db11-1296 %0 Journal Article %J Eur Heart J %D 2012 %T Eight genetic loci associated with variation in lipoprotein-associated phospholipase A2 mass and activity and coronary heart disease: meta-analysis of genome-wide association studies from five community-based studies. %A Grallert, Harald %A Dupuis, Josée %A Bis, Joshua C %A Dehghan, Abbas %A Barbalic, Maja %A Baumert, Jens %A Lu, Chen %A Smith, Nicholas L %A Uitterlinden, André G %A Roberts, Robert %A Khuseyinova, Natalie %A Schnabel, Renate B %A Rice, Kenneth M %A Rivadeneira, Fernando %A Hoogeveen, Ron C %A Fontes, João Daniel %A Meisinger, Christa %A Keaney, John F %A Lemaitre, Rozenn %A Aulchenko, Yurii S %A Vasan, Ramachandran S %A Ellis, Stephen %A Hazen, Stanley L %A van Duijn, Cornelia M %A Nelson, Jeanenne J %A März, Winfried %A Schunkert, Heribert %A McPherson, Ruth M %A Stirnadel-Farrant, Heide A %A Psaty, Bruce M %A Gieger, Christian %A Siscovick, David %A Hofman, Albert %A Illig, Thomas %A Cushman, Mary %A Yamamoto, Jennifer F %A Rotter, Jerome I %A Larson, Martin G %A Stewart, Alexandre F R %A Boerwinkle, Eric %A Witteman, Jacqueline C M %A Tracy, Russell P %A Koenig, Wolfgang %A Benjamin, Emelia J %A Ballantyne, Christie M %K 1-Alkyl-2-acetylglycerophosphocholine Esterase %K Aged %K Coronary Artery Disease %K Coronary Disease %K Female %K Genetic Loci %K Genome-Wide Association Study %K Humans %K Male %K Middle Aged %K Phospholipases A2 %K Polymorphism, Single Nucleotide %X

AIMS: Lipoprotein-associated phospholipase A2 (Lp-PLA2) generates proinflammatory and proatherogenic compounds in the arterial vascular wall and is a potential therapeutic target in coronary heart disease (CHD). We searched for genetic loci related to Lp-PLA2 mass or activity by a genome-wide association study as part of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium.

METHODS AND RESULTS: In meta-analyses of findings from five population-based studies, comprising 13 664 subjects, variants at two loci (PLA2G7, CETP) were associated with Lp-PLA2 mass. The strongest signal was at rs1805017 in PLA2G7 [P = 2.4 × 10(-23), log Lp-PLA2 difference per allele (beta): 0.043]. Variants at six loci were associated with Lp-PLA2 activity (PLA2G7, APOC1, CELSR2, LDL, ZNF259, SCARB1), among which the strongest signals were at rs4420638, near the APOE-APOC1-APOC4-APOC2 cluster [P = 4.9 × 10(-30); log Lp-PLA2 difference per allele (beta): -0.054]. There were no significant gene-environment interactions between these eight polymorphisms associated with Lp-PLA2 mass or activity and age, sex, body mass index, or smoking status. Four of the polymorphisms (in APOC1, CELSR2, SCARB1, ZNF259), but not PLA2G7, were significantly associated with CHD in a second study.

CONCLUSION: Levels of Lp-PLA2 mass and activity were associated with PLA2G7, the gene coding for this protein. Lipoprotein-associated phospholipase A2 activity was also strongly associated with genetic variants related to low-density lipoprotein cholesterol levels.

%B Eur Heart J %V 33 %P 238-51 %8 2012 Jan %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/22003152?dopt=Abstract %R 10.1093/eurheartj/ehr372 %0 Journal Article %J PLoS One %D 2012 %T Evaluation of the metabochip genotyping array in African Americans and implications for fine mapping of GWAS-identified loci: the PAGE study. %A Buyske, Steven %A Wu, Ying %A Carty, Cara L %A Cheng, Iona %A Assimes, Themistocles L %A Dumitrescu, Logan %A Hindorff, Lucia A %A Mitchell, Sabrina %A Ambite, Jose Luis %A Boerwinkle, Eric %A Bůzková, Petra %A Carlson, Chris S %A Cochran, Barbara %A Duggan, David %A Eaton, Charles B %A Fesinmeyer, Megan D %A Franceschini, Nora %A Haessler, Jeffrey %A Jenny, Nancy %A Kang, Hyun Min %A Kooperberg, Charles %A Lin, Yi %A Le Marchand, Loïc %A Matise, Tara C %A Robinson, Jennifer G %A Rodriguez, Carlos %A Schumacher, Fredrick R %A Voight, Benjamin F %A Young, Alicia %A Manolio, Teri A %A Mohlke, Karen L %A Haiman, Christopher A %A Peters, Ulrike %A Crawford, Dana C %A North, Kari E %K African Americans %K Cardiovascular Diseases %K Cholesterol Ester Transfer Proteins %K Cholesterol, HDL %K Cholesterol, LDL %K Chromosomes, Human %K Cohort Studies %K Gene Frequency %K Genome-Wide Association Study %K Genotype %K Humans %K Metabolic Diseases %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %X

The Metabochip is a custom genotyping array designed for replication and fine mapping of metabolic, cardiovascular, and anthropometric trait loci and includes low frequency variation content identified from the 1000 Genomes Project. It has 196,725 SNPs concentrated in 257 genomic regions. We evaluated the Metabochip in 5,863 African Americans; 89% of all SNPs passed rigorous quality control with a call rate of 99.9%. Two examples illustrate the value of fine mapping with the Metabochip in African-ancestry populations. At CELSR2/PSRC1/SORT1, we found the strongest associated SNP for LDL-C to be rs12740374 (p = 3.5 × 10(-11)), a SNP indistinguishable from multiple SNPs in European ancestry samples due to high correlation. Its distinct signal supports functional studies elsewhere suggesting a causal role in LDL-C. At CETP we found rs17231520, with risk allele frequency 0.07 in African Americans, to be associated with HDL-C (p = 7.2 × 10(-36)). This variant is very rare in Europeans and not tagged in common GWAS arrays, but was identified as associated with HDL-C in African Americans in a single-gene study. Our results, one narrowing the risk interval and the other revealing an associated variant not found in Europeans, demonstrate the advantages of high-density genotyping of common and rare variation for fine mapping of trait loci in African American samples.

%B PLoS One %V 7 %P e35651 %8 2012 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/22539988?dopt=Abstract %R 10.1371/journal.pone.0035651 %0 Journal Article %J PLoS Genet %D 2012 %T Fine-mapping and initial characterization of QT interval loci in African Americans. %A Avery, Christy L %A Sethupathy, Praveen %A Buyske, Steven %A He, Qianchuan %A Lin, Dan-Yu %A Arking, Dan E %A Carty, Cara L %A Duggan, David %A Fesinmeyer, Megan D %A Hindorff, Lucia A %A Jeff, Janina M %A Klein, Liviu %A Patton, Kristen K %A Peters, Ulrike %A Shohet, Ralph V %A Sotoodehnia, Nona %A Young, Alicia M %A Kooperberg, Charles %A Haiman, Christopher A %A Mohlke, Karen L %A Whitsel, Eric A %A North, Kari E %K African Americans %K Aged %K Computational Biology %K Electrocardiography %K European Continental Ancestry Group %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Linkage Disequilibrium %K Male %K Metagenomics %K Middle Aged %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %K Quantitative Trait, Heritable %K Risk Factors %K Tachycardia %K United States %X

The QT interval (QT) is heritable and its prolongation is a risk factor for ventricular tachyarrhythmias and sudden death. Most genetic studies of QT have examined European ancestral populations; however, the increased genetic diversity in African Americans provides opportunities to narrow association signals and identify population-specific variants. We therefore evaluated 6,670 SNPs spanning eleven previously identified QT loci in 8,644 African American participants from two Population Architecture using Genomics and Epidemiology (PAGE) studies: the Atherosclerosis Risk in Communities study and Women's Health Initiative Clinical Trial. Of the fifteen known independent QT variants at the eleven previously identified loci, six were significantly associated with QT in African American populations (P≤1.20×10(-4)): ATP1B1, PLN1, KCNQ1, NDRG4, and two NOS1AP independent signals. We also identified three population-specific signals significantly associated with QT in African Americans (P≤1.37×10(-5)): one at NOS1AP and two at ATP1B1. Linkage disequilibrium (LD) patterns in African Americans assisted in narrowing the region likely to contain the functional variants for several loci. For example, African American LD patterns showed that 0 SNPs were in LD with NOS1AP signal rs12143842, compared with European LD patterns that indicated 87 SNPs, which spanned 114.2 Kb, were in LD with rs12143842. Finally, bioinformatic-based characterization of the nine African American signals pointed to functional candidates located exclusively within non-coding regions, including predicted binding sites for transcription factors such as TBX5, which has been implicated in cardiac structure and conductance. In this detailed evaluation of QT loci, we identified several African Americans SNPs that better define the association with QT and successfully narrowed intervals surrounding established loci. These results demonstrate that the same loci influence variation in QT across multiple populations, that novel signals exist in African Americans, and that the SNPs identified as strong candidates for functional evaluation implicate gene regulatory dysfunction in QT prolongation.

%B PLoS Genet %V 8 %P e1002870 %8 2012 %G eng %N 8 %1 http://www.ncbi.nlm.nih.gov/pubmed/22912591?dopt=Abstract %R 10.1371/journal.pgen.1002870 %0 Journal Article %J Nature %D 2012 %T FTO genotype is associated with phenotypic variability of body mass index. %A Yang, Jian %A Loos, Ruth J F %A Powell, Joseph E %A Medland, Sarah E %A Speliotes, Elizabeth K %A Chasman, Daniel I %A Rose, Lynda M %A Thorleifsson, Gudmar %A Steinthorsdottir, Valgerdur %A Mägi, Reedik %A Waite, Lindsay %A Smith, Albert Vernon %A Yerges-Armstrong, Laura M %A Monda, Keri L %A Hadley, David %A Mahajan, Anubha %A Li, Guo %A Kapur, Karen %A Vitart, Veronique %A Huffman, Jennifer E %A Wang, Sophie R %A Palmer, Cameron %A Esko, Tõnu %A Fischer, Krista %A Zhao, Jing Hua %A Demirkan, Ayse %A Isaacs, Aaron %A Feitosa, Mary F %A Luan, Jian'an %A Heard-Costa, Nancy L %A White, Charles %A Jackson, Anne U %A Preuss, Michael %A Ziegler, Andreas %A Eriksson, Joel %A Kutalik, Zoltán %A Frau, Francesca %A Nolte, Ilja M %A van Vliet-Ostaptchouk, Jana V %A Hottenga, Jouke-Jan %A Jacobs, Kevin B %A Verweij, Niek %A Goel, Anuj %A Medina-Gómez, Carolina %A Estrada, Karol %A Bragg-Gresham, Jennifer Lynn %A Sanna, Serena %A Sidore, Carlo %A Tyrer, Jonathan %A Teumer, Alexander %A Prokopenko, Inga %A Mangino, Massimo %A Lindgren, Cecilia M %A Assimes, Themistocles L %A Shuldiner, Alan R %A Hui, Jennie %A Beilby, John P %A McArdle, Wendy L %A Hall, Per %A Haritunians, Talin %A Zgaga, Lina %A Kolcic, Ivana %A Polasek, Ozren %A Zemunik, Tatijana %A Oostra, Ben A %A Junttila, M Juhani %A Grönberg, Henrik %A Schreiber, Stefan %A Peters, Annette %A Hicks, Andrew A %A Stephens, Jonathan %A Foad, Nicola S %A Laitinen, Jaana %A Pouta, Anneli %A Kaakinen, Marika %A Willemsen, Gonneke %A Vink, Jacqueline M %A Wild, Sarah H %A Navis, Gerjan %A Asselbergs, Folkert W %A Homuth, Georg %A John, Ulrich %A Iribarren, Carlos %A Harris, Tamara %A Launer, Lenore %A Gudnason, Vilmundur %A O'Connell, Jeffrey R %A Boerwinkle, Eric %A Cadby, Gemma %A Palmer, Lyle J %A James, Alan L %A Musk, Arthur W %A Ingelsson, Erik %A Psaty, Bruce M %A Beckmann, Jacques S %A Waeber, Gérard %A Vollenweider, Peter %A Hayward, Caroline %A Wright, Alan F %A Rudan, Igor %A Groop, Leif C %A Metspalu, Andres %A Khaw, Kay Tee %A van Duijn, Cornelia M %A Borecki, Ingrid B %A Province, Michael A %A Wareham, Nicholas J %A Tardif, Jean-Claude %A Huikuri, Heikki V %A Cupples, L Adrienne %A Atwood, Larry D %A Fox, Caroline S %A Boehnke, Michael %A Collins, Francis S %A Mohlke, Karen L %A Erdmann, Jeanette %A Schunkert, Heribert %A Hengstenberg, Christian %A Stark, Klaus %A Lorentzon, Mattias %A Ohlsson, Claes %A Cusi, Daniele %A Staessen, Jan A %A van der Klauw, Melanie M %A Pramstaller, Peter P %A Kathiresan, Sekar %A Jolley, Jennifer D %A Ripatti, Samuli %A Jarvelin, Marjo-Riitta %A de Geus, Eco J C %A Boomsma, Dorret I %A Penninx, Brenda %A Wilson, James F %A Campbell, Harry %A Chanock, Stephen J %A van der Harst, Pim %A Hamsten, Anders %A Watkins, Hugh %A Hofman, Albert %A Witteman, Jacqueline C %A Zillikens, M Carola %A Uitterlinden, André G %A Rivadeneira, Fernando %A Zillikens, M Carola %A Kiemeney, Lambertus A %A Vermeulen, Sita H %A Abecasis, Goncalo R %A Schlessinger, David %A Schipf, Sabine %A Stumvoll, Michael %A Tönjes, Anke %A Spector, Tim D %A North, Kari E %A Lettre, Guillaume %A McCarthy, Mark I %A Berndt, Sonja I %A Heath, Andrew C %A Madden, Pamela A F %A Nyholt, Dale R %A Montgomery, Grant W %A Martin, Nicholas G %A McKnight, Barbara %A Strachan, David P %A Hill, William G %A Snieder, Harold %A Ridker, Paul M %A Thorsteinsdottir, Unnur %A Stefansson, Kari %A Frayling, Timothy M %A Hirschhorn, Joel N %A Goddard, Michael E %A Visscher, Peter M %K Alpha-Ketoglutarate-Dependent Dioxygenase FTO %K Body Height %K Body Mass Index %K Co-Repressor Proteins %K Female %K Genetic Variation %K Genome-Wide Association Study %K Humans %K Male %K Nerve Tissue Proteins %K Phenotype %K Polymorphism, Single Nucleotide %K Proteins %K Repressor Proteins %X

There is evidence across several species for genetic control of phenotypic variation of complex traits, such that the variance among phenotypes is genotype dependent. Understanding genetic control of variability is important in evolutionary biology, agricultural selection programmes and human medicine, yet for complex traits, no individual genetic variants associated with variance, as opposed to the mean, have been identified. Here we perform a meta-analysis of genome-wide association studies of phenotypic variation using ∼170,000 samples on height and body mass index (BMI) in human populations. We report evidence that the single nucleotide polymorphism (SNP) rs7202116 at the FTO gene locus, which is known to be associated with obesity (as measured by mean BMI for each rs7202116 genotype), is also associated with phenotypic variability. We show that the results are not due to scale effects or other artefacts, and find no other experiment-wise significant evidence for effects on variability, either at loci other than FTO for BMI or at any locus for height. The difference in variance for BMI among individuals with opposite homozygous genotypes at the FTO locus is approximately 7%, corresponding to a difference of ∼0.5 kilograms in the standard deviation of weight. Our results indicate that genetic variants can be discovered that are associated with variability, and that between-person variability in obesity can partly be explained by the genotype at the FTO locus. The results are consistent with reported FTO by environment interactions for BMI, possibly mediated by DNA methylation. Our BMI results for other SNPs and our height results for all SNPs suggest that most genetic variants, including those that influence mean height or mean BMI, are not associated with phenotypic variance, or that their effects on variability are too small to detect even with samples sizes greater than 100,000.

%B Nature %V 490 %P 267-72 %8 2012 Oct 11 %G eng %N 7419 %1 http://www.ncbi.nlm.nih.gov/pubmed/22982992?dopt=Abstract %R 10.1038/nature11401 %0 Journal Article %J Lancet Neurol %D 2012 %T Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE collaboration): a meta-analysis of genome-wide association studies. %A Traylor, Matthew %A Farrall, Martin %A Holliday, Elizabeth G %A Sudlow, Cathie %A Hopewell, Jemma C %A Cheng, Yu-Ching %A Fornage, Myriam %A Ikram, M Arfan %A Malik, Rainer %A Bevan, Steve %A Thorsteinsdottir, Unnur %A Nalls, Mike A %A Longstreth, Wt %A Wiggins, Kerri L %A Yadav, Sunaina %A Parati, Eugenio A %A DeStefano, Anita L %A Worrall, Bradford B %A Kittner, Steven J %A Khan, Muhammad Saleem %A Reiner, Alex P %A Helgadottir, Anna %A Achterberg, Sefanja %A Fernandez-Cadenas, Israel %A Abboud, Sherine %A Schmidt, Reinhold %A Walters, Matthew %A Chen, Wei-Min %A Ringelstein, E Bernd %A O'Donnell, Martin %A Ho, Weang Kee %A Pera, Joanna %A Lemmens, Robin %A Norrving, Bo %A Higgins, Peter %A Benn, Marianne %A Sale, Michele %A Kuhlenbäumer, Gregor %A Doney, Alexander S F %A Vicente, Astrid M %A Delavaran, Hossein %A Algra, Ale %A Davies, Gail %A Oliveira, Sofia A %A Palmer, Colin N A %A Deary, Ian %A Schmidt, Helena %A Pandolfo, Massimo %A Montaner, Joan %A Carty, Cara %A de Bakker, Paul I W %A Kostulas, Konstantinos %A Ferro, Jose M %A van Zuydam, Natalie R %A Valdimarsson, Einar %A Nordestgaard, Børge G %A Lindgren, Arne %A Thijs, Vincent %A Slowik, Agnieszka %A Saleheen, Danish %A Paré, Guillaume %A Berger, Klaus %A Thorleifsson, Gudmar %A Hofman, Albert %A Mosley, Thomas H %A Mitchell, Braxton D %A Furie, Karen %A Clarke, Robert %A Levi, Christopher %A Seshadri, Sudha %A Gschwendtner, Andreas %A Boncoraglio, Giorgio B %A Sharma, Pankaj %A Bis, Joshua C %A Gretarsdottir, Solveig %A Psaty, Bruce M %A Rothwell, Peter M %A Rosand, Jonathan %A Meschia, James F %A Stefansson, Kari %A Dichgans, Martin %A Markus, Hugh S %K Brain Ischemia %K Databases, Genetic %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Risk Factors %K Stroke %X

BACKGROUND: Various genome-wide association studies (GWAS) have been done in ischaemic stroke, identifying a few loci associated with the disease, but sample sizes have been 3500 cases or less. We established the METASTROKE collaboration with the aim of validating associations from previous GWAS and identifying novel genetic associations through meta-analysis of GWAS datasets for ischaemic stroke and its subtypes.

METHODS: We meta-analysed data from 15 ischaemic stroke cohorts with a total of 12 389 individuals with ischaemic stroke and 62 004 controls, all of European ancestry. For the associations reaching genome-wide significance in METASTROKE, we did a further analysis, conditioning on the lead single nucleotide polymorphism in every associated region. Replication of novel suggestive signals was done in 13 347 cases and 29 083 controls.

FINDINGS: We verified previous associations for cardioembolic stroke near PITX2 (p=2·8×10(-16)) and ZFHX3 (p=2·28×10(-8)), and for large-vessel stroke at a 9p21 locus (p=3·32×10(-5)) and HDAC9 (p=2·03×10(-12)). Additionally, we verified that all associations were subtype specific. Conditional analysis in the three regions for which the associations reached genome-wide significance (PITX2, ZFHX3, and HDAC9) indicated that all the signal in each region could be attributed to one risk haplotype. We also identified 12 potentially novel loci at p<5×10(-6). However, we were unable to replicate any of these novel associations in the replication cohort.

INTERPRETATION: Our results show that, although genetic variants can be detected in patients with ischaemic stroke when compared with controls, all associations we were able to confirm are specific to a stroke subtype. This finding has two implications. First, to maximise success of genetic studies in ischaemic stroke, detailed stroke subtyping is required. Second, different genetic pathophysiological mechanisms seem to be associated with different stroke subtypes.

FUNDING: Wellcome Trust, UK Medical Research Council (MRC), Australian National and Medical Health Research Council, National Institutes of Health (NIH) including National Heart, Lung and Blood Institute (NHLBI), the National Institute on Aging (NIA), the National Human Genome Research Institute (NHGRI), and the National Institute of Neurological Disorders and Stroke (NINDS).

%B Lancet Neurol %V 11 %P 951-62 %8 2012 Nov %G eng %N 11 %1 http://www.ncbi.nlm.nih.gov/pubmed/23041239?dopt=Abstract %R 10.1016/S1474-4422(12)70234-X %0 Journal Article %J PLoS Genet %D 2012 %T Genome-wide association and functional follow-up reveals new loci for kidney function. %A Pattaro, Cristian %A Köttgen, Anna %A Teumer, Alexander %A Garnaas, Maija %A Böger, Carsten A %A Fuchsberger, Christian %A Olden, Matthias %A Chen, Ming-Huei %A Tin, Adrienne %A Taliun, Daniel %A Li, Man %A Gao, Xiaoyi %A Gorski, Mathias %A Yang, Qiong %A Hundertmark, Claudia %A Foster, Meredith C %A O'Seaghdha, Conall M %A Glazer, Nicole %A Isaacs, Aaron %A Liu, Ching-Ti %A Smith, Albert V %A O'Connell, Jeffrey R %A Struchalin, Maksim %A Tanaka, Toshiko %A Li, Guo %A Johnson, Andrew D %A Gierman, Hinco J %A Feitosa, Mary %A Hwang, Shih-Jen %A Atkinson, Elizabeth J %A Lohman, Kurt %A Cornelis, Marilyn C %A Johansson, Asa %A Tönjes, Anke %A Dehghan, Abbas %A Chouraki, Vincent %A Holliday, Elizabeth G %A Sorice, Rossella %A Kutalik, Zoltán %A Lehtimäki, Terho %A Esko, Tõnu %A Deshmukh, Harshal %A Ulivi, Sheila %A Chu, Audrey Y %A Murgia, Federico %A Trompet, Stella %A Imboden, Medea %A Kollerits, Barbara %A Pistis, Giorgio %A Harris, Tamara B %A Launer, Lenore J %A Aspelund, Thor %A Eiriksdottir, Gudny %A Mitchell, Braxton D %A Boerwinkle, Eric %A Schmidt, Helena %A Cavalieri, Margherita %A Rao, Madhumathi %A Hu, Frank B %A Demirkan, Ayse %A Oostra, Ben A %A de Andrade, Mariza %A Turner, Stephen T %A Ding, Jingzhong %A Andrews, Jeanette S %A Freedman, Barry I %A Koenig, Wolfgang %A Illig, Thomas %A Döring, Angela %A Wichmann, H-Erich %A Kolcic, Ivana %A Zemunik, Tatijana %A Boban, Mladen %A Minelli, Cosetta %A Wheeler, Heather E %A Igl, Wilmar %A Zaboli, Ghazal %A Wild, Sarah H %A Wright, Alan F %A Campbell, Harry %A Ellinghaus, David %A Nöthlings, Ute %A Jacobs, Gunnar %A Biffar, Reiner %A Endlich, Karlhans %A Ernst, Florian %A Homuth, Georg %A Kroemer, Heyo K %A Nauck, Matthias %A Stracke, Sylvia %A Völker, Uwe %A Völzke, Henry %A Kovacs, Peter %A Stumvoll, Michael %A Mägi, Reedik %A Hofman, Albert %A Uitterlinden, André G %A Rivadeneira, Fernando %A Aulchenko, Yurii S %A Polasek, Ozren %A Hastie, Nick %A Vitart, Veronique %A Helmer, Catherine %A Wang, Jie Jin %A Ruggiero, Daniela %A Bergmann, Sven %A Kähönen, Mika %A Viikari, Jorma %A Nikopensius, Tiit %A Province, Michael %A Ketkar, Shamika %A Colhoun, Helen %A Doney, Alex %A Robino, Antonietta %A Giulianini, Franco %A Krämer, Bernhard K %A Portas, Laura %A Ford, Ian %A Buckley, Brendan M %A Adam, Martin %A Thun, Gian-Andri %A Paulweber, Bernhard %A Haun, Margot %A Sala, Cinzia %A Metzger, Marie %A Mitchell, Paul %A Ciullo, Marina %A Kim, Stuart K %A Vollenweider, Peter %A Raitakari, Olli %A Metspalu, Andres %A Palmer, Colin %A Gasparini, Paolo %A Pirastu, Mario %A Jukema, J Wouter %A Probst-Hensch, Nicole M %A Kronenberg, Florian %A Toniolo, Daniela %A Gudnason, Vilmundur %A Shuldiner, Alan R %A Coresh, Josef %A Schmidt, Reinhold %A Ferrucci, Luigi %A Siscovick, David S %A van Duijn, Cornelia M %A Borecki, Ingrid %A Kardia, Sharon L R %A Liu, Yongmei %A Curhan, Gary C %A Rudan, Igor %A Gyllensten, Ulf %A Wilson, James F %A Franke, Andre %A Pramstaller, Peter P %A Rettig, Rainer %A Prokopenko, Inga %A Witteman, Jacqueline C M %A Hayward, Caroline %A Ridker, Paul %A Parsa, Afshin %A Bochud, Murielle %A Heid, Iris M %A Goessling, Wolfram %A Chasman, Daniel I %A Kao, W H Linda %A Fox, Caroline S %K African Americans %K Aged %K Animals %K Caspase 9 %K Cyclin-Dependent Kinases %K DEAD-box RNA Helicases %K DNA Helicases %K European Continental Ancestry Group %K Female %K Follow-Up Studies %K Gene Knockdown Techniques %K Genome-Wide Association Study %K Glomerular Filtration Rate %K Humans %K Kidney %K Kidney Failure, Chronic %K Male %K Middle Aged %K Phosphoric Diester Hydrolases %K Zebrafish %X

Chronic kidney disease (CKD) is an important public health problem with a genetic component. We performed genome-wide association studies in up to 130,600 European ancestry participants overall, and stratified for key CKD risk factors. We uncovered 6 new loci in association with estimated glomerular filtration rate (eGFR), the primary clinical measure of CKD, in or near MPPED2, DDX1, SLC47A1, CDK12, CASP9, and INO80. Morpholino knockdown of mpped2 and casp9 in zebrafish embryos revealed podocyte and tubular abnormalities with altered dextran clearance, suggesting a role for these genes in renal function. By providing new insights into genes that regulate renal function, these results could further our understanding of the pathogenesis of CKD.

%B PLoS Genet %V 8 %P e1002584 %8 2012 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/22479191?dopt=Abstract %R 10.1371/journal.pgen.1002584 %0 Journal Article %J Am J Respir Crit Care Med %D 2012 %T Genome-wide association studies identify CHRNA5/3 and HTR4 in the development of airflow obstruction. %A Wilk, Jemma B %A Shrine, Nick R G %A Loehr, Laura R %A Zhao, Jing Hua %A Manichaikul, Ani %A Lopez, Lorna M %A Smith, Albert Vernon %A Heckbert, Susan R %A Smolonska, Joanna %A Tang, Wenbo %A Loth, Daan W %A Curjuric, Ivan %A Hui, Jennie %A Cho, Michael H %A Latourelle, Jeanne C %A Henry, Amanda P %A Aldrich, Melinda %A Bakke, Per %A Beaty, Terri H %A Bentley, Amy R %A Borecki, Ingrid B %A Brusselle, Guy G %A Burkart, Kristin M %A Chen, Ting-Hsu %A Couper, David %A Crapo, James D %A Davies, Gail %A Dupuis, Josée %A Franceschini, Nora %A Gulsvik, Amund %A Hancock, Dana B %A Harris, Tamara B %A Hofman, Albert %A Imboden, Medea %A James, Alan L %A Khaw, Kay-Tee %A Lahousse, Lies %A Launer, Lenore J %A Litonjua, Augusto %A Liu, Yongmei %A Lohman, Kurt K %A Lomas, David A %A Lumley, Thomas %A Marciante, Kristin D %A McArdle, Wendy L %A Meibohm, Bernd %A Morrison, Alanna C %A Musk, Arthur W %A Myers, Richard H %A North, Kari E %A Postma, Dirkje S %A Psaty, Bruce M %A Rich, Stephen S %A Rivadeneira, Fernando %A Rochat, Thierry %A Rotter, Jerome I %A Soler Artigas, Maria %A Starr, John M %A Uitterlinden, André G %A Wareham, Nicholas J %A Wijmenga, Cisca %A Zanen, Pieter %A Province, Michael A %A Silverman, Edwin K %A Deary, Ian J %A Palmer, Lyle J %A Cassano, Patricia A %A Gudnason, Vilmundur %A Barr, R Graham %A Loos, Ruth J F %A Strachan, David P %A London, Stephanie J %A Boezen, H Marike %A Probst-Hensch, Nicole %A Gharib, Sina A %A Hall, Ian P %A O'Connor, George T %A Tobin, Martin D %A Stricker, Bruno H %K Aged %K Female %K Forced Expiratory Volume %K Genome-Wide Association Study %K Humans %K Male %K Middle Aged %K Nerve Tissue Proteins %K Polymorphism, Single Nucleotide %K Pulmonary Disease, Chronic Obstructive %K Receptors, Nicotinic %K Receptors, Serotonin, 5-HT4 %K Smoking %K Vital Capacity %X

RATIONALE: Genome-wide association studies (GWAS) have identified loci influencing lung function, but fewer genes influencing chronic obstructive pulmonary disease (COPD) are known.

OBJECTIVES: Perform meta-analyses of GWAS for airflow obstruction, a key pathophysiologic characteristic of COPD assessed by spirometry, in population-based cohorts examining all participants, ever smokers, never smokers, asthma-free participants, and more severe cases.

METHODS: Fifteen cohorts were studied for discovery (3,368 affected; 29,507 unaffected), and a population-based family study and a meta-analysis of case-control studies were used for replication and regional follow-up (3,837 cases; 4,479 control subjects). Airflow obstruction was defined as FEV(1) and its ratio to FVC (FEV(1)/FVC) both less than their respective lower limits of normal as determined by published reference equations.

MEASUREMENTS AND MAIN RESULTS: The discovery meta-analyses identified one region on chromosome 15q25.1 meeting genome-wide significance in ever smokers that includes AGPHD1, IREB2, and CHRNA5/CHRNA3 genes. The region was also modestly associated among never smokers. Gene expression studies confirmed the presence of CHRNA5/3 in lung, airway smooth muscle, and bronchial epithelial cells. A single-nucleotide polymorphism in HTR4, a gene previously related to FEV(1)/FVC, achieved genome-wide statistical significance in combined meta-analysis. Top single-nucleotide polymorphisms in ADAM19, RARB, PPAP2B, and ADAMTS19 were nominally replicated in the COPD meta-analysis.

CONCLUSIONS: These results suggest an important role for the CHRNA5/3 region as a genetic risk factor for airflow obstruction that may be independent of smoking and implicate the HTR4 gene in the etiology of airflow obstruction.

%B Am J Respir Crit Care Med %V 186 %P 622-32 %8 2012 Oct 01 %G eng %N 7 %1 http://www.ncbi.nlm.nih.gov/pubmed/22837378?dopt=Abstract %R 10.1164/rccm.201202-0366OC %0 Journal Article %J Blood %D 2012 %T Genome-wide association study for circulating levels of PAI-1 provides novel insights into its regulation. %A Huang, Jie %A Sabater-Lleal, Maria %A Asselbergs, Folkert W %A Tregouet, David %A Shin, So-Youn %A Ding, Jingzhong %A Baumert, Jens %A Oudot-Mellakh, Tiphaine %A Folkersen, Lasse %A Johnson, Andrew D %A Smith, Nicholas L %A Williams, Scott M %A Ikram, Mohammad A %A Kleber, Marcus E %A Becker, Diane M %A Truong, Vinh %A Mychaleckyj, Josyf C %A Tang, Weihong %A Yang, Qiong %A Sennblad, Bengt %A Moore, Jason H %A Williams, Frances M K %A Dehghan, Abbas %A Silbernagel, Günther %A Schrijvers, Elisabeth M C %A Smith, Shelly %A Karakas, Mahir %A Tofler, Geoffrey H %A Silveira, Angela %A Navis, Gerjan J %A Lohman, Kurt %A Chen, Ming-Huei %A Peters, Annette %A Goel, Anuj %A Hopewell, Jemma C %A Chambers, John C %A Saleheen, Danish %A Lundmark, Per %A Psaty, Bruce M %A Strawbridge, Rona J %A Boehm, Bernhard O %A Carter, Angela M %A Meisinger, Christa %A Peden, John F %A Bis, Joshua C %A McKnight, Barbara %A Ohrvik, John %A Taylor, Kent %A Franzosi, Maria Grazia %A Seedorf, Udo %A Collins, Rory %A Franco-Cereceda, Anders %A Syvänen, Ann-Christine %A Goodall, Alison H %A Yanek, Lisa R %A Cushman, Mary %A Müller-Nurasyid, Martina %A Folsom, Aaron R %A Basu, Saonli %A Matijevic, Nena %A van Gilst, Wiek H %A Kooner, Jaspal S %A Hofman, Albert %A Danesh, John %A Clarke, Robert %A Meigs, James B %A Kathiresan, Sekar %A Reilly, Muredach P %A Klopp, Norman %A Harris, Tamara B %A Winkelmann, Bernhard R %A Grant, Peter J %A Hillege, Hans L %A Watkins, Hugh %A Spector, Timothy D %A Becker, Lewis C %A Tracy, Russell P %A März, Winfried %A Uitterlinden, André G %A Eriksson, Per %A Cambien, Francois %A Morange, Pierre-Emmanuel %A Koenig, Wolfgang %A Soranzo, Nicole %A van der Harst, Pim %A Liu, Yongmei %A O'Donnell, Christopher J %A Hamsten, Anders %K Adaptor Proteins, Signal Transducing %K ARNTL Transcription Factors %K ATPases Associated with Diverse Cellular Activities %K Cell Line %K Cell Line, Tumor %K Cohort Studies %K Coronary Artery Disease %K Diabetes Mellitus, Type 2 %K Gene Expression Profiling %K Gene Expression Regulation %K Gene Frequency %K Genome-Wide Association Study %K Genotype %K Humans %K LIM Domain Proteins %K Meta-Analysis as Topic %K Monocytes %K Mucin-3 %K Plasminogen Activator Inhibitor 1 %K Polymorphism, Single Nucleotide %K PPAR gamma %K Proteasome Endopeptidase Complex %K RNA Interference %K Transcription Factors %X

We conducted a genome-wide association study to identify novel associations between genetic variants and circulating plasminogen activator inhibitor-1 (PAI-1) concentration, and examined functional implications of variants and genes that were discovered. A discovery meta-analysis was performed in 19 599 subjects, followed by replication analysis of genome-wide significant (P < 5 × 10(-8)) single nucleotide polymorphisms (SNPs) in 10 796 independent samples. We further examined associations with type 2 diabetes and coronary artery disease, assessed the functional significance of the SNPs for gene expression in human tissues, and conducted RNA-silencing experiments for one novel association. We confirmed the association of the 4G/5G proxy SNP rs2227631 in the promoter region of SERPINE1 (7q22.1) and discovered genome-wide significant associations at 3 additional loci: chromosome 7q22.1 close to SERPINE1 (rs6976053, discovery P = 3.4 × 10(-10)); chromosome 11p15.2 within ARNTL (rs6486122, discovery P = 3.0 × 10(-8)); and chromosome 3p25.2 within PPARG (rs11128603, discovery P = 2.9 × 10(-8)). Replication was achieved for the 7q22.1 and 11p15.2 loci. There was nominal association with type 2 diabetes and coronary artery disease at ARNTL (P < .05). Functional studies identified MUC3 as a candidate gene for the second association signal on 7q22.1. In summary, SNPs in SERPINE1 and ARNTL and an SNP associated with the expression of MUC3 were robustly associated with circulating levels of PAI-1.

%B Blood %V 120 %P 4873-81 %8 2012 Dec 06 %G eng %N 24 %1 http://www.ncbi.nlm.nih.gov/pubmed/22990020?dopt=Abstract %R 10.1182/blood-2012-06-436188 %0 Journal Article %J Hum Mol Genet %D 2012 %T A genome-wide association study identifies a potential novel gene locus for keratoconus, one of the commonest causes for corneal transplantation in developed countries. %A Li, Xiaohui %A Bykhovskaya, Yelena %A Haritunians, Talin %A Siscovick, David %A Aldave, Anthony %A Szczotka-Flynn, Loretta %A Iyengar, Sudha K %A Rotter, Jerome I %A Taylor, Kent D %A Rabinowitz, Yaron S %K Case-Control Studies %K Chromosomes, Human, Pair 2 %K Cohort Studies %K Corneal Transplantation %K Developed Countries %K Genome-Wide Association Study %K Humans %K Keratoconus %K Polymorphism, Single Nucleotide %X

Keratoconus is a condition in which the cornea progressively thins over time, and is a major cause for cornea transplantation. To identify keratoconus susceptibility regions, we performed a comprehensive genome-wide association study (GWAS) using a discovery and replication design. A discovery panel of 222 keratoconus Caucasian patients and 3324 Caucasian controls was genotyped using Illumina 370K beadchips. Further associated and fine-mapping single nucleotide polymorphisms (SNPs) (n= 4905) were genotyped in an independent replication case-control panel of 304 cases and 518 controls and a family panel of 307 subjects in 70 families. Logistic regression models implemented in PLINK were performed to test associations in case-control samples with and without principal component (PC) adjustments. Generalized estimation equation models accounting for familial correlations implemented in GWAF were used for association testing in families. No genome-wide associations were identified in the discovery GWAS panel. From the initial testing without adjustments for PCs, the top three SNPs located at 3p26 (rs6442925), 2q21.3 (rs4954218) and 19q13.3 (rs1428642) were identified with unadjusted P-values of 6.5 × 10(-8), 2.4 × 10(-7) and 3.1 × 10(-7), respectively. After adjustments for PCs, rs1428642 became the most significant through the genome with a P-value of 1.4 × 10(-6), while rs6442925 and rs4954218 were less significant (P= 1.9 × 10(-5) and 2.6 × 10(-4)). SNP rs4954218 was confirmed in two independent replication panels with P-values of 0.004 and 0.009, respectively. Meta-analysis revealed a highest association at rs4954218 with adjusted P= 1.6 × 10(-7) (unadjusted P= 1.2 × 10(-9)). These findings suggest SNP rs4954218, located near the RAB3GAP1 gene, previously reported to be associated with corneal malformation, is a potential susceptibility locus for keratoconus.

%B Hum Mol Genet %V 21 %P 421-9 %8 2012 Jan 15 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/21979947?dopt=Abstract %R 10.1093/hmg/ddr460 %0 Journal Article %J PLoS Genet %D 2012 %T Genome-wide joint meta-analysis of SNP and SNP-by-smoking interaction identifies novel loci for pulmonary function. %A Hancock, Dana B %A Soler Artigas, Maria %A Gharib, Sina A %A Henry, Amanda %A Manichaikul, Ani %A Ramasamy, Adaikalavan %A Loth, Daan W %A Imboden, Medea %A Koch, Beate %A McArdle, Wendy L %A Smith, Albert V %A Smolonska, Joanna %A Sood, Akshay %A Tang, Wenbo %A Wilk, Jemma B %A Zhai, Guangju %A Zhao, Jing Hua %A Aschard, Hugues %A Burkart, Kristin M %A Curjuric, Ivan %A Eijgelsheim, Mark %A Elliott, Paul %A Gu, Xiangjun %A Harris, Tamara B %A Janson, Christer %A Homuth, Georg %A Hysi, Pirro G %A Liu, Jason Z %A Loehr, Laura R %A Lohman, Kurt %A Loos, Ruth J F %A Manning, Alisa K %A Marciante, Kristin D %A Obeidat, Ma'en %A Postma, Dirkje S %A Aldrich, Melinda C %A Brusselle, Guy G %A Chen, Ting-Hsu %A Eiriksdottir, Gudny %A Franceschini, Nora %A Heinrich, Joachim %A Rotter, Jerome I %A Wijmenga, Cisca %A Williams, O Dale %A Bentley, Amy R %A Hofman, Albert %A Laurie, Cathy C %A Lumley, Thomas %A Morrison, Alanna C %A Joubert, Bonnie R %A Rivadeneira, Fernando %A Couper, David J %A Kritchevsky, Stephen B %A Liu, Yongmei %A Wjst, Matthias %A Wain, Louise V %A Vonk, Judith M %A Uitterlinden, André G %A Rochat, Thierry %A Rich, Stephen S %A Psaty, Bruce M %A O'Connor, George T %A North, Kari E %A Mirel, Daniel B %A Meibohm, Bernd %A Launer, Lenore J %A Khaw, Kay-Tee %A Hartikainen, Anna-Liisa %A Hammond, Christopher J %A Gläser, Sven %A Marchini, Jonathan %A Kraft, Peter %A Wareham, Nicholas J %A Völzke, Henry %A Stricker, Bruno H C %A Spector, Timothy D %A Probst-Hensch, Nicole M %A Jarvis, Deborah %A Jarvelin, Marjo-Riitta %A Heckbert, Susan R %A Gudnason, Vilmundur %A Boezen, H Marike %A Barr, R Graham %A Cassano, Patricia A %A Strachan, David P %A Fornage, Myriam %A Hall, Ian P %A Dupuis, Josée %A Tobin, Martin D %A London, Stephanie J %K Forced Expiratory Volume %K Gene Expression %K Genome, Human %K Genome-Wide Association Study %K HLA-DQ Antigens %K HLA-DQ beta-Chains %K Humans %K Lung %K Nerve Tissue Proteins %K Polymorphism, Single Nucleotide %K Potassium Channels, Inwardly Rectifying %K Pulmonary Disease, Chronic Obstructive %K Receptors, Cell Surface %K Smoking %K SOX9 Transcription Factor %K Vital Capacity %X

Genome-wide association studies have identified numerous genetic loci for spirometic measures of pulmonary function, forced expiratory volume in one second (FEV(1)), and its ratio to forced vital capacity (FEV(1)/FVC). Given that cigarette smoking adversely affects pulmonary function, we conducted genome-wide joint meta-analyses (JMA) of single nucleotide polymorphism (SNP) and SNP-by-smoking (ever-smoking or pack-years) associations on FEV(1) and FEV(1)/FVC across 19 studies (total N = 50,047). We identified three novel loci not previously associated with pulmonary function. SNPs in or near DNER (smallest P(JMA = )5.00×10(-11)), HLA-DQB1 and HLA-DQA2 (smallest P(JMA = )4.35×10(-9)), and KCNJ2 and SOX9 (smallest P(JMA = )1.28×10(-8)) were associated with FEV(1)/FVC or FEV(1) in meta-analysis models including SNP main effects, smoking main effects, and SNP-by-smoking (ever-smoking or pack-years) interaction. The HLA region has been widely implicated for autoimmune and lung phenotypes, unlike the other novel loci, which have not been widely implicated. We evaluated DNER, KCNJ2, and SOX9 and found them to be expressed in human lung tissue. DNER and SOX9 further showed evidence of differential expression in human airway epithelium in smokers compared to non-smokers. Our findings demonstrated that joint testing of SNP and SNP-by-environment interaction identified novel loci associated with complex traits that are missed when considering only the genetic main effects.

%B PLoS Genet %V 8 %P e1003098 %8 2012 %G eng %N 12 %1 http://www.ncbi.nlm.nih.gov/pubmed/23284291?dopt=Abstract %R 10.1371/journal.pgen.1003098 %0 Journal Article %J Transl Psychiatry %D 2012 %T Genome-wide meta-analyses of smoking behaviors in African Americans. %A David, S P %A Hamidovic, A %A Chen, G K %A Bergen, A W %A Wessel, J %A Kasberger, J L %A Brown, W M %A Petruzella, S %A Thacker, E L %A Kim, Y %A Nalls, M A %A Tranah, G J %A Sung, Y J %A Ambrosone, C B %A Arnett, D %A Bandera, E V %A Becker, D M %A Becker, L %A Berndt, S I %A Bernstein, L %A Blot, W J %A Broeckel, U %A Buxbaum, S G %A Caporaso, N %A Casey, G %A Chanock, S J %A Deming, S L %A Diver, W R %A Eaton, C B %A Evans, D S %A Evans, M K %A Fornage, M %A Franceschini, N %A Harris, T B %A Henderson, B E %A Hernandez, D G %A Hitsman, B %A Hu, J J %A Hunt, S C %A Ingles, S A %A John, E M %A Kittles, R %A Kolb, S %A Kolonel, L N %A Le Marchand, L %A Liu, Y %A Lohman, K K %A McKnight, B %A Millikan, R C %A Murphy, A %A Neslund-Dudas, C %A Nyante, S %A Press, M %A Psaty, B M %A Rao, D C %A Redline, S %A Rodriguez-Gil, J L %A Rybicki, B A %A Signorello, L B %A Singleton, A B %A Smoller, J %A Snively, B %A Spring, B %A Stanford, J L %A Strom, S S %A Swan, G E %A Taylor, K D %A Thun, M J %A Wilson, A F %A Witte, J S %A Yamamura, Y %A Yanek, L R %A Yu, K %A Zheng, W %A Ziegler, R G %A Zonderman, A B %A Jorgenson, E %A Haiman, C A %A Furberg, H %K Adult %K African Americans %K Aged %K Chromosomes, Human, Pair 10 %K Chromosomes, Human, Pair 15 %K Female %K Genetic Loci %K Genetic Predisposition to Disease %K Genetic Variation %K Genome-Wide Association Study %K Genotype %K Humans %K Male %K Middle Aged %K Nerve Tissue Proteins %K Phenotype %K Polymorphism, Single Nucleotide %K Proteoglycans %K Receptors, Nicotinic %K Smoking %K Statistics as Topic %X

The identification and exploration of genetic loci that influence smoking behaviors have been conducted primarily in populations of the European ancestry. Here we report results of the first genome-wide association study meta-analysis of smoking behavior in African Americans in the Study of Tobacco in Minority Populations Genetics Consortium (n = 32,389). We identified one non-coding single-nucleotide polymorphism (SNP; rs2036527[A]) on chromosome 15q25.1 associated with smoking quantity (cigarettes per day), which exceeded genome-wide significance (β = 0.040, s.e. = 0.007, P = 1.84 × 10(-8)). This variant is present in the 5'-distal enhancer region of the CHRNA5 gene and defines the primary index signal reported in studies of the European ancestry. No other SNP reached genome-wide significance for smoking initiation (SI, ever vs never smoking), age of SI, or smoking cessation (SC, former vs current smoking). Informative associations that approached genome-wide significance included three modestly correlated variants, at 15q25.1 within PSMA4, CHRNA5 and CHRNA3 for smoking quantity, which are associated with a second signal previously reported in studies in European ancestry populations, and a signal represented by three SNPs in the SPOCK2 gene on chr10q22.1. The association at 15q25.1 confirms this region as an important susceptibility locus for smoking quantity in men and women of African ancestry. Larger studies will be needed to validate the suggestive loci that did not reach genome-wide significance and further elucidate the contribution of genetic variation to disparities in cigarette consumption, SC and smoking-attributable disease between African Americans and European Americans.

%B Transl Psychiatry %V 2 %P e119 %8 2012 %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/22832964?dopt=Abstract %R 10.1038/tp.2012.41 %0 Journal Article %J Nat Genet %D 2012 %T Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture. %A Estrada, Karol %A Styrkarsdottir, Unnur %A Evangelou, Evangelos %A Hsu, Yi-Hsiang %A Duncan, Emma L %A Ntzani, Evangelia E %A Oei, Ling %A Albagha, Omar M E %A Amin, Najaf %A Kemp, John P %A Koller, Daniel L %A Li, Guo %A Liu, Ching-Ti %A Minster, Ryan L %A Moayyeri, Alireza %A Vandenput, Liesbeth %A Willner, Dana %A Xiao, Su-Mei %A Yerges-Armstrong, Laura M %A Zheng, Hou-Feng %A Alonso, Nerea %A Eriksson, Joel %A Kammerer, Candace M %A Kaptoge, Stephen K %A Leo, Paul J %A Thorleifsson, Gudmar %A Wilson, Scott G %A Wilson, James F %A Aalto, Ville %A Alen, Markku %A Aragaki, Aaron K %A Aspelund, Thor %A Center, Jacqueline R %A Dailiana, Zoe %A Duggan, David J %A Garcia, Melissa %A García-Giralt, Natalia %A Giroux, Sylvie %A Hallmans, Göran %A Hocking, Lynne J %A Husted, Lise Bjerre %A Jameson, Karen A %A Khusainova, Rita %A Kim, Ghi Su %A Kooperberg, Charles %A Koromila, Theodora %A Kruk, Marcin %A Laaksonen, Marika %A LaCroix, Andrea Z %A Lee, Seung Hun %A Leung, Ping C %A Lewis, Joshua R %A Masi, Laura %A Mencej-Bedrac, Simona %A Nguyen, Tuan V %A Nogues, Xavier %A Patel, Millan S %A Prezelj, Janez %A Rose, Lynda M %A Scollen, Serena %A Siggeirsdottir, Kristin %A Smith, Albert V %A Svensson, Olle %A Trompet, Stella %A Trummer, Olivia %A van Schoor, Natasja M %A Woo, Jean %A Zhu, Kun %A Balcells, Susana %A Brandi, Maria Luisa %A Buckley, Brendan M %A Cheng, Sulin %A Christiansen, Claus %A Cooper, Cyrus %A Dedoussis, George %A Ford, Ian %A Frost, Morten %A Goltzman, David %A González-Macías, Jesús %A Kähönen, Mika %A Karlsson, Magnus %A Khusnutdinova, Elza %A Koh, Jung-Min %A Kollia, Panagoula %A Langdahl, Bente Lomholt %A Leslie, William D %A Lips, Paul %A Ljunggren, Osten %A Lorenc, Roman S %A Marc, Janja %A Mellström, Dan %A Obermayer-Pietsch, Barbara %A Olmos, José M %A Pettersson-Kymmer, Ulrika %A Reid, David M %A Riancho, José A %A Ridker, Paul M %A Rousseau, François %A Slagboom, P Eline %A Tang, Nelson L S %A Urreizti, Roser %A Van Hul, Wim %A Viikari, Jorma %A Zarrabeitia, María T %A Aulchenko, Yurii S %A Castano-Betancourt, Martha %A Grundberg, Elin %A Herrera, Lizbeth %A Ingvarsson, Thorvaldur %A Johannsdottir, Hrefna %A Kwan, Tony %A Li, Rui %A Luben, Robert %A Medina-Gómez, Carolina %A Palsson, Stefan Th %A Reppe, Sjur %A Rotter, Jerome I %A Sigurdsson, Gunnar %A van Meurs, Joyce B J %A Verlaan, Dominique %A Williams, Frances M K %A Wood, Andrew R %A Zhou, Yanhua %A Gautvik, Kaare M %A Pastinen, Tomi %A Raychaudhuri, Soumya %A Cauley, Jane A %A Chasman, Daniel I %A Clark, Graeme R %A Cummings, Steven R %A Danoy, Patrick %A Dennison, Elaine M %A Eastell, Richard %A Eisman, John A %A Gudnason, Vilmundur %A Hofman, Albert %A Jackson, Rebecca D %A Jones, Graeme %A Jukema, J Wouter %A Khaw, Kay-Tee %A Lehtimäki, Terho %A Liu, Yongmei %A Lorentzon, Mattias %A McCloskey, Eugene %A Mitchell, Braxton D %A Nandakumar, Kannabiran %A Nicholson, Geoffrey C %A Oostra, Ben A %A Peacock, Munro %A Pols, Huibert A P %A Prince, Richard L %A Raitakari, Olli %A Reid, Ian R %A Robbins, John %A Sambrook, Philip N %A Sham, Pak Chung %A Shuldiner, Alan R %A Tylavsky, Frances A %A van Duijn, Cornelia M %A Wareham, Nick J %A Cupples, L Adrienne %A Econs, Michael J %A Evans, David M %A Harris, Tamara B %A Kung, Annie Wai Chee %A Psaty, Bruce M %A Reeve, Jonathan %A Spector, Timothy D %A Streeten, Elizabeth A %A Zillikens, M Carola %A Thorsteinsdottir, Unnur %A Ohlsson, Claes %A Karasik, David %A Richards, J Brent %A Brown, Matthew A %A Stefansson, Kari %A Uitterlinden, André G %A Ralston, Stuart H %A Ioannidis, John P A %A Kiel, Douglas P %A Rivadeneira, Fernando %K Bone Density %K Computational Biology %K European Continental Ancestry Group %K Extracellular Matrix Proteins %K Female %K Femur Neck %K Fractures, Bone %K Gene Expression Profiling %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genotype %K Glycoproteins %K Humans %K Intercellular Signaling Peptides and Proteins %K Low Density Lipoprotein Receptor-Related Protein-5 %K Lumbar Vertebrae %K Male %K Mitochondrial Membrane Transport Proteins %K Osteoporosis %K Phosphoproteins %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %K Risk Factors %K Spectrin %X

Bone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 × 10(-8)). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 × 10(-4), Bonferroni corrected), of which six reached P < 5 × 10(-8), including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.

%B Nat Genet %V 44 %P 491-501 %8 2012 Apr 15 %G eng %N 5 %R 10.1038/ng.2249 %0 Journal Article %J Hum Mol Genet %D 2012 %T Genome-wide meta-analysis points to CTC1 and ZNF676 as genes regulating telomere homeostasis in humans. %A Mangino, Massimo %A Hwang, Shih-Jen %A Spector, Timothy D %A Hunt, Steven C %A Kimura, Masayuki %A Fitzpatrick, Annette L %A Christiansen, Lene %A Petersen, Inge %A Elbers, Clara C %A Harris, Tamara %A Chen, Wei %A Srinivasan, Sathanur R %A Kark, Jeremy D %A Benetos, Athanase %A El Shamieh, Said %A Visvikis-Siest, Sophie %A Christensen, Kaare %A Berenson, Gerald S %A Valdes, Ana M %A Viñuela, Ana %A Garcia, Melissa %A Arnett, Donna K %A Broeckel, Ulrich %A Province, Michael A %A Pankow, James S %A Kammerer, Candace %A Liu, Yongmei %A Nalls, Michael %A Tishkoff, Sarah %A Thomas, Fridtjof %A Ziv, Elad %A Psaty, Bruce M %A Bis, Joshua C %A Rotter, Jerome I %A Taylor, Kent D %A Smith, Erin %A Schork, Nicholas J %A Levy, Daniel %A Aviv, Abraham %K Genome-Wide Association Study %K Humans %K Kruppel-Like Transcription Factors %K Telomere %K Telomere Homeostasis %K Telomere-Binding Proteins %X

Leukocyte telomere length (LTL) is associated with a number of common age-related diseases and is a heritable trait. Previous genome-wide association studies (GWASs) identified two loci on chromosomes 3q26.2 (TERC) and 10q24.33 (OBFC1) that are associated with the inter-individual LTL variation. We performed a meta-analysis of 9190 individuals from six independent GWAS and validated our findings in 2226 individuals from four additional studies. We confirmed previously reported associations with OBFC1 (rs9419958 P = 9.1 × 10(-11)) and with the telomerase RNA component TERC (rs1317082, P = 1.1 × 10(-8)). We also identified two novel genomic regions associated with LTL variation that map near a conserved telomere maintenance complex component 1 (CTC1; rs3027234, P = 3.6 × 10(-8)) on chromosome17p13.1 and zinc finger protein 676 (ZNF676; rs412658, P = 3.3 × 10(-8)) on 19p12. The minor allele of rs3027234 was associated with both shorter LTL and lower expression of CTC1. Our findings are consistent with the recent observations that point mutations in CTC1 cause short telomeres in both Arabidopsis and humans affected by a rare Mendelian syndrome. Overall, our results provide novel insights into the genetic architecture of inter-individual LTL variation in the general population.

%B Hum Mol Genet %V 21 %P 5385-94 %8 2012 Dec 15 %G eng %N 24 %1 http://www.ncbi.nlm.nih.gov/pubmed/23001564?dopt=Abstract %R 10.1093/hmg/dds382 %0 Journal Article %J Circ Cardiovasc Genet %D 2012 %T Impact of ancestry and common genetic variants on QT interval in African Americans. %A Smith, J Gustav %A Avery, Christy L %A Evans, Daniel S %A Nalls, Michael A %A Meng, Yan A %A Smith, Erin N %A Palmer, Cameron %A Tanaka, Toshiko %A Mehra, Reena %A Butler, Anne M %A Young, Taylor %A Buxbaum, Sarah G %A Kerr, Kathleen F %A Berenson, Gerald S %A Schnabel, Renate B %A Li, Guo %A Ellinor, Patrick T %A Magnani, Jared W %A Chen, Wei %A Bis, Joshua C %A Curb, J David %A Hsueh, Wen-Chi %A Rotter, Jerome I %A Liu, Yongmei %A Newman, Anne B %A Limacher, Marian C %A North, Kari E %A Reiner, Alexander P %A Quibrera, P Miguel %A Schork, Nicholas J %A Singleton, Andrew B %A Psaty, Bruce M %A Soliman, Elsayed Z %A Solomon, Allen J %A Srinivasan, Sathanur R %A Alonso, Alvaro %A Wallace, Robert %A Redline, Susan %A Zhang, Zhu-Ming %A Post, Wendy S %A Zonderman, Alan B %A Taylor, Herman A %A Murray, Sarah S %A Ferrucci, Luigi %A Arking, Dan E %A Evans, Michele K %A Fox, Ervin R %A Sotoodehnia, Nona %A Heckbert, Susan R %A Whitsel, Eric A %A Newton-Cheh, Christopher %K Adult %K African Americans %K Aged %K Electrocardiography %K European Continental Ancestry Group %K Female %K Genealogy and Heraldry %K Genetic Variation %K Genome, Human %K Genome-Wide Association Study %K Humans %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %X

BACKGROUND: Ethnic differences in cardiac arrhythmia incidence have been reported, with a particularly high incidence of sudden cardiac death and low incidence of atrial fibrillation in individuals of African ancestry. We tested the hypotheses that African ancestry and common genetic variants are associated with prolonged duration of cardiac repolarization, a central pathophysiological determinant of arrhythmia, as measured by the electrocardiographic QT interval.

METHODS AND RESULTS: First, individual estimates of African and European ancestry were inferred from genome-wide single-nucleotide polymorphism (SNP) data in 7 population-based cohorts of African Americans (n=12,097) and regressed on measured QT interval from ECGs. Second, imputation was performed for 2.8 million SNPs, and a genome-wide association study of QT interval was performed in 10 cohorts (n=13,105). There was no evidence of association between genetic ancestry and QT interval (P=0.94). Genome-wide significant associations (P<2.5 × 10(-8)) were identified with SNPs at 2 loci, upstream of the genes NOS1AP (rs12143842, P=2 × 10(-15)) and ATP1B1 (rs1320976, P=2 × 10(-10)). The most significant SNP in NOS1AP was the same as the strongest SNP previously associated with QT interval in individuals of European ancestry. Low probability values (P<10(-5)) were observed for SNPs at several other loci previously identified in genome-wide association studies in individuals of European ancestry, including KCNQ1, KCNH2, LITAF, and PLN.

CONCLUSIONS: We observed no difference in duration of cardiac repolarization with global genetic indices of African American ancestry. In addition, our genome-wide association study extends the association of polymorphisms at several loci associated with repolarization in individuals of European ancestry to include individuals of African ancestry.

%B Circ Cardiovasc Genet %V 5 %P 647-55 %8 2012 Dec %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/23166209?dopt=Abstract %R 10.1161/CIRCGENETICS.112.962787 %0 Journal Article %J Nat Genet %D 2012 %T Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways. %A Scott, Robert A %A Lagou, Vasiliki %A Welch, Ryan P %A Wheeler, Eleanor %A Montasser, May E %A Luan, Jian'an %A Mägi, Reedik %A Strawbridge, Rona J %A Rehnberg, Emil %A Gustafsson, Stefan %A Kanoni, Stavroula %A Rasmussen-Torvik, Laura J %A Yengo, Loic %A Lecoeur, Cécile %A Shungin, Dmitry %A Sanna, Serena %A Sidore, Carlo %A Johnson, Paul C D %A Jukema, J Wouter %A Johnson, Toby %A Mahajan, Anubha %A Verweij, Niek %A Thorleifsson, Gudmar %A Hottenga, Jouke-Jan %A Shah, Sonia %A Smith, Albert V %A Sennblad, Bengt %A Gieger, Christian %A Salo, Perttu %A Perola, Markus %A Timpson, Nicholas J %A Evans, David M %A Pourcain, Beate St %A Wu, Ying %A Andrews, Jeanette S %A Hui, Jennie %A Bielak, Lawrence F %A Zhao, Wei %A Horikoshi, Momoko %A Navarro, Pau %A Isaacs, Aaron %A O'Connell, Jeffrey R %A Stirrups, Kathleen %A Vitart, Veronique %A Hayward, Caroline %A Esko, Tõnu %A Mihailov, Evelin %A Fraser, Ross M %A Fall, Tove %A Voight, Benjamin F %A Raychaudhuri, Soumya %A Chen, Han %A Lindgren, Cecilia M %A Morris, Andrew P %A Rayner, Nigel W %A Robertson, Neil %A Rybin, Denis %A Liu, Ching-Ti %A Beckmann, Jacques S %A Willems, Sara M %A Chines, Peter S %A Jackson, Anne U %A Kang, Hyun Min %A Stringham, Heather M %A Song, Kijoung %A Tanaka, Toshiko %A Peden, John F %A Goel, Anuj %A Hicks, Andrew A %A An, Ping %A Müller-Nurasyid, Martina %A Franco-Cereceda, Anders %A Folkersen, Lasse %A Marullo, Letizia %A Jansen, Hanneke %A Oldehinkel, Albertine J %A Bruinenberg, Marcel %A Pankow, James S %A North, Kari E %A Forouhi, Nita G %A Loos, Ruth J F %A Edkins, Sarah %A Varga, Tibor V %A Hallmans, Göran %A Oksa, Heikki %A Antonella, Mulas %A Nagaraja, Ramaiah %A Trompet, Stella %A Ford, Ian %A Bakker, Stephan J L %A Kong, Augustine %A Kumari, Meena %A Gigante, Bruna %A Herder, Christian %A Munroe, Patricia B %A Caulfield, Mark %A Antti, Jula %A Mangino, Massimo %A Small, Kerrin %A Miljkovic, Iva %A Liu, Yongmei %A Atalay, Mustafa %A Kiess, Wieland %A James, Alan L %A Rivadeneira, Fernando %A Uitterlinden, André G %A Palmer, Colin N A %A Doney, Alex S F %A Willemsen, Gonneke %A Smit, Johannes H %A Campbell, Susan %A Polasek, Ozren %A Bonnycastle, Lori L %A Hercberg, Serge %A Dimitriou, Maria %A Bolton, Jennifer L %A Fowkes, Gerard R %A Kovacs, Peter %A Lindström, Jaana %A Zemunik, Tatijana %A Bandinelli, Stefania %A Wild, Sarah H %A Basart, Hanneke V %A Rathmann, Wolfgang %A Grallert, Harald %A Maerz, Winfried %A Kleber, Marcus E %A Boehm, Bernhard O %A Peters, Annette %A Pramstaller, Peter P %A Province, Michael A %A Borecki, Ingrid B %A Hastie, Nicholas D %A Rudan, Igor %A Campbell, Harry %A Watkins, Hugh %A Farrall, Martin %A Stumvoll, Michael %A Ferrucci, Luigi %A Waterworth, Dawn M %A Bergman, Richard N %A Collins, Francis S %A Tuomilehto, Jaakko %A Watanabe, Richard M %A de Geus, Eco J C %A Penninx, Brenda W %A Hofman, Albert %A Oostra, Ben A %A Psaty, Bruce M %A Vollenweider, Peter %A Wilson, James F %A Wright, Alan F %A Hovingh, G Kees %A Metspalu, Andres %A Uusitupa, Matti %A Magnusson, Patrik K E %A Kyvik, Kirsten O %A Kaprio, Jaakko %A Price, Jackie F %A Dedoussis, George V %A Deloukas, Panos %A Meneton, Pierre %A Lind, Lars %A Boehnke, Michael %A Shuldiner, Alan R %A van Duijn, Cornelia M %A Morris, Andrew D %A Toenjes, Anke %A Peyser, Patricia A %A Beilby, John P %A Körner, Antje %A Kuusisto, Johanna %A Laakso, Markku %A Bornstein, Stefan R %A Schwarz, Peter E H %A Lakka, Timo A %A Rauramaa, Rainer %A Adair, Linda S %A Smith, George Davey %A Spector, Tim D %A Illig, Thomas %A de Faire, Ulf %A Hamsten, Anders %A Gudnason, Vilmundur %A Kivimaki, Mika %A Hingorani, Aroon %A Keinanen-Kiukaanniemi, Sirkka M %A Saaristo, Timo E %A Boomsma, Dorret I %A Stefansson, Kari %A van der Harst, Pim %A Dupuis, Josée %A Pedersen, Nancy L %A Sattar, Naveed %A Harris, Tamara B %A Cucca, Francesco %A Ripatti, Samuli %A Salomaa, Veikko %A Mohlke, Karen L %A Balkau, Beverley %A Froguel, Philippe %A Pouta, Anneli %A Jarvelin, Marjo-Riitta %A Wareham, Nicholas J %A Bouatia-Naji, Nabila %A McCarthy, Mark I %A Franks, Paul W %A Meigs, James B %A Teslovich, Tanya M %A Florez, Jose C %A Langenberg, Claudia %A Ingelsson, Erik %A Prokopenko, Inga %A Barroso, Inês %K Adult %K Animals %K Blood Glucose %K Fasting %K Female %K Gene Frequency %K Genome-Wide Association Study %K Humans %K Insulin %K Male %K Metabolic Networks and Pathways %K Mice %K Osmolar Concentration %K Quantitative Trait Loci %X

Through genome-wide association meta-analyses of up to 133,010 individuals of European ancestry without diabetes, including individuals newly genotyped using the Metabochip, we have increased the number of confirmed loci influencing glycemic traits to 53, of which 33 also increase type 2 diabetes risk (q < 0.05). Loci influencing fasting insulin concentration showed association with lipid levels and fat distribution, suggesting impact on insulin resistance. Gene-based analyses identified further biologically plausible loci, suggesting that additional loci beyond those reaching genome-wide significance are likely to represent real associations. This conclusion is supported by an excess of directionally consistent and nominally significant signals between discovery and follow-up studies. Functional analysis of these newly discovered loci will further improve our understanding of glycemic control.

%B Nat Genet %V 44 %P 991-1005 %8 2012 Sep %G eng %N 9 %1 http://www.ncbi.nlm.nih.gov/pubmed/22885924?dopt=Abstract %R 10.1038/ng.2385 %0 Journal Article %J Nat Genet %D 2012 %T Meta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways. %A Stolk, Lisette %A Perry, John R B %A Chasman, Daniel I %A He, Chunyan %A Mangino, Massimo %A Sulem, Patrick %A Barbalic, Maja %A Broer, Linda %A Byrne, Enda M %A Ernst, Florian %A Esko, Tõnu %A Franceschini, Nora %A Gudbjartsson, Daniel F %A Hottenga, Jouke-Jan %A Kraft, Peter %A McArdle, Patrick F %A Porcu, Eleonora %A Shin, So-Youn %A Smith, Albert V %A van Wingerden, Sophie %A Zhai, Guangju %A Zhuang, Wei V %A Albrecht, Eva %A Alizadeh, Behrooz Z %A Aspelund, Thor %A Bandinelli, Stefania %A Lauc, Lovorka Barac %A Beckmann, Jacques S %A Boban, Mladen %A Boerwinkle, Eric %A Broekmans, Frank J %A Burri, Andrea %A Campbell, Harry %A Chanock, Stephen J %A Chen, Constance %A Cornelis, Marilyn C %A Corre, Tanguy %A Coviello, Andrea D %A D'Adamo, Pio %A Davies, Gail %A de Faire, Ulf %A de Geus, Eco J C %A Deary, Ian J %A Dedoussis, George V Z %A Deloukas, Panagiotis %A Ebrahim, Shah %A Eiriksdottir, Gudny %A Emilsson, Valur %A Eriksson, Johan G %A Fauser, Bart C J M %A Ferreli, Liana %A Ferrucci, Luigi %A Fischer, Krista %A Folsom, Aaron R %A Garcia, Melissa E %A Gasparini, Paolo %A Gieger, Christian %A Glazer, Nicole %A Grobbee, Diederick E %A Hall, Per %A Haller, Toomas %A Hankinson, Susan E %A Hass, Merli %A Hayward, Caroline %A Heath, Andrew C %A Hofman, Albert %A Ingelsson, Erik %A Janssens, A Cecile J W %A Johnson, Andrew D %A Karasik, David %A Kardia, Sharon L R %A Keyzer, Jules %A Kiel, Douglas P %A Kolcic, Ivana %A Kutalik, Zoltán %A Lahti, Jari %A Lai, Sandra %A Laisk, Triin %A Laven, Joop S E %A Lawlor, Debbie A %A Liu, Jianjun %A Lopez, Lorna M %A Louwers, Yvonne V %A Magnusson, Patrik K E %A Marongiu, Mara %A Martin, Nicholas G %A Klaric, Irena Martinovic %A Masciullo, Corrado %A McKnight, Barbara %A Medland, Sarah E %A Melzer, David %A Mooser, Vincent %A Navarro, Pau %A Newman, Anne B %A Nyholt, Dale R %A Onland-Moret, N Charlotte %A Palotie, Aarno %A Paré, Guillaume %A Parker, Alex N %A Pedersen, Nancy L %A Peeters, Petra H M %A Pistis, Giorgio %A Plump, Andrew S %A Polasek, Ozren %A Pop, Victor J M %A Psaty, Bruce M %A Räikkönen, Katri %A Rehnberg, Emil %A Rotter, Jerome I %A Rudan, Igor %A Sala, Cinzia %A Salumets, Andres %A Scuteri, Angelo %A Singleton, Andrew %A Smith, Jennifer A %A Snieder, Harold %A Soranzo, Nicole %A Stacey, Simon N %A Starr, John M %A Stathopoulou, Maria G %A Stirrups, Kathleen %A Stolk, Ronald P %A Styrkarsdottir, Unnur %A Sun, Yan V %A Tenesa, Albert %A Thorand, Barbara %A Toniolo, Daniela %A Tryggvadottir, Laufey %A Tsui, Kim %A Ulivi, Sheila %A van Dam, Rob M %A van der Schouw, Yvonne T %A van Gils, Carla H %A van Nierop, Peter %A Vink, Jacqueline M %A Visscher, Peter M %A Voorhuis, Marlies %A Waeber, Gérard %A Wallaschofski, Henri %A Wichmann, H Erich %A Widen, Elisabeth %A Wijnands-van Gent, Colette J M %A Willemsen, Gonneke %A Wilson, James F %A Wolffenbuttel, Bruce H R %A Wright, Alan F %A Yerges-Armstrong, Laura M %A Zemunik, Tatijana %A Zgaga, Lina %A Zillikens, M Carola %A Zygmunt, Marek %A Arnold, Alice M %A Boomsma, Dorret I %A Buring, Julie E %A Crisponi, Laura %A Demerath, Ellen W %A Gudnason, Vilmundur %A Harris, Tamara B %A Hu, Frank B %A Hunter, David J %A Launer, Lenore J %A Metspalu, Andres %A Montgomery, Grant W %A Oostra, Ben A %A Ridker, Paul M %A Sanna, Serena %A Schlessinger, David %A Spector, Tim D %A Stefansson, Kari %A Streeten, Elizabeth A %A Thorsteinsdottir, Unnur %A Uda, Manuela %A Uitterlinden, André G %A van Duijn, Cornelia M %A Völzke, Henry %A Murray, Anna %A Murabito, Joanne M %A Visser, Jenny A %A Lunetta, Kathryn L %K Age Factors %K DNA Helicases %K DNA Polymerase gamma %K DNA Primase %K DNA Repair %K DNA Repair Enzymes %K DNA-Directed DNA Polymerase %K European Continental Ancestry Group %K Exodeoxyribonucleases %K Female %K Genetic Loci %K Genome-Wide Association Study %K Humans %K Immunity %K Menopause %K Polymorphism, Single Nucleotide %K Proteins %X

To newly identify loci for age at natural menopause, we carried out a meta-analysis of 22 genome-wide association studies (GWAS) in 38,968 women of European descent, with replication in up to 14,435 women. In addition to four known loci, we identified 13 loci newly associated with age at natural menopause (at P < 5 × 10(-8)). Candidate genes located at these newly associated loci include genes implicated in DNA repair (EXO1, HELQ, UIMC1, FAM175A, FANCI, TLK1, POLG and PRIM1) and immune function (IL11, NLRP11 and PRRC2A (also known as BAT2)). Gene-set enrichment pathway analyses using the full GWAS data set identified exoDNase, NF-κB signaling and mitochondrial dysfunction as biological processes related to timing of menopause.

%B Nat Genet %V 44 %P 260-8 %8 2012 Jan 22 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/22267201?dopt=Abstract %R 10.1038/ng.1051 %0 Journal Article %J Nat Genet %D 2012 %T Meta-analysis identifies six new susceptibility loci for atrial fibrillation. %A Ellinor, Patrick T %A Lunetta, Kathryn L %A Albert, Christine M %A Glazer, Nicole L %A Ritchie, Marylyn D %A Smith, Albert V %A Arking, Dan E %A Müller-Nurasyid, Martina %A Krijthe, Bouwe P %A Lubitz, Steven A %A Bis, Joshua C %A Chung, Mina K %A Dörr, Marcus %A Ozaki, Kouichi %A Roberts, Jason D %A Smith, J Gustav %A Pfeufer, Arne %A Sinner, Moritz F %A Lohman, Kurt %A Ding, Jingzhong %A Smith, Nicholas L %A Smith, Jonathan D %A Rienstra, Michiel %A Rice, Kenneth M %A Van Wagoner, David R %A Magnani, Jared W %A Wakili, Reza %A Clauss, Sebastian %A Rotter, Jerome I %A Steinbeck, Gerhard %A Launer, Lenore J %A Davies, Robert W %A Borkovich, Matthew %A Harris, Tamara B %A Lin, Honghuang %A Völker, Uwe %A Völzke, Henry %A Milan, David J %A Hofman, Albert %A Boerwinkle, Eric %A Chen, Lin Y %A Soliman, Elsayed Z %A Voight, Benjamin F %A Li, Guo %A Chakravarti, Aravinda %A Kubo, Michiaki %A Tedrow, Usha B %A Rose, Lynda M %A Ridker, Paul M %A Conen, David %A Tsunoda, Tatsuhiko %A Furukawa, Tetsushi %A Sotoodehnia, Nona %A Xu, Siyan %A Kamatani, Naoyuki %A Levy, Daniel %A Nakamura, Yusuke %A Parvez, Babar %A Mahida, Saagar %A Furie, Karen L %A Rosand, Jonathan %A Muhammad, Raafia %A Psaty, Bruce M %A Meitinger, Thomas %A Perz, Siegfried %A Wichmann, H-Erich %A Witteman, Jacqueline C M %A Kao, W H Linda %A Kathiresan, Sekar %A Roden, Dan M %A Uitterlinden, André G %A Rivadeneira, Fernando %A McKnight, Barbara %A Sjögren, Marketa %A Newman, Anne B %A Liu, Yongmei %A Gollob, Michael H %A Melander, Olle %A Tanaka, Toshihiro %A Stricker, Bruno H Ch %A Felix, Stephan B %A Alonso, Alvaro %A Darbar, Dawood %A Barnard, John %A Chasman, Daniel I %A Heckbert, Susan R %A Benjamin, Emelia J %A Gudnason, Vilmundur %A Kääb, Stefan %K Adolescent %K Adult %K Aged %K Aged, 80 and over %K Asian Continental Ancestry Group %K Atrial Fibrillation %K Child %K Child, Preschool %K European Continental Ancestry Group %K Female %K Genetic Loci %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Infant %K Infant, Newborn %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Risk Factors %K Young Adult %X

Atrial fibrillation is a highly prevalent arrhythmia and a major risk factor for stroke, heart failure and death. We conducted a genome-wide association study (GWAS) in individuals of European ancestry, including 6,707 with and 52,426 without atrial fibrillation. Six new atrial fibrillation susceptibility loci were identified and replicated in an additional sample of individuals of European ancestry, including 5,381 subjects with and 10,030 subjects without atrial fibrillation (P < 5 × 10(-8)). Four of the loci identified in Europeans were further replicated in silico in a GWAS of Japanese individuals, including 843 individuals with and 3,350 individuals without atrial fibrillation. The identified loci implicate candidate genes that encode transcription factors related to cardiopulmonary development, cardiac-expressed ion channels and cell signaling molecules.

%B Nat Genet %V 44 %P 670-5 %8 2012 Apr 29 %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/22544366?dopt=Abstract %R 10.1038/ng.2261 %0 Journal Article %J Circ Cardiovasc Genet %D 2012 %T Novel loci associated with PR interval in a genome-wide association study of 10 African American cohorts. %A Butler, Anne M %A Yin, Xiaoyan %A Evans, Daniel S %A Nalls, Michael A %A Smith, Erin N %A Tanaka, Toshiko %A Li, Guo %A Buxbaum, Sarah G %A Whitsel, Eric A %A Alonso, Alvaro %A Arking, Dan E %A Benjamin, Emelia J %A Berenson, Gerald S %A Bis, Josh C %A Chen, Wei %A Deo, Rajat %A Ellinor, Patrick T %A Heckbert, Susan R %A Heiss, Gerardo %A Hsueh, Wen-Chi %A Keating, Brendan J %A Kerr, Kathleen F %A Li, Yun %A Limacher, Marian C %A Liu, Yongmei %A Lubitz, Steven A %A Marciante, Kristin D %A Mehra, Reena %A Meng, Yan A %A Newman, Anne B %A Newton-Cheh, Christopher %A North, Kari E %A Palmer, Cameron D %A Psaty, Bruce M %A Quibrera, P Miguel %A Redline, Susan %A Reiner, Alex P %A Rotter, Jerome I %A Schnabel, Renate B %A Schork, Nicholas J %A Singleton, Andrew B %A Smith, J Gustav %A Soliman, Elsayed Z %A Srinivasan, Sathanur R %A Zhang, Zhu-Ming %A Zonderman, Alan B %A Ferrucci, Luigi %A Murray, Sarah S %A Evans, Michele K %A Sotoodehnia, Nona %A Magnani, Jared W %A Avery, Christy L %K Adult %K African Americans %K Cohort Studies %K Electrocardiography %K Female %K Genetic Loci %K Genome-Wide Association Study %K Humans %K Male %K Meta-Analysis as Topic %K Middle Aged %K Polymorphism, Single Nucleotide %X

BACKGROUND: The PR interval, as measured by the resting, standard 12-lead ECG, reflects the duration of atrial/atrioventricular nodal depolarization. Substantial evidence exists for a genetic contribution to PR, including genome-wide association studies that have identified common genetic variants at 9 loci influencing PR in populations of European and Asian descent. However, few studies have examined loci associated with PR in African Americans.

METHODS AND RESULTS: We present results from the largest genome-wide association study to date of PR in 13 415 adults of African descent from 10 cohorts. We tested for association between PR (ms) and ≈2.8 million genotyped and imputed single-nucleotide polymorphisms. Imputation was performed using HapMap 2 YRI and CEU panels. Study-specific results, adjusted for global ancestry and clinical correlates of PR, were meta-analyzed using the inverse variance method. Variation in genome-wide test statistic distributions was noted within studies (λ range: 0.9-1.1), although not after genomic control correction was applied to the overall meta-analysis (λ: 1.008). In addition to generalizing previously reported associations with MEIS1, SCN5A, ARHGAP24, CAV1, and TBX5 to African American populations at the genome-wide significance level (P<5.0 × 10(-8)), we also identified a novel locus: ITGA9, located in a region previously implicated in SCN5A expression. The 3p21 region harboring SCN5A also contained 2 additional independent secondary signals influencing PR (P<5.0 × 10(-8)).

CONCLUSIONS: This study demonstrates the ability to map novel loci in African Americans as well as the generalizability of loci associated with PR across populations of African, European, and Asian descent.

%B Circ Cardiovasc Genet %V 5 %P 639-46 %8 2012 Dec %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/23139255?dopt=Abstract %R 10.1161/CIRCGENETICS.112.963991 %0 Journal Article %J PLoS Genet %D 2012 %T Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals. %A Dastani, Zari %A Hivert, Marie-France %A Timpson, Nicholas %A Perry, John R B %A Yuan, Xin %A Scott, Robert A %A Henneman, Peter %A Heid, Iris M %A Kizer, Jorge R %A Lyytikäinen, Leo-Pekka %A Fuchsberger, Christian %A Tanaka, Toshiko %A Morris, Andrew P %A Small, Kerrin %A Isaacs, Aaron %A Beekman, Marian %A Coassin, Stefan %A Lohman, Kurt %A Qi, Lu %A Kanoni, Stavroula %A Pankow, James S %A Uh, Hae-Won %A Wu, Ying %A Bidulescu, Aurelian %A Rasmussen-Torvik, Laura J %A Greenwood, Celia M T %A Ladouceur, Martin %A Grimsby, Jonna %A Manning, Alisa K %A Liu, Ching-Ti %A Kooner, Jaspal %A Mooser, Vincent E %A Vollenweider, Peter %A Kapur, Karen A %A Chambers, John %A Wareham, Nicholas J %A Langenberg, Claudia %A Frants, Rune %A Willems-Vandijk, Ko %A Oostra, Ben A %A Willems, Sara M %A Lamina, Claudia %A Winkler, Thomas W %A Psaty, Bruce M %A Tracy, Russell P %A Brody, Jennifer %A Chen, Ida %A Viikari, Jorma %A Kähönen, Mika %A Pramstaller, Peter P %A Evans, David M %A St Pourcain, Beate %A Sattar, Naveed %A Wood, Andrew R %A Bandinelli, Stefania %A Carlson, Olga D %A Egan, Josephine M %A Böhringer, Stefan %A van Heemst, Diana %A Kedenko, Lyudmyla %A Kristiansson, Kati %A Nuotio, Marja-Liisa %A Loo, Britt-Marie %A Harris, Tamara %A Garcia, Melissa %A Kanaya, Alka %A Haun, Margot %A Klopp, Norman %A Wichmann, H-Erich %A Deloukas, Panos %A Katsareli, Efi %A Couper, David J %A Duncan, Bruce B %A Kloppenburg, Margreet %A Adair, Linda S %A Borja, Judith B %A Wilson, James G %A Musani, Solomon %A Guo, Xiuqing %A Johnson, Toby %A Semple, Robert %A Teslovich, Tanya M %A Allison, Matthew A %A Redline, Susan %A Buxbaum, Sarah G %A Mohlke, Karen L %A Meulenbelt, Ingrid %A Ballantyne, Christie M %A Dedoussis, George V %A Hu, Frank B %A Liu, Yongmei %A Paulweber, Bernhard %A Spector, Timothy D %A Slagboom, P Eline %A Ferrucci, Luigi %A Jula, Antti %A Perola, Markus %A Raitakari, Olli %A Florez, Jose C %A Salomaa, Veikko %A Eriksson, Johan G %A Frayling, Timothy M %A Hicks, Andrew A %A Lehtimäki, Terho %A Smith, George Davey %A Siscovick, David S %A Kronenberg, Florian %A van Duijn, Cornelia %A Loos, Ruth J F %A Waterworth, Dawn M %A Meigs, James B %A Dupuis, Josée %A Richards, J Brent %A Voight, Benjamin F %A Scott, Laura J %A Steinthorsdottir, Valgerdur %A Dina, Christian %A Welch, Ryan P %A Zeggini, Eleftheria %A Huth, Cornelia %A Aulchenko, Yurii S %A Thorleifsson, Gudmar %A McCulloch, Laura J %A Ferreira, Teresa %A Grallert, Harald %A Amin, Najaf %A Wu, Guanming %A Willer, Cristen J %A Raychaudhuri, Soumya %A McCarroll, Steve A %A Hofmann, Oliver M %A Segrè, Ayellet V %A van Hoek, Mandy %A Navarro, Pau %A Ardlie, Kristin %A Balkau, Beverley %A Benediktsson, Rafn %A Bennett, Amanda J %A Blagieva, Roza %A Boerwinkle, Eric %A Bonnycastle, Lori L %A Boström, Kristina Bengtsson %A Bravenboer, Bert %A Bumpstead, Suzannah %A Burtt, Noel P %A Charpentier, Guillaume %A Chines, Peter S %A Cornelis, Marilyn %A Crawford, Gabe %A Doney, Alex S F %A Elliott, Katherine S %A Elliott, Amanda L %A Erdos, Michael R %A Fox, Caroline S %A Franklin, Christopher S %A Ganser, Martha %A Gieger, Christian %A Grarup, Niels %A Green, Todd %A Griffin, Simon %A Groves, Christopher J %A Guiducci, Candace %A Hadjadj, Samy %A Hassanali, Neelam %A Herder, Christian %A Isomaa, Bo %A Jackson, Anne U %A Johnson, Paul R V %A Jørgensen, Torben %A Kao, Wen H L %A Kong, Augustine %A Kraft, Peter %A Kuusisto, Johanna %A Lauritzen, Torsten %A Li, Man %A Lieverse, Aloysius %A Lindgren, Cecilia M %A Lyssenko, Valeriya %A Marre, Michel %A Meitinger, Thomas %A Midthjell, Kristian %A Morken, Mario A %A Narisu, Narisu %A Nilsson, Peter %A Owen, Katharine R %A Payne, Felicity %A Petersen, Ann-Kristin %A Platou, Carl %A Proença, Christine %A Prokopenko, Inga %A Rathmann, Wolfgang %A Rayner, N William %A Robertson, Neil R %A Rocheleau, Ghislain %A Roden, Michael %A Sampson, Michael J %A Saxena, Richa %A Shields, Beverley M %A Shrader, Peter %A Sigurdsson, Gunnar %A Sparsø, Thomas %A Strassburger, Klaus %A Stringham, Heather M %A Sun, Qi %A Swift, Amy J %A Thorand, Barbara %A Tichet, Jean %A Tuomi, Tiinamaija %A van Dam, Rob M %A van Haeften, Timon W %A van Herpt, Thijs %A van Vliet-Ostaptchouk, Jana V %A Walters, G Bragi %A Weedon, Michael N %A Wijmenga, Cisca %A Witteman, Jacqueline %A Bergman, Richard N %A Cauchi, Stephane %A Collins, Francis S %A Gloyn, Anna L %A Gyllensten, Ulf %A Hansen, Torben %A Hide, Winston A %A Hitman, Graham A %A Hofman, Albert %A Hunter, David J %A Hveem, Kristian %A Laakso, Markku %A Morris, Andrew D %A Palmer, Colin N A %A Rudan, Igor %A Sijbrands, Eric %A Stein, Lincoln D %A Tuomilehto, Jaakko %A Uitterlinden, Andre %A Walker, Mark %A Watanabe, Richard M %A Abecasis, Goncalo R %A Boehm, Bernhard O %A Campbell, Harry %A Daly, Mark J %A Hattersley, Andrew T %A Pedersen, Oluf %A Barroso, Inês %A Groop, Leif %A Sladek, Rob %A Thorsteinsdottir, Unnur %A Wilson, James F %A Illig, Thomas %A Froguel, Philippe %A van Duijn, Cornelia M %A Stefansson, Kari %A Altshuler, David %A Boehnke, Michael %A McCarthy, Mark I %A Soranzo, Nicole %A Wheeler, Eleanor %A Glazer, Nicole L %A Bouatia-Naji, Nabila %A Mägi, Reedik %A Randall, Joshua %A Elliott, Paul %A Rybin, Denis %A Dehghan, Abbas %A Hottenga, Jouke Jan %A Song, Kijoung %A Goel, Anuj %A Lajunen, Taina %A Doney, Alex %A Cavalcanti-Proença, Christine %A Kumari, Meena %A Timpson, Nicholas J %A Zabena, Carina %A Ingelsson, Erik %A An, Ping %A O'Connell, Jeffrey %A Luan, Jian'an %A Elliott, Amanda %A McCarroll, Steven A %A Roccasecca, Rosa Maria %A Pattou, François %A Sethupathy, Praveen %A Ariyurek, Yavuz %A Barter, Philip %A Beilby, John P %A Ben-Shlomo, Yoav %A Bergmann, Sven %A Bochud, Murielle %A Bonnefond, Amélie %A Borch-Johnsen, Knut %A Böttcher, Yvonne %A Brunner, Eric %A Bumpstead, Suzannah J %A Chen, Yii-Der Ida %A Chines, Peter %A Clarke, Robert %A Coin, Lachlan J M %A Cooper, Matthew N %A Crisponi, Laura %A Day, Ian N M %A de Geus, Eco J C %A Delplanque, Jerome %A Fedson, Annette C %A Fischer-Rosinsky, Antje %A Forouhi, Nita G %A Franzosi, Maria Grazia %A Galan, Pilar %A Goodarzi, Mark O %A Graessler, Jürgen %A Grundy, Scott %A Gwilliam, Rhian %A Hallmans, Göran %A Hammond, Naomi %A Han, Xijing %A Hartikainen, Anna-Liisa %A Hayward, Caroline %A Heath, Simon C %A Hercberg, Serge %A Hillman, David R %A Hingorani, Aroon D %A Hui, Jennie %A Hung, Joe %A Kaakinen, Marika %A Kaprio, Jaakko %A Kesaniemi, Y Antero %A Kivimaki, Mika %A Knight, Beatrice %A Koskinen, Seppo %A Kovacs, Peter %A Kyvik, Kirsten Ohm %A Lathrop, G Mark %A Lawlor, Debbie A %A Le Bacquer, Olivier %A Lecoeur, Cécile %A Li, Yun %A Mahley, Robert %A Mangino, Massimo %A Martínez-Larrad, María Teresa %A McAteer, Jarred B %A McPherson, Ruth %A Meisinger, Christa %A Melzer, David %A Meyre, David %A Mitchell, Braxton D %A Mukherjee, Sutapa %A Naitza, Silvia %A Neville, Matthew J %A Orrù, Marco %A Pakyz, Ruth %A Paolisso, Giuseppe %A Pattaro, Cristian %A Pearson, Daniel %A Peden, John F %A Pedersen, Nancy L %A Pfeiffer, Andreas F H %A Pichler, Irene %A Polasek, Ozren %A Posthuma, Danielle %A Potter, Simon C %A Pouta, Anneli %A Province, Michael A %A Rayner, Nigel W %A Rice, Kenneth %A Ripatti, Samuli %A Rivadeneira, Fernando %A Rolandsson, Olov %A Sandbaek, Annelli %A Sandhu, Manjinder %A Sanna, Serena %A Sayer, Avan Aihie %A Scheet, Paul %A Seedorf, Udo %A Sharp, Stephen J %A Shields, Beverley %A Sigurðsson, Gunnar %A Sijbrands, Eric J G %A Silveira, Angela %A Simpson, Laila %A Singleton, Andrew %A Smith, Nicholas L %A Sovio, Ulla %A Swift, Amy %A Syddall, Holly %A Syvänen, Ann-Christine %A Tönjes, Anke %A Uitterlinden, André G %A van Dijk, Ko Willems %A Varma, Dhiraj %A Visvikis-Siest, Sophie %A Vitart, Veronique %A Vogelzangs, Nicole %A Waeber, Gérard %A Wagner, Peter J %A Walley, Andrew %A Ward, Kim L %A Watkins, Hugh %A Wild, Sarah H %A Willemsen, Gonneke %A Witteman, Jaqueline C M %A Yarnell, John W G %A Zelenika, Diana %A Zethelius, Björn %A Zhai, Guangju %A Zhao, Jing Hua %A Zillikens, M Carola %A Borecki, Ingrid B %A Meneton, Pierre %A Magnusson, Patrik K E %A Nathan, David M %A Williams, Gordon H %A Silander, Kaisa %A Bornstein, Stefan R %A Schwarz, Peter %A Spranger, Joachim %A Karpe, Fredrik %A Shuldiner, Alan R %A Cooper, Cyrus %A Serrano-Ríos, Manuel %A Lind, Lars %A Palmer, Lyle J %A Hu, Frank B %A Franks, Paul W %A Ebrahim, Shah %A Marmot, Michael %A Kao, W H Linda %A Pramstaller, Peter Paul %A Wright, Alan F %A Stumvoll, Michael %A Hamsten, Anders %A Buchanan, Thomas A %A Valle, Timo T %A Rotter, Jerome I %A Penninx, Brenda W J H %A Boomsma, Dorret I %A Cao, Antonio %A Scuteri, Angelo %A Schlessinger, David %A Uda, Manuela %A Ruokonen, Aimo %A Jarvelin, Marjo-Riitta %A Peltonen, Leena %A Mooser, Vincent %A Sladek, Robert %A Musunuru, Kiran %A Smith, Albert V %A Edmondson, Andrew C %A Stylianou, Ioannis M %A Koseki, Masahiro %A Pirruccello, James P %A Chasman, Daniel I %A Johansen, Christopher T %A Fouchier, Sigrid W %A Peloso, Gina M %A Barbalic, Maja %A Ricketts, Sally L %A Bis, Joshua C %A Feitosa, Mary F %A Orho-Melander, Marju %A Melander, Olle %A Li, Xiaohui %A Li, Mingyao %A Cho, Yoon Shin %A Go, Min Jin %A Kim, Young Jin %A Lee, Jong-Young %A Park, Taesung %A Kim, Kyunga %A Sim, Xueling %A Ong, Rick Twee-Hee %A Croteau-Chonka, Damien C %A Lange, Leslie A %A Smith, Joshua D %A Ziegler, Andreas %A Zhang, Weihua %A Zee, Robert Y L %A Whitfield, John B %A Thompson, John R %A Surakka, Ida %A Spector, Tim D %A Smit, Johannes H %A Sinisalo, Juha %A Scott, James %A Saharinen, Juha %A Sabatti, Chiara %A Rose, Lynda M %A Roberts, Robert %A Rieder, Mark %A Parker, Alex N %A Paré, Guillaume %A O'Donnell, Christopher J %A Nieminen, Markku S %A Nickerson, Deborah A %A Montgomery, Grant W %A McArdle, Wendy %A Masson, David %A Martin, Nicholas G %A Marroni, Fabio %A Lucas, Gavin %A Luben, Robert %A Lokki, Marja-Liisa %A Lettre, Guillaume %A Launer, Lenore J %A Lakatta, Edward G %A Laaksonen, Reijo %A Kyvik, Kirsten O %A König, Inke R %A Khaw, Kay-Tee %A Kaplan, Lee M %A Johansson, Asa %A Janssens, A Cecile J W %A Igl, Wilmar %A Hovingh, G Kees %A Hengstenberg, Christian %A Havulinna, Aki S %A Hastie, Nicholas D %A Harris, Tamara B %A Haritunians, Talin %A Hall, Alistair S %A Groop, Leif C %A Gonzalez, Elena %A Freimer, Nelson B %A Erdmann, Jeanette %A Ejebe, Kenechi G %A Döring, Angela %A Dominiczak, Anna F %A Demissie, Serkalem %A Deloukas, Panagiotis %A de Faire, Ulf %A Crawford, Gabriel %A Chen, Yii-der I %A Caulfield, Mark J %A Boekholdt, S Matthijs %A Assimes, Themistocles L %A Quertermous, Thomas %A Seielstad, Mark %A Wong, Tien Y %A Tai, E-Shyong %A Feranil, Alan B %A Kuzawa, Christopher W %A Taylor, Herman A %A Gabriel, Stacey B %A Holm, Hilma %A Gudnason, Vilmundur %A Krauss, Ronald M %A Ordovas, Jose M %A Munroe, Patricia B %A Kooner, Jaspal S %A Tall, Alan R %A Hegele, Robert A %A Kastelein, John J P %A Schadt, Eric E %A Strachan, David P %A Reilly, Muredach P %A Samani, Nilesh J %A Schunkert, Heribert %A Cupples, L Adrienne %A Sandhu, Manjinder S %A Ridker, Paul M %A Rader, Daniel J %A Kathiresan, Sekar %K Adiponectin %K African Americans %K Asian Continental Ancestry Group %K Cholesterol, HDL %K Diabetes Mellitus, Type 2 %K European Continental Ancestry Group %K Female %K Gene Expression %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Glucose Tolerance Test %K Humans %K Insulin Resistance %K Male %K Metabolic Networks and Pathways %K Polymorphism, Single Nucleotide %K Waist-Hip Ratio %X

Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10(-8)-1.2×10(-43)). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p<3×10(-4)). We next developed a multi-SNP genotypic risk score to test the association of adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This risk score was associated with increased risk of T2D (p = 4.3×10(-3), n = 22,044), increased triglycerides (p = 2.6×10(-14), n = 93,440), increased waist-to-hip ratio (p = 1.8×10(-5), n = 77,167), increased glucose two hours post oral glucose tolerance testing (p = 4.4×10(-3), n = 15,234), increased fasting insulin (p = 0.015, n = 48,238), but with lower in HDL-cholesterol concentrations (p = 4.5×10(-13), n = 96,748) and decreased BMI (p = 1.4×10(-4), n = 121,335). These findings identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance.

%B PLoS Genet %V 8 %P e1002607 %8 2012 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/22479202?dopt=Abstract %R 10.1371/journal.pgen.1002607 %0 Journal Article %J Invest Ophthalmol Vis Sci %D 2012 %T Variation in the lysyl oxidase (LOX) gene is associated with keratoconus in family-based and case-control studies. %A Bykhovskaya, Yelena %A Li, Xiaohui %A Epifantseva, Irina %A Haritunians, Talin %A Siscovick, David %A Aldave, Anthony %A Szczotka-Flynn, Loretta %A Iyengar, Sudha K %A Taylor, Kent D %A Rotter, Jerome I %A Rabinowitz, Yaron S %K Case-Control Studies %K Cornea %K Corneal Topography %K DNA %K Family %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genotype %K Humans %K Keratoconus %K Polymorphism, Genetic %K Protein-Lysine 6-Oxidase %X

PURPOSE: Keratoconus is a bilateral noninflammatory progressive corneal disorder with complex genetic inheritance and a common cause for cornea transplantation in young adults. A genomewide linkage scan in keratoconus families identified a locus at 5q23.2, overlapping the gene coding for the lysyl oxidase (LOX). LOX encodes an enzyme responsible for collagen cross-linking in a variety of tissues including the cornea. Corneal collagen cross-linking with long-wave ultraviolet light and riboflavin is a promising new treatment for keratoconus. To determine whether LOX is a genetic determinant of the pathogenesis of keratoconus, we analyzed association results of LOX polymorphisms in two independent case-control samples and in keratoconus families.

METHODS: Association results were analyzed of single-nucleotide polymorphisms (SNPs) in the LOX gene from a Genome-Wide Association Study (GWAS) investigation in two independent panels of patients with keratoconus and controls and in keratoconus families.

RESULTS: Evidence of association was found at SNPs rs10519694 and rs2956540 located in intron 4 of LOX in the GWAS discovery case-control panel with P values of 2.3×10(-3) and 7×10(-3), respectively. The same two SNPs were found to be associated with keratoconus by family-based association testing with P values of 2.7×10(-3) and 7.7×10(-4), respectively. Meta P values of 4.0×10(-5) and 4.0×10(-7) were calculated for SNPs rs10519694 and rs2956540 by analyzing case-control and family samples simultaneously. Sequencing of LOX exons in a subset of keratoconus patients identified two polymorphisms, rs1800449 and rs2288393, located in LOX transcripts I and II, associated with keratoconus in case-control and family samples with a meta P value of 0.02.

CONCLUSIONS: Results provided strong genetic evidence that LOX variants lead to increased susceptibility to developing of keratoconus.

%B Invest Ophthalmol Vis Sci %V 53 %P 4152-7 %8 2012 Jun 28 %G eng %N 7 %1 http://www.ncbi.nlm.nih.gov/pubmed/22661479?dopt=Abstract %R 10.1167/iovs.11-9268 %0 Journal Article %J Am J Epidemiol %D 2013 %T Association of functional polymorphism rs2231142 (Q141K) in the ABCG2 gene with serum uric acid and gout in 4 US populations: the PAGE Study. %A Zhang, Lili %A Spencer, Kylee L %A Voruganti, V Saroja %A Jorgensen, Neal W %A Fornage, Myriam %A Best, Lyle G %A Brown-Gentry, Kristin D %A Cole, Shelley A %A Crawford, Dana C %A Deelman, Ewa %A Franceschini, Nora %A Gaffo, Angelo L %A Glenn, Kimberly R %A Heiss, Gerardo %A Jenny, Nancy S %A Köttgen, Anna %A Li, Qiong %A Liu, Kiang %A Matise, Tara C %A North, Kari E %A Umans, Jason G %A Kao, W H Linda %K Adult %K African Americans %K Age Distribution %K ATP-Binding Cassette Transporters %K Comorbidity %K European Continental Ancestry Group %K Female %K Genetic Predisposition to Disease %K Genetics, Population %K Genome-Wide Association Study %K Gout %K Hormone Replacement Therapy %K Humans %K Indians, North American %K Male %K Mexican Americans %K Middle Aged %K Neoplasm Proteins %K Polymorphism, Genetic %K Postmenopause %K Sex Distribution %K United States %K Uric Acid %X

A loss-of-function mutation (Q141K, rs2231142) in the ATP-binding cassette, subfamily G, member 2 gene (ABCG2) has been shown to be associated with serum uric acid levels and gout in Asians, Europeans, and European and African Americans; however, less is known about these associations in other populations. Rs2231142 was genotyped in 22,734 European Americans, 9,720 African Americans, 3,849 Mexican Americans, and 3,550 American Indians in the Population Architecture using Genomics and Epidemiology (PAGE) Study (2008-2012). Rs2231142 was significantly associated with serum uric acid levels (P = 2.37 × 10(-67), P = 3.98 × 10(-5), P = 6.97 × 10(-9), and P = 5.33 × 10(-4) in European Americans, African Americans, Mexican Americans, and American Indians, respectively) and gout (P = 2.83 × 10(-10), P = 0.01, and P = 0.01 in European Americans, African Americans, and Mexican Americans, respectively). Overall, the T allele was associated with a 0.24-mg/dL increase in serum uric acid level (P = 1.37 × 10(-80)) and a 1.75-fold increase in the odds of gout (P = 1.09 × 10(-12)). The association between rs2231142 and serum uric acid was significantly stronger in men, postmenopausal women, and hormone therapy users compared with their counterparts. The association with gout was also significantly stronger in men than in women. These results highlight a possible role of sex hormones in the regulation of ABCG2 urate transporter and its potential implications for the prevention, diagnosis, and treatment of hyperuricemia and gout.

%B Am J Epidemiol %V 177 %P 923-32 %8 2013 May 1 %G eng %N 9 %1 http://www.ncbi.nlm.nih.gov/pubmed/23552988?dopt=Abstract %R 10.1093/aje/kws330 %0 Journal Article %J Circ Cardiovasc Genet %D 2013 %T Association of genome-wide variation with highly sensitive cardiac troponin-T levels in European Americans and Blacks: a meta-analysis from atherosclerosis risk in communities and cardiovascular health studies. %A Yu, Bing %A Barbalic, Maja %A Brautbar, Ariel %A Nambi, Vijay %A Hoogeveen, Ron C %A Tang, Weihong %A Mosley, Thomas H %A Rotter, Jerome I %A deFilippi, Christopher R %A O'Donnell, Christopher J %A Kathiresan, Sekar %A Rice, Ken %A Heckbert, Susan R %A Ballantyne, Christie M %A Psaty, Bruce M %A Boerwinkle, Eric %K African Continental Ancestry Group %K Atherosclerosis %K European Continental Ancestry Group %K Female %K Genome-Wide Association Study %K Humans %K Male %K Middle Aged %K Nuclear Receptor Coactivator 2 %K Polymorphism, Single Nucleotide %K Prospective Studies %K Residence Characteristics %K Risk Factors %K Troponin T %X

BACKGROUND: High levels of cardiac troponin T, measured by a highly sensitive assay (hs-cTnT), are strongly associated with incident coronary heart disease and heart failure. To date, no large-scale genome-wide association study of hs-cTnT has been reported. We sought to identify novel genetic variants that are associated with hs-cTnT levels.

METHODS AND RESULTS: We performed a genome-wide association in 9491 European Americans and 2053 blacks free of coronary heart disease and heart failure from 2 prospective cohorts: the Atherosclerosis Risk in Communities Study and the Cardiovascular Health Study. Genome-wide association studies were conducted in each study and race stratum. Fixed-effect meta-analyses combined the results of linear regression from 2 cohorts within each race stratum and then across race strata to produce overall estimates and probability values. The meta-analysis identified a significant association at chromosome 8q13 (rs10091374; P=9.06×10(-9)) near the nuclear receptor coactivator 2 (NCOA2) gene. Overexpression of NCOA2 can be detected in myoblasts. An additional analysis using logistic regression and the clinically motivated 99th percentile cut point detected a significant association at 1q32 (rs12564445; P=4.73×10(-8)) in the gene TNNT2, which encodes the cardiac troponin T protein itself. The hs-cTnT-associated single-nucleotide polymorphisms were not associated with coronary heart disease in a large case-control study, but rs12564445 was significantly associated with incident heart failure in Atherosclerosis Risk in Communities Study European Americans (hazard ratio=1.16; P=0.004).

CONCLUSIONS: We identified 2 loci, near NCOA2 and in the TNNT2 gene, at which variation was significantly associated with hs-cTnT levels. Further use of the new assay should enable replication of these results.

%B Circ Cardiovasc Genet %V 6 %P 82-8 %8 2013 Feb %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/23247143?dopt=Abstract %R 10.1161/CIRCGENETICS.112.963058 %0 Journal Article %J Epidemiology %D 2013 %T The Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium as a model of collaborative science. %A Psaty, Bruce M %A Sitlani, Colleen %K Aging %K Cohort Studies %K Cooperative Behavior %K Genome-Wide Association Study %K Heart Failure %K Humans %K Incidence %K Multicenter Studies as Topic %K Myocardial Infarction %K Research Support as Topic %K Stroke %K United States %B Epidemiology %V 24 %P 346-8 %8 2013 May %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/23549178?dopt=Abstract %R 10.1097/EDE.0b013e31828b2cbb %0 Journal Article %J Heart Rhythm %D 2013 %T Common genetic variation near the connexin-43 gene is associated with resting heart rate in African Americans: a genome-wide association study of 13,372 participants. %A Deo, R %A Nalls, M A %A Avery, C L %A Smith, J G %A Evans, D S %A Keller, M F %A Butler, A M %A Buxbaum, S G %A Li, G %A Miguel Quibrera, P %A Smith, E N %A Tanaka, T %A Akylbekova, E L %A Alonso, A %A Arking, D E %A Benjamin, E J %A Berenson, G S %A Bis, J C %A Chen, L Y %A Chen, W %A Cummings, S R %A Ellinor, P T %A Evans, M K %A Ferrucci, L %A Fox, E R %A Heckbert, S R %A Heiss, G %A Hsueh, W C %A Kerr, K F %A Limacher, M C %A Liu, Y %A Lubitz, S A %A Magnani, J W %A Mehra, R %A Marcus, G M %A Murray, S S %A Newman, A B %A Njajou, O %A North, K E %A Paltoo, D N %A Psaty, B M %A Redline, S S %A Reiner, A P %A Robinson, J G %A Rotter, J I %A Samdarshi, T E %A Schnabel, R B %A Schork, N J %A Singleton, A B %A Siscovick, D %A Soliman, E Z %A Sotoodehnia, N %A Srinivasan, S R %A Taylor, H A %A Trevisan, M %A Zhang, Z %A Zonderman, A B %A Newton-Cheh, C %A Whitsel, E A %K Adult %K African Americans %K Aged %K Arrhythmias, Cardiac %K Connexin 43 %K Electrocardiography %K Female %K Genetic Variation %K Genome-Wide Association Study %K Genotype %K Heart Rate %K Humans %K Male %K Meta-Analysis as Topic %K Middle Aged %K Polymorphism, Single Nucleotide %K Rest %K United States %X

BACKGROUND: Genome-wide association studies have identified several genetic loci associated with variation in resting heart rate in European and Asian populations. No study has evaluated genetic variants associated with heart rate in African Americans.

OBJECTIVE: To identify novel genetic variants associated with resting heart rate in African Americans.

METHODS: Ten cohort studies participating in the Candidate-gene Association Resource and Continental Origins and Genetic Epidemiology Network consortia performed genome-wide genotyping of single nucleotide polymorphisms (SNPs) and imputed 2,954,965 SNPs using HapMap YRI and CEU panels in 13,372 participants of African ancestry. Each study measured the RR interval (ms) from 10-second resting 12-lead electrocardiograms and estimated RR-SNP associations using covariate-adjusted linear regression. Random-effects meta-analysis was used to combine cohort-specific measures of association and identify genome-wide significant loci (P≤2.5×10(-8)).

RESULTS: Fourteen SNPs on chromosome 6q22 exceeded the genome-wide significance threshold. The most significant association was for rs9320841 (+13 ms per minor allele; P = 4.98×10(-15)). This SNP was approximately 350 kb downstream of GJA1, a locus previously identified as harboring SNPs associated with heart rate in Europeans. Adjustment for rs9320841 also attenuated the association between the remaining 13 SNPs in this region and heart rate. In addition, SNPs in MYH6, which have been identified in European genome-wide association study, were associated with similar changes in the resting heart rate as this population of African Americans.

CONCLUSIONS: An intergenic region downstream of GJA1 (the gene encoding connexin 43, the major protein of the human myocardial gap junction) and an intragenic region within MYH6 are associated with variation in resting heart rate in African Americans as well as in populations of European and Asian origin.

%B Heart Rhythm %V 10 %P 401-8 %8 2013 Mar %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/23183192?dopt=Abstract %R 10.1016/j.hrthm.2012.11.014 %0 Journal Article %J J Am Soc Nephrol %D 2013 %T Common variants in Mendelian kidney disease genes and their association with renal function. %A Parsa, Afshin %A Fuchsberger, Christian %A Köttgen, Anna %A O'Seaghdha, Conall M %A Pattaro, Cristian %A de Andrade, Mariza %A Chasman, Daniel I %A Teumer, Alexander %A Endlich, Karlhans %A Olden, Matthias %A Chen, Ming-Huei %A Tin, Adrienne %A Kim, Young J %A Taliun, Daniel %A Li, Man %A Feitosa, Mary %A Gorski, Mathias %A Yang, Qiong %A Hundertmark, Claudia %A Foster, Meredith C %A Glazer, Nicole %A Isaacs, Aaron %A Rao, Madhumathi %A Smith, Albert V %A O'Connell, Jeffrey R %A Struchalin, Maksim %A Tanaka, Toshiko %A Li, Guo %A Hwang, Shih-Jen %A Atkinson, Elizabeth J %A Lohman, Kurt %A Cornelis, Marilyn C %A Johansson, Asa %A Tönjes, Anke %A Dehghan, Abbas %A Couraki, Vincent %A Holliday, Elizabeth G %A Sorice, Rossella %A Kutalik, Zoltán %A Lehtimäki, Terho %A Esko, Tõnu %A Deshmukh, Harshal %A Ulivi, Sheila %A Chu, Audrey Y %A Murgia, Federico %A Trompet, Stella %A Imboden, Medea %A Kollerits, Barbara %A Pistis, Giorgio %A Harris, Tamara B %A Launer, Lenore J %A Aspelund, Thor %A Eiriksdottir, Gudny %A Mitchell, Braxton D %A Boerwinkle, Eric %A Schmidt, Helena %A Hofer, Edith %A Hu, Frank %A Demirkan, Ayse %A Oostra, Ben A %A Turner, Stephen T %A Ding, Jingzhong %A Andrews, Jeanette S %A Freedman, Barry I %A Giulianini, Franco %A Koenig, Wolfgang %A Illig, Thomas %A Döring, Angela %A Wichmann, H-Erich %A Zgaga, Lina %A Zemunik, Tatijana %A Boban, Mladen %A Minelli, Cosetta %A Wheeler, Heather E %A Igl, Wilmar %A Zaboli, Ghazal %A Wild, Sarah H %A Wright, Alan F %A Campbell, Harry %A Ellinghaus, David %A Nöthlings, Ute %A Jacobs, Gunnar %A Biffar, Reiner %A Ernst, Florian %A Homuth, Georg %A Kroemer, Heyo K %A Nauck, Matthias %A Stracke, Sylvia %A Völker, Uwe %A Völzke, Henry %A Kovacs, Peter %A Stumvoll, Michael %A Mägi, Reedik %A Hofman, Albert %A Uitterlinden, André G %A Rivadeneira, Fernando %A Aulchenko, Yurii S %A Polasek, Ozren %A Hastie, Nick %A Vitart, Veronique %A Helmer, Catherine %A Wang, Jie Jin %A Stengel, Bénédicte %A Ruggiero, Daniela %A Bergmann, Sven %A Kähönen, Mika %A Viikari, Jorma %A Nikopensius, Tiit %A Province, Michael %A Colhoun, Helen %A Doney, Alex %A Robino, Antonietta %A Krämer, Bernhard K %A Portas, Laura %A Ford, Ian %A Buckley, Brendan M %A Adam, Martin %A Thun, Gian-Andri %A Paulweber, Bernhard %A Haun, Margot %A Sala, Cinzia %A Mitchell, Paul %A Ciullo, Marina %A Vollenweider, Peter %A Raitakari, Olli %A Metspalu, Andres %A Palmer, Colin %A Gasparini, Paolo %A Pirastu, Mario %A Jukema, J Wouter %A Probst-Hensch, Nicole M %A Kronenberg, Florian %A Toniolo, Daniela %A Gudnason, Vilmundur %A Shuldiner, Alan R %A Coresh, Josef %A Schmidt, Reinhold %A Ferrucci, Luigi %A van Duijn, Cornelia M %A Borecki, Ingrid %A Kardia, Sharon L R %A Liu, Yongmei %A Curhan, Gary C %A Rudan, Igor %A Gyllensten, Ulf %A Wilson, James F %A Franke, Andre %A Pramstaller, Peter P %A Rettig, Rainer %A Prokopenko, Inga %A Witteman, Jacqueline %A Hayward, Caroline %A Ridker, Paul M %A Bochud, Murielle %A Heid, Iris M %A Siscovick, David S %A Fox, Caroline S %A Kao, W Linda %A Böger, Carsten A %K Databases, Genetic %K European Continental Ancestry Group %K Gene Frequency %K Genetic Variation %K Genome-Wide Association Study %K Humans %K Kidney %K Mendelian Randomization Analysis %K Phenotype %K Polymorphism, Single Nucleotide %K Renal Insufficiency, Chronic %X

Many common genetic variants identified by genome-wide association studies for complex traits map to genes previously linked to rare inherited Mendelian disorders. A systematic analysis of common single-nucleotide polymorphisms (SNPs) in genes responsible for Mendelian diseases with kidney phenotypes has not been performed. We thus developed a comprehensive database of genes for Mendelian kidney conditions and evaluated the association between common genetic variants within these genes and kidney function in the general population. Using the Online Mendelian Inheritance in Man database, we identified 731 unique disease entries related to specific renal search terms and confirmed a kidney phenotype in 218 of these entries, corresponding to mutations in 258 genes. We interrogated common SNPs (minor allele frequency >5%) within these genes for association with the estimated GFR in 74,354 European-ancestry participants from the CKDGen Consortium. However, the top four candidate SNPs (rs6433115 at LRP2, rs1050700 at TSC1, rs249942 at PALB2, and rs9827843 at ROBO2) did not achieve significance in a stage 2 meta-analysis performed in 56,246 additional independent individuals, indicating that these common SNPs are not associated with estimated GFR. The effect of less common or rare variants in these genes on kidney function in the general population and disease-specific cohorts requires further research.

%B J Am Soc Nephrol %V 24 %P 2105-17 %8 2013 Dec %G eng %N 12 %1 http://www.ncbi.nlm.nih.gov/pubmed/24029420?dopt=Abstract %R 10.1681/ASN.2012100983 %0 Journal Article %J Nat Genet %D 2013 %T Discovery and refinement of loci associated with lipid levels. %A Willer, Cristen J %A Schmidt, Ellen M %A Sengupta, Sebanti %A Peloso, Gina M %A Gustafsson, Stefan %A Kanoni, Stavroula %A Ganna, Andrea %A Chen, Jin %A Buchkovich, Martin L %A Mora, Samia %A Beckmann, Jacques S %A Bragg-Gresham, Jennifer L %A Chang, Hsing-Yi %A Demirkan, Ayse %A Den Hertog, Heleen M %A Do, Ron %A Donnelly, Louise A %A Ehret, Georg B %A Esko, Tõnu %A Feitosa, Mary F %A Ferreira, Teresa %A Fischer, Krista %A Fontanillas, Pierre %A Fraser, Ross M %A Freitag, Daniel F %A Gurdasani, Deepti %A Heikkilä, Kauko %A Hyppönen, Elina %A Isaacs, Aaron %A Jackson, Anne U %A Johansson, Asa %A Johnson, Toby %A Kaakinen, Marika %A Kettunen, Johannes %A Kleber, Marcus E %A Li, Xiaohui %A Luan, Jian'an %A Lyytikäinen, Leo-Pekka %A Magnusson, Patrik K E %A Mangino, Massimo %A Mihailov, Evelin %A Montasser, May E %A Müller-Nurasyid, Martina %A Nolte, Ilja M %A O'Connell, Jeffrey R %A Palmer, Cameron D %A Perola, Markus %A Petersen, Ann-Kristin %A Sanna, Serena %A Saxena, Richa %A Service, Susan K %A Shah, Sonia %A Shungin, Dmitry %A Sidore, Carlo %A Song, Ci %A Strawbridge, Rona J %A Surakka, Ida %A Tanaka, Toshiko %A Teslovich, Tanya M %A Thorleifsson, Gudmar %A van den Herik, Evita G %A Voight, Benjamin F %A Volcik, Kelly A %A Waite, Lindsay L %A Wong, Andrew %A Wu, Ying %A Zhang, Weihua %A Absher, Devin %A Asiki, Gershim %A Barroso, Inês %A Been, Latonya F %A Bolton, Jennifer L %A Bonnycastle, Lori L %A Brambilla, Paolo %A Burnett, Mary S %A Cesana, Giancarlo %A Dimitriou, Maria %A Doney, Alex S F %A Döring, Angela %A Elliott, Paul %A Epstein, Stephen E %A Ingi Eyjolfsson, Gudmundur %A Gigante, Bruna %A Goodarzi, Mark O %A Grallert, Harald %A Gravito, Martha L %A Groves, Christopher J %A Hallmans, Göran %A Hartikainen, Anna-Liisa %A Hayward, Caroline %A Hernandez, Dena %A Hicks, Andrew A %A Holm, Hilma %A Hung, Yi-Jen %A Illig, Thomas %A Jones, Michelle R %A Kaleebu, Pontiano %A Kastelein, John J P %A Khaw, Kay-Tee %A Kim, Eric %A Klopp, Norman %A Komulainen, Pirjo %A Kumari, Meena %A Langenberg, Claudia %A Lehtimäki, Terho %A Lin, Shih-Yi %A Lindström, Jaana %A Loos, Ruth J F %A Mach, François %A McArdle, Wendy L %A Meisinger, Christa %A Mitchell, Braxton D %A Müller, Gabrielle %A Nagaraja, Ramaiah %A Narisu, Narisu %A Nieminen, Tuomo V M %A Nsubuga, Rebecca N %A Olafsson, Isleifur %A Ong, Ken K %A Palotie, Aarno %A Papamarkou, Theodore %A Pomilla, Cristina %A Pouta, Anneli %A Rader, Daniel J %A Reilly, Muredach P %A Ridker, Paul M %A Rivadeneira, Fernando %A Rudan, Igor %A Ruokonen, Aimo %A Samani, Nilesh %A Scharnagl, Hubert %A Seeley, Janet %A Silander, Kaisa %A Stančáková, Alena %A Stirrups, Kathleen %A Swift, Amy J %A Tiret, Laurence %A Uitterlinden, André G %A van Pelt, L Joost %A Vedantam, Sailaja %A Wainwright, Nicholas %A Wijmenga, Cisca %A Wild, Sarah H %A Willemsen, Gonneke %A Wilsgaard, Tom %A Wilson, James F %A Young, Elizabeth H %A Zhao, Jing Hua %A Adair, Linda S %A Arveiler, Dominique %A Assimes, Themistocles L %A Bandinelli, Stefania %A Bennett, Franklyn %A Bochud, Murielle %A Boehm, Bernhard O %A Boomsma, Dorret I %A Borecki, Ingrid B %A Bornstein, Stefan R %A Bovet, Pascal %A Burnier, Michel %A Campbell, Harry %A Chakravarti, Aravinda %A Chambers, John C %A Chen, Yii-Der Ida %A Collins, Francis S %A Cooper, Richard S %A Danesh, John %A Dedoussis, George %A de Faire, Ulf %A Feranil, Alan B %A Ferrieres, Jean %A Ferrucci, Luigi %A Freimer, Nelson B %A Gieger, Christian %A Groop, Leif C %A Gudnason, Vilmundur %A Gyllensten, Ulf %A Hamsten, Anders %A Harris, Tamara B %A Hingorani, Aroon %A Hirschhorn, Joel N %A Hofman, Albert %A Hovingh, G Kees %A Hsiung, Chao Agnes %A Humphries, Steve E %A Hunt, Steven C %A Hveem, Kristian %A Iribarren, Carlos %A Jarvelin, Marjo-Riitta %A Jula, Antti %A Kähönen, Mika %A Kaprio, Jaakko %A Kesäniemi, Antero %A Kivimaki, Mika %A Kooner, Jaspal S %A Koudstaal, Peter J %A Krauss, Ronald M %A Kuh, Diana %A Kuusisto, Johanna %A Kyvik, Kirsten O %A Laakso, Markku %A Lakka, Timo A %A Lind, Lars %A Lindgren, Cecilia M %A Martin, Nicholas G %A März, Winfried %A McCarthy, Mark I %A McKenzie, Colin A %A Meneton, Pierre %A Metspalu, Andres %A Moilanen, Leena %A Morris, Andrew D %A Munroe, Patricia B %A Njølstad, Inger %A Pedersen, Nancy L %A Power, Chris %A Pramstaller, Peter P %A Price, Jackie F %A Psaty, Bruce M %A Quertermous, Thomas %A Rauramaa, Rainer %A Saleheen, Danish %A Salomaa, Veikko %A Sanghera, Dharambir K %A Saramies, Jouko %A Schwarz, Peter E H %A Sheu, Wayne H-H %A Shuldiner, Alan R %A Siegbahn, Agneta %A Spector, Tim D %A Stefansson, Kari %A Strachan, David P %A Tayo, Bamidele O %A Tremoli, Elena %A Tuomilehto, Jaakko %A Uusitupa, Matti %A van Duijn, Cornelia M %A Vollenweider, Peter %A Wallentin, Lars %A Wareham, Nicholas J %A Whitfield, John B %A Wolffenbuttel, Bruce H R %A Ordovas, Jose M %A Boerwinkle, Eric %A Palmer, Colin N A %A Thorsteinsdottir, Unnur %A Chasman, Daniel I %A Rotter, Jerome I %A Franks, Paul W %A Ripatti, Samuli %A Cupples, L Adrienne %A Sandhu, Manjinder S %A Rich, Stephen S %A Boehnke, Michael %A Deloukas, Panos %A Kathiresan, Sekar %A Mohlke, Karen L %A Ingelsson, Erik %A Abecasis, Goncalo R %K African Continental Ancestry Group %K Asian Continental Ancestry Group %K Cholesterol, HDL %K Cholesterol, LDL %K Coronary Artery Disease %K European Continental Ancestry Group %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genotype %K Humans %K Lipids %K Triglycerides %X

Levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and total cholesterol are heritable, modifiable risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,577 individuals using genome-wide and custom genotyping arrays. We identify and annotate 157 loci associated with lipid levels at P < 5 × 10(-8), including 62 loci not previously associated with lipid levels in humans. Using dense genotyping in individuals of European, East Asian, South Asian and African ancestry, we narrow association signals in 12 loci. We find that loci associated with blood lipid levels are often associated with cardiovascular and metabolic traits, including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio and body mass index. Our results demonstrate the value of using genetic data from individuals of diverse ancestry and provide insights into the biological mechanisms regulating blood lipids to guide future genetic, biological and therapeutic research.

%B Nat Genet %V 45 %P 1274-1283 %8 2013 Nov %G eng %N 11 %1 http://www.ncbi.nlm.nih.gov/pubmed/24097068?dopt=Abstract %R 10.1038/ng.2797 %0 Journal Article %J Am J Hum Genet %D 2013 %T Fine Mapping and Identification of BMI Loci in African Americans. %A Gong, Jian %A Schumacher, Fredrick %A Lim, Unhee %A Hindorff, Lucia A %A Haessler, Jeff %A Buyske, Steven %A Carlson, Christopher S %A Rosse, Stephanie %A Bůzková, Petra %A Fornage, Myriam %A Gross, Myron %A Pankratz, Nathan %A Pankow, James S %A Schreiner, Pamela J %A Cooper, Richard %A Ehret, Georg %A Gu, C Charles %A Houston, Denise %A Irvin, Marguerite R %A Jackson, Rebecca %A Kuller, Lew %A Henderson, Brian %A Cheng, Iona %A Wilkens, Lynne %A Leppert, Mark %A Lewis, Cora E %A Li, Rongling %A Nguyen, Khanh-Dung H %A Goodloe, Robert %A Farber-Eger, Eric %A Boston, Jonathan %A Dilks, Holli H %A Ritchie, Marylyn D %A Fowke, Jay %A Pooler, Loreall %A Graff, Misa %A Fernandez-Rhodes, Lindsay %A Cochrane, Barbara %A Boerwinkle, Eric %A Kooperberg, Charles %A Matise, Tara C %A Le Marchand, Loïc %A Crawford, Dana C %A Haiman, Christopher A %A North, Kari E %A Peters, Ulrike %K Adult %K African Americans %K Aged %K Aged, 80 and over %K Body Mass Index %K Female %K Genetic Loci %K Genetic Predisposition to Disease %K Genome, Human %K Genome-Wide Association Study %K Genotype %K Humans %K Linkage Disequilibrium %K Male %K Middle Aged %K Obesity %K Polymorphism, Single Nucleotide %K Young Adult %X

Genome-wide association studies (GWASs) primarily performed in European-ancestry (EA) populations have identified numerous loci associated with body mass index (BMI). However, it is still unclear whether these GWAS loci can be generalized to other ethnic groups, such as African Americans (AAs). Furthermore, the putative functional variant or variants in these loci mostly remain under investigation. The overall lower linkage disequilibrium in AA compared to EA populations provides the opportunity to narrow in or fine-map these BMI-related loci. Therefore, we used the Metabochip to densely genotype and evaluate 21 BMI GWAS loci identified in EA studies in 29,151 AAs from the Population Architecture using Genomics and Epidemiology (PAGE) study. Eight of the 21 loci (SEC16B, TMEM18, ETV5, GNPDA2, TFAP2B, BDNF, FTO, and MC4R) were found to be associated with BMI in AAs at 5.8 × 10(-5). Within seven out of these eight loci, we found that, on average, a substantially smaller number of variants was correlated (r(2) > 0.5) with the most significant SNP in AA than in EA populations (16 versus 55). Conditional analyses revealed GNPDA2 harboring a potential additional independent signal. Moreover, Metabochip-wide discovery analyses revealed two BMI-related loci, BRE (rs116612809, p = 3.6 × 10(-8)) and DHX34 (rs4802349, p = 1.2 × 10(-7)), which were significant when adjustment was made for the total number of SNPs tested across the chip. These results demonstrate that fine mapping in AAs is a powerful approach for both narrowing in on the underlying causal variants in known loci and discovering BMI-related loci.

%B Am J Hum Genet %V 93 %P 661-71 %8 2013 Oct 3 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/24094743?dopt=Abstract %R 10.1016/j.ajhg.2013.08.012 %0 Journal Article %J PLoS Biol %D 2013 %T Generalization and dilution of association results from European GWAS in populations of non-European ancestry: the PAGE study. %A Carlson, Christopher S %A Matise, Tara C %A North, Kari E %A Haiman, Christopher A %A Fesinmeyer, Megan D %A Buyske, Steven %A Schumacher, Fredrick R %A Peters, Ulrike %A Franceschini, Nora %A Ritchie, Marylyn D %A Duggan, David J %A Spencer, Kylee L %A Dumitrescu, Logan %A Eaton, Charles B %A Thomas, Fridtjof %A Young, Alicia %A Carty, Cara %A Heiss, Gerardo %A Le Marchand, Loïc %A Crawford, Dana C %A Hindorff, Lucia A %A Kooperberg, Charles L %K African Americans %K Asian Americans %K Body Mass Index %K Diabetes Mellitus, Type 2 %K European Continental Ancestry Group %K Gene Frequency %K Genetic Predisposition to Disease %K Genetic Variation %K Genome-Wide Association Study %K Hispanic Americans %K Humans %K Indians, North American %K Lipids %K Metagenomics %K Oceanic Ancestry Group %K Polymorphism, Single Nucleotide %X

The vast majority of genome-wide association study (GWAS) findings reported to date are from populations with European Ancestry (EA), and it is not yet clear how broadly the genetic associations described will generalize to populations of diverse ancestry. The Population Architecture Using Genomics and Epidemiology (PAGE) study is a consortium of multi-ancestry, population-based studies formed with the objective of refining our understanding of the genetic architecture of common traits emerging from GWAS. In the present analysis of five common diseases and traits, including body mass index, type 2 diabetes, and lipid levels, we compare direction and magnitude of effects for GWAS-identified variants in multiple non-EA populations against EA findings. We demonstrate that, in all populations analyzed, a significant majority of GWAS-identified variants have allelic associations in the same direction as in EA, with none showing a statistically significant effect in the opposite direction, after adjustment for multiple testing. However, 25% of tagSNPs identified in EA GWAS have significantly different effect sizes in at least one non-EA population, and these differential effects were most frequent in African Americans where all differential effects were diluted toward the null. We demonstrate that differential LD between tagSNPs and functional variants within populations contributes significantly to dilute effect sizes in this population. Although most variants identified from GWAS in EA populations generalize to all non-EA populations assessed, genetic models derived from GWAS findings in EA may generate spurious results in non-EA populations due to differential effect sizes. Regardless of the origin of the differential effects, caution should be exercised in applying any genetic risk prediction model based on tagSNPs outside of the ancestry group in which it was derived. Models based directly on functional variation may generalize more robustly, but the identification of functional variants remains challenging.

%B PLoS Biol %V 11 %P e1001661 %8 2013 Sep %G eng %N 9 %1 http://www.ncbi.nlm.nih.gov/pubmed/24068893?dopt=Abstract %R 10.1371/journal.pbio.1001661 %0 Journal Article %J Invest Ophthalmol Vis Sci %D 2013 %T Genetic association of COL5A1 variants in keratoconus patients suggests a complex connection between corneal thinning and keratoconus. %A Li, Xiaohui %A Bykhovskaya, Yelena %A Canedo, Ana Laura Caiado %A Haritunians, Talin %A Siscovick, David %A Aldave, Anthony J %A Szczotka-Flynn, Loretta %A Iyengar, Sudha K %A Rotter, Jerome I %A Taylor, Kent D %A Rabinowitz, Yaron S %K Adult %K Aged %K Collagen Type V %K Cornea %K Corneal Topography %K DNA %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genotype %K Humans %K Keratoconus %K Male %K Microscopy, Acoustic %K Middle Aged %K Polymorphism, Single Nucleotide %K Tomography, Optical Coherence %X

PURPOSE: Single nucleotide polymorphisms (SNPs) located near or within the COL5A1 gene, at 9q34.2-q34.3 chromosomal region have been reported in association with central corneal thickness (CCT). Using family linkage analysis, we identified a keratoconus susceptibility locus at 9q34. These findings led us to perform an association study between COL5A1 variation and keratoconus susceptibility.

METHODS: A Caucasian case-control cohort of 222 keratoconus patients and 3324 controls was selected as the discovery panel. An independent case-control panel of 304 cases and 518 controls and a family panel of 186 subjects were replicated for genotyping and association. Forty-four SNPs (21 for discovery and 23 for fine-mapping) spanning 300 kilobases in and around COL5A1 were genotyped and tested for genetic association. Logistic regression models implemented in PLINK were used to test for association in case controls. Generalized estimating equation models accounting for familial correlations implemented in genome-wide interaction analyses with family data were used for association testing in families.

RESULTS: Two CCT associated SNPs (rs1536482 and rs7044529 near and within COL5A1) were identified in the keratoconus discovery cohort (P values of 6.5 × 10(-3) and 7.4 × 10(-3)). SNP rs1536482 was replicated in the second case-control sample (P = 0.02), and SNP rs7044529 was replicated in a keratoconus family panel (P = 0.03). Meta P values of rs1536482 and rs7044529 in the keratoconus cohorts were 1.5 × 10(-4) (odds ratio [OR] = 1.30) and 2.9 × 10(-3) (OR = 1.39). After Bonferroni correction, the association of SNP rs1536482 remained significant (P = 6.5 × 10(-3)).

CONCLUSIONS: SNPs in the COL5A1 region, which regulate normal variation in CCT, may play a role in the thinning associated with keratoconus.

%B Invest Ophthalmol Vis Sci %V 54 %P 2696-704 %8 2013 Apr 12 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/23513063?dopt=Abstract %R 10.1167/iovs.13-11601 %0 Journal Article %J PLoS One %D 2013 %T Genetic loci for retinal arteriolar microcirculation. %A Sim, Xueling %A Jensen, Richard A %A Ikram, M Kamran %A Cotch, Mary Frances %A Li, Xiaohui %A Macgregor, Stuart %A Xie, Jing %A Smith, Albert Vernon %A Boerwinkle, Eric %A Mitchell, Paul %A Klein, Ronald %A Klein, Barbara E K %A Glazer, Nicole L %A Lumley, Thomas %A McKnight, Barbara %A Psaty, Bruce M %A de Jong, Paulus T V M %A Hofman, Albert %A Rivadeneira, Fernando %A Uitterlinden, André G %A van Duijn, Cornelia M %A Aspelund, Thor %A Eiriksdottir, Gudny %A Harris, Tamara B %A Jonasson, Fridbert %A Launer, Lenore J %A Attia, John %A Baird, Paul N %A Harrap, Stephen %A Holliday, Elizabeth G %A Inouye, Michael %A Rochtchina, Elena %A Scott, Rodney J %A Viswanathan, Ananth %A Li, Guo %A Smith, Nicholas L %A Wiggins, Kerri L %A Kuo, Jane Z %A Taylor, Kent D %A Hewitt, Alex W %A Martin, Nicholas G %A Montgomery, Grant W %A Sun, Cong %A Young, Terri L %A Mackey, David A %A van Zuydam, Natalie R %A Doney, Alex S F %A Palmer, Colin N A %A Morris, Andrew D %A Rotter, Jerome I %A Tai, E Shyong %A Gudnason, Vilmundur %A Vingerling, Johannes R %A Siscovick, David S %A Wang, Jie Jin %A Wong, Tien Y %K Aged %K Aged, 80 and over %K Arterioles %K Chromosomes, Human, Pair 5 %K European Continental Ancestry Group %K Female %K Genetic Loci %K Genome-Wide Association Study %K Genotype %K Humans %K Male %K MEF2 Transcription Factors %K Microcirculation %K Middle Aged %K Models, Genetic %K Retinal Vessels %X

Narrow arterioles in the retina have been shown to predict hypertension as well as other vascular diseases, likely through an increase in the peripheral resistance of the microcirculatory flow. In this study, we performed a genome-wide association study in 18,722 unrelated individuals of European ancestry from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium and the Blue Mountain Eye Study, to identify genetic determinants associated with variations in retinal arteriolar caliber. Retinal vascular calibers were measured on digitized retinal photographs using a standardized protocol. One variant (rs2194025 on chromosome 5q14 near the myocyte enhancer factor 2C MEF2C gene) was associated with retinal arteriolar caliber in the meta-analysis of the discovery cohorts at genome-wide significance of P-value <5×10(-8). This variant was replicated in an additional 3,939 individuals of European ancestry from the Australian Twins Study and Multi-Ethnic Study of Atherosclerosis (rs2194025, P-value = 2.11×10(-12) in combined meta-analysis of discovery and replication cohorts). In independent studies of modest sample sizes, no significant association was found between this variant and clinical outcomes including coronary artery disease, stroke, myocardial infarction or hypertension. In conclusion, we found one novel loci which underlie genetic variation in microvasculature which may be relevant to vascular disease. The relevance of these findings to clinical outcomes remains to be determined.

%B PLoS One %V 8 %P e65804 %8 2013 %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/23776548?dopt=Abstract %R 10.1371/journal.pone.0065804 %0 Journal Article %J Obesity (Silver Spring) %D 2013 %T Genetic risk factors for BMI and obesity in an ethnically diverse population: results from the population architecture using genomics and epidemiology (PAGE) study. %A Fesinmeyer, Megan D %A North, Kari E %A Ritchie, Marylyn D %A Lim, Unhee %A Franceschini, Nora %A Wilkens, Lynne R %A Gross, Myron D %A Bůzková, Petra %A Glenn, Kimberly %A Quibrera, P Miguel %A Fernandez-Rhodes, Lindsay %A Li, Qiong %A Fowke, Jay H %A Li, Rongling %A Carlson, Christopher S %A Prentice, Ross L %A Kuller, Lewis H %A Manson, JoAnn E %A Matise, Tara C %A Cole, Shelley A %A Chen, Christina T L %A Howard, Barbara V %A Kolonel, Laurence N %A Henderson, Brian E %A Monroe, Kristine R %A Crawford, Dana C %A Hindorff, Lucia A %A Buyske, Steven %A Haiman, Christopher A %A Le Marchand, Loïc %A Peters, Ulrike %K Alleles %K Body Mass Index %K Ethnic Groups %K Gene Frequency %K Genetic Loci %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Linkage Disequilibrium %K Metagenomics %K Obesity %K Phenotype %K Polymorphism, Single Nucleotide %K Risk Factors %X

OBJECTIVE: Several genome-wide association studies (GWAS) have demonstrated that common genetic variants contribute to obesity. However, studies of this complex trait have focused on ancestrally European populations, despite the high prevalence of obesity in some minority groups.

DESIGN AND METHODS: As part of the "Population Architecture using Genomics and Epidemiology (PAGE)" Consortium, we investigated the association between 13 GWAS-identified single-nucleotide polymorphisms (SNPs) and BMI and obesity in 69,775 subjects, including 6,149 American Indians, 15,415 African-Americans, 2,438 East Asians, 7,346 Hispanics, 604 Pacific Islanders, and 37,823 European Americans. For the BMI-increasing allele of each SNP, we calculated β coefficients using linear regression (for BMI) and risk estimates using logistic regression (for obesity defined as BMI ≥ 30) followed by fixed-effects meta-analysis to combine results across PAGE sites. Analyses stratified by racial/ethnic group assumed an additive genetic model and were adjusted for age, sex, and current smoking. We defined "replicating SNPs" (in European Americans) and "generalizing SNPs" (in other racial/ethnic groups) as those associated with an allele frequency-specific increase in BMI.

RESULTS: By this definition, we replicated 9/13 SNP associations (5 out of 8 loci) in European Americans. We also generalized 8/13 SNP associations (5/8 loci) in East Asians, 7/13 (5/8 loci) in African Americans, 6/13 (4/8 loci) in Hispanics, 5/8 in Pacific Islanders (5/8 loci), and 5/9 (4/8 loci) in American Indians.

CONCLUSION: Linkage disequilibrium patterns suggest that tagSNPs selected for European Americans may not adequately tag causal variants in other ancestry groups. Accordingly, fine-mapping in large samples is needed to comprehensively explore these loci in diverse populations.

%B Obesity (Silver Spring) %V 21 %P 835-46 %8 2013 Apr %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/23712987?dopt=Abstract %R 10.1002/oby.20268 %0 Journal Article %J BMC Med Genet %D 2013 %T Genetic variants associated with fasting glucose and insulin concentrations in an ethnically diverse population: results from the Population Architecture using Genomics and Epidemiology (PAGE) study. %A Fesinmeyer, Megan D %A Meigs, James B %A North, Kari E %A Schumacher, Fredrick R %A Bůzková, Petra %A Franceschini, Nora %A Haessler, Jeffrey %A Goodloe, Robert %A Spencer, Kylee L %A Voruganti, Venkata Saroja %A Howard, Barbara V %A Jackson, Rebecca %A Kolonel, Laurence N %A Liu, Simin %A Manson, JoAnn E %A Monroe, Kristine R %A Mukamal, Kenneth %A Dilks, Holli H %A Pendergrass, Sarah A %A Nato, Andrew %A Wan, Peggy %A Wilkens, Lynne R %A Le Marchand, Loïc %A Ambite, Jose Luis %A Buyske, Steven %A Florez, Jose C %A Crawford, Dana C %A Hindorff, Lucia A %A Haiman, Christopher A %A Peters, Ulrike %A Pankow, James S %K Adaptor Proteins, Signal Transducing %K Adult %K African Americans %K Aged %K Alleles %K Asian Continental Ancestry Group %K Blood Glucose %K Diabetes Mellitus, Type 2 %K European Continental Ancestry Group %K Female %K Gene Frequency %K Genetic Loci %K Genome-Wide Association Study %K Genomics %K Hispanic Americans %K Humans %K Indians, North American %K Insulin %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Transcription Factor 7-Like 2 Protein %X

BACKGROUND: Multiple genome-wide association studies (GWAS) within European populations have implicated common genetic variants associated with insulin and glucose concentrations. In contrast, few studies have been conducted within minority groups, which carry the highest burden of impaired glucose homeostasis and type 2 diabetes in the U.S.

METHODS: As part of the 'Population Architecture using Genomics and Epidemiology (PAGE) Consortium, we investigated the association of up to 10 GWAS-identified single nucleotide polymorphisms (SNPs) in 8 genetic regions with glucose or insulin concentrations in up to 36,579 non-diabetic subjects including 23,323 European Americans (EA) and 7,526 African Americans (AA), 3,140 Hispanics, 1,779 American Indians (AI), and 811 Asians. We estimated the association between each SNP and fasting glucose or log-transformed fasting insulin, followed by meta-analysis to combine results across PAGE sites.

RESULTS: Overall, our results show that 9/9 GWAS SNPs are associated with glucose in EA (p = 0.04 to 9 × 10-15), versus 3/9 in AA (p= 0.03 to 6 × 10-5), 3/4 SNPs in Hispanics, 2/4 SNPs in AI, and 1/2 SNPs in Asians. For insulin we observed a significant association with rs780094/GCKR in EA, Hispanics and AI only.

CONCLUSIONS: Generalization of results across multiple racial/ethnic groups helps confirm the relevance of some of these loci for glucose and insulin metabolism. Lack of association in non-EA groups may be due to insufficient power, or to unique patterns of linkage disequilibrium.

%B BMC Med Genet %V 14 %P 98 %8 2013 Sep 25 %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/24063630?dopt=Abstract %R 10.1186/1471-2350-14-98 %0 Journal Article %J Hum Mol Genet %D 2013 %T Genome-wide and gene-centric analyses of circulating myeloperoxidase levels in the charge and care consortia. %A Reiner, Alexander P %A Hartiala, Jaana %A Zeller, Tanja %A Bis, Joshua C %A Dupuis, Josée %A Fornage, Myriam %A Baumert, Jens %A Kleber, Marcus E %A Wild, Philipp S %A Baldus, Stephan %A Bielinski, Suzette J %A Fontes, João D %A Illig, Thomas %A Keating, Brendan J %A Lange, Leslie A %A Ojeda, Francisco %A Müller-Nurasyid, Martina %A Munzel, Thomas F %A Psaty, Bruce M %A Rice, Kenneth %A Rotter, Jerome I %A Schnabel, Renate B %A Tang, W H Wilson %A Thorand, Barbara %A Erdmann, Jeanette %A Jacobs, David R %A Wilson, James G %A Koenig, Wolfgang %A Tracy, Russell P %A Blankenberg, Stefan %A März, Winfried %A Gross, Myron D %A Benjamin, Emelia J %A Hazen, Stanley L %A Allayee, Hooman %K Adult %K African Americans %K Aged %K Case-Control Studies %K Complement Factor H %K Coronary Artery Disease %K European Continental Ancestry Group %K Female %K Gene Expression Regulation, Enzymologic %K Genetic Association Studies %K Genetic Variation %K Genome-Wide Association Study %K Genotype %K Humans %K Male %K Middle Aged %K Peroxidase %K Polymorphism, Single Nucleotide %K Young Adult %X

Increased systemic levels of myeloperoxidase (MPO) are associated with the risk of coronary artery disease (CAD). To identify the genetic factors that are associated with circulating MPO levels, we carried out a genome-wide association study (GWAS) and a gene-centric analysis in subjects of European ancestry and African Americans (AAs). A locus on chromosome 1q31.1 containing the complement factor H (CFH) gene was strongly associated with serum MPO levels in 9305 subjects of European ancestry (lead SNP rs800292; P = 4.89 × 10(-41)) and in 1690 AA subjects (rs505102; P = 1.05 × 10(-8)). Gene-centric analyses in 8335 subjects of European ancestry additionally identified two rare MPO coding sequence variants that were associated with serum MPO levels (rs28730837, P = 5.21 × 10(-12); rs35897051, P = 3.32 × 10(-8)). A GWAS for plasma MPO levels in 9260 European ancestry subjects identified a chromosome 17q22 region near MPO that was significantly associated (lead SNP rs6503905; P = 2.94 × 10(-12)), but the CFH locus did not exhibit evidence of association with plasma MPO levels. Functional analyses revealed that rs800292 was associated with levels of complement proteins in serum. Variants at chromosome 17q22 also had pleiotropic cis effects on gene expression. In a case-control analysis of ∼80 000 subjects from CARDIoGRAM, none of the identified single-nucleotide polymorphisms (SNPs) were associated with CAD. These results suggest that distinct genetic factors regulate serum and plasma MPO levels, which may have relevance for various acute and chronic inflammatory disorders. The clinical implications for CAD and a better understanding of the functional basis for the association of CFH and MPO variants with circulating MPO levels require further study.

%B Hum Mol Genet %V 22 %P 3381-93 %8 2013 Aug 15 %G eng %N 16 %1 http://www.ncbi.nlm.nih.gov/pubmed/23620142?dopt=Abstract %R 10.1093/hmg/ddt189 %0 Journal Article %J Nat Genet %D 2013 %T Genome-wide association analyses identify 18 new loci associated with serum urate concentrations. %A Köttgen, Anna %A Albrecht, Eva %A Teumer, Alexander %A Vitart, Veronique %A Krumsiek, Jan %A Hundertmark, Claudia %A Pistis, Giorgio %A Ruggiero, Daniela %A O'Seaghdha, Conall M %A Haller, Toomas %A Yang, Qiong %A Tanaka, Toshiko %A Johnson, Andrew D %A Kutalik, Zoltán %A Smith, Albert V %A Shi, Julia %A Struchalin, Maksim %A Middelberg, Rita P S %A Brown, Morris J %A Gaffo, Angelo L %A Pirastu, Nicola %A Li, Guo %A Hayward, Caroline %A Zemunik, Tatijana %A Huffman, Jennifer %A Yengo, Loic %A Zhao, Jing Hua %A Demirkan, Ayse %A Feitosa, Mary F %A Liu, Xuan %A Malerba, Giovanni %A Lopez, Lorna M %A van der Harst, Pim %A Li, Xinzhong %A Kleber, Marcus E %A Hicks, Andrew A %A Nolte, Ilja M %A Johansson, Asa %A Murgia, Federico %A Wild, Sarah H %A Bakker, Stephan J L %A Peden, John F %A Dehghan, Abbas %A Steri, Maristella %A Tenesa, Albert %A Lagou, Vasiliki %A Salo, Perttu %A Mangino, Massimo %A Rose, Lynda M %A Lehtimäki, Terho %A Woodward, Owen M %A Okada, Yukinori %A Tin, Adrienne %A Müller, Christian %A Oldmeadow, Christopher %A Putku, Margus %A Czamara, Darina %A Kraft, Peter %A Frogheri, Laura %A Thun, Gian Andri %A Grotevendt, Anne %A Gislason, Gauti Kjartan %A Harris, Tamara B %A Launer, Lenore J %A McArdle, Patrick %A Shuldiner, Alan R %A Boerwinkle, Eric %A Coresh, Josef %A Schmidt, Helena %A Schallert, Michael %A Martin, Nicholas G %A Montgomery, Grant W %A Kubo, Michiaki %A Nakamura, Yusuke %A Tanaka, Toshihiro %A Munroe, Patricia B %A Samani, Nilesh J %A Jacobs, David R %A Liu, Kiang %A D'Adamo, Pio %A Ulivi, Sheila %A Rotter, Jerome I %A Psaty, Bruce M %A Vollenweider, Peter %A Waeber, Gérard %A Campbell, Susan %A Devuyst, Olivier %A Navarro, Pau %A Kolcic, Ivana %A Hastie, Nicholas %A Balkau, Beverley %A Froguel, Philippe %A Esko, Tõnu %A Salumets, Andres %A Khaw, Kay Tee %A Langenberg, Claudia %A Wareham, Nicholas J %A Isaacs, Aaron %A Kraja, Aldi %A Zhang, Qunyuan %A Wild, Philipp S %A Scott, Rodney J %A Holliday, Elizabeth G %A Org, Elin %A Viigimaa, Margus %A Bandinelli, Stefania %A Metter, Jeffrey E %A Lupo, Antonio %A Trabetti, Elisabetta %A Sorice, Rossella %A Döring, Angela %A Lattka, Eva %A Strauch, Konstantin %A Theis, Fabian %A Waldenberger, Melanie %A Wichmann, H-Erich %A Davies, Gail %A Gow, Alan J %A Bruinenberg, Marcel %A Stolk, Ronald P %A Kooner, Jaspal S %A Zhang, Weihua %A Winkelmann, Bernhard R %A Boehm, Bernhard O %A Lucae, Susanne %A Penninx, Brenda W %A Smit, Johannes H %A Curhan, Gary %A Mudgal, Poorva %A Plenge, Robert M %A Portas, Laura %A Persico, Ivana %A Kirin, Mirna %A Wilson, James F %A Mateo Leach, Irene %A van Gilst, Wiek H %A Goel, Anuj %A Ongen, Halit %A Hofman, Albert %A Rivadeneira, Fernando %A Uitterlinden, André G %A Imboden, Medea %A von Eckardstein, Arnold %A Cucca, Francesco %A Nagaraja, Ramaiah %A Piras, Maria Grazia %A Nauck, Matthias %A Schurmann, Claudia %A Budde, Kathrin %A Ernst, Florian %A Farrington, Susan M %A Theodoratou, Evropi %A Prokopenko, Inga %A Stumvoll, Michael %A Jula, Antti %A Perola, Markus %A Salomaa, Veikko %A Shin, So-Youn %A Spector, Tim D %A Sala, Cinzia %A Ridker, Paul M %A Kähönen, Mika %A Viikari, Jorma %A Hengstenberg, Christian %A Nelson, Christopher P %A Meschia, James F %A Nalls, Michael A %A Sharma, Pankaj %A Singleton, Andrew B %A Kamatani, Naoyuki %A Zeller, Tanja %A Burnier, Michel %A Attia, John %A Laan, Maris %A Klopp, Norman %A Hillege, Hans L %A Kloiber, Stefan %A Choi, Hyon %A Pirastu, Mario %A Tore, Silvia %A Probst-Hensch, Nicole M %A Völzke, Henry %A Gudnason, Vilmundur %A Parsa, Afshin %A Schmidt, Reinhold %A Whitfield, John B %A Fornage, Myriam %A Gasparini, Paolo %A Siscovick, David S %A Polasek, Ozren %A Campbell, Harry %A Rudan, Igor %A Bouatia-Naji, Nabila %A Metspalu, Andres %A Loos, Ruth J F %A van Duijn, Cornelia M %A Borecki, Ingrid B %A Ferrucci, Luigi %A Gambaro, Giovanni %A Deary, Ian J %A Wolffenbuttel, Bruce H R %A Chambers, John C %A März, Winfried %A Pramstaller, Peter P %A Snieder, Harold %A Gyllensten, Ulf %A Wright, Alan F %A Navis, Gerjan %A Watkins, Hugh %A Witteman, Jacqueline C M %A Sanna, Serena %A Schipf, Sabine %A Dunlop, Malcolm G %A Tönjes, Anke %A Ripatti, Samuli %A Soranzo, Nicole %A Toniolo, Daniela %A Chasman, Daniel I %A Raitakari, Olli %A Kao, W H Linda %A Ciullo, Marina %A Fox, Caroline S %A Caulfield, Mark %A Bochud, Murielle %A Gieger, Christian %K Analysis of Variance %K European Continental Ancestry Group %K Gene Frequency %K Genetic Loci %K Genome-Wide Association Study %K Glucose %K Gout %K Humans %K Inhibins %K Polymorphism, Single Nucleotide %K Signal Transduction %K Uric Acid %X

Elevated serum urate concentrations can cause gout, a prevalent and painful inflammatory arthritis. By combining data from >140,000 individuals of European ancestry within the Global Urate Genetics Consortium (GUGC), we identified and replicated 28 genome-wide significant loci in association with serum urate concentrations (18 new regions in or near TRIM46, INHBB, SFMBT1, TMEM171, VEGFA, BAZ1B, PRKAG2, STC1, HNF4G, A1CF, ATXN2, UBE2Q2, IGF1R, NFAT5, MAF, HLF, ACVR1B-ACVRL1 and B3GNT4). Associations for many of the loci were of similar magnitude in individuals of non-European ancestry. We further characterized these loci for associations with gout, transcript expression and the fractional excretion of urate. Network analyses implicate the inhibins-activins signaling pathways and glucose metabolism in systemic urate control. New candidate genes for serum urate concentration highlight the importance of metabolic control of urate production and excretion, which may have implications for the treatment and prevention of gout.

%B Nat Genet %V 45 %P 145-54 %8 2013 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/23263486?dopt=Abstract %R 10.1038/ng.2500 %0 Journal Article %J PLoS Genet %D 2013 %T Genome-wide association of body fat distribution in African ancestry populations suggests new loci. %A Liu, Ching-Ti %A Monda, Keri L %A Taylor, Kira C %A Lange, Leslie %A Demerath, Ellen W %A Palmas, Walter %A Wojczynski, Mary K %A Ellis, Jaclyn C %A Vitolins, Mara Z %A Liu, Simin %A Papanicolaou, George J %A Irvin, Marguerite R %A Xue, Luting %A Griffin, Paula J %A Nalls, Michael A %A Adeyemo, Adebowale %A Liu, Jiankang %A Li, Guo %A Ruiz-Narvaez, Edward A %A Chen, Wei-Min %A Chen, Fang %A Henderson, Brian E %A Millikan, Robert C %A Ambrosone, Christine B %A Strom, Sara S %A Guo, Xiuqing %A Andrews, Jeanette S %A Sun, Yan V %A Mosley, Thomas H %A Yanek, Lisa R %A Shriner, Daniel %A Haritunians, Talin %A Rotter, Jerome I %A Speliotes, Elizabeth K %A Smith, Megan %A Rosenberg, Lynn %A Mychaleckyj, Josyf %A Nayak, Uma %A Spruill, Ida %A Garvey, W Timothy %A Pettaway, Curtis %A Nyante, Sarah %A Bandera, Elisa V %A Britton, Angela F %A Zonderman, Alan B %A Rasmussen-Torvik, Laura J %A Chen, Yii-Der Ida %A Ding, Jingzhong %A Lohman, Kurt %A Kritchevsky, Stephen B %A Zhao, Wei %A Peyser, Patricia A %A Kardia, Sharon L R %A Kabagambe, Edmond %A Broeckel, Ulrich %A Chen, Guanjie %A Zhou, Jie %A Wassertheil-Smoller, Sylvia %A Neuhouser, Marian L %A Rampersaud, Evadnie %A Psaty, Bruce %A Kooperberg, Charles %A Manson, JoAnn E %A Kuller, Lewis H %A Ochs-Balcom, Heather M %A Johnson, Karen C %A Sucheston, Lara %A Ordovas, Jose M %A Palmer, Julie R %A Haiman, Christopher A %A McKnight, Barbara %A Howard, Barbara V %A Becker, Diane M %A Bielak, Lawrence F %A Liu, Yongmei %A Allison, Matthew A %A Grant, Struan F A %A Burke, Gregory L %A Patel, Sanjay R %A Schreiner, Pamela J %A Borecki, Ingrid B %A Evans, Michele K %A Taylor, Herman %A Sale, Michèle M %A Howard, Virginia %A Carlson, Christopher S %A Rotimi, Charles N %A Cushman, Mary %A Harris, Tamara B %A Reiner, Alexander P %A Cupples, L Adrienne %A North, Kari E %A Fox, Caroline S %K Adiposity %K African Continental Ancestry Group %K Body Fat Distribution %K European Continental Ancestry Group %K Female %K Genetic Loci %K Genome-Wide Association Study %K Humans %K Male %K Obesity %K Polymorphism, Single Nucleotide %K Waist-Hip Ratio %X

Central obesity, measured by waist circumference (WC) or waist-hip ratio (WHR), is a marker of body fat distribution. Although obesity disproportionately affects minority populations, few studies have conducted genome-wide association study (GWAS) of fat distribution among those of predominantly African ancestry (AA). We performed GWAS of WC and WHR, adjusted and unadjusted for BMI, in up to 33,591 and 27,350 AA individuals, respectively. We identified loci associated with fat distribution in AA individuals using meta-analyses of GWA results for WC and WHR (stage 1). Overall, 25 SNPs with single genomic control (GC)-corrected p-values<5.0 × 10(-6) were followed-up (stage 2) in AA with WC and with WHR. Additionally, we interrogated genomic regions of previously identified European ancestry (EA) WHR loci among AA. In joint analysis of association results including both Stage 1 and 2 cohorts, 2 SNPs demonstrated association, rs2075064 at LHX2, p = 2.24×10(-8) for WC-adjusted-for-BMI, and rs6931262 at RREB1, p = 2.48×10(-8) for WHR-adjusted-for-BMI. However, neither signal was genome-wide significant after double GC-correction (LHX2: p = 6.5 × 10(-8); RREB1: p = 5.7 × 10(-8)). Six of fourteen previously reported loci for waist in EA populations were significant (p<0.05 divided by the number of independent SNPs within the region) in AA studied here (TBX15-WARS2, GRB14, ADAMTS9, LY86, RSPO3, ITPR2-SSPN). Further, we observed associations with metabolic traits: rs13389219 at GRB14 associated with HDL-cholesterol, triglycerides, and fasting insulin, and rs13060013 at ADAMTS9 with HDL-cholesterol and fasting insulin. Finally, we observed nominal evidence for sexual dimorphism, with stronger results in AA women at the GRB14 locus (p for interaction = 0.02). In conclusion, we identified two suggestive loci associated with fat distribution in AA populations in addition to confirming 6 loci previously identified in populations of EA. These findings reinforce the concept that there are fat distribution loci that are independent of generalized adiposity.

%B PLoS Genet %V 9 %P e1003681 %8 2013 %G eng %N 8 %1 http://www.ncbi.nlm.nih.gov/pubmed/23966867?dopt=Abstract %R 10.1371/journal.pgen.1003681 %0 Journal Article %J Genet Epidemiol %D 2013 %T A genome-wide association study for venous thromboembolism: the extended cohorts for heart and aging research in genomic epidemiology (CHARGE) consortium. %A Tang, Weihong %A Teichert, Martina %A Chasman, Daniel I %A Heit, John A %A Morange, Pierre-Emmanuel %A Li, Guo %A Pankratz, Nathan %A Leebeek, Frank W %A Paré, Guillaume %A de Andrade, Mariza %A Tzourio, Christophe %A Psaty, Bruce M %A Basu, Saonli %A Ruiter, Rikje %A Rose, Lynda %A Armasu, Sebastian M %A Lumley, Thomas %A Heckbert, Susan R %A Uitterlinden, André G %A Lathrop, Mark %A Rice, Kenneth M %A Cushman, Mary %A Hofman, Albert %A Lambert, Jean-Charles %A Glazer, Nicole L %A Pankow, James S %A Witteman, Jacqueline C %A Amouyel, Philippe %A Bis, Joshua C %A Bovill, Edwin G %A Kong, Xiaoxiao %A Tracy, Russell P %A Boerwinkle, Eric %A Rotter, Jerome I %A Trégouët, David-Alexandre %A Loth, Daan W %A Stricker, Bruno H Ch %A Ridker, Paul M %A Folsom, Aaron R %A Smith, Nicholas L %K Aged %K Aging %K Case-Control Studies %K Cohort Studies %K Female %K Genome-Wide Association Study %K Humans %K Male %K Meta-Analysis as Topic %K Middle Aged %K Polymorphism, Single Nucleotide %K Regression Analysis %K Risk Factors %K Venous Thromboembolism %X

Venous thromboembolism (VTE) is a common, heritable disease resulting in high rates of hospitalization and mortality. Yet few associations between VTE and genetic variants, all in the coagulation pathway, have been established. To identify additional genetic determinants of VTE, we conducted a two-stage genome-wide association study (GWAS) among individuals of European ancestry in the extended cohorts for heart and aging research in genomic epidemiology (CHARGE) VTE consortium. The discovery GWAS comprised 1,618 incident VTE cases out of 44,499 participants from six community-based studies. Genotypes for genome-wide single-nucleotide polymorphisms (SNPs) were imputed to approximately 2.5 million SNPs in HapMap and association with VTE assessed using study-design appropriate regression methods. Meta-analysis of these results identified two known loci, in F5 and ABO. Top 1,047 tag SNPs (P ≤ 0.0016) from the discovery GWAS were tested for association in an additional 3,231 cases and 3,536 controls from three case-control studies. In the combined data from these two stages, additional genome-wide significant associations were observed on 4q35 at F11 (top SNP rs4253399, intronic to F11) and on 4q28 at FGG (rs6536024, 9.7 kb from FGG; P < 5.0 × 10(-13) for both). The associations at the FGG locus were not completely explained by previously reported variants. Loci at or near SUSD1 and OTUD7A showed borderline yet novel associations (P < 5.0 × 10(-6) ) and constitute new candidate genes. In conclusion, this large GWAS replicated key genetic associations in F5 and ABO, and confirmed the importance of F11 and FGG loci for VTE. Future studies are warranted to better characterize the associations with F11 and FGG and to replicate the new candidate associations.

%B Genet Epidemiol %V 37 %P 512-521 %8 2013 Jul %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/23650146?dopt=Abstract %R 10.1002/gepi.21731 %0 Journal Article %J Circ Cardiovasc Genet %D 2013 %T Genome-wide association study identifies novel loci associated with concentrations of four plasma phospholipid fatty acids in the de novo lipogenesis pathway: results from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortiu %A Wu, Jason H Y %A Lemaitre, Rozenn N %A Manichaikul, Ani %A Guan, Weihua %A Tanaka, Toshiko %A Foy, Millennia %A Kabagambe, Edmond K %A Djoussé, Luc %A Siscovick, David %A Fretts, Amanda M %A Johnson, Catherine %A King, Irena B %A Psaty, Bruce M %A McKnight, Barbara %A Rich, Stephen S %A Chen, Yii-der I %A Nettleton, Jennifer A %A Tang, Weihong %A Bandinelli, Stefania %A Jacobs, David R %A Browning, Brian L %A Laurie, Cathy C %A Gu, Xiangjun %A Tsai, Michael Y %A Steffen, Lyn M %A Ferrucci, Luigi %A Fornage, Myriam %A Mozaffarian, Dariush %K Adult %K Aged %K Chromosomes, Human, Pair 2 %K Cohort Studies %K Coronary Disease %K Diabetes Mellitus, Type 2 %K Fatty Acids, Monounsaturated %K Female %K Genetic Loci %K Genome-Wide Association Study %K Genotype %K Humans %K Linkage Disequilibrium %K Lipogenesis %K Male %K Middle Aged %K Oleic Acid %K Palmitic Acid %K Polymorphism, Single Nucleotide %K Stearic Acids %X

BACKGROUND- Palmitic acid (16:0), stearic acid (18:0), palmitoleic acid (16:1n-7), and oleic acid (18:1n-9) are major saturated and monounsaturated fatty acids that affect cellular signaling and metabolic pathways. They are synthesized via de novo lipogenesis and are the main saturated and monounsaturated fatty acids in the diet. Levels of these fatty acids have been linked to diseases including type 2 diabetes mellitus and coronary heart disease. METHODS AND RESULTS- Genome-wide association studies were conducted in 5 population-based cohorts comprising 8961 participants of European ancestry to investigate the association of common genetic variation with plasma levels of these 4 fatty acids. We identified polymorphisms in 7 novel loci associated with circulating levels of ≥1 of these fatty acids. ALG14 (asparagine-linked glycosylation 14 homolog) polymorphisms were associated with higher 16:0 (P=2.7×10(-11)) and lower 18:0 (P=2.2×10(-18)). FADS1 and FADS2 (desaturases) polymorphisms were associated with higher 16:1n-7 (P=6.6×10(-13)) and 18:1n-9 (P=2.2×10(-32)) and lower 18:0 (P=1.3×10(-20)). LPGAT1 (lysophosphatidylglycerol acyltransferase) polymorphisms were associated with lower 18:0 (P=2.8×10(-9)). GCKR (glucokinase regulator; P=9.8×10(-10)) and HIF1AN (factor inhibiting hypoxia-inducible factor-1; P=5.7×10(-9)) polymorphisms were associated with higher 16:1n-7, whereas PKD2L1 (polycystic kidney disease 2-like 1; P=5.7×10(-15)) and a locus on chromosome 2 (not near known genes) were associated with lower 16:1n-7 (P=4.1×10(-8)). CONCLUSIONS- Our findings provide novel evidence that common variations in genes with diverse functions, including protein-glycosylation, polyunsaturated fatty acid metabolism, phospholipid modeling, and glucose- and oxygen-sensing pathways, are associated with circulating levels of 4 fatty acids in the de novo lipogenesis pathway. These results expand our knowledge of genetic factors relevant to de novo lipogenesis and fatty acid biology.

%B Circ Cardiovasc Genet %V 6 %P 171-83 %8 2013 Apr %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/23362303?dopt=Abstract %R 10.1161/CIRCGENETICS.112.964619 %0 Journal Article %J Circ Cardiovasc Genet %D 2013 %T Genome-wide association study of cardiac structure and systolic function in African Americans: the Candidate Gene Association Resource (CARe) study. %A Fox, Ervin R %A Musani, Solomon K %A Barbalic, Maja %A Lin, Honghuang %A Yu, Bing %A Ogunyankin, Kofo O %A Smith, Nicholas L %A Kutlar, Abdullah %A Glazer, Nicole L %A Post, Wendy S %A Paltoo, Dina N %A Dries, Daniel L %A Farlow, Deborah N %A Duarte, Christine W %A Kardia, Sharon L %A Meyers, Kristin J %A Sun, Yan V %A Arnett, Donna K %A Patki, Amit A %A Sha, Jin %A Cui, Xiangqui %A Samdarshi, Tandaw E %A Penman, Alan D %A Bibbins-Domingo, Kirsten %A Bůzková, Petra %A Benjamin, Emelia J %A Bluemke, David A %A Morrison, Alanna C %A Heiss, Gerardo %A Carr, J Jeffrey %A Tracy, Russell P %A Mosley, Thomas H %A Taylor, Herman A %A Psaty, Bruce M %A Heckbert, Susan R %A Cappola, Thomas P %A Vasan, Ramachandran S %K African Americans %K Aged %K Cohort Studies %K Diastole %K Echocardiography %K European Continental Ancestry Group %K Female %K Genome-Wide Association Study %K Genotype %K Heart %K Humans %K Male %K Middle Aged %K Phenotype %K Polymorphism, Single Nucleotide %K Systole %X

BACKGROUND: Using data from 4 community-based cohorts of African Americans, we tested the association between genome-wide markers (single-nucleotide polymorphisms) and cardiac phenotypes in the Candidate-gene Association Resource study.

METHODS AND RESULTS: Among 6765 African Americans, we related age, sex, height, and weight-adjusted residuals for 9 cardiac phenotypes (assessed by echocardiogram or magnetic resonance imaging) to 2.5 million single-nucleotide polymorphisms genotyped using Genome-wide Affymetrix Human SNP Array 6.0 (Affy6.0) and the remainder imputed. Within the cohort, genome-wide association analysis was conducted, followed by meta-analysis across cohorts using inverse variance weights (genome-wide significance threshold=4.0 ×10(-7)). Supplementary pathway analysis was performed. We attempted replication in 3 smaller cohorts of African ancestry and tested lookups in 1 consortium of European ancestry (EchoGEN). Across the 9 phenotypes, variants in 4 genetic loci reached genome-wide significance: rs4552931 in UBE2V2 (P=1.43×10(-7)) for left ventricular mass, rs7213314 in WIPI1 (P=1.68×10(-7)) for left ventricular internal diastolic diameter, rs1571099 in PPAPDC1A (P=2.57×10(-8)) for interventricular septal wall thickness, and rs9530176 in KLF5 (P=4.02×10(-7)) for ejection fraction. Associated variants were enriched in 3 signaling pathways involved in cardiac remodeling. None of the 4 loci replicated in cohorts of African ancestry was confirmed in lookups in EchoGEN.

CONCLUSIONS: In the largest genome-wide association study of cardiac structure and function to date in African Americans, we identified 4 genetic loci related to left ventricular mass, interventricular septal wall thickness, left ventricular internal diastolic diameter, and ejection fraction, which reached genome-wide significance. Replication results suggest that these loci may be unique to individuals of African ancestry. Additional large-scale studies are warranted for these complex phenotypes.

%B Circ Cardiovasc Genet %V 6 %P 37-46 %8 2013 Feb %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/23275298?dopt=Abstract %R 10.1161/CIRCGENETICS.111.962365 %0 Journal Article %J Biol Psychiatry %D 2013 %T A genome-wide association study of depressive symptoms. %A Hek, Karin %A Demirkan, Ayse %A Lahti, Jari %A Terracciano, Antonio %A Teumer, Alexander %A Cornelis, Marilyn C %A Amin, Najaf %A Bakshis, Erin %A Baumert, Jens %A Ding, Jingzhong %A Liu, Yongmei %A Marciante, Kristin %A Meirelles, Osorio %A Nalls, Michael A %A Sun, Yan V %A Vogelzangs, Nicole %A Yu, Lei %A Bandinelli, Stefania %A Benjamin, Emelia J %A Bennett, David A %A Boomsma, Dorret %A Cannas, Alessandra %A Coker, Laura H %A de Geus, Eco %A De Jager, Philip L %A Diez-Roux, Ana V %A Purcell, Shaun %A Hu, Frank B %A Rimma, Eric B %A Hunter, David J %A Jensen, Majken K %A Curhan, Gary %A Rice, Kenneth %A Penman, Alan D %A Rotter, Jerome I %A Sotoodehnia, Nona %A Emeny, Rebecca %A Eriksson, Johan G %A Evans, Denis A %A Ferrucci, Luigi %A Fornage, Myriam %A Gudnason, Vilmundur %A Hofman, Albert %A Illig, Thomas %A Kardia, Sharon %A Kelly-Hayes, Margaret %A Koenen, Karestan %A Kraft, Peter %A Kuningas, Maris %A Massaro, Joseph M %A Melzer, David %A Mulas, Antonella %A Mulder, Cornelis L %A Murray, Anna %A Oostra, Ben A %A Palotie, Aarno %A Penninx, Brenda %A Petersmann, Astrid %A Pilling, Luke C %A Psaty, Bruce %A Rawal, Rajesh %A Reiman, Eric M %A Schulz, Andrea %A Shulman, Joshua M %A Singleton, Andrew B %A Smith, Albert V %A Sutin, Angelina R %A Uitterlinden, André G %A Völzke, Henry %A Widen, Elisabeth %A Yaffe, Kristine %A Zonderman, Alan B %A Cucca, Francesco %A Harris, Tamara %A Ladwig, Karl-Heinz %A Llewellyn, David J %A Räikkönen, Katri %A Tanaka, Toshiko %A van Duijn, Cornelia M %A Grabe, Hans J %A Launer, Lenore J %A Lunetta, Kathryn L %A Mosley, Thomas H %A Newman, Anne B %A Tiemeier, Henning %A Murabito, Joanne %K Aged %K Aged, 80 and over %K Chromosomes, Human, Pair 5 %K Depression %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %X

BACKGROUND: Depression is a heritable trait that exists on a continuum of varying severity and duration. Yet, the search for genetic variants associated with depression has had few successes. We exploit the entire continuum of depression to find common variants for depressive symptoms.

METHODS: In this genome-wide association study, we combined the results of 17 population-based studies assessing depressive symptoms with the Center for Epidemiological Studies Depression Scale. Replication of the independent top hits (p<1×10(-5)) was performed in five studies assessing depressive symptoms with other instruments. In addition, we performed a combined meta-analysis of all 22 discovery and replication studies.

RESULTS: The discovery sample comprised 34,549 individuals (mean age of 66.5) and no loci reached genome-wide significance (lowest p = 1.05×10(-7)). Seven independent single nucleotide polymorphisms were considered for replication. In the replication set (n = 16,709), we found suggestive association of one single nucleotide polymorphism with depressive symptoms (rs161645, 5q21, p = 9.19×10(-3)). This 5q21 region reached genome-wide significance (p = 4.78×10(-8)) in the overall meta-analysis combining discovery and replication studies (n = 51,258).

CONCLUSIONS: The results suggest that only a large sample comprising more than 50,000 subjects may be sufficiently powered to detect genes for depressive symptoms.

%B Biol Psychiatry %V 73 %P 667-78 %8 2013 Apr 01 %G eng %N 7 %1 http://www.ncbi.nlm.nih.gov/pubmed/23290196?dopt=Abstract %R 10.1016/j.biopsych.2012.09.033 %0 Journal Article %J Hum Mol Genet %D 2013 %T A genome-wide association study of early menopause and the combined impact of identified variants. %A Perry, John R B %A Corre, Tanguy %A Esko, Tõnu %A Chasman, Daniel I %A Fischer, Krista %A Franceschini, Nora %A He, Chunyan %A Kutalik, Zoltán %A Mangino, Massimo %A Rose, Lynda M %A Vernon Smith, Albert %A Stolk, Lisette %A Sulem, Patrick %A Weedon, Michael N %A Zhuang, Wei V %A Arnold, Alice %A Ashworth, Alan %A Bergmann, Sven %A Buring, Julie E %A Burri, Andrea %A Chen, Constance %A Cornelis, Marilyn C %A Couper, David J %A Goodarzi, Mark O %A Gudnason, Vilmundur %A Harris, Tamara %A Hofman, Albert %A Jones, Michael %A Kraft, Peter %A Launer, Lenore %A Laven, Joop S E %A Li, Guo %A McKnight, Barbara %A Masciullo, Corrado %A Milani, Lili %A Orr, Nicholas %A Psaty, Bruce M %A Ridker, Paul M %A Rivadeneira, Fernando %A Sala, Cinzia %A Salumets, Andres %A Schoemaker, Minouk %A Traglia, Michela %A Waeber, Gérard %A Chanock, Stephen J %A Demerath, Ellen W %A Garcia, Melissa %A Hankinson, Susan E %A Hu, Frank B %A Hunter, David J %A Lunetta, Kathryn L %A Metspalu, Andres %A Montgomery, Grant W %A Murabito, Joanne M %A Newman, Anne B %A Ong, Ken K %A Spector, Tim D %A Stefansson, Kari %A Swerdlow, Anthony J %A Thorsteinsdottir, Unnur %A van Dam, Rob M %A Uitterlinden, André G %A Visser, Jenny A %A Vollenweider, Peter %A Toniolo, Daniela %A Murray, Anna %K Case-Control Studies %K Female %K Gene Frequency %K Genome-Wide Association Study %K Humans %K Menopause, Premature %K Polymorphism, Single Nucleotide %K Primary Ovarian Insufficiency %K Quantitative Trait Loci %K Risk %X

Early menopause (EM) affects up to 10% of the female population, reducing reproductive lifespan considerably. Currently, it constitutes the leading cause of infertility in the western world, affecting mainly those women who postpone their first pregnancy beyond the age of 30 years. The genetic aetiology of EM is largely unknown in the majority of cases. We have undertaken a meta-analysis of genome-wide association studies (GWASs) in 3493 EM cases and 13 598 controls from 10 independent studies. No novel genetic variants were discovered, but the 17 variants previously associated with normal age at natural menopause as a quantitative trait (QT) were also associated with EM and primary ovarian insufficiency (POI). Thus, EM has a genetic aetiology which overlaps variation in normal age at menopause and is at least partly explained by the additive effects of the same polygenic variants. The combined effect of the common variants captured by the single nucleotide polymorphism arrays was estimated to account for ∼30% of the variance in EM. The association between the combined 17 variants and the risk of EM was greater than the best validated non-genetic risk factor, smoking.

%B Hum Mol Genet %V 22 %P 1465-72 %8 2013 Apr 01 %G eng %N 7 %1 http://www.ncbi.nlm.nih.gov/pubmed/23307926?dopt=Abstract %R 10.1093/hmg/dds551 %0 Journal Article %J PLoS One %D 2013 %T Genome-wide association study of retinopathy in individuals without diabetes. %A Jensen, Richard A %A Sim, Xueling %A Li, Xiaohui %A Cotch, Mary Frances %A Ikram, M Kamran %A Holliday, Elizabeth G %A Eiriksdottir, Gudny %A Harris, Tamara B %A Jonasson, Fridbert %A Klein, Barbara E K %A Launer, Lenore J %A Smith, Albert Vernon %A Boerwinkle, Eric %A Cheung, Ning %A Hewitt, Alex W %A Liew, Gerald %A Mitchell, Paul %A Wang, Jie Jin %A Attia, John %A Scott, Rodney %A Glazer, Nicole L %A Lumley, Thomas %A McKnight, Barbara %A Psaty, Bruce M %A Taylor, Kent %A Hofman, Albert %A de Jong, Paulus T V M %A Rivadeneira, Fernando %A Uitterlinden, André G %A Tay, Wan-Ting %A Teo, Yik Ying %A Seielstad, Mark %A Liu, Jianjun %A Cheng, Ching-Yu %A Saw, Seang-Mei %A Aung, Tin %A Ganesh, Santhi K %A O'Donnell, Christopher J %A Nalls, Mike A %A Wiggins, Kerri L %A Kuo, Jane Z %A van Duijn, Cornelia M %A Gudnason, Vilmundur %A Klein, Ronald %A Siscovick, David S %A Rotter, Jerome I %A Tai, E Shong %A Vingerling, Johannes %A Wong, Tien Y %K Aged %K Aged, 80 and over %K Female %K Genome-Wide Association Study %K Genotype %K Histone Deacetylases %K Humans %K Hypertension %K Male %K Polymorphism, Single Nucleotide %K Repressor Proteins %K Retinal Diseases %X

BACKGROUND: Mild retinopathy (microaneurysms or dot-blot hemorrhages) is observed in persons without diabetes or hypertension and may reflect microvascular disease in other organs. We conducted a genome-wide association study (GWAS) of mild retinopathy in persons without diabetes.

METHODS: A working group agreed on phenotype harmonization, covariate selection and analytic plans for within-cohort GWAS. An inverse-variance weighted fixed effects meta-analysis was performed with GWAS results from six cohorts of 19,411 Caucasians. The primary analysis included individuals without diabetes and secondary analyses were stratified by hypertension status. We also singled out the results from single nucleotide polymorphisms (SNPs) previously shown to be associated with diabetes and hypertension, the two most common causes of retinopathy.

RESULTS: No SNPs reached genome-wide significance in the primary analysis or the secondary analysis of participants with hypertension. SNP, rs12155400, in the histone deacetylase 9 gene (HDAC9) on chromosome 7, was associated with retinopathy in analysis of participants without hypertension, -1.3±0.23 (beta ± standard error), p = 6.6×10(-9). Evidence suggests this was a false positive finding. The minor allele frequency was low (∼2%), the quality of the imputation was moderate (r(2) ∼0.7), and no other common variants in the HDAC9 gene were associated with the outcome. SNPs found to be associated with diabetes and hypertension in other GWAS were not associated with retinopathy in persons without diabetes or in subgroups with or without hypertension.

CONCLUSIONS: This GWAS of retinopathy in individuals without diabetes showed little evidence of genetic associations. Further studies are needed to identify genes associated with these signs in order to help unravel novel pathways and determinants of microvascular diseases.

%B PLoS One %V 8 %P e54232 %8 2013 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/23393555?dopt=Abstract %R 10.1371/journal.pone.0054232 %0 Journal Article %J Nat Genet %D 2013 %T Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture. %A Berndt, Sonja I %A Gustafsson, Stefan %A Mägi, Reedik %A Ganna, Andrea %A Wheeler, Eleanor %A Feitosa, Mary F %A Justice, Anne E %A Monda, Keri L %A Croteau-Chonka, Damien C %A Day, Felix R %A Esko, Tõnu %A Fall, Tove %A Ferreira, Teresa %A Gentilini, Davide %A Jackson, Anne U %A Luan, Jian'an %A Randall, Joshua C %A Vedantam, Sailaja %A Willer, Cristen J %A Winkler, Thomas W %A Wood, Andrew R %A Workalemahu, Tsegaselassie %A Hu, Yi-Juan %A Lee, Sang Hong %A Liang, Liming %A Lin, Dan-Yu %A Min, Josine L %A Neale, Benjamin M %A Thorleifsson, Gudmar %A Yang, Jian %A Albrecht, Eva %A Amin, Najaf %A Bragg-Gresham, Jennifer L %A Cadby, Gemma %A den Heijer, Martin %A Eklund, Niina %A Fischer, Krista %A Goel, Anuj %A Hottenga, Jouke-Jan %A Huffman, Jennifer E %A Jarick, Ivonne %A Johansson, Asa %A Johnson, Toby %A Kanoni, Stavroula %A Kleber, Marcus E %A König, Inke R %A Kristiansson, Kati %A Kutalik, Zoltán %A Lamina, Claudia %A Lecoeur, Cécile %A Li, Guo %A Mangino, Massimo %A McArdle, Wendy L %A Medina-Gómez, Carolina %A Müller-Nurasyid, Martina %A Ngwa, Julius S %A Nolte, Ilja M %A Paternoster, Lavinia %A Pechlivanis, Sonali %A Perola, Markus %A Peters, Marjolein J %A Preuss, Michael %A Rose, Lynda M %A Shi, Jianxin %A Shungin, Dmitry %A Smith, Albert Vernon %A Strawbridge, Rona J %A Surakka, Ida %A Teumer, Alexander %A Trip, Mieke D %A Tyrer, Jonathan %A van Vliet-Ostaptchouk, Jana V %A Vandenput, Liesbeth %A Waite, Lindsay L %A Zhao, Jing Hua %A Absher, Devin %A Asselbergs, Folkert W %A Atalay, Mustafa %A Attwood, Antony P %A Balmforth, Anthony J %A Basart, Hanneke %A Beilby, John %A Bonnycastle, Lori L %A Brambilla, Paolo %A Bruinenberg, Marcel %A Campbell, Harry %A Chasman, Daniel I %A Chines, Peter S %A Collins, Francis S %A Connell, John M %A Cookson, William O %A de Faire, Ulf %A de Vegt, Femmie %A Dei, Mariano %A Dimitriou, Maria %A Edkins, Sarah %A Estrada, Karol %A Evans, David M %A Farrall, Martin %A Ferrario, Marco M %A Ferrieres, Jean %A Franke, Lude %A Frau, Francesca %A Gejman, Pablo V %A Grallert, Harald %A Grönberg, Henrik %A Gudnason, Vilmundur %A Hall, Alistair S %A Hall, Per %A Hartikainen, Anna-Liisa %A Hayward, Caroline %A Heard-Costa, Nancy L %A Heath, Andrew C %A Hebebrand, Johannes %A Homuth, Georg %A Hu, Frank B %A Hunt, Sarah E %A Hyppönen, Elina %A Iribarren, Carlos %A Jacobs, Kevin B %A Jansson, John-Olov %A Jula, Antti %A Kähönen, Mika %A Kathiresan, Sekar %A Kee, Frank %A Khaw, Kay-Tee %A Kivimaki, Mika %A Koenig, Wolfgang %A Kraja, Aldi T %A Kumari, Meena %A Kuulasmaa, Kari %A Kuusisto, Johanna %A Laitinen, Jaana H %A Lakka, Timo A %A Langenberg, Claudia %A Launer, Lenore J %A Lind, Lars %A Lindström, Jaana %A Liu, Jianjun %A Liuzzi, Antonio %A Lokki, Marja-Liisa %A Lorentzon, Mattias %A Madden, Pamela A %A Magnusson, Patrik K %A Manunta, Paolo %A Marek, Diana %A März, Winfried %A Mateo Leach, Irene %A McKnight, Barbara %A Medland, Sarah E %A Mihailov, Evelin %A Milani, Lili %A Montgomery, Grant W %A Mooser, Vincent %A Mühleisen, Thomas W %A Munroe, Patricia B %A Musk, Arthur W %A Narisu, Narisu %A Navis, Gerjan %A Nicholson, George %A Nohr, Ellen A %A Ong, Ken K %A Oostra, Ben A %A Palmer, Colin N A %A Palotie, Aarno %A Peden, John F %A Pedersen, Nancy %A Peters, Annette %A Polasek, Ozren %A Pouta, Anneli %A Pramstaller, Peter P %A Prokopenko, Inga %A Pütter, Carolin %A Radhakrishnan, Aparna %A Raitakari, Olli %A Rendon, Augusto %A Rivadeneira, Fernando %A Rudan, Igor %A Saaristo, Timo E %A Sambrook, Jennifer G %A Sanders, Alan R %A Sanna, Serena %A Saramies, Jouko %A Schipf, Sabine %A Schreiber, Stefan %A Schunkert, Heribert %A Shin, So-Youn %A Signorini, Stefano %A Sinisalo, Juha %A Skrobek, Boris %A Soranzo, Nicole %A Stančáková, Alena %A Stark, Klaus %A Stephens, Jonathan C %A Stirrups, Kathleen %A Stolk, Ronald P %A Stumvoll, Michael %A Swift, Amy J %A Theodoraki, Eirini V %A Thorand, Barbara %A Trégouët, David-Alexandre %A Tremoli, Elena %A van der Klauw, Melanie M %A van Meurs, Joyce B J %A Vermeulen, Sita H %A Viikari, Jorma %A Virtamo, Jarmo %A Vitart, Veronique %A Waeber, Gérard %A Wang, Zhaoming %A Widen, Elisabeth %A Wild, Sarah H %A Willemsen, Gonneke %A Winkelmann, Bernhard R %A Witteman, Jacqueline C M %A Wolffenbuttel, Bruce H R %A Wong, Andrew %A Wright, Alan F %A Zillikens, M Carola %A Amouyel, Philippe %A Boehm, Bernhard O %A Boerwinkle, Eric %A Boomsma, Dorret I %A Caulfield, Mark J %A Chanock, Stephen J %A Cupples, L Adrienne %A Cusi, Daniele %A Dedoussis, George V %A Erdmann, Jeanette %A Eriksson, Johan G %A Franks, Paul W %A Froguel, Philippe %A Gieger, Christian %A Gyllensten, Ulf %A Hamsten, Anders %A Harris, Tamara B %A Hengstenberg, Christian %A Hicks, Andrew A %A Hingorani, Aroon %A Hinney, Anke %A Hofman, Albert %A Hovingh, Kees G %A Hveem, Kristian %A Illig, Thomas %A Jarvelin, Marjo-Riitta %A Jöckel, Karl-Heinz %A Keinanen-Kiukaanniemi, Sirkka M %A Kiemeney, Lambertus A %A Kuh, Diana %A Laakso, Markku %A Lehtimäki, Terho %A Levinson, Douglas F %A Martin, Nicholas G %A Metspalu, Andres %A Morris, Andrew D %A Nieminen, Markku S %A Njølstad, Inger %A Ohlsson, Claes %A Oldehinkel, Albertine J %A Ouwehand, Willem H %A Palmer, Lyle J %A Penninx, Brenda %A Power, Chris %A Province, Michael A %A Psaty, Bruce M %A Qi, Lu %A Rauramaa, Rainer %A Ridker, Paul M %A Ripatti, Samuli %A Salomaa, Veikko %A Samani, Nilesh J %A Snieder, Harold %A Sørensen, Thorkild I A %A Spector, Timothy D %A Stefansson, Kari %A Tönjes, Anke %A Tuomilehto, Jaakko %A Uitterlinden, André G %A Uusitupa, Matti %A van der Harst, Pim %A Vollenweider, Peter %A Wallaschofski, Henri %A Wareham, Nicholas J %A Watkins, Hugh %A Wichmann, H-Erich %A Wilson, James F %A Abecasis, Goncalo R %A Assimes, Themistocles L %A Barroso, Inês %A Boehnke, Michael %A Borecki, Ingrid B %A Deloukas, Panos %A Fox, Caroline S %A Frayling, Timothy %A Groop, Leif C %A Haritunian, Talin %A Heid, Iris M %A Hunter, David %A Kaplan, Robert C %A Karpe, Fredrik %A Moffatt, Miriam F %A Mohlke, Karen L %A O'Connell, Jeffrey R %A Pawitan, Yudi %A Schadt, Eric E %A Schlessinger, David %A Steinthorsdottir, Valgerdur %A Strachan, David P %A Thorsteinsdottir, Unnur %A van Duijn, Cornelia M %A Visscher, Peter M %A Di Blasio, Anna Maria %A Hirschhorn, Joel N %A Lindgren, Cecilia M %A Morris, Andrew P %A Meyre, David %A Scherag, Andre %A McCarthy, Mark I %A Speliotes, Elizabeth K %A North, Kari E %A Loos, Ruth J F %A Ingelsson, Erik %K Anthropometry %K Body Height %K Body Mass Index %K Case-Control Studies %K European Continental Ancestry Group %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genotype %K Humans %K Meta-Analysis as Topic %K Obesity %K Phenotype %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %K Waist-Hip Ratio %X

Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.

%B Nat Genet %V 45 %P 501-12 %8 2013 May %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/23563607?dopt=Abstract %R 10.1038/ng.2606 %0 Journal Article %J Am J Clin Nutr %D 2013 %T Genome-wide meta-analysis of observational studies shows common genetic variants associated with macronutrient intake. %A Tanaka, Toshiko %A Ngwa, Julius S %A van Rooij, Frank J A %A Zillikens, M Carola %A Wojczynski, Mary K %A Frazier-Wood, Alexis C %A Houston, Denise K %A Kanoni, Stavroula %A Lemaitre, Rozenn N %A Luan, Jian'an %A Mikkilä, Vera %A Renstrom, Frida %A Sonestedt, Emily %A Zhao, Jing Hua %A Chu, Audrey Y %A Qi, Lu %A Chasman, Daniel I %A de Oliveira Otto, Marcia C %A Dhurandhar, Emily J %A Feitosa, Mary F %A Johansson, Ingegerd %A Khaw, Kay-Tee %A Lohman, Kurt K %A Manichaikul, Ani %A McKeown, Nicola M %A Mozaffarian, Dariush %A Singleton, Andrew %A Stirrups, Kathleen %A Viikari, Jorma %A Ye, Zheng %A Bandinelli, Stefania %A Barroso, Inês %A Deloukas, Panos %A Forouhi, Nita G %A Hofman, Albert %A Liu, Yongmei %A Lyytikäinen, Leo-Pekka %A North, Kari E %A Dimitriou, Maria %A Hallmans, Göran %A Kähönen, Mika %A Langenberg, Claudia %A Ordovas, Jose M %A Uitterlinden, André G %A Hu, Frank B %A Kalafati, Ioanna-Panagiota %A Raitakari, Olli %A Franco, Oscar H %A Johnson, Andrew %A Emilsson, Valur %A Schrack, Jennifer A %A Semba, Richard D %A Siscovick, David S %A Arnett, Donna K %A Borecki, Ingrid B %A Franks, Paul W %A Kritchevsky, Stephen B %A Lehtimäki, Terho %A Loos, Ruth J F %A Orho-Melander, Marju %A Rotter, Jerome I %A Wareham, Nicholas J %A Witteman, Jacqueline C M %A Ferrucci, Luigi %A Dedoussis, George %A Cupples, L Adrienne %A Nettleton, Jennifer A %K Alleles %K Atherosclerosis %K Body Mass Index %K Dietary Carbohydrates %K Dietary Fats %K Dietary Proteins %K Energy Intake %K European Continental Ancestry Group %K Fibroblast Growth Factors %K Follow-Up Studies %K Gene-Environment Interaction %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genotype %K Humans %K Life Style %K Obesity %K Polymorphism, Single Nucleotide %K Prospective Studies %K Quantitative Trait Loci %K Surveys and Questionnaires %X

BACKGROUND: Macronutrient intake varies substantially between individuals, and there is evidence that this variation is partly accounted for by genetic variants.

OBJECTIVE: The objective of the study was to identify common genetic variants that are associated with macronutrient intake.

DESIGN: We performed 2-stage genome-wide association (GWA) meta-analysis of macronutrient intake in populations of European descent. Macronutrients were assessed by using food-frequency questionnaires and analyzed as percentages of total energy consumption from total fat, protein, and carbohydrate. From the discovery GWA (n = 38,360), 35 independent loci associated with macronutrient intake at P < 5 × 10(-6) were identified and taken forward to replication in 3 additional cohorts (n = 33,533) from the DietGen Consortium. For one locus, fat mass obesity-associated protein (FTO), cohorts with Illumina MetaboChip genotype data (n = 7724) provided additional replication data.

RESULTS: A variant in the chromosome 19 locus (rs838145) was associated with higher carbohydrate (β ± SE: 0.25 ± 0.04%; P = 1.68 × 10(-8)) and lower fat (β ± SE: -0.21 ± 0.04%; P = 1.57 × 10(-9)) consumption. A candidate gene in this region, fibroblast growth factor 21 (FGF21), encodes a fibroblast growth factor involved in glucose and lipid metabolism. The variants in this locus were associated with circulating FGF21 protein concentrations (P < 0.05) but not mRNA concentrations in blood or brain. The body mass index (BMI)-increasing allele of the FTO variant (rs1421085) was associated with higher protein intake (β ± SE: 0.10 ± 0.02%; P = 9.96 × 10(-10)), independent of BMI (after adjustment for BMI, β ± SE: 0.08 ± 0.02%; P = 3.15 × 10(-7)).

CONCLUSION: Our results indicate that variants in genes involved in nutrient metabolism and obesity are associated with macronutrient consumption in humans. Trials related to this study were registered at clinicaltrials.gov as NCT00005131 (Atherosclerosis Risk in Communities), NCT00005133 (Cardiovascular Health Study), NCT00005136 (Family Heart Study), NCT00005121 (Framingham Heart Study), NCT00083369 (Genetic and Environmental Determinants of Triglycerides), NCT01331512 (InCHIANTI Study), and NCT00005487 (Multi-Ethnic Study of Atherosclerosis).

%B Am J Clin Nutr %V 97 %P 1395-402 %8 2013 Jun %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/23636237?dopt=Abstract %R 10.3945/ajcn.112.052183 %0 Journal Article %J Hum Genet %D 2013 %T Genome-wide study identifies two loci associated with lung function decline in mild to moderate COPD. %A Hansel, Nadia N %A Ruczinski, Ingo %A Rafaels, Nicholas %A Sin, Don D %A Daley, Denise %A Malinina, Alla %A Huang, Lili %A Sandford, Andrew %A Murray, Tanda %A Kim, Yoonhee %A Vergara, Candelaria %A Heckbert, Susan R %A Psaty, Bruce M %A Li, Guo %A Elliott, W Mark %A Aminuddin, Farzian %A Dupuis, Josée %A O'Connor, George T %A Doheny, Kimberly %A Scott, Alan F %A Boezen, H Marike %A Postma, Dirkje S %A Smolonska, Joanna %A Zanen, Pieter %A Mohamed Hoesein, Firdaus A %A de Koning, Harry J %A Crystal, Ronald G %A Tanaka, Toshiko %A Ferrucci, Luigi %A Silverman, Edwin %A Wan, Emily %A Vestbo, Jorgen %A Lomas, David A %A Connett, John %A Wise, Robert A %A Neptune, Enid R %A Mathias, Rasika A %A Paré, Peter D %A Beaty, Terri H %A Barnes, Kathleen C %K Adult %K Ankyrins %K Chromosomes, Human, Pair 10 %K Chromosomes, Human, Pair 14 %K Cohort Studies %K Female %K Genome-Wide Association Study %K Hepatocyte Nuclear Factor 3-alpha %K Humans %K Linkage Disequilibrium %K Lung %K Male %K Membrane Proteins %K Middle Aged %K Polymorphism, Single Nucleotide %K Pulmonary Disease, Chronic Obstructive %X

Accelerated lung function decline is a key COPD phenotype; however, its genetic control remains largely unknown. We performed a genome-wide association study using the Illumina Human660W-Quad v.1_A BeadChip. Generalized estimation equations were used to assess genetic contributions to lung function decline over a 5-year period in 4,048 European American Lung Health Study participants with largely mild COPD. Genotype imputation was performed using reference HapMap II data. To validate regions meeting genome-wide significance, replication of top SNPs was attempted in independent cohorts. Three genes (TMEM26, ANK3 and FOXA1) within the regions of interest were selected for tissue expression studies using immunohistochemistry. Two intergenic SNPs (rs10761570, rs7911302) on chromosome 10 and one SNP on chromosome 14 (rs177852) met genome-wide significance after Bonferroni. Further support for the chromosome 10 region was obtained by imputation, the most significantly associated imputed SNPs (rs10761571, rs7896712) being flanked by observed markers rs10761570 and rs7911302. Results were not replicated in four general population cohorts or a smaller cohort of subjects with moderate to severe COPD; however, we show novel expression of genes near regions of significantly associated SNPS, including TMEM26 and FOXA1 in airway epithelium and lung parenchyma, and ANK3 in alveolar macrophages. Levels of expression were associated with lung function and COPD status. We identified two novel regions associated with lung function decline in mild COPD. Genes within these regions were expressed in relevant lung cells and their expression related to airflow limitation suggesting they may represent novel candidate genes for COPD susceptibility.

%B Hum Genet %V 132 %P 79-90 %8 2013 Jan %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/22986903?dopt=Abstract %R 10.1007/s00439-012-1219-6 %0 Journal Article %J Nat Genet %D 2013 %T Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders. %A den Hoed, Marcel %A Eijgelsheim, Mark %A Esko, Tõnu %A Brundel, Bianca J J M %A Peal, David S %A Evans, David M %A Nolte, Ilja M %A Segrè, Ayellet V %A Holm, Hilma %A Handsaker, Robert E %A Westra, Harm-Jan %A Johnson, Toby %A Isaacs, Aaron %A Yang, Jian %A Lundby, Alicia %A Zhao, Jing Hua %A Kim, Young Jin %A Go, Min Jin %A Almgren, Peter %A Bochud, Murielle %A Boucher, Gabrielle %A Cornelis, Marilyn C %A Gudbjartsson, Daniel %A Hadley, David %A van der Harst, Pim %A Hayward, Caroline %A den Heijer, Martin %A Igl, Wilmar %A Jackson, Anne U %A Kutalik, Zoltán %A Luan, Jian'an %A Kemp, John P %A Kristiansson, Kati %A Ladenvall, Claes %A Lorentzon, Mattias %A Montasser, May E %A Njajou, Omer T %A O'Reilly, Paul F %A Padmanabhan, Sandosh %A St Pourcain, Beate %A Rankinen, Tuomo %A Salo, Perttu %A Tanaka, Toshiko %A Timpson, Nicholas J %A Vitart, Veronique %A Waite, Lindsay %A Wheeler, William %A Zhang, Weihua %A Draisma, Harmen H M %A Feitosa, Mary F %A Kerr, Kathleen F %A Lind, Penelope A %A Mihailov, Evelin %A Onland-Moret, N Charlotte %A Song, Ci %A Weedon, Michael N %A Xie, Weijia %A Yengo, Loic %A Absher, Devin %A Albert, Christine M %A Alonso, Alvaro %A Arking, Dan E %A de Bakker, Paul I W %A Balkau, Beverley %A Barlassina, Cristina %A Benaglio, Paola %A Bis, Joshua C %A Bouatia-Naji, Nabila %A Brage, Søren %A Chanock, Stephen J %A Chines, Peter S %A Chung, Mina %A Darbar, Dawood %A Dina, Christian %A Dörr, Marcus %A Elliott, Paul %A Felix, Stephan B %A Fischer, Krista %A Fuchsberger, Christian %A de Geus, Eco J C %A Goyette, Philippe %A Gudnason, Vilmundur %A Harris, Tamara B %A Hartikainen, Anna-Liisa %A Havulinna, Aki S %A Heckbert, Susan R %A Hicks, Andrew A %A Hofman, Albert %A Holewijn, Suzanne %A Hoogstra-Berends, Femke %A Hottenga, Jouke-Jan %A Jensen, Majken K %A Johansson, Asa %A Junttila, Juhani %A Kääb, Stefan %A Kanon, Bart %A Ketkar, Shamika %A Khaw, Kay-Tee %A Knowles, Joshua W %A Kooner, Angrad S %A Kors, Jan A %A Kumari, Meena %A Milani, Lili %A Laiho, Päivi %A Lakatta, Edward G %A Langenberg, Claudia %A Leusink, Maarten %A Liu, Yongmei %A Luben, Robert N %A Lunetta, Kathryn L %A Lynch, Stacey N %A Markus, Marcello R P %A Marques-Vidal, Pedro %A Mateo Leach, Irene %A McArdle, Wendy L %A McCarroll, Steven A %A Medland, Sarah E %A Miller, Kathryn A %A Montgomery, Grant W %A Morrison, Alanna C %A Müller-Nurasyid, Martina %A Navarro, Pau %A Nelis, Mari %A O'Connell, Jeffrey R %A O'Donnell, Christopher J %A Ong, Ken K %A Newman, Anne B %A Peters, Annette %A Polasek, Ozren %A Pouta, Anneli %A Pramstaller, Peter P %A Psaty, Bruce M %A Rao, Dabeeru C %A Ring, Susan M %A Rossin, Elizabeth J %A Rudan, Diana %A Sanna, Serena %A Scott, Robert A %A Sehmi, Jaban S %A Sharp, Stephen %A Shin, Jordan T %A Singleton, Andrew B %A Smith, Albert V %A Soranzo, Nicole %A Spector, Tim D %A Stewart, Chip %A Stringham, Heather M %A Tarasov, Kirill V %A Uitterlinden, André G %A Vandenput, Liesbeth %A Hwang, Shih-Jen %A Whitfield, John B %A Wijmenga, Cisca %A Wild, Sarah H %A Willemsen, Gonneke %A Wilson, James F %A Witteman, Jacqueline C M %A Wong, Andrew %A Wong, Quenna %A Jamshidi, Yalda %A Zitting, Paavo %A Boer, Jolanda M A %A Boomsma, Dorret I %A Borecki, Ingrid B %A van Duijn, Cornelia M %A Ekelund, Ulf %A Forouhi, Nita G %A Froguel, Philippe %A Hingorani, Aroon %A Ingelsson, Erik %A Kivimaki, Mika %A Kronmal, Richard A %A Kuh, Diana %A Lind, Lars %A Martin, Nicholas G %A Oostra, Ben A %A Pedersen, Nancy L %A Quertermous, Thomas %A Rotter, Jerome I %A van der Schouw, Yvonne T %A Verschuren, W M Monique %A Walker, Mark %A Albanes, Demetrius %A Arnar, David O %A Assimes, Themistocles L %A Bandinelli, Stefania %A Boehnke, Michael %A de Boer, Rudolf A %A Bouchard, Claude %A Caulfield, W L Mark %A Chambers, John C %A Curhan, Gary %A Cusi, Daniele %A Eriksson, Johan %A Ferrucci, Luigi %A van Gilst, Wiek H %A Glorioso, Nicola %A de Graaf, Jacqueline %A Groop, Leif %A Gyllensten, Ulf %A Hsueh, Wen-Chi %A Hu, Frank B %A Huikuri, Heikki V %A Hunter, David J %A Iribarren, Carlos %A Isomaa, Bo %A Jarvelin, Marjo-Riitta %A Jula, Antti %A Kähönen, Mika %A Kiemeney, Lambertus A %A van der Klauw, Melanie M %A Kooner, Jaspal S %A Kraft, Peter %A Iacoviello, Licia %A Lehtimäki, Terho %A Lokki, Marja-Liisa L %A Mitchell, Braxton D %A Navis, Gerjan %A Nieminen, Markku S %A Ohlsson, Claes %A Poulter, Neil R %A Qi, Lu %A Raitakari, Olli T %A Rimm, Eric B %A Rioux, John D %A Rizzi, Federica %A Rudan, Igor %A Salomaa, Veikko %A Sever, Peter S %A Shields, Denis C %A Shuldiner, Alan R %A Sinisalo, Juha %A Stanton, Alice V %A Stolk, Ronald P %A Strachan, David P %A Tardif, Jean-Claude %A Thorsteinsdottir, Unnur %A Tuomilehto, Jaako %A van Veldhuisen, Dirk J %A Virtamo, Jarmo %A Viikari, Jorma %A Vollenweider, Peter %A Waeber, Gérard %A Widen, Elisabeth %A Cho, Yoon Shin %A Olsen, Jesper V %A Visscher, Peter M %A Willer, Cristen %A Franke, Lude %A Erdmann, Jeanette %A Thompson, John R %A Pfeufer, Arne %A Sotoodehnia, Nona %A Newton-Cheh, Christopher %A Ellinor, Patrick T %A Stricker, Bruno H Ch %A Metspalu, Andres %A Perola, Markus %A Beckmann, Jacques S %A Smith, George Davey %A Stefansson, Kari %A Wareham, Nicholas J %A Munroe, Patricia B %A Sibon, Ody C M %A Milan, David J %A Snieder, Harold %A Samani, Nilesh J %A Loos, Ruth J F %K Animals %K Arrhythmias, Cardiac %K Gene Frequency %K Genetic Loci %K Genome-Wide Association Study %K Heart Conduction System %K Heart Rate %K Humans %K Metabolic Networks and Pathways %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %X

Elevated resting heart rate is associated with greater risk of cardiovascular disease and mortality. In a 2-stage meta-analysis of genome-wide association studies in up to 181,171 individuals, we identified 14 new loci associated with heart rate and confirmed associations with all 7 previously established loci. Experimental downregulation of gene expression in Drosophila melanogaster and Danio rerio identified 20 genes at 11 loci that are relevant for heart rate regulation and highlight a role for genes involved in signal transmission, embryonic cardiac development and the pathophysiology of dilated cardiomyopathy, congenital heart failure and/or sudden cardiac death. In addition, genetic susceptibility to increased heart rate is associated with altered cardiac conduction and reduced risk of sick sinus syndrome, and both heart rate-increasing and heart rate-decreasing variants associate with risk of atrial fibrillation. Our findings provide fresh insights into the mechanisms regulating heart rate and identify new therapeutic targets.

%B Nat Genet %V 45 %P 621-31 %8 2013 Jun %G eng %N 6 %R 10.1038/ng.2610 %0 Journal Article %J PLoS One %D 2013 %T Insights into the genetic architecture of early stage age-related macular degeneration: a genome-wide association study meta-analysis. %A Holliday, Elizabeth G %A Smith, Albert V %A Cornes, Belinda K %A Buitendijk, Gabriëlle H S %A Jensen, Richard A %A Sim, Xueling %A Aspelund, Thor %A Aung, Tin %A Baird, Paul N %A Boerwinkle, Eric %A Cheng, Ching Yu %A van Duijn, Cornelia M %A Eiriksdottir, Gudny %A Gudnason, Vilmundur %A Harris, Tamara %A Hewitt, Alex W %A Inouye, Michael %A Jonasson, Fridbert %A Klein, Barbara E K %A Launer, Lenore %A Li, Xiaohui %A Liew, Gerald %A Lumley, Thomas %A McElduff, Patrick %A McKnight, Barbara %A Mitchell, Paul %A Psaty, Bruce M %A Rochtchina, Elena %A Rotter, Jerome I %A Scott, Rodney J %A Tay, Wanting %A Taylor, Kent %A Teo, Yik Ying %A Uitterlinden, André G %A Viswanathan, Ananth %A Xie, Sophia %A Vingerling, Johannes R %A Klaver, Caroline C W %A Tai, E Shyong %A Siscovick, David %A Klein, Ronald %A Cotch, Mary Frances %A Wong, Tien Y %A Attia, John %A Wang, Jie Jin %K Apolipoproteins E %K Complement Factor H %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genotype %K Humans %K Kruppel-Like Transcription Factors %K Macular Degeneration %K Nerve Tissue Proteins %K Polymorphism, Single Nucleotide %K Proteins %K Risk Factors %K Zinc Finger Protein Gli3 %X

Genetic factors explain a majority of risk variance for age-related macular degeneration (AMD). While genome-wide association studies (GWAS) for late AMD implicate genes in complement, inflammatory and lipid pathways, the genetic architecture of early AMD has been relatively under studied. We conducted a GWAS meta-analysis of early AMD, including 4,089 individuals with prevalent signs of early AMD (soft drusen and/or retinal pigment epithelial changes) and 20,453 individuals without these signs. For various published late AMD risk loci, we also compared effect sizes between early and late AMD using an additional 484 individuals with prevalent late AMD. GWAS meta-analysis confirmed previously reported association of variants at the complement factor H (CFH) (peak P = 1.5×10(-31)) and age-related maculopathy susceptibility 2 (ARMS2) (P = 4.3×10(-24)) loci, and suggested Apolipoprotein E (ApoE) polymorphisms (rs2075650; P = 1.1×10(-6)) associated with early AMD. Other possible loci that did not reach GWAS significance included variants in the zinc finger protein gene GLI3 (rs2049622; P = 8.9×10(-6)) and upstream of GLI2 (rs6721654; P = 6.5×10(-6)), encoding retinal Sonic hedgehog signalling regulators, and in the tyrosinase (TYR) gene (rs621313; P = 3.5×10(-6)), involved in melanin biosynthesis. For a range of published, late AMD risk loci, estimated effect sizes were significantly lower for early than late AMD. This study confirms the involvement of multiple established AMD risk variants in early AMD, but suggests weaker genetic effects on the risk of early AMD relative to late AMD. Several biological processes were suggested to be potentially specific for early AMD, including pathways regulating RPE cell melanin content and signalling pathways potentially involved in retinal regeneration, generating hypotheses for further investigation.

%B PLoS One %V 8 %P e53830 %8 2013 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/23326517?dopt=Abstract %R 10.1371/journal.pone.0053830 %0 Journal Article %J BMC Genet %D 2013 %T Investigation of gene-by-sex interactions for lipid traits in diverse populations from the population architecture using genomics and epidemiology study. %A Taylor, Kira C %A Carty, Cara L %A Dumitrescu, Logan %A Bůzková, Petra %A Cole, Shelley A %A Hindorff, Lucia %A Schumacher, Fred R %A Wilkens, Lynne R %A Shohet, Ralph V %A Quibrera, P Miguel %A Johnson, Karen C %A Henderson, Brian E %A Haessler, Jeff %A Franceschini, Nora %A Eaton, Charles B %A Duggan, David J %A Cochran, Barbara %A Cheng, Iona %A Carlson, Chris S %A Brown-Gentry, Kristin %A Anderson, Garnet %A Ambite, Jose Luis %A Haiman, Christopher %A Le Marchand, Loïc %A Kooperberg, Charles %A Crawford, Dana C %A Buyske, Steven %A North, Kari E %A Fornage, Myriam %K Female %K Genetic Heterogeneity %K Genome, Human %K Genome-Wide Association Study %K Humans %K Lipids %K Male %K Polymorphism, Single Nucleotide %K Population Groups %X

BACKGROUND: High-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) levels are influenced by both genes and the environment. Genome-wide association studies (GWAS) have identified ~100 common genetic variants associated with HDL-C, LDL-C, and/or TG levels, mostly in populations of European descent, but little is known about the modifiers of these associations. Here, we investigated whether GWAS-identified SNPs for lipid traits exhibited heterogeneity by sex in the Population Architecture using Genomics and Epidemiology (PAGE) study.

RESULTS: A sex-stratified meta-analysis was performed for 49 GWAS-identified SNPs for fasting HDL-C, LDL-C, and ln(TG) levels among adults self-identified as European American (25,013). Heterogeneity by sex was established when phet < 0.001. There was evidence for heterogeneity by sex for two SNPs for ln(TG) in the APOA1/C3/A4/A5/BUD13 gene cluster: rs28927680 (p(het) = 7.4 x 10(-7)) and rs3135506 (p(het) = 4.3 x 10(-4)one SNP in PLTP for HDL levels (rs7679; p(het) = 9.9 x 10(-4)), and one in HMGCR for LDL levels (rs12654264; p(het) = 3.1 x 10(-5)). We replicated heterogeneity by sex in five of seventeen loci previously reported by genome-wide studies (binomial p = 0.0009). We also present results for other racial/ethnic groups in the supplementary materials, to provide a resource for future meta-analyses.

CONCLUSIONS: We provide further evidence for sex-specific effects of SNPs in the APOA1/C3/A4/A5/BUD13 gene cluster, PLTP, and HMGCR on fasting triglyceride levels in European Americans from the PAGE study. Our findings emphasize the need for considering context-specific effects when interpreting genetic associations emerging from GWAS, and also highlight the difficulties in replicating interaction effects across studies and across racial/ethnic groups.

%B BMC Genet %V 14 %P 33 %8 2013 %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/23634756?dopt=Abstract %R 10.1186/1471-2156-14-33 %0 Journal Article %J Ann Neurol %D 2013 %T Ischemic stroke is associated with the ABO locus: the EuroCLOT study. %A Williams, Frances M K %A Carter, Angela M %A Hysi, Pirro G %A Surdulescu, Gabriela %A Hodgkiss, Dylan %A Soranzo, Nicole %A Traylor, Matthew %A Bevan, Steve %A Dichgans, Martin %A Rothwell, Peter M W %A Sudlow, Cathie %A Farrall, Martin %A Silander, Kaisa %A Kaunisto, Mari %A Wagner, Peter %A Saarela, Olli %A Kuulasmaa, Kari %A Virtamo, Jarmo %A Salomaa, Veikko %A Amouyel, Philippe %A Arveiler, Dominique %A Ferrieres, Jean %A Wiklund, Per-Gunnar %A Ikram, M Arfan %A Hofman, Albert %A Boncoraglio, Giorgio B %A Parati, Eugenio A %A Helgadottir, Anna %A Gretarsdottir, Solveig %A Thorsteinsdottir, Unnur %A Thorleifsson, Gudmar %A Stefansson, Kari %A Seshadri, Sudha %A DeStefano, Anita %A Gschwendtner, Andreas %A Psaty, Bruce %A Longstreth, Will %A Mitchell, Braxton D %A Cheng, Yu-Ching %A Clarke, Robert %A Ferrario, Marco %A Bis, Joshua C %A Levi, Christopher %A Attia, John %A Holliday, Elizabeth G %A Scott, Rodney J %A Fornage, Myriam %A Sharma, Pankaj %A Furie, Karen L %A Rosand, Jonathan %A Nalls, Mike %A Meschia, James %A Mosely, Thomas H %A Evans, Alun %A Palotie, Aarno %A Markus, Hugh S %A Grant, Peter J %A Spector, Tim D %K ABO Blood-Group System %K Adolescent %K Adult %K Aged %K Aged, 80 and over %K Blood Coagulation %K Brain Ischemia %K Cohort Studies %K Europe %K Female %K Genetic Loci %K Genetic Predisposition to Disease %K Genetic Variation %K Genome-Wide Association Study %K Humans %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Stroke %K Young Adult %X

OBJECTIVE: End-stage coagulation and the structure/function of fibrin are implicated in the pathogenesis of ischemic stroke. We explored whether genetic variants associated with end-stage coagulation in healthy volunteers account for the genetic predisposition to ischemic stroke and examined their influence on stroke subtype.

METHODS: Common genetic variants identified through genome-wide association studies of coagulation factors and fibrin structure/function in healthy twins (n = 2,100, Stage 1) were examined in ischemic stroke (n = 4,200 cases) using 2 independent samples of European ancestry (Stage 2). A third clinical collection having stroke subtyping (total 8,900 cases, 55,000 controls) was used for replication (Stage 3).

RESULTS: Stage 1 identified 524 single nucleotide polymorphisms (SNPs) from 23 linkage disequilibrium blocks having significant association (p < 5 × 10(-8)) with 1 or more coagulation/fibrin phenotypes. The most striking associations included SNP rs5985 with factor XIII activity (p = 2.6 × 10(-186)), rs10665 with FVII (p = 2.4 × 10(-47)), and rs505922 in the ABO gene with both von Willebrand factor (p = 4.7 × 10(-57)) and factor VIII (p = 1.2 × 10(-36)). In Stage 2, the 23 independent SNPs were examined in stroke cases/noncases using MOnica Risk, Genetics, Archiving and Monograph (MORGAM) and Wellcome Trust Case Control Consortium 2 collections. SNP rs505922 was nominally associated with ischemic stroke (odds ratio = 0.94, 95% confidence interval = 0.88-0.99, p = 0.023). Independent replication in Meta-Stroke confirmed the rs505922 association with stroke, beta (standard error, SE) = 0.066 (0.02), p = 0.001, a finding specific to large-vessel and cardioembolic stroke (p = 0.001 and p = < 0.001, respectively) but not seen with small-vessel stroke (p = 0.811).

INTERPRETATION: ABO gene variants are associated with large-vessel and cardioembolic stroke but not small-vessel disease. This work sheds light on the different pathogenic mechanisms underpinning stroke subtype.

%B Ann Neurol %V 73 %P 16-31 %8 2013 Jan %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/23381943?dopt=Abstract %R 10.1002/ana.23838 %0 Journal Article %J Nat Genet %D 2013 %T A meta-analysis identifies new loci associated with body mass index in individuals of African ancestry. %A Monda, Keri L %A Chen, Gary K %A Taylor, Kira C %A Palmer, Cameron %A Edwards, Todd L %A Lange, Leslie A %A Ng, Maggie C Y %A Adeyemo, Adebowale A %A Allison, Matthew A %A Bielak, Lawrence F %A Chen, Guanjie %A Graff, Mariaelisa %A Irvin, Marguerite R %A Rhie, Suhn K %A Li, Guo %A Liu, Yongmei %A Liu, Youfang %A Lu, Yingchang %A Nalls, Michael A %A Sun, Yan V %A Wojczynski, Mary K %A Yanek, Lisa R %A Aldrich, Melinda C %A Ademola, Adeyinka %A Amos, Christopher I %A Bandera, Elisa V %A Bock, Cathryn H %A Britton, Angela %A Broeckel, Ulrich %A Cai, Quiyin %A Caporaso, Neil E %A Carlson, Chris S %A Carpten, John %A Casey, Graham %A Chen, Wei-Min %A Chen, Fang %A Chen, Yii-der I %A Chiang, Charleston W K %A Coetzee, Gerhard A %A Demerath, Ellen %A Deming-Halverson, Sandra L %A Driver, Ryan W %A Dubbert, Patricia %A Feitosa, Mary F %A Feng, Ye %A Freedman, Barry I %A Gillanders, Elizabeth M %A Gottesman, Omri %A Guo, Xiuqing %A Haritunians, Talin %A Harris, Tamara %A Harris, Curtis C %A Hennis, Anselm J M %A Hernandez, Dena G %A McNeill, Lorna H %A Howard, Timothy D %A Howard, Barbara V %A Howard, Virginia J %A Johnson, Karen C %A Kang, Sun J %A Keating, Brendan J %A Kolb, Suzanne %A Kuller, Lewis H %A Kutlar, Abdullah %A Langefeld, Carl D %A Lettre, Guillaume %A Lohman, Kurt %A Lotay, Vaneet %A Lyon, Helen %A Manson, JoAnn E %A Maixner, William %A Meng, Yan A %A Monroe, Kristine R %A Morhason-Bello, Imran %A Murphy, Adam B %A Mychaleckyj, Josyf C %A Nadukuru, Rajiv %A Nathanson, Katherine L %A Nayak, Uma %A N'diaye, Amidou %A Nemesure, Barbara %A Wu, Suh-Yuh %A Leske, M Cristina %A Neslund-Dudas, Christine %A Neuhouser, Marian %A Nyante, Sarah %A Ochs-Balcom, Heather %A Ogunniyi, Adesola %A Ogundiran, Temidayo O %A Ojengbede, Oladosu %A Olopade, Olufunmilayo I %A Palmer, Julie R %A Ruiz-Narvaez, Edward A %A Palmer, Nicholette D %A Press, Michael F %A Rampersaud, Evandine %A Rasmussen-Torvik, Laura J %A Rodriguez-Gil, Jorge L %A Salako, Babatunde %A Schadt, Eric E %A Schwartz, Ann G %A Shriner, Daniel A %A Siscovick, David %A Smith, Shad B %A Wassertheil-Smoller, Sylvia %A Speliotes, Elizabeth K %A Spitz, Margaret R %A Sucheston, Lara %A Taylor, Herman %A Tayo, Bamidele O %A Tucker, Margaret A %A Van Den Berg, David J %A Edwards, Digna R Velez %A Wang, Zhaoming %A Wiencke, John K %A Winkler, Thomas W %A Witte, John S %A Wrensch, Margaret %A Wu, Xifeng %A Yang, James J %A Levin, Albert M %A Young, Taylor R %A Zakai, Neil A %A Cushman, Mary %A Zanetti, Krista A %A Zhao, Jing Hua %A Zhao, Wei %A Zheng, Yonglan %A Zhou, Jie %A Ziegler, Regina G %A Zmuda, Joseph M %A Fernandes, Jyotika K %A Gilkeson, Gary S %A Kamen, Diane L %A Hunt, Kelly J %A Spruill, Ida J %A Ambrosone, Christine B %A Ambs, Stefan %A Arnett, Donna K %A Atwood, Larry %A Becker, Diane M %A Berndt, Sonja I %A Bernstein, Leslie %A Blot, William J %A Borecki, Ingrid B %A Bottinger, Erwin P %A Bowden, Donald W %A Burke, Gregory %A Chanock, Stephen J %A Cooper, Richard S %A Ding, Jingzhong %A Duggan, David %A Evans, Michele K %A Fox, Caroline %A Garvey, W Timothy %A Bradfield, Jonathan P %A Hakonarson, Hakon %A Grant, Struan F A %A Hsing, Ann %A Chu, Lisa %A Hu, Jennifer J %A Huo, Dezheng %A Ingles, Sue A %A John, Esther M %A Jordan, Joanne M %A Kabagambe, Edmond K %A Kardia, Sharon L R %A Kittles, Rick A %A Goodman, Phyllis J %A Klein, Eric A %A Kolonel, Laurence N %A Le Marchand, Loïc %A Liu, Simin %A McKnight, Barbara %A Millikan, Robert C %A Mosley, Thomas H %A Padhukasahasram, Badri %A Williams, L Keoki %A Patel, Sanjay R %A Peters, Ulrike %A Pettaway, Curtis A %A Peyser, Patricia A %A Psaty, Bruce M %A Redline, Susan %A Rotimi, Charles N %A Rybicki, Benjamin A %A Sale, Michèle M %A Schreiner, Pamela J %A Signorello, Lisa B %A Singleton, Andrew B %A Stanford, Janet L %A Strom, Sara S %A Thun, Michael J %A Vitolins, Mara %A Zheng, Wei %A Moore, Jason H %A Williams, Scott M %A Ketkar, Shamika %A Zhu, Xiaofeng %A Zonderman, Alan B %A Kooperberg, Charles %A Papanicolaou, George J %A Henderson, Brian E %A Reiner, Alex P %A Hirschhorn, Joel N %A Loos, Ruth J F %A North, Kari E %A Haiman, Christopher A %K African Americans %K Body Mass Index %K Case-Control Studies %K Gene Frequency %K Genetic Loci %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Linkage Disequilibrium %K Obesity %K Polymorphism, Single Nucleotide %X

Genome-wide association studies (GWAS) have identified 36 loci associated with body mass index (BMI), predominantly in populations of European ancestry. We conducted a meta-analysis to examine the association of >3.2 million SNPs with BMI in 39,144 men and women of African ancestry and followed up the most significant associations in an additional 32,268 individuals of African ancestry. We identified one new locus at 5q33 (GALNT10, rs7708584, P = 3.4 × 10(-11)) and another at 7p15 when we included data from the GIANT consortium (MIR148A-NFE2L3, rs10261878, P = 1.2 × 10(-10)). We also found suggestive evidence of an association at a third locus at 6q16 in the African-ancestry sample (KLHL32, rs974417, P = 6.9 × 10(-8)). Thirty-two of the 36 previously established BMI variants showed directionally consistent effect estimates in our GWAS (binomial P = 9.7 × 10(-7)), five of which reached genome-wide significance. These findings provide strong support for shared BMI loci across populations, as well as for the utility of studying ancestrally diverse populations.

%B Nat Genet %V 45 %P 690-6 %8 2013 Jun %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/23583978?dopt=Abstract %R 10.1038/ng.2608 %0 Journal Article %J Nat Genet %D 2013 %T Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. %A Lambert, J C %A Ibrahim-Verbaas, C A %A Harold, D %A Naj, A C %A Sims, R %A Bellenguez, C %A DeStafano, A L %A Bis, J C %A Beecham, G W %A Grenier-Boley, B %A Russo, G %A Thorton-Wells, T A %A Jones, N %A Smith, A V %A Chouraki, V %A Thomas, C %A Ikram, M A %A Zelenika, D %A Vardarajan, B N %A Kamatani, Y %A Lin, C F %A Gerrish, A %A Schmidt, H %A Kunkle, B %A Dunstan, M L %A Ruiz, A %A Bihoreau, M T %A Choi, S H %A Reitz, C %A Pasquier, F %A Cruchaga, C %A Craig, D %A Amin, N %A Berr, C %A Lopez, O L %A De Jager, P L %A Deramecourt, V %A Johnston, J A %A Evans, D %A Lovestone, S %A Letenneur, L %A Morón, F J %A Rubinsztein, D C %A Eiriksdottir, G %A Sleegers, K %A Goate, A M %A Fiévet, N %A Huentelman, M W %A Gill, M %A Brown, K %A Kamboh, M I %A Keller, L %A Barberger-Gateau, P %A McGuiness, B %A Larson, E B %A Green, R %A Myers, A J %A Dufouil, C %A Todd, S %A Wallon, D %A Love, S %A Rogaeva, E %A Gallacher, J %A St George-Hyslop, P %A Clarimon, J %A Lleo, A %A Bayer, A %A Tsuang, D W %A Yu, L %A Tsolaki, M %A Bossù, P %A Spalletta, G %A Proitsi, P %A Collinge, J %A Sorbi, S %A Sanchez-Garcia, F %A Fox, N C %A Hardy, J %A Deniz Naranjo, M C %A Bosco, P %A Clarke, R %A Brayne, C %A Galimberti, D %A Mancuso, M %A Matthews, F %A Moebus, S %A Mecocci, P %A Del Zompo, M %A Maier, W %A Hampel, H %A Pilotto, A %A Bullido, M %A Panza, F %A Caffarra, P %A Nacmias, B %A Gilbert, J R %A Mayhaus, M %A Lannefelt, L %A Hakonarson, H %A Pichler, S %A Carrasquillo, M M %A Ingelsson, M %A Beekly, D %A Alvarez, V %A Zou, F %A Valladares, O %A Younkin, S G %A Coto, E %A Hamilton-Nelson, K L %A Gu, W %A Razquin, C %A Pastor, P %A Mateo, I %A Owen, M J %A Faber, K M %A Jonsson, P V %A Combarros, O %A O'Donovan, M C %A Cantwell, L B %A Soininen, H %A Blacker, D %A Mead, S %A Mosley, T H %A Bennett, D A %A Harris, T B %A Fratiglioni, L %A Holmes, C %A de Bruijn, R F %A Passmore, P %A Montine, T J %A Bettens, K %A Rotter, J I %A Brice, A %A Morgan, K %A Foroud, T M %A Kukull, W A %A Hannequin, D %A Powell, J F %A Nalls, M A %A Ritchie, K %A Lunetta, K L %A Kauwe, J S %A Boerwinkle, E %A Riemenschneider, M %A Boada, M %A Hiltuenen, M %A Martin, E R %A Schmidt, R %A Rujescu, D %A Wang, L S %A Dartigues, J F %A Mayeux, R %A Tzourio, C %A Hofman, A %A Nöthen, M M %A Graff, C %A Psaty, B M %A Jones, L %A Haines, J L %A Holmans, P A %A Lathrop, M %A Pericak-Vance, M A %A Launer, L J %A Farrer, L A %A van Duijn, C M %A Van Broeckhoven, C %A Moskvina, V %A Seshadri, S %A Williams, J %A Schellenberg, G D %A Amouyel, P %K Age of Onset %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Case-Control Studies %K Cohort Studies %K Female %K Genetic Loci %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %X

Eleven susceptibility loci for late-onset Alzheimer's disease (LOAD) were identified by previous studies; however, a large portion of the genetic risk for this disease remains unexplained. We conducted a large, two-stage meta-analysis of genome-wide association studies (GWAS) in individuals of European ancestry. In stage 1, we used genotyped and imputed data (7,055,881 SNPs) to perform meta-analysis on 4 previously published GWAS data sets consisting of 17,008 Alzheimer's disease cases and 37,154 controls. In stage 2, 11,632 SNPs were genotyped and tested for association in an independent set of 8,572 Alzheimer's disease cases and 11,312 controls. In addition to the APOE locus (encoding apolipoprotein E), 19 loci reached genome-wide significance (P < 5 × 10(-8)) in the combined stage 1 and stage 2 analysis, of which 11 are newly associated with Alzheimer's disease.

%B Nat Genet %V 45 %P 1452-8 %8 2013 Dec %G eng %N 12 %1 http://www.ncbi.nlm.nih.gov/pubmed/24162737?dopt=Abstract %R 10.1038/ng.2802 %0 Journal Article %J PLoS Genet %D 2013 %T Meta-analysis of genome-wide association studies identifies six new Loci for serum calcium concentrations. %A O'Seaghdha, Conall M %A Wu, Hongsheng %A Yang, Qiong %A Kapur, Karen %A Guessous, Idris %A Zuber, Annie Mercier %A Köttgen, Anna %A Stoudmann, Candice %A Teumer, Alexander %A Kutalik, Zoltán %A Mangino, Massimo %A Dehghan, Abbas %A Zhang, Weihua %A Eiriksdottir, Gudny %A Li, Guo %A Tanaka, Toshiko %A Portas, Laura %A Lopez, Lorna M %A Hayward, Caroline %A Lohman, Kurt %A Matsuda, Koichi %A Padmanabhan, Sandosh %A Firsov, Dmitri %A Sorice, Rossella %A Ulivi, Sheila %A Brockhaus, A Catharina %A Kleber, Marcus E %A Mahajan, Anubha %A Ernst, Florian D %A Gudnason, Vilmundur %A Launer, Lenore J %A Mace, Aurelien %A Boerwinckle, Eric %A Arking, Dan E %A Tanikawa, Chizu %A Nakamura, Yusuke %A Brown, Morris J %A Gaspoz, Jean-Michel %A Theler, Jean-Marc %A Siscovick, David S %A Psaty, Bruce M %A Bergmann, Sven %A Vollenweider, Peter %A Vitart, Veronique %A Wright, Alan F %A Zemunik, Tatijana %A Boban, Mladen %A Kolcic, Ivana %A Navarro, Pau %A Brown, Edward M %A Estrada, Karol %A Ding, Jingzhong %A Harris, Tamara B %A Bandinelli, Stefania %A Hernandez, Dena %A Singleton, Andrew B %A Girotto, Giorgia %A Ruggiero, Daniela %A d'Adamo, Adamo Pio %A Robino, Antonietta %A Meitinger, Thomas %A Meisinger, Christa %A Davies, Gail %A Starr, John M %A Chambers, John C %A Boehm, Bernhard O %A Winkelmann, Bernhard R %A Huang, Jie %A Murgia, Federico %A Wild, Sarah H %A Campbell, Harry %A Morris, Andrew P %A Franco, Oscar H %A Hofman, Albert %A Uitterlinden, André G %A Rivadeneira, Fernando %A Völker, Uwe %A Hannemann, Anke %A Biffar, Reiner %A Hoffmann, Wolfgang %A Shin, So-Youn %A Lescuyer, Pierre %A Henry, Hughes %A Schurmann, Claudia %A Munroe, Patricia B %A Gasparini, Paolo %A Pirastu, Nicola %A Ciullo, Marina %A Gieger, Christian %A März, Winfried %A Lind, Lars %A Spector, Tim D %A Smith, Albert V %A Rudan, Igor %A Wilson, James F %A Polasek, Ozren %A Deary, Ian J %A Pirastu, Mario %A Ferrucci, Luigi %A Liu, Yongmei %A Kestenbaum, Bryan %A Kooner, Jaspal S %A Witteman, Jacqueline C M %A Nauck, Matthias %A Kao, W H Linda %A Wallaschofski, Henri %A Bonny, Olivier %A Fox, Caroline S %A Bochud, Murielle %K Animals %K Bone and Bones %K Bone Density %K Calcium %K European Continental Ancestry Group %K Gene Expression Regulation %K Genome-Wide Association Study %K Homeostasis %K Humans %K Kidney %K Mice %K Polymorphism, Single Nucleotide %X

Calcium is vital to the normal functioning of multiple organ systems and its serum concentration is tightly regulated. Apart from CASR, the genes associated with serum calcium are largely unknown. We conducted a genome-wide association meta-analysis of 39,400 individuals from 17 population-based cohorts and investigated the 14 most strongly associated loci in ≤ 21,679 additional individuals. Seven loci (six new regions) in association with serum calcium were identified and replicated. Rs1570669 near CYP24A1 (P = 9.1E-12), rs10491003 upstream of GATA3 (P = 4.8E-09) and rs7481584 in CARS (P = 1.2E-10) implicate regions involved in Mendelian calcemic disorders: Rs1550532 in DGKD (P = 8.2E-11), also associated with bone density, and rs7336933 near DGKH/KIAA0564 (P = 9.1E-10) are near genes that encode distinct isoforms of diacylglycerol kinase. Rs780094 is in GCKR. We characterized the expression of these genes in gut, kidney, and bone, and demonstrate modulation of gene expression in bone in response to dietary calcium in mice. Our results shed new light on the genetics of calcium homeostasis.

%B PLoS Genet %V 9 %P e1003796 %8 2013 %G eng %N 9 %1 http://www.ncbi.nlm.nih.gov/pubmed/24068962?dopt=Abstract %R 10.1371/journal.pgen.1003796 %0 Journal Article %J PLoS Genet %D 2013 %T A meta-analysis of thyroid-related traits reveals novel loci and gender-specific differences in the regulation of thyroid function. %A Porcu, Eleonora %A Medici, Marco %A Pistis, Giorgio %A Volpato, Claudia B %A Wilson, Scott G %A Cappola, Anne R %A Bos, Steffan D %A Deelen, Joris %A den Heijer, Martin %A Freathy, Rachel M %A Lahti, Jari %A Liu, Chunyu %A Lopez, Lorna M %A Nolte, Ilja M %A O'Connell, Jeffrey R %A Tanaka, Toshiko %A Trompet, Stella %A Arnold, Alice %A Bandinelli, Stefania %A Beekman, Marian %A Böhringer, Stefan %A Brown, Suzanne J %A Buckley, Brendan M %A Camaschella, Clara %A de Craen, Anton J M %A Davies, Gail %A de Visser, Marieke C H %A Ford, Ian %A Forsen, Tom %A Frayling, Timothy M %A Fugazzola, Laura %A Gögele, Martin %A Hattersley, Andrew T %A Hermus, Ad R %A Hofman, Albert %A Houwing-Duistermaat, Jeanine J %A Jensen, Richard A %A Kajantie, Eero %A Kloppenburg, Margreet %A Lim, Ee M %A Masciullo, Corrado %A Mariotti, Stefano %A Minelli, Cosetta %A Mitchell, Braxton D %A Nagaraja, Ramaiah %A Netea-Maier, Romana T %A Palotie, Aarno %A Persani, Luca %A Piras, Maria G %A Psaty, Bruce M %A Räikkönen, Katri %A Richards, J Brent %A Rivadeneira, Fernando %A Sala, Cinzia %A Sabra, Mona M %A Sattar, Naveed %A Shields, Beverley M %A Soranzo, Nicole %A Starr, John M %A Stott, David J %A Sweep, Fred C G J %A Usala, Gianluca %A van der Klauw, Melanie M %A van Heemst, Diana %A van Mullem, Alies %A Vermeulen, Sita H %A Visser, W Edward %A Walsh, John P %A Westendorp, Rudi G J %A Widen, Elisabeth %A Zhai, Guangju %A Cucca, Francesco %A Deary, Ian J %A Eriksson, Johan G %A Ferrucci, Luigi %A Fox, Caroline S %A Jukema, J Wouter %A Kiemeney, Lambertus A %A Pramstaller, Peter P %A Schlessinger, David %A Shuldiner, Alan R %A Slagboom, Eline P %A Uitterlinden, André G %A Vaidya, Bijay %A Visser, Theo J %A Wolffenbuttel, Bruce H R %A Meulenbelt, Ingrid %A Rotter, Jerome I %A Spector, Tim D %A Hicks, Andrew A %A Toniolo, Daniela %A Sanna, Serena %A Peeters, Robin P %A Naitza, Silvia %K Female %K Genome-Wide Association Study %K Humans %K Hyperthyroidism %K Hypothyroidism %K Male %K Phenotype %K Polymorphism, Genetic %K Polymorphism, Single Nucleotide %K Sex Characteristics %K Signal Transduction %K Thyroid Gland %K Thyrotropin %K Thyroxine %X

Thyroid hormone is essential for normal metabolism and development, and overt abnormalities in thyroid function lead to common endocrine disorders affecting approximately 10% of individuals over their life span. In addition, even mild alterations in thyroid function are associated with weight changes, atrial fibrillation, osteoporosis, and psychiatric disorders. To identify novel variants underlying thyroid function, we performed a large meta-analysis of genome-wide association studies for serum levels of the highly heritable thyroid function markers TSH and FT4, in up to 26,420 and 17,520 euthyroid subjects, respectively. Here we report 26 independent associations, including several novel loci for TSH (PDE10A, VEGFA, IGFBP5, NFIA, SOX9, PRDM11, FGF7, INSR, ABO, MIR1179, NRG1, MBIP, ITPK1, SASH1, GLIS3) and FT4 (LHX3, FOXE1, AADAT, NETO1/FBXO15, LPCAT2/CAPNS2). Notably, only limited overlap was detected between TSH and FT4 associated signals, in spite of the feedback regulation of their circulating levels by the hypothalamic-pituitary-thyroid axis. Five of the reported loci (PDE8B, PDE10A, MAF/LOC440389, NETO1/FBXO15, and LPCAT2/CAPNS2) show strong gender-specific differences, which offer clues for the known sexual dimorphism in thyroid function and related pathologies. Importantly, the TSH-associated loci contribute not only to variation within the normal range, but also to TSH values outside the reference range, suggesting that they may be involved in thyroid dysfunction. Overall, our findings explain, respectively, 5.64% and 2.30% of total TSH and FT4 trait variance, and they improve the current knowledge of the regulation of hypothalamic-pituitary-thyroid axis function and the consequences of genetic variation for hypo- or hyperthyroidism.

%B PLoS Genet %V 9 %P e1003266 %8 2013 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/23408906?dopt=Abstract %R 10.1371/journal.pgen.1003266 %0 Journal Article %J Circulation %D 2013 %T Multiethnic meta-analysis of genome-wide association studies in >100 000 subjects identifies 23 fibrinogen-associated Loci but no strong evidence of a causal association between circulating fibrinogen and cardiovascular disease. %A Sabater-Lleal, Maria %A Huang, Jie %A Chasman, Daniel %A Naitza, Silvia %A Dehghan, Abbas %A Johnson, Andrew D %A Teumer, Alexander %A Reiner, Alex P %A Folkersen, Lasse %A Basu, Saonli %A Rudnicka, Alicja R %A Trompet, Stella %A Mälarstig, Anders %A Baumert, Jens %A Bis, Joshua C %A Guo, Xiuqing %A Hottenga, Jouke J %A Shin, So-Youn %A Lopez, Lorna M %A Lahti, Jari %A Tanaka, Toshiko %A Yanek, Lisa R %A Oudot-Mellakh, Tiphaine %A Wilson, James F %A Navarro, Pau %A Huffman, Jennifer E %A Zemunik, Tatijana %A Redline, Susan %A Mehra, Reena %A Pulanic, Drazen %A Rudan, Igor %A Wright, Alan F %A Kolcic, Ivana %A Polasek, Ozren %A Wild, Sarah H %A Campbell, Harry %A Curb, J David %A Wallace, Robert %A Liu, Simin %A Eaton, Charles B %A Becker, Diane M %A Becker, Lewis C %A Bandinelli, Stefania %A Räikkönen, Katri %A Widen, Elisabeth %A Palotie, Aarno %A Fornage, Myriam %A Green, David %A Gross, Myron %A Davies, Gail %A Harris, Sarah E %A Liewald, David C %A Starr, John M %A Williams, Frances M K %A Grant, Peter J %A Spector, Timothy D %A Strawbridge, Rona J %A Silveira, Angela %A Sennblad, Bengt %A Rivadeneira, Fernando %A Uitterlinden, André G %A Franco, Oscar H %A Hofman, Albert %A van Dongen, Jenny %A Willemsen, Gonneke %A Boomsma, Dorret I %A Yao, Jie %A Swords Jenny, Nancy %A Haritunians, Talin %A McKnight, Barbara %A Lumley, Thomas %A Taylor, Kent D %A Rotter, Jerome I %A Psaty, Bruce M %A Peters, Annette %A Gieger, Christian %A Illig, Thomas %A Grotevendt, Anne %A Homuth, Georg %A Völzke, Henry %A Kocher, Thomas %A Goel, Anuj %A Franzosi, Maria Grazia %A Seedorf, Udo %A Clarke, Robert %A Steri, Maristella %A Tarasov, Kirill V %A Sanna, Serena %A Schlessinger, David %A Stott, David J %A Sattar, Naveed %A Buckley, Brendan M %A Rumley, Ann %A Lowe, Gordon D %A McArdle, Wendy L %A Chen, Ming-Huei %A Tofler, Geoffrey H %A Song, Jaejoon %A Boerwinkle, Eric %A Folsom, Aaron R %A Rose, Lynda M %A Franco-Cereceda, Anders %A Teichert, Martina %A Ikram, M Arfan %A Mosley, Thomas H %A Bevan, Steve %A Dichgans, Martin %A Rothwell, Peter M %A Sudlow, Cathie L M %A Hopewell, Jemma C %A Chambers, John C %A Saleheen, Danish %A Kooner, Jaspal S %A Danesh, John %A Nelson, Christopher P %A Erdmann, Jeanette %A Reilly, Muredach P %A Kathiresan, Sekar %A Schunkert, Heribert %A Morange, Pierre-Emmanuel %A Ferrucci, Luigi %A Eriksson, Johan G %A Jacobs, David %A Deary, Ian J %A Soranzo, Nicole %A Witteman, Jacqueline C M %A de Geus, Eco J C %A Tracy, Russell P %A Hayward, Caroline %A Koenig, Wolfgang %A Cucca, Francesco %A Jukema, J Wouter %A Eriksson, Per %A Seshadri, Sudha %A Markus, Hugh S %A Watkins, Hugh %A Samani, Nilesh J %A Wallaschofski, Henri %A Smith, Nicholas L %A Tregouet, David %A Ridker, Paul M %A Tang, Weihong %A Strachan, David P %A Hamsten, Anders %A O'Donnell, Christopher J %K Adolescent %K Adult %K African Continental Ancestry Group %K Aged %K Aged, 80 and over %K Cardiovascular Diseases %K Coronary Artery Disease %K European Continental Ancestry Group %K Female %K Fibrinogen %K Genetic Loci %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Hispanic Americans %K Humans %K Male %K Middle Aged %K Myocardial Infarction %K Polymorphism, Single Nucleotide %K Risk Factors %K Stroke %K Venous Thromboembolism %K Young Adult %X

BACKGROUND: Estimates of the heritability of plasma fibrinogen concentration, an established predictor of cardiovascular disease, range from 34% to 50%. Genetic variants so far identified by genome-wide association studies explain only a small proportion (<2%) of its variation.

METHODS AND RESULTS: We conducted a meta-analysis of 28 genome-wide association studies including >90 000 subjects of European ancestry, the first genome-wide association meta-analysis of fibrinogen levels in 7 studies in blacks totaling 8289 samples, and a genome-wide association study in Hispanics totaling 1366 samples. Evaluation for association of single-nucleotide polymorphisms with clinical outcomes included a total of 40 695 cases and 85 582 controls for coronary artery disease, 4752 cases and 24 030 controls for stroke, and 3208 cases and 46 167 controls for venous thromboembolism. Overall, we identified 24 genome-wide significant (P<5×10(-8)) independent signals in 23 loci, including 15 novel associations, together accounting for 3.7% of plasma fibrinogen variation. Gene-set enrichment analysis highlighted key roles in fibrinogen regulation for the 3 structural fibrinogen genes and pathways related to inflammation, adipocytokines, and thyrotrophin-releasing hormone signaling. Whereas lead single-nucleotide polymorphisms in a few loci were significantly associated with coronary artery disease, the combined effect of all 24 fibrinogen-associated lead single-nucleotide polymorphisms was not significant for coronary artery disease, stroke, or venous thromboembolism.

CONCLUSIONS: We identify 23 robustly associated fibrinogen loci, 15 of which are new. Clinical outcome analysis of these loci does not support a causal relationship between circulating levels of fibrinogen and coronary artery disease, stroke, or venous thromboembolism.

%B Circulation %V 128 %P 1310-24 %8 2013 Sep 17 %G eng %N 12 %1 http://www.ncbi.nlm.nih.gov/pubmed/23969696?dopt=Abstract %R 10.1161/CIRCULATIONAHA.113.002251 %0 Journal Article %J Hum Genet %D 2013 %T No evidence of interaction between known lipid-associated genetic variants and smoking in the multi-ethnic PAGE population. %A Dumitrescu, Logan %A Carty, Cara L %A Franceschini, Nora %A Hindorff, Lucia A %A Cole, Shelley A %A Bůzková, Petra %A Schumacher, Fredrick R %A Eaton, Charles B %A Goodloe, Robert J %A Duggan, David J %A Haessler, Jeff %A Cochran, Barbara %A Henderson, Brian E %A Cheng, Iona %A Johnson, Karen C %A Carlson, Chris S %A Love, Shelly-Anne %A Brown-Gentry, Kristin %A Nato, Alejandro Q %A Quibrera, Miguel %A Shohet, Ralph V %A Ambite, Jose Luis %A Wilkens, Lynne R %A Le Marchand, Loïc %A Haiman, Christopher A %A Buyske, Steven %A Kooperberg, Charles %A North, Kari E %A Fornage, Myriam %A Crawford, Dana C %K Cholesterol, HDL %K Cholesterol, LDL %K Cohort Studies %K Ethnic Groups %K Female %K Gene Frequency %K Gene-Environment Interaction %K Genetics, Population %K Genome-Wide Association Study %K Humans %K Lipid Metabolism %K Male %K Polymorphism, Single Nucleotide %K Prevalence %K Smoking %K Triglycerides %K Young Adult %X

Genome-wide association studies (GWAS) have identified many variants that influence high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and/or triglycerides. However, environmental modifiers, such as smoking, of these known genotype-phenotype associations are just recently emerging in the literature. We have tested for interactions between smoking and 49 GWAS-identified variants in over 41,000 racially/ethnically diverse samples with lipid levels from the Population Architecture Using Genomics and Epidemiology (PAGE) study. Despite their biological plausibility, we were unable to detect significant SNP × smoking interactions.

%B Hum Genet %V 132 %P 1427-31 %8 2013 Dec %G eng %N 12 %1 http://www.ncbi.nlm.nih.gov/pubmed/24100633?dopt=Abstract %R 10.1007/s00439-013-1375-3 %0 Journal Article %J Ann Hum Genet %D 2013 %T Post-genome-wide association study challenges for lipid traits: describing age as a modifier of gene-lipid associations in the Population Architecture using Genomics and Epidemiology (PAGE) study. %A Dumitrescu, Logan %A Carty, Cara L %A Franceschini, Nora %A Hindorff, Lucia A %A Cole, Shelley A %A Bůzková, Petra %A Schumacher, Fredrick R %A Eaton, Charles B %A Goodloe, Robert J %A Duggan, David J %A Haessler, Jeff %A Cochran, Barbara %A Henderson, Brian E %A Cheng, Iona %A Johnson, Karen C %A Carlson, Chris S %A Love, Shelly-Ann %A Brown-Gentry, Kristin %A Nato, Alejandro Q %A Quibrera, Miguel %A Anderson, Garnet %A Shohet, Ralph V %A Ambite, Jose Luis %A Wilkens, Lynne R %A Marchand, Loic Le %A Haiman, Christopher A %A Buyske, Steven %A Kooperberg, Charles %A North, Kari E %A Fornage, Myriam %A Crawford, Dana C %K Adult %K Aged %K European Continental Ancestry Group %K Female %K Genetic Association Studies %K Genome-Wide Association Study %K Humans %K Lipids %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %K Quantitative Trait, Heritable %K Risk Factors %X

Numerous common genetic variants that influence plasma high-density lipoprotein cholesterol, low-density lipoprotein cholesterol (LDL-C), and triglyceride distributions have been identified via genome-wide association studies (GWAS). However, whether or not these associations are age-dependent has largely been overlooked. We conducted an association study and meta-analysis in more than 22,000 European Americans between 49 previously identified GWAS variants and the three lipid traits, stratified by age (males: <50 or ≥50 years of age; females: pre- or postmenopausal). For each variant, a test of heterogeneity was performed between the two age strata and significant Phet values were used as evidence of age-specific genetic effects. We identified seven associations in females and eight in males that displayed suggestive heterogeneity by age (Phet < 0.05). The association between rs174547 (FADS1) and LDL-C in males displayed the most evidence for heterogeneity between age groups (Phet = 1.74E-03, I(2) = 89.8), with a significant association in older males (P = 1.39E-06) but not younger males (P = 0.99). However, none of the suggestive modifying effects survived adjustment for multiple testing, highlighting the challenges of identifying modifiers of modest SNP-trait associations despite large sample sizes.

%B Ann Hum Genet %V 77 %P 416-25 %8 2013 Sep %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/23808484?dopt=Abstract %R 10.1111/ahg.12027 %0 Journal Article %J Hum Reprod %D 2013 %T Replication of genetic loci for ages at menarche and menopause in the multi-ethnic Population Architecture using Genomics and Epidemiology (PAGE) study. %A Carty, C L %A Spencer, K L %A Setiawan, V W %A Fernandez-Rhodes, L %A Malinowski, J %A Buyske, S %A Young, A %A Jorgensen, N W %A Cheng, I %A Carlson, C S %A Brown-Gentry, K %A Goodloe, R %A Park, A %A Parikh, N I %A Henderson, B %A Le Marchand, L %A Wactawski-Wende, J %A Fornage, M %A Matise, T C %A Hindorff, L A %A Arnold, A M %A Haiman, C A %A Franceschini, N %A Peters, U %A Crawford, D C %K Age Factors %K Cross-Sectional Studies %K Female %K Genome-Wide Association Study %K Genotype %K Humans %K Menarche %K Menopause %K Polymorphism, Single Nucleotide %X

STUDY QUESTION: Do genetic associations identified in genome-wide association studies (GWAS) of age at menarche (AM) and age at natural menopause (ANM) replicate in women of diverse race/ancestry from the Population Architecture using Genomics and Epidemiology (PAGE) Study?

SUMMARY ANSWER: We replicated GWAS reproductive trait single nucleotide polymorphisms (SNPs) in our European descent population and found that many SNPs were also associated with AM and ANM in populations of diverse ancestry.

WHAT IS KNOWN ALREADY: Menarche and menopause mark the reproductive lifespan in women and are important risk factors for chronic diseases including obesity, cardiovascular disease and cancer. Both events are believed to be influenced by environmental and genetic factors, and vary in populations differing by genetic ancestry and geography. Most genetic variants associated with these traits have been identified in GWAS of European-descent populations.

STUDY DESIGN, SIZE, DURATION: A total of 42 251 women of diverse ancestry from PAGE were included in cross-sectional analyses of AM and ANM.

MATERIALS, SETTING, METHODS: SNPs previously associated with ANM (n = 5 SNPs) and AM (n = 3 SNPs) in GWAS were genotyped in American Indians, African Americans, Asians, European Americans, Hispanics and Native Hawaiians. To test SNP associations with ANM or AM, we used linear regression models stratified by race/ethnicity and PAGE sub-study. Results were then combined in race-specific fixed effect meta-analyses for each outcome. For replication and generalization analyses, significance was defined at P < 0.01 for ANM analyses and P < 0.017 for AM analyses.

MAIN RESULTS AND THE ROLE OF CHANCE: We replicated findings for AM SNPs in the LIN28B locus and an intergenic region on 9q31 in European Americans. The LIN28B SNPs (rs314277 and rs314280) were also significantly associated with AM in Asians, but not in other race/ethnicity groups. Linkage disequilibrium (LD) patterns at this locus varied widely among the ancestral groups. With the exception of an intergenic SNP at 13q34, all ANM SNPs replicated in European Americans. Three were significantly associated with ANM in other race/ethnicity populations: rs2153157 (6p24.2/SYCP2L), rs365132 (5q35/UIMC1) and rs16991615 (20p12.3/MCM8). While rs1172822 (19q13/BRSK1) was not significant in the populations of non-European descent, effect sizes showed similar trends.

LIMITATIONS, REASONS FOR CAUTION: Lack of association for the GWAS SNPs in the non-European American groups may be due to differences in locus LD patterns between these groups and the European-descent populations included in the GWAS discovery studies; and in some cases, lower power may also contribute to non-significant findings.

WIDER IMPLICATIONS OF THE FINDINGS: The discovery of genetic variants associated with the reproductive traits provides an important opportunity to elucidate the biological mechanisms involved with normal variation and disorders of menarche and menopause. In this study we replicated most, but not all reported SNPs in European descent populations and examined the epidemiologic architecture of these early reported variants, describing their generalizability and effect size across differing ancestral populations. Such data will be increasingly important for prioritizing GWAS SNPs for follow-up in fine-mapping and resequencing studies, as well as in translational research.

%B Hum Reprod %V 28 %P 1695-706 %8 2013 Jun %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/23508249?dopt=Abstract %R 10.1093/humrep/det071 %0 Journal Article %J PLoS Genet %D 2013 %T Sex-stratified genome-wide association studies including 270,000 individuals show sexual dimorphism in genetic loci for anthropometric traits. %A Randall, Joshua C %A Winkler, Thomas W %A Kutalik, Zoltán %A Berndt, Sonja I %A Jackson, Anne U %A Monda, Keri L %A Kilpeläinen, Tuomas O %A Esko, Tõnu %A Mägi, Reedik %A Li, Shengxu %A Workalemahu, Tsegaselassie %A Feitosa, Mary F %A Croteau-Chonka, Damien C %A Day, Felix R %A Fall, Tove %A Ferreira, Teresa %A Gustafsson, Stefan %A Locke, Adam E %A Mathieson, Iain %A Scherag, Andre %A Vedantam, Sailaja %A Wood, Andrew R %A Liang, Liming %A Steinthorsdottir, Valgerdur %A Thorleifsson, Gudmar %A Dermitzakis, Emmanouil T %A Dimas, Antigone S %A Karpe, Fredrik %A Min, Josine L %A Nicholson, George %A Clegg, Deborah J %A Person, Thomas %A Krohn, Jon P %A Bauer, Sabrina %A Buechler, Christa %A Eisinger, Kristina %A Bonnefond, Amélie %A Froguel, Philippe %A Hottenga, Jouke-Jan %A Prokopenko, Inga %A Waite, Lindsay L %A Harris, Tamara B %A Smith, Albert Vernon %A Shuldiner, Alan R %A McArdle, Wendy L %A Caulfield, Mark J %A Munroe, Patricia B %A Grönberg, Henrik %A Chen, Yii-Der Ida %A Li, Guo %A Beckmann, Jacques S %A Johnson, Toby %A Thorsteinsdottir, Unnur %A Teder-Laving, Maris %A Khaw, Kay-Tee %A Wareham, Nicholas J %A Zhao, Jing Hua %A Amin, Najaf %A Oostra, Ben A %A Kraja, Aldi T %A Province, Michael A %A Cupples, L Adrienne %A Heard-Costa, Nancy L %A Kaprio, Jaakko %A Ripatti, Samuli %A Surakka, Ida %A Collins, Francis S %A Saramies, Jouko %A Tuomilehto, Jaakko %A Jula, Antti %A Salomaa, Veikko %A Erdmann, Jeanette %A Hengstenberg, Christian %A Loley, Christina %A Schunkert, Heribert %A Lamina, Claudia %A Wichmann, H Erich %A Albrecht, Eva %A Gieger, Christian %A Hicks, Andrew A %A Johansson, Asa %A Pramstaller, Peter P %A Kathiresan, Sekar %A Speliotes, Elizabeth K %A Penninx, Brenda %A Hartikainen, Anna-Liisa %A Jarvelin, Marjo-Riitta %A Gyllensten, Ulf %A Boomsma, Dorret I %A Campbell, Harry %A Wilson, James F %A Chanock, Stephen J %A Farrall, Martin %A Goel, Anuj %A Medina-Gómez, Carolina %A Rivadeneira, Fernando %A Estrada, Karol %A Uitterlinden, André G %A Hofman, Albert %A Zillikens, M Carola %A den Heijer, Martin %A Kiemeney, Lambertus A %A Maschio, Andrea %A Hall, Per %A Tyrer, Jonathan %A Teumer, Alexander %A Völzke, Henry %A Kovacs, Peter %A Tönjes, Anke %A Mangino, Massimo %A Spector, Tim D %A Hayward, Caroline %A Rudan, Igor %A Hall, Alistair S %A Samani, Nilesh J %A Attwood, Antony Paul %A Sambrook, Jennifer G %A Hung, Joseph %A Palmer, Lyle J %A Lokki, Marja-Liisa %A Sinisalo, Juha %A Boucher, Gabrielle %A Huikuri, Heikki %A Lorentzon, Mattias %A Ohlsson, Claes %A Eklund, Niina %A Eriksson, Johan G %A Barlassina, Cristina %A Rivolta, Carlo %A Nolte, Ilja M %A Snieder, Harold %A van der Klauw, Melanie M %A van Vliet-Ostaptchouk, Jana V %A Gejman, Pablo V %A Shi, Jianxin %A Jacobs, Kevin B %A Wang, Zhaoming %A Bakker, Stephan J L %A Mateo Leach, Irene %A Navis, Gerjan %A van der Harst, Pim %A Martin, Nicholas G %A Medland, Sarah E %A Montgomery, Grant W %A Yang, Jian %A Chasman, Daniel I %A Ridker, Paul M %A Rose, Lynda M %A Lehtimäki, Terho %A Raitakari, Olli %A Absher, Devin %A Iribarren, Carlos %A Basart, Hanneke %A Hovingh, Kees G %A Hyppönen, Elina %A Power, Chris %A Anderson, Denise %A Beilby, John P %A Hui, Jennie %A Jolley, Jennifer %A Sager, Hendrik %A Bornstein, Stefan R %A Schwarz, Peter E H %A Kristiansson, Kati %A Perola, Markus %A Lindström, Jaana %A Swift, Amy J %A Uusitupa, Matti %A Atalay, Mustafa %A Lakka, Timo A %A Rauramaa, Rainer %A Bolton, Jennifer L %A Fowkes, Gerry %A Fraser, Ross M %A Price, Jackie F %A Fischer, Krista %A Krjutå Kov, Kaarel %A Metspalu, Andres %A Mihailov, Evelin %A Langenberg, Claudia %A Luan, Jian'an %A Ong, Ken K %A Chines, Peter S %A Keinanen-Kiukaanniemi, Sirkka M %A Saaristo, Timo E %A Edkins, Sarah %A Franks, Paul W %A Hallmans, Göran %A Shungin, Dmitry %A Morris, Andrew David %A Palmer, Colin N A %A Erbel, Raimund %A Moebus, Susanne %A Nöthen, Markus M %A Pechlivanis, Sonali %A Hveem, Kristian %A Narisu, Narisu %A Hamsten, Anders %A Humphries, Steve E %A Strawbridge, Rona J %A Tremoli, Elena %A Grallert, Harald %A Thorand, Barbara %A Illig, Thomas %A Koenig, Wolfgang %A Müller-Nurasyid, Martina %A Peters, Annette %A Boehm, Bernhard O %A Kleber, Marcus E %A März, Winfried %A Winkelmann, Bernhard R %A Kuusisto, Johanna %A Laakso, Markku %A Arveiler, Dominique %A Cesana, Giancarlo %A Kuulasmaa, Kari %A Virtamo, Jarmo %A Yarnell, John W G %A Kuh, Diana %A Wong, Andrew %A Lind, Lars %A de Faire, Ulf %A Gigante, Bruna %A Magnusson, Patrik K E %A Pedersen, Nancy L %A Dedoussis, George %A Dimitriou, Maria %A Kolovou, Genovefa %A Kanoni, Stavroula %A Stirrups, Kathleen %A Bonnycastle, Lori L %A Njølstad, Inger %A Wilsgaard, Tom %A Ganna, Andrea %A Rehnberg, Emil %A Hingorani, Aroon %A Kivimaki, Mika %A Kumari, Meena %A Assimes, Themistocles L %A Barroso, Inês %A Boehnke, Michael %A Borecki, Ingrid B %A Deloukas, Panos %A Fox, Caroline S %A Frayling, Timothy %A Groop, Leif C %A Haritunians, Talin %A Hunter, David %A Ingelsson, Erik %A Kaplan, Robert %A Mohlke, Karen L %A O'Connell, Jeffrey R %A Schlessinger, David %A Strachan, David P %A Stefansson, Kari %A van Duijn, Cornelia M %A Abecasis, Goncalo R %A McCarthy, Mark I %A Hirschhorn, Joel N %A Qi, Lu %A Loos, Ruth J F %A Lindgren, Cecilia M %A North, Kari E %A Heid, Iris M %K Anthropometry %K Body Height %K Body Mass Index %K Body Weight %K Body Weights and Measures %K Female %K Genetic Loci %K Genome, Human %K Genome-Wide Association Study %K Humans %K Male %K Polymorphism, Single Nucleotide %K Sex Characteristics %K Waist Circumference %K Waist-Hip Ratio %X

Given the anthropometric differences between men and women and previous evidence of sex-difference in genetic effects, we conducted a genome-wide search for sexually dimorphic associations with height, weight, body mass index, waist circumference, hip circumference, and waist-to-hip-ratio (133,723 individuals) and took forward 348 SNPs into follow-up (additional 137,052 individuals) in a total of 94 studies. Seven loci displayed significant sex-difference (FDR<5%), including four previously established (near GRB14/COBLL1, LYPLAL1/SLC30A10, VEGFA, ADAMTS9) and three novel anthropometric trait loci (near MAP3K1, HSD17B4, PPARG), all of which were genome-wide significant in women (P<5×10(-8)), but not in men. Sex-differences were apparent only for waist phenotypes, not for height, weight, BMI, or hip circumference. Moreover, we found no evidence for genetic effects with opposite directions in men versus women. The PPARG locus is of specific interest due to its role in diabetes genetics and therapy. Our results demonstrate the value of sex-specific GWAS to unravel the sexually dimorphic genetic underpinning of complex traits.

%B PLoS Genet %V 9 %P e1003500 %8 2013 Jun %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/23754948?dopt=Abstract %R 10.1371/journal.pgen.1003500 %0 Journal Article %J Arterioscler Thromb Vasc Biol %D 2013 %T Soluble CD14: genomewide association analysis and relationship to cardiovascular risk and mortality in older adults. %A Reiner, Alex P %A Lange, Ethan M %A Jenny, Nancy S %A Chaves, Paulo H M %A Ellis, Jaclyn %A Li, Jin %A Walston, Jeremy %A Lange, Leslie A %A Cushman, Mary %A Tracy, Russell P %K African Americans %K Age Factors %K Aged %K Biomarkers %K Cardiovascular Diseases %K Chromosomes, Human, Pair 5 %K European Continental Ancestry Group %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Haplotypes %K Hexosyltransferases %K Humans %K Incidence %K Inflammation Mediators %K Linear Models %K Lipopolysaccharide Receptors %K Logistic Models %K Male %K Membrane Proteins %K Multivariate Analysis %K Phenotype %K Polymorphism, Single Nucleotide %K Principal Component Analysis %K Prognosis %K Proportional Hazards Models %K Prospective Studies %K Risk Assessment %K Risk Factors %K Time Factors %K United States %X

OBJECTIVE: CD14 is a glycosylphosphotidylinositol-anchored membrane glycoprotein expressed on neutrophils and monocytes/macrophages that also circulates as a soluble form (sCD14). Despite the well-recognized role of CD14 in inflammation, relatively little is known about the genetic determinants of sCD14 or the relationship of sCD14 to vascular- and aging-related phenotypes.

METHODS AND RESULTS: We measured baseline levels of sCD14 in >5000 European-American and black adults aged 65 years and older from the Cardiovascular Health Study, who were well characterized at baseline for atherosclerotic risk factors and subclinical cardiovascular disease, and who have been followed for clinical cardiovascular disease and mortality outcomes up to 20 years. At baseline, sCD14 generally showed strong positive correlations with traditional cardio-metabolic risk factors and with subclinical measures of vascular disease such as carotid wall thickness and ankle-brachial index (independently of traditional cardiovascular disease risk factors), and was also inversely correlated with body mass index. In genomewide association analyses of sCD14, we (1) confirmed the importance of the CD14 locus on chromosome 5q21 in European-American; (2) identified a novel African ancestry-specific allele of CD14 associated with lower sCD14 in blacks; and (3) identified a putative novel association in European-American of a nonsynonymous variant of PIGC, which encodes an enzyme required for the first step in glycosylphosphotidylinositol anchor biosynthesis. Finally, we show that, like other acute phase inflammatory biomarkers, sCD14 predicts incident cardiovascular disease, and strongly and independently predicts all-cause mortality in older adults.

CONCLUSIONS: CD14 independently predicts risk mortality in older adults.

%B Arterioscler Thromb Vasc Biol %V 33 %P 158-64 %8 2013 Jan %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/23162014?dopt=Abstract %R 10.1161/ATVBAHA.112.300421 %0 Journal Article %J Genet Epidemiol %D 2013 %T Strategy to control type I error increases power to identify genetic variation using the full biological trajectory. %A Benke, K S %A Wu, Y %A Fallin, D M %A Maher, B %A Palmer, L J %K Cohort Studies %K Computer Simulation %K Genetic Variation %K Genome-Wide Association Study %K Humans %K Linear Models %K Models, Genetic %K Polymorphism, Single Nucleotide %X

Genome-wide association studies have been successful in identifying loci that underlie continuous traits measured at a single time point. To additionally consider continuous traits longitudinally, it is desirable to look at SNP effects at baseline and over time using linear-mixed effects models. Estimation and interpretation of two coefficients in the same model raises concern regarding the optimal control of type I error. To investigate this issue, we calculate type I error and power under an alternative for joint tests, including the two degree of freedom likelihood ratio test, and compare this to single degree of freedom tests for each effect separately at varying alpha levels. We show which joint tests are the optimal way to control the type I error and also illustrate that information can be gained by joint testing in situations where either or both SNP effects are underpowered. We also show that closed form power calculations can approximate simulated power for the case of balanced data, provide reasonable approximations for imbalanced data, but overestimate power for complicated residual error structures. We conclude that a two degree of freedom test is an attractive strategy in a hypothesis-free genome-wide setting and recommend its use for genome-wide studies employing linear-mixed effects models.

%B Genet Epidemiol %V 37 %P 419-30 %8 2013 Jul %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/23633177?dopt=Abstract %R 10.1002/gepi.21733 %0 Journal Article %J PLoS Genet %D 2013 %T A systematic mapping approach of 16q12.2/FTO and BMI in more than 20,000 African Americans narrows in on the underlying functional variation: results from the Population Architecture using Genomics and Epidemiology (PAGE) study. %A Peters, Ulrike %A North, Kari E %A Sethupathy, Praveen %A Buyske, Steve %A Haessler, Jeff %A Jiao, Shuo %A Fesinmeyer, Megan D %A Jackson, Rebecca D %A Kuller, Lew H %A Rajkovic, Aleksandar %A Lim, Unhee %A Cheng, Iona %A Schumacher, Fred %A Wilkens, Lynne %A Li, Rongling %A Monda, Keri %A Ehret, Georg %A Nguyen, Khanh-Dung H %A Cooper, Richard %A Lewis, Cora E %A Leppert, Mark %A Irvin, Marguerite R %A Gu, C Charles %A Houston, Denise %A Bůzková, Petra %A Ritchie, Marylyn %A Matise, Tara C %A Le Marchand, Loïc %A Hindorff, Lucia A %A Crawford, Dana C %A Haiman, Christopher A %A Kooperberg, Charles %K Adaptor Proteins, Signal Transducing %K Adult %K African Americans %K Aged %K Aged, 80 and over %K Alleles %K Body Mass Index %K Chromosome Mapping %K Continental Population Groups %K European Continental Ancestry Group %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Linkage Disequilibrium %K Male %K Metagenomics %K Middle Aged %K Obesity %K Proteins %X

Genetic variants in intron 1 of the fat mass- and obesity-associated (FTO) gene have been consistently associated with body mass index (BMI) in Europeans. However, follow-up studies in African Americans (AA) have shown no support for some of the most consistently BMI-associated FTO index single nucleotide polymorphisms (SNPs). This is most likely explained by different race-specific linkage disequilibrium (LD) patterns and lower correlation overall in AA, which provides the opportunity to fine-map this region and narrow in on the functional variant. To comprehensively explore the 16q12.2/FTO locus and to search for second independent signals in the broader region, we fine-mapped a 646-kb region, encompassing the large FTO gene and the flanking gene RPGRIP1L by investigating a total of 3,756 variants (1,529 genotyped and 2,227 imputed variants) in 20,488 AAs across five studies. We observed associations between BMI and variants in the known FTO intron 1 locus: the SNP with the most significant p-value, rs56137030 (8.3 × 10(-6)) had not been highlighted in previous studies. While rs56137030was correlated at r(2)>0.5 with 103 SNPs in Europeans (including the GWAS index SNPs), this number was reduced to 28 SNPs in AA. Among rs56137030 and the 28 correlated SNPs, six were located within candidate intronic regulatory elements, including rs1421085, for which we predicted allele-specific binding affinity for the transcription factor CUX1, which has recently been implicated in the regulation of FTO. We did not find strong evidence for a second independent signal in the broader region. In summary, this large fine-mapping study in AA has substantially reduced the number of common alleles that are likely to be functional candidates of the known FTO locus. Importantly our study demonstrated that comprehensive fine-mapping in AA provides a powerful approach to narrow in on the functional candidate(s) underlying the initial GWAS findings in European populations.

%B PLoS Genet %V 9 %P e1003171 %8 2013 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/23341774?dopt=Abstract %R 10.1371/journal.pgen.1003171 %0 Journal Article %J PLoS Genet %D 2013 %T Trans-ethnic fine-mapping of lipid loci identifies population-specific signals and allelic heterogeneity that increases the trait variance explained. %A Wu, Ying %A Waite, Lindsay L %A Jackson, Anne U %A Sheu, Wayne H-H %A Buyske, Steven %A Absher, Devin %A Arnett, Donna K %A Boerwinkle, Eric %A Bonnycastle, Lori L %A Carty, Cara L %A Cheng, Iona %A Cochran, Barbara %A Croteau-Chonka, Damien C %A Dumitrescu, Logan %A Eaton, Charles B %A Franceschini, Nora %A Guo, Xiuqing %A Henderson, Brian E %A Hindorff, Lucia A %A Kim, Eric %A Kinnunen, Leena %A Komulainen, Pirjo %A Lee, Wen-Jane %A Le Marchand, Loïc %A Lin, Yi %A Lindström, Jaana %A Lingaas-Holmen, Oddgeir %A Mitchell, Sabrina L %A Narisu, Narisu %A Robinson, Jennifer G %A Schumacher, Fred %A Stančáková, Alena %A Sundvall, Jouko %A Sung, Yun-Ju %A Swift, Amy J %A Wang, Wen-Chang %A Wilkens, Lynne %A Wilsgaard, Tom %A Young, Alicia M %A Adair, Linda S %A Ballantyne, Christie M %A Bůzková, Petra %A Chakravarti, Aravinda %A Collins, Francis S %A Duggan, David %A Feranil, Alan B %A Ho, Low-Tone %A Hung, Yi-Jen %A Hunt, Steven C %A Hveem, Kristian %A Juang, Jyh-Ming J %A Kesäniemi, Antero Y %A Kuusisto, Johanna %A Laakso, Markku %A Lakka, Timo A %A Lee, I-Te %A Leppert, Mark F %A Matise, Tara C %A Moilanen, Leena %A Njølstad, Inger %A Peters, Ulrike %A Quertermous, Thomas %A Rauramaa, Rainer %A Rotter, Jerome I %A Saramies, Jouko %A Tuomilehto, Jaakko %A Uusitupa, Matti %A Wang, Tzung-Dau %A Boehnke, Michael %A Haiman, Christopher A %A Chen, Yii-der I %A Kooperberg, Charles %A Assimes, Themistocles L %A Crawford, Dana C %A Hsiung, Chao A %A North, Kari E %A Mohlke, Karen L %K African Americans %K Apolipoproteins A %K Cholesterol, HDL %K Cholesterol, LDL %K European Continental Ancestry Group %K Genome-Wide Association Study %K Humans %K Lipoproteins, HDL %K Lipoproteins, LDL %K Proprotein Convertases %K Serine Endopeptidases %K Triglycerides %X

Genome-wide association studies (GWAS) have identified ~100 loci associated with blood lipid levels, but much of the trait heritability remains unexplained, and at most loci the identities of the trait-influencing variants remain unknown. We conducted a trans-ethnic fine-mapping study at 18, 22, and 18 GWAS loci on the Metabochip for their association with triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C), respectively, in individuals of African American (n = 6,832), East Asian (n = 9,449), and European (n = 10,829) ancestry. We aimed to identify the variants with strongest association at each locus, identify additional and population-specific signals, refine association signals, and assess the relative significance of previously described functional variants. Among the 58 loci, 33 exhibited evidence of association at P<1 × 10(-4) in at least one ancestry group. Sequential conditional analyses revealed that ten, nine, and four loci in African Americans, Europeans, and East Asians, respectively, exhibited two or more signals. At these loci, accounting for all signals led to a 1.3- to 1.8-fold increase in the explained phenotypic variance compared to the strongest signals. Distinct signals across ancestry groups were identified at PCSK9 and APOA5. Trans-ethnic analyses narrowed the signals to smaller sets of variants at GCKR, PPP1R3B, ABO, LCAT, and ABCA1. Of 27 variants reported previously to have functional effects, 74% exhibited the strongest association at the respective signal. In conclusion, trans-ethnic high-density genotyping and analysis confirm the presence of allelic heterogeneity, allow the identification of population-specific variants, and limit the number of candidate SNPs for functional studies.

%B PLoS Genet %V 9 %P e1003379 %8 2013 Mar %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/23555291?dopt=Abstract %R 10.1371/journal.pgen.1003379 %0 Journal Article %J Nat Genet %D 2013 %T Whole-genome sequence-based analysis of high-density lipoprotein cholesterol. %A Morrison, Alanna C %A Voorman, Arend %A Johnson, Andrew D %A Liu, Xiaoming %A Yu, Jin %A Li, Alexander %A Muzny, Donna %A Yu, Fuli %A Rice, Kenneth %A Zhu, Chengsong %A Bis, Joshua %A Heiss, Gerardo %A O'Donnell, Christopher J %A Psaty, Bruce M %A Cupples, L Adrienne %A Gibbs, Richard %A Boerwinkle, Eric %K Cholesterol, HDL %K Computational Biology %K Databases, Genetic %K Genetic Variation %K Genome, Human %K Genome-Wide Association Study %K Genomics %K Heterozygote %K Humans %K Open Reading Frames %X

We describe initial steps for interrogating whole-genome sequence data to characterize the genetic architecture of a complex trait, levels of high-density lipoprotein cholesterol (HDL-C). We report whole-genome sequencing and analysis of 962 individuals from the Cohorts for Heart and Aging Research in Genetic Epidemiology (CHARGE) studies. From this analysis, we estimate that common variation contributes more to heritability of HDL-C levels than rare variation, and screening for mendelian variants for dyslipidemia identified individuals with extreme HDL-C levels. Whole-genome sequencing analyses highlight the value of regulatory and non-protein-coding regions of the genome in addition to protein-coding regions.

%B Nat Genet %V 45 %P 899-901 %8 2013 Aug %G eng %N 8 %1 http://www.ncbi.nlm.nih.gov/pubmed/23770607?dopt=Abstract %R 10.1038/ng.2671 %0 Journal Article %J Circ Cardiovasc Genet %D 2014 %T ADAM19 and HTR4 variants and pulmonary function: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study. %A London, Stephanie J %A Gao, Wei %A Gharib, Sina A %A Hancock, Dana B %A Wilk, Jemma B %A House, John S %A Gibbs, Richard A %A Muzny, Donna M %A Lumley, Thomas %A Franceschini, Nora %A North, Kari E %A Psaty, Bruce M %A Kovar, Christie L %A Coresh, Josef %A Zhou, Yanhua %A Heckbert, Susan R %A Brody, Jennifer A %A Morrison, Alanna C %A Dupuis, Josée %K ADAM Proteins %K Aged %K Aged, 80 and over %K Aging %K Cohort Studies %K Female %K Genetic Variation %K Genome-Wide Association Study %K Genomics %K Heart Diseases %K Humans %K Lung %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Sequence Analysis, DNA %X

BACKGROUND: The pulmonary function measures of forced expiratory volume in 1 second (FEV1) and its ratio to forced vital capacity (FVC) are used in the diagnosis and monitoring of lung diseases and predict cardiovascular mortality in the general population. Genome-wide association studies (GWASs) have identified numerous loci associated with FEV1 and FEV1/FVC, but the causal variants remain uncertain. We hypothesized that novel or rare variants poorly tagged by GWASs may explain the significant associations between FEV1/FVC and 2 genes: ADAM19 and HTR4.

METHODS AND RESULTS: We sequenced ADAM19 and its promoter region along with the ≈21-kb portion of HTR4 harboring GWAS single-nucleotide polymorphisms for pulmonary function and analyzed associations with FEV1/FVC among 3983 participants of European ancestry from Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Meta-analysis of common variants in each region identified statistically significant associations (316 tests; P<1.58×10(-4)) with FEV1/FVC for 14 ADAM19 single-nucleotide polymorphisms and 24 HTR4 single-nucleotide polymorphisms. After conditioning on the sentinel GWASs hit in each gene (ADAM19 rs1422795, minor allele frequency=0.33 and HTR4 rs11168048, minor allele frequency=0.40], 1 single-nucleotide polymorphism remained statistically significant (ADAM19 rs13155908, minor allele frequency=0.12; P=1.56×10(-4)). Analysis of rare variants (minor allele frequency <1%) using sequence kernel association test did not identify associations with either region.

CONCLUSIONS: Sequencing identified 1 common variant associated with FEV1/FVC independent of the sentinel ADAM19 GWAS hit and supports the original HTR4 GWAS findings. Rare variants do not seem to underlie GWAS associations with pulmonary function for common variants in ADAM19 and HTR4.

%B Circ Cardiovasc Genet %V 7 %P 350-8 %8 2014 Jun %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/24951661?dopt=Abstract %R 10.1161/CIRCGENETICS.113.000066 %0 Journal Article %J Circ Cardiovasc Genet %D 2014 %T Association of levels of fasting glucose and insulin with rare variants at the chromosome 11p11.2-MADD locus: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study. %A Cornes, Belinda K %A Brody, Jennifer A %A Nikpoor, Naghmeh %A Morrison, Alanna C %A Chu, Huan %A Ahn, Byung Soo %A Wang, Shuai %A Dauriz, Marco %A Barzilay, Joshua I %A Dupuis, Josée %A Florez, Jose C %A Coresh, Josef %A Gibbs, Richard A %A Kao, W H Linda %A Liu, Ching-Ti %A McKnight, Barbara %A Muzny, Donna %A Pankow, James S %A Reid, Jeffrey G %A White, Charles C %A Johnson, Andrew D %A Wong, Tien Y %A Psaty, Bruce M %A Boerwinkle, Eric %A Rotter, Jerome I %A Siscovick, David S %A Sladek, Robert %A Meigs, James B %K Aged %K Aged, 80 and over %K Aging %K Blood Glucose %K Chromosomes, Human, Pair 11 %K Cohort Studies %K Death Domain Receptor Signaling Adaptor Proteins %K Diabetes Mellitus, Type 2 %K Fasting %K Female %K Gene Frequency %K Genetic Variation %K Genome-Wide Association Study %K Genomics %K Guanine Nucleotide Exchange Factors %K Heart Diseases %K Humans %K Insulin %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Sequence Analysis, DNA %X

BACKGROUND: Common variation at the 11p11.2 locus, encompassing MADD, ACP2, NR1H3, MYBPC3, and SPI1, has been associated in genome-wide association studies with fasting glucose and insulin (FI). In the Cohorts for Heart and Aging Research in Genomic Epidemiology Targeted Sequencing Study, we sequenced 5 gene regions at 11p11.2 to identify rare, potentially functional variants influencing fasting glucose or FI levels.

METHODS AND RESULTS: Sequencing (mean depth, 38×) across 16.1 kb in 3566 individuals without diabetes mellitus identified 653 variants, 79.9% of which were rare (minor allele frequency <1%) and novel. We analyzed rare variants in 5 gene regions with FI or fasting glucose using the sequence kernel association test. At NR1H3, 53 rare variants were jointly associated with FI (P=2.73×10(-3)); of these, 7 were predicted to have regulatory function and showed association with FI (P=1.28×10(-3)). Conditioning on 2 previously associated variants at MADD (rs7944584, rs10838687) did not attenuate this association, suggesting that there are >2 independent signals at 11p11.2. One predicted regulatory variant, chr11:47227430 (hg18; minor allele frequency=0.00068), contributed 20.6% to the overall sequence kernel association test score at NR1H3, lies in intron 2 of NR1H3, and is a predicted binding site for forkhead box A1 (FOXA1), a transcription factor associated with insulin regulation. In human HepG2 hepatoma cells, the rare chr11:47227430 A allele disrupted FOXA1 binding and reduced FOXA1-dependent transcriptional activity.

CONCLUSIONS: Sequencing at 11p11.2-NR1H3 identified rare variation associated with FI. One variant, chr11:47227430, seems to be functional, with the rare A allele reducing transcription factor FOXA1 binding and FOXA1-dependent transcriptional activity.

%B Circ Cardiovasc Genet %V 7 %P 374-382 %8 2014 Jun %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/24951664?dopt=Abstract %R 10.1161/CIRCGENETICS.113.000169 %0 Journal Article %J PLoS One %D 2014 %T The challenges of genome-wide interaction studies: lessons to learn from the analysis of HDL blood levels. %A van Leeuwen, Elisabeth M %A Smouter, Françoise A S %A Kam-Thong, Tony %A Karbalai, Nazanin %A Smith, Albert V %A Harris, Tamara B %A Launer, Lenore J %A Sitlani, Colleen M %A Li, Guo %A Brody, Jennifer A %A Bis, Joshua C %A White, Charles C %A Jaiswal, Alok %A Oostra, Ben A %A Hofman, Albert %A Rivadeneira, Fernando %A Uitterlinden, André G %A Boerwinkle, Eric %A Ballantyne, Christie M %A Gudnason, Vilmundur %A Psaty, Bruce M %A Cupples, L Adrienne %A Jarvelin, Marjo-Riitta %A Ripatti, Samuli %A Isaacs, Aaron %A Müller-Myhsok, Bertram %A Karssen, Lennart C %A van Duijn, Cornelia M %K Cholesterol, HDL %K Female %K Genome-Wide Association Study %K Humans %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %X

Genome-wide association studies (GWAS) have revealed 74 single nucleotide polymorphisms (SNPs) associated with high-density lipoprotein cholesterol (HDL) blood levels. This study is, to our knowledge, the first genome-wide interaction study (GWIS) to identify SNP×SNP interactions associated with HDL levels. We performed a GWIS in the Rotterdam Study (RS) cohort I (RS-I) using the GLIDE tool which leverages the massively parallel computing power of Graphics Processing Units (GPUs) to perform linear regression on all genome-wide pairs of SNPs. By performing a meta-analysis together with Rotterdam Study cohorts II and III (RS-II and RS-III), we were able to filter 181 interaction terms with a p-value<1 · 10-8 that replicated in the two independent cohorts. We were not able to replicate any of these interaction term in the AGES, ARIC, CHS, ERF, FHS and NFBC-66 cohorts (Ntotal = 30,011) when adjusting for multiple testing. Our GWIS resulted in the consistent finding of a possible interaction between rs774801 in ARMC8 (ENSG00000114098) and rs12442098 in SPATA8 (ENSG00000185594) being associated with HDL levels. However, p-values do not reach the preset Bonferroni correction of the p-values. Our study suggest that even for highly genetically determined traits such as HDL the sample sizes needed to detect SNP×SNP interactions are large and the 2-step filtering approaches do not yield a solution. Here we present our analysis plan and our reservations concerning GWIS.

%B PLoS One %V 9 %P e109290 %8 2014 %G eng %N 10 %1 http://www.ncbi.nlm.nih.gov/pubmed/25329471?dopt=Abstract %R 10.1371/journal.pone.0109290 %0 Journal Article %J Pharmacogenomics J %D 2014 %T Drug-gene interactions and the search for missing heritability: a cross-sectional pharmacogenomics study of the QT interval. %A Avery, C L %A Sitlani, C M %A Arking, D E %A Arnett, D K %A Bis, J C %A Boerwinkle, E %A Buckley, B M %A Ida Chen, Y-D %A de Craen, A J M %A Eijgelsheim, M %A Enquobahrie, D %A Evans, D S %A Ford, I %A Garcia, M E %A Gudnason, V %A Harris, T B %A Heckbert, S R %A Hochner, H %A Hofman, A %A Hsueh, W-C %A Isaacs, A %A Jukema, J W %A Knekt, P %A Kors, J A %A Krijthe, B P %A Kristiansson, K %A Laaksonen, M %A Liu, Y %A Li, X %A Macfarlane, P W %A Newton-Cheh, C %A Nieminen, M S %A Oostra, B A %A Peloso, G M %A Porthan, K %A Rice, K %A Rivadeneira, F F %A Rotter, J I %A Salomaa, V %A Sattar, N %A Siscovick, D S %A Slagboom, P E %A Smith, A V %A Sotoodehnia, N %A Stott, D J %A Stricker, B H %A Stürmer, T %A Trompet, S %A Uitterlinden, A G %A van Duijn, C %A Westendorp, R G J %A Witteman, J C %A Whitsel, E A %A Psaty, B M %K Computer Simulation %K Cross-Sectional Studies %K Drug-Related Side Effects and Adverse Reactions %K Electrocardiography %K European Continental Ancestry Group %K Gene-Environment Interaction %K Genome-Wide Association Study %K Humans %K Linear Models %K Long QT Syndrome %K Markov Chains %K Pharmacogenetics %K Polymorphism, Single Nucleotide %K Quantitative Trait, Heritable %X

Variability in response to drug use is common and heritable, suggesting that genome-wide pharmacogenomics studies may help explain the 'missing heritability' of complex traits. Here, we describe four independent analyses in 33 781 participants of European ancestry from 10 cohorts that were designed to identify genetic variants modifying the effects of drugs on QT interval duration (QT). Each analysis cross-sectionally examined four therapeutic classes: thiazide diuretics (prevalence of use=13.0%), tri/tetracyclic antidepressants (2.6%), sulfonylurea hypoglycemic agents (2.9%) and QT-prolonging drugs as classified by the University of Arizona Center for Education and Research on Therapeutics (4.4%). Drug-gene interactions were estimated using covariable-adjusted linear regression and results were combined with fixed-effects meta-analysis. Although drug-single-nucleotide polymorphism (SNP) interactions were biologically plausible and variables were well-measured, findings from the four cross-sectional meta-analyses were null (Pinteraction>5.0 × 10(-8)). Simulations suggested that additional efforts, including longitudinal modeling to increase statistical power, are likely needed to identify potentially important pharmacogenomic effects.

%B Pharmacogenomics J %V 14 %P 6-13 %8 2014 Feb %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/23459443?dopt=Abstract %R 10.1038/tpj.2013.4 %0 Journal Article %J Am J Hum Genet %D 2014 %T Effects of long-term averaging of quantitative blood pressure traits on the detection of genetic associations. %A Ganesh, Santhi K %A Chasman, Daniel I %A Larson, Martin G %A Guo, Xiuqing %A Verwoert, Germain %A Bis, Joshua C %A Gu, Xiangjun %A Smith, Albert V %A Yang, Min-Lee %A Zhang, Yan %A Ehret, Georg %A Rose, Lynda M %A Hwang, Shih-Jen %A Papanicolau, George J %A Sijbrands, Eric J %A Rice, Kenneth %A Eiriksdottir, Gudny %A Pihur, Vasyl %A Ridker, Paul M %A Vasan, Ramachandran S %A Newton-Cheh, Christopher %A Raffel, Leslie J %A Amin, Najaf %A Rotter, Jerome I %A Liu, Kiang %A Launer, Lenore J %A Xu, Ming %A Caulfield, Mark %A Morrison, Alanna C %A Johnson, Andrew D %A Vaidya, Dhananjay %A Dehghan, Abbas %A Li, Guo %A Bouchard, Claude %A Harris, Tamara B %A Zhang, He %A Boerwinkle, Eric %A Siscovick, David S %A Gao, Wei %A Uitterlinden, André G %A Rivadeneira, Fernando %A Hofman, Albert %A Willer, Cristen J %A Franco, Oscar H %A Huo, Yong %A Witteman, Jacqueline C M %A Munroe, Patricia B %A Gudnason, Vilmundur %A Palmas, Walter %A van Duijn, Cornelia %A Fornage, Myriam %A Levy, Daniel %A Psaty, Bruce M %A Chakravarti, Aravinda %K Blood Pressure %K Genome-Wide Association Study %K Humans %K Longitudinal Studies %K Phenotype %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %X

Blood pressure (BP) is a heritable, quantitative trait with intraindividual variability and susceptibility to measurement error. Genetic studies of BP generally use single-visit measurements and thus cannot remove variability occurring over months or years. We leveraged the idea that averaging BP measured across time would improve phenotypic accuracy and thereby increase statistical power to detect genetic associations. We studied systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), and pulse pressure (PP) averaged over multiple years in 46,629 individuals of European ancestry. We identified 39 trait-variant associations across 19 independent loci (p < 5 × 10(-8)); five associations (in four loci) uniquely identified by our LTA analyses included those of SBP and MAP at 2p23 (rs1275988, near KCNK3), DBP at 2q11.2 (rs7599598, in FER1L5), and PP at 6p21 (rs10948071, near CRIP3) and 7p13 (rs2949837, near IGFBP3). Replication analyses conducted in cohorts with single-visit BP data showed positive replication of associations and a nominal association (p < 0.05). We estimated a 20% gain in statistical power with long-term average (LTA) as compared to single-visit BP association studies. Using LTA analysis, we identified genetic loci influencing BP. LTA might be one way of increasing the power of genetic associations for continuous traits in extant samples for other phenotypes that are measured serially over time.

%B Am J Hum Genet %V 95 %P 49-65 %8 2014 Jul 03 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/24975945?dopt=Abstract %R 10.1016/j.ajhg.2014.06.002 %0 Journal Article %J Hum Mol Genet %D 2014 %T Gene-centric meta-analyses for central adiposity traits in up to 57 412 individuals of European descent confirm known loci and reveal several novel associations. %A Yoneyama, Sachiko %A Guo, Yiran %A Lanktree, Matthew B %A Barnes, Michael R %A Elbers, Clara C %A Karczewski, Konrad J %A Padmanabhan, Sandosh %A Bauer, Florianne %A Baumert, Jens %A Beitelshees, Amber %A Berenson, Gerald S %A Boer, Jolanda M A %A Burke, Gregory %A Cade, Brian %A Chen, Wei %A Cooper-Dehoff, Rhonda M %A Gaunt, Tom R %A Gieger, Christian %A Gong, Yan %A Gorski, Mathias %A Heard-Costa, Nancy %A Johnson, Toby %A Lamonte, Michael J %A McDonough, Caitrin %A Monda, Keri L %A Onland-Moret, N Charlotte %A Nelson, Christopher P %A O'Connell, Jeffrey R %A Ordovas, Jose %A Peter, Inga %A Peters, Annette %A Shaffer, Jonathan %A Shen, Haiqinq %A Smith, Erin %A Speilotes, Liz %A Thomas, Fridtjof %A Thorand, Barbara %A Monique Verschuren, W M %A Anand, Sonia S %A Dominiczak, Anna %A Davidson, Karina W %A Hegele, Robert A %A Heid, Iris %A Hofker, Marten H %A Huggins, Gordon S %A Illig, Thomas %A Johnson, Julie A %A Kirkland, Susan %A König, Wolfgang %A Langaee, Taimour Y %A McCaffery, Jeanne %A Melander, Olle %A Mitchell, Braxton D %A Munroe, Patricia %A Murray, Sarah S %A Papanicolaou, George %A Redline, Susan %A Reilly, Muredach %A Samani, Nilesh J %A Schork, Nicholas J %A van der Schouw, Yvonne T %A Shimbo, Daichi %A Shuldiner, Alan R %A Tobin, Martin D %A Wijmenga, Cisca %A Yusuf, Salim %A Hakonarson, Hakon %A Lange, Leslie A %A Demerath, Ellen W %A Fox, Caroline S %A North, Kari E %A Reiner, Alex P %A Keating, Brendan %A Taylor, Kira C %K Adiposity %K Adult %K Aged %K Aged, 80 and over %K Body Mass Index %K European Continental Ancestry Group %K Female %K Genome-Wide Association Study %K Humans %K Male %K Middle Aged %K Waist Circumference %K Waist-Hip Ratio %K Young Adult %X

Waist circumference (WC) and waist-to-hip ratio (WHR) are surrogate measures of central adiposity that are associated with adverse cardiovascular events, type 2 diabetes and cancer independent of body mass index (BMI). WC and WHR are highly heritable with multiple susceptibility loci identified to date. We assessed the association between SNPs and BMI-adjusted WC and WHR and unadjusted WC in up to 57 412 individuals of European descent from 22 cohorts collaborating with the NHLBI's Candidate Gene Association Resource (CARe) project. The study population consisted of women and men aged 20-80 years. Study participants were genotyped using the ITMAT/Broad/CARE array, which includes ∼50 000 cosmopolitan tagged SNPs across ∼2100 cardiovascular-related genes. Each trait was modeled as a function of age, study site and principal components to control for population stratification, and we conducted a fixed-effects meta-analysis. No new loci for WC were observed. For WHR analyses, three novel loci were significantly associated (P < 2.4 × 10(-6)). Previously unreported rs2811337-G near TMCC1 was associated with increased WHR (β ± SE, 0.048 ± 0.008, P = 7.7 × 10(-9)) as was rs7302703-G in HOXC10 (β = 0.044 ± 0.008, P = 2.9 × 10(-7)) and rs936108-C in PEMT (β = 0.035 ± 0.007, P = 1.9 × 10(-6)). Sex-stratified analyses revealed two additional novel signals among females only, rs12076073-A in SHC1 (β = 0.10 ± 0.02, P = 1.9 × 10(-6)) and rs1037575-A in ATBDB4 (β = 0.046 ± 0.01, P = 2.2 × 10(-6)), supporting an already established sexual dimorphism of central adiposity-related genetic variants. Functional analysis using ENCODE and eQTL databases revealed that several of these loci are in regulatory regions or regions with differential expression in adipose tissue.

%B Hum Mol Genet %V 23 %P 2498-510 %8 2014 May 01 %G eng %N 9 %1 http://www.ncbi.nlm.nih.gov/pubmed/24345515?dopt=Abstract %R 10.1093/hmg/ddt626 %0 Journal Article %J Nat Genet %D 2014 %T Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization. %A Arking, Dan E %A Pulit, Sara L %A Crotti, Lia %A van der Harst, Pim %A Munroe, Patricia B %A Koopmann, Tamara T %A Sotoodehnia, Nona %A Rossin, Elizabeth J %A Morley, Michael %A Wang, Xinchen %A Johnson, Andrew D %A Lundby, Alicia %A Gudbjartsson, Daniel F %A Noseworthy, Peter A %A Eijgelsheim, Mark %A Bradford, Yuki %A Tarasov, Kirill V %A Dörr, Marcus %A Müller-Nurasyid, Martina %A Lahtinen, Annukka M %A Nolte, Ilja M %A Smith, Albert Vernon %A Bis, Joshua C %A Isaacs, Aaron %A Newhouse, Stephen J %A Evans, Daniel S %A Post, Wendy S %A Waggott, Daryl %A Lyytikäinen, Leo-Pekka %A Hicks, Andrew A %A Eisele, Lewin %A Ellinghaus, David %A Hayward, Caroline %A Navarro, Pau %A Ulivi, Sheila %A Tanaka, Toshiko %A Tester, David J %A Chatel, Stéphanie %A Gustafsson, Stefan %A Kumari, Meena %A Morris, Richard W %A Naluai, Åsa T %A Padmanabhan, Sandosh %A Kluttig, Alexander %A Strohmer, Bernhard %A Panayiotou, Andrie G %A Torres, Maria %A Knoflach, Michael %A Hubacek, Jaroslav A %A Slowikowski, Kamil %A Raychaudhuri, Soumya %A Kumar, Runjun D %A Harris, Tamara B %A Launer, Lenore J %A Shuldiner, Alan R %A Alonso, Alvaro %A Bader, Joel S %A Ehret, Georg %A Huang, Hailiang %A Kao, W H Linda %A Strait, James B %A Macfarlane, Peter W %A Brown, Morris %A Caulfield, Mark J %A Samani, Nilesh J %A Kronenberg, Florian %A Willeit, Johann %A Smith, J Gustav %A Greiser, Karin H %A Meyer Zu Schwabedissen, Henriette %A Werdan, Karl %A Carella, Massimo %A Zelante, Leopoldo %A Heckbert, Susan R %A Psaty, Bruce M %A Rotter, Jerome I %A Kolcic, Ivana %A Polasek, Ozren %A Wright, Alan F %A Griffin, Maura %A Daly, Mark J %A Arnar, David O %A Holm, Hilma %A Thorsteinsdottir, Unnur %A Denny, Joshua C %A Roden, Dan M %A Zuvich, Rebecca L %A Emilsson, Valur %A Plump, Andrew S %A Larson, Martin G %A O'Donnell, Christopher J %A Yin, Xiaoyan %A Bobbo, Marco %A D'Adamo, Adamo P %A Iorio, Annamaria %A Sinagra, Gianfranco %A Carracedo, Angel %A Cummings, Steven R %A Nalls, Michael A %A Jula, Antti %A Kontula, Kimmo K %A Marjamaa, Annukka %A Oikarinen, Lasse %A Perola, Markus %A Porthan, Kimmo %A Erbel, Raimund %A Hoffmann, Per %A Jöckel, Karl-Heinz %A Kälsch, Hagen %A Nöthen, Markus M %A den Hoed, Marcel %A Loos, Ruth J F %A Thelle, Dag S %A Gieger, Christian %A Meitinger, Thomas %A Perz, Siegfried %A Peters, Annette %A Prucha, Hanna %A Sinner, Moritz F %A Waldenberger, Melanie %A de Boer, Rudolf A %A Franke, Lude %A van der Vleuten, Pieter A %A Beckmann, Britt Maria %A Martens, Eimo %A Bardai, Abdennasser %A Hofman, Nynke %A Wilde, Arthur A M %A Behr, Elijah R %A Dalageorgou, Chrysoula %A Giudicessi, John R %A Medeiros-Domingo, Argelia %A Barc, Julien %A Kyndt, Florence %A Probst, Vincent %A Ghidoni, Alice %A Insolia, Roberto %A Hamilton, Robert M %A Scherer, Stephen W %A Brandimarto, Jeffrey %A Margulies, Kenneth %A Moravec, Christine E %A del Greco M, Fabiola %A Fuchsberger, Christian %A O'Connell, Jeffrey R %A Lee, Wai K %A Watt, Graham C M %A Campbell, Harry %A Wild, Sarah H %A El Mokhtari, Nour E %A Frey, Norbert %A Asselbergs, Folkert W %A Mateo Leach, Irene %A Navis, Gerjan %A van den Berg, Maarten P %A van Veldhuisen, Dirk J %A Kellis, Manolis %A Krijthe, Bouwe P %A Franco, Oscar H %A Hofman, Albert %A Kors, Jan A %A Uitterlinden, André G %A Witteman, Jacqueline C M %A Kedenko, Lyudmyla %A Lamina, Claudia %A Oostra, Ben A %A Abecasis, Goncalo R %A Lakatta, Edward G %A Mulas, Antonella %A Orrù, Marco %A Schlessinger, David %A Uda, Manuela %A Markus, Marcello R P %A Völker, Uwe %A Snieder, Harold %A Spector, Timothy D %A Arnlöv, Johan %A Lind, Lars %A Sundström, Johan %A Syvänen, Ann-Christine %A Kivimaki, Mika %A Kähönen, Mika %A Mononen, Nina %A Raitakari, Olli T %A Viikari, Jorma S %A Adamkova, Vera %A Kiechl, Stefan %A Brion, Maria %A Nicolaides, Andrew N %A Paulweber, Bernhard %A Haerting, Johannes %A Dominiczak, Anna F %A Nyberg, Fredrik %A Whincup, Peter H %A Hingorani, Aroon D %A Schott, Jean-Jacques %A Bezzina, Connie R %A Ingelsson, Erik %A Ferrucci, Luigi %A Gasparini, Paolo %A Wilson, James F %A Rudan, Igor %A Franke, Andre %A Mühleisen, Thomas W %A Pramstaller, Peter P %A Lehtimäki, Terho J %A Paterson, Andrew D %A Parsa, Afshin %A Liu, Yongmei %A van Duijn, Cornelia M %A Siscovick, David S %A Gudnason, Vilmundur %A Jamshidi, Yalda %A Salomaa, Veikko %A Felix, Stephan B %A Sanna, Serena %A Ritchie, Marylyn D %A Stricker, Bruno H %A Stefansson, Kari %A Boyer, Laurie A %A Cappola, Thomas P %A Olsen, Jesper V %A Lage, Kasper %A Schwartz, Peter J %A Kääb, Stefan %A Chakravarti, Aravinda %A Ackerman, Michael J %A Pfeufer, Arne %A de Bakker, Paul I W %A Newton-Cheh, Christopher %K Adult %K Aged %K Arrhythmias, Cardiac %K Calcium Signaling %K Death, Sudden, Cardiac %K Electrocardiography %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genotype %K Heart Ventricles %K Humans %K Long QT Syndrome %K Male %K Middle Aged %K Myocardium %K Polymorphism, Single Nucleotide %X

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.

%B Nat Genet %V 46 %P 826-36 %8 2014 Aug %G eng %N 8 %1 http://www.ncbi.nlm.nih.gov/pubmed/24952745?dopt=Abstract %R 10.1038/ng.3014 %0 Journal Article %J BMC Genet %D 2014 %T Genetic diversity is a predictor of mortality in humans. %A Bihlmeyer, Nathan A %A Brody, Jennifer A %A Smith, Albert Vernon %A Lunetta, Kathryn L %A Nalls, Mike %A Smith, Jennifer A %A Tanaka, Toshiko %A Davies, Gail %A Yu, Lei %A Mirza, Saira Saeed %A Teumer, Alexander %A Coresh, Josef %A Pankow, James S %A Franceschini, Nora %A Scaria, Anish %A Oshima, Junko %A Psaty, Bruce M %A Gudnason, Vilmundur %A Eiriksdottir, Gudny %A Harris, Tamara B %A Li, Hanyue %A Karasik, David %A Kiel, Douglas P %A Garcia, Melissa %A Liu, Yongmei %A Faul, Jessica D %A Kardia, Sharon Lr %A Zhao, Wei %A Ferrucci, Luigi %A Allerhand, Michael %A Liewald, David C %A Redmond, Paul %A Starr, John M %A De Jager, Philip L %A Evans, Denis A %A Direk, Nese %A Ikram, Mohammed Arfan %A Uitterlinden, Andre %A Homuth, Georg %A Lorbeer, Roberto %A Grabe, Hans J %A Launer, Lenore %A Murabito, Joanne M %A Singleton, Andrew B %A Weir, David R %A Bandinelli, Stefania %A Deary, Ian J %A Bennett, David A %A Tiemeier, Henning %A Kocher, Thomas %A Lumley, Thomas %A Arking, Dan E %K Genome-Wide Association Study %K Heterozygote %K Humans %K Mortality %K Polymorphism, Single Nucleotide %K Proportional Hazards Models %X

BACKGROUND: It has been well-established, both by population genetics theory and direct observation in many organisms, that increased genetic diversity provides a survival advantage. However, given the limitations of both sample size and genome-wide metrics, this hypothesis has not been comprehensively tested in human populations. Moreover, the presence of numerous segregating small effect alleles that influence traits that directly impact health directly raises the question as to whether global measures of genomic variation are themselves associated with human health and disease.

RESULTS: We performed a meta-analysis of 17 cohorts followed prospectively, with a combined sample size of 46,716 individuals, including a total of 15,234 deaths. We find a significant association between increased heterozygosity and survival (P = 0.03). We estimate that within a single population, every standard deviation of heterozygosity an individual has over the mean decreases that person's risk of death by 1.57%.

CONCLUSIONS: This effect was consistent between European and African ancestry cohorts, men and women, and major causes of death (cancer and cardiovascular disease), demonstrating the broad positive impact of genomic diversity on human survival.

%B BMC Genet %V 15 %P 159 %8 2014 %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/25543667?dopt=Abstract %R 10.1186/s12863-014-0159-7 %0 Journal Article %J PLoS One %D 2014 %T Gene-wide analysis detects two new susceptibility genes for Alzheimer's disease. %A Escott-Price, Valentina %A Bellenguez, Céline %A Wang, Li-San %A Choi, Seung-Hoan %A Harold, Denise %A Jones, Lesley %A Holmans, Peter %A Gerrish, Amy %A Vedernikov, Alexey %A Richards, Alexander %A DeStefano, Anita L %A Lambert, Jean-Charles %A Ibrahim-Verbaas, Carla A %A Naj, Adam C %A Sims, Rebecca %A Jun, Gyungah %A Bis, Joshua C %A Beecham, Gary W %A Grenier-Boley, Benjamin %A Russo, Giancarlo %A Thornton-Wells, Tricia A %A Denning, Nicola %A Smith, Albert V %A Chouraki, Vincent %A Thomas, Charlene %A Ikram, M Arfan %A Zelenika, Diana %A Vardarajan, Badri N %A Kamatani, Yoichiro %A Lin, Chiao-Feng %A Schmidt, Helena %A Kunkle, Brian %A Dunstan, Melanie L %A Vronskaya, Maria %A Johnson, Andrew D %A Ruiz, Agustin %A Bihoreau, Marie-Thérèse %A Reitz, Christiane %A Pasquier, Florence %A Hollingworth, Paul %A Hanon, Olivier %A Fitzpatrick, Annette L %A Buxbaum, Joseph D %A Campion, Dominique %A Crane, Paul K %A Baldwin, Clinton %A Becker, Tim %A Gudnason, Vilmundur %A Cruchaga, Carlos %A Craig, David %A Amin, Najaf %A Berr, Claudine %A Lopez, Oscar L %A De Jager, Philip L %A Deramecourt, Vincent %A Johnston, Janet A %A Evans, Denis %A Lovestone, Simon %A Letenneur, Luc %A Hernandez, Isabel %A Rubinsztein, David C %A Eiriksdottir, Gudny %A Sleegers, Kristel %A Goate, Alison M %A Fiévet, Nathalie %A Huentelman, Matthew J %A Gill, Michael %A Brown, Kristelle %A Kamboh, M Ilyas %A Keller, Lina %A Barberger-Gateau, Pascale %A McGuinness, Bernadette %A Larson, Eric B %A Myers, Amanda J %A Dufouil, Carole %A Todd, Stephen %A Wallon, David %A Love, Seth %A Rogaeva, Ekaterina %A Gallacher, John %A George-Hyslop, Peter St %A Clarimon, Jordi %A Lleo, Alberto %A Bayer, Anthony %A Tsuang, Debby W %A Yu, Lei %A Tsolaki, Magda %A Bossù, Paola %A Spalletta, Gianfranco %A Proitsi, Petra %A Collinge, John %A Sorbi, Sandro %A Garcia, Florentino Sanchez %A Fox, Nick C %A Hardy, John %A Naranjo, Maria Candida Deniz %A Bosco, Paolo %A Clarke, Robert %A Brayne, Carol %A Galimberti, Daniela %A Scarpini, Elio %A Bonuccelli, Ubaldo %A Mancuso, Michelangelo %A Siciliano, Gabriele %A Moebus, Susanne %A Mecocci, Patrizia %A Zompo, Maria Del %A Maier, Wolfgang %A Hampel, Harald %A Pilotto, Alberto %A Frank-García, Ana %A Panza, Francesco %A Solfrizzi, Vincenzo %A Caffarra, Paolo %A Nacmias, Benedetta %A Perry, William %A Mayhaus, Manuel %A Lannfelt, Lars %A Hakonarson, Hakon %A Pichler, Sabrina %A Carrasquillo, Minerva M %A Ingelsson, Martin %A Beekly, Duane %A Alvarez, Victoria %A Zou, Fanggeng %A Valladares, Otto %A Younkin, Steven G %A Coto, Eliecer %A Hamilton-Nelson, Kara L %A Gu, Wei %A Razquin, Cristina %A Pastor, Pau %A Mateo, Ignacio %A Owen, Michael J %A Faber, Kelley M %A Jonsson, Palmi V %A Combarros, Onofre %A O'Donovan, Michael C %A Cantwell, Laura B %A Soininen, Hilkka %A Blacker, Deborah %A Mead, Simon %A Mosley, Thomas H %A Bennett, David A %A Harris, Tamara B %A Fratiglioni, Laura %A Holmes, Clive %A de Bruijn, Renee F A G %A Passmore, Peter %A Montine, Thomas J %A Bettens, Karolien %A Rotter, Jerome I %A Brice, Alexis %A Morgan, Kevin %A Foroud, Tatiana M %A Kukull, Walter A %A Hannequin, Didier %A Powell, John F %A Nalls, Michael A %A Ritchie, Karen %A Lunetta, Kathryn L %A Kauwe, John S K %A Boerwinkle, Eric %A Riemenschneider, Matthias %A Boada, Merce %A Hiltunen, Mikko %A Martin, Eden R %A Schmidt, Reinhold %A Rujescu, Dan %A Dartigues, Jean-François %A Mayeux, Richard %A Tzourio, Christophe %A Hofman, Albert %A Nöthen, Markus M %A Graff, Caroline %A Psaty, Bruce M %A Haines, Jonathan L %A Lathrop, Mark %A Pericak-Vance, Margaret A %A Launer, Lenore J %A Van Broeckhoven, Christine %A Farrer, Lindsay A %A van Duijn, Cornelia M %A Ramirez, Alfredo %A Seshadri, Sudha %A Schellenberg, Gerard D %A Amouyel, Philippe %A Williams, Julie %K Alzheimer Disease %K Carrier Proteins %K Case-Control Studies %K Genome-Wide Association Study %K Heat-Shock Proteins %K Humans %K Polymorphism, Single Nucleotide %K Receptors, Antigen, B-Cell %X

BACKGROUND: Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls.

PRINCIPAL FINDINGS: In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4×10-6) and 14 (IGHV1-67 p = 7.9×10-8) which indexed novel susceptibility loci.

SIGNIFICANCE: The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.

%B PLoS One %V 9 %P e94661 %8 2014 %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/24922517?dopt=Abstract %R 10.1371/journal.pone.0094661 %0 Journal Article %J Nat Genet %D 2014 %T Genome-wide association analysis identifies six new loci associated with forced vital capacity. %A Loth, Daan W %A Soler Artigas, Maria %A Gharib, Sina A %A Wain, Louise V %A Franceschini, Nora %A Koch, Beate %A Pottinger, Tess D %A Smith, Albert Vernon %A Duan, Qing %A Oldmeadow, Chris %A Lee, Mi Kyeong %A Strachan, David P %A James, Alan L %A Huffman, Jennifer E %A Vitart, Veronique %A Ramasamy, Adaikalavan %A Wareham, Nicholas J %A Kaprio, Jaakko %A Wang, Xin-Qun %A Trochet, Holly %A Kähönen, Mika %A Flexeder, Claudia %A Albrecht, Eva %A Lopez, Lorna M %A de Jong, Kim %A Thyagarajan, Bharat %A Alves, Alexessander Couto %A Enroth, Stefan %A Omenaas, Ernst %A Joshi, Peter K %A Fall, Tove %A Viñuela, Ana %A Launer, Lenore J %A Loehr, Laura R %A Fornage, Myriam %A Li, Guo %A Wilk, Jemma B %A Tang, Wenbo %A Manichaikul, Ani %A Lahousse, Lies %A Harris, Tamara B %A North, Kari E %A Rudnicka, Alicja R %A Hui, Jennie %A Gu, Xiangjun %A Lumley, Thomas %A Wright, Alan F %A Hastie, Nicholas D %A Campbell, Susan %A Kumar, Rajesh %A Pin, Isabelle %A Scott, Robert A %A Pietiläinen, Kirsi H %A Surakka, Ida %A Liu, Yongmei %A Holliday, Elizabeth G %A Schulz, Holger %A Heinrich, Joachim %A Davies, Gail %A Vonk, Judith M %A Wojczynski, Mary %A Pouta, Anneli %A Johansson, Asa %A Wild, Sarah H %A Ingelsson, Erik %A Rivadeneira, Fernando %A Völzke, Henry %A Hysi, Pirro G %A Eiriksdottir, Gudny %A Morrison, Alanna C %A Rotter, Jerome I %A Gao, Wei %A Postma, Dirkje S %A White, Wendy B %A Rich, Stephen S %A Hofman, Albert %A Aspelund, Thor %A Couper, David %A Smith, Lewis J %A Psaty, Bruce M %A Lohman, Kurt %A Burchard, Esteban G %A Uitterlinden, André G %A Garcia, Melissa %A Joubert, Bonnie R %A McArdle, Wendy L %A Musk, A Bill %A Hansel, Nadia %A Heckbert, Susan R %A Zgaga, Lina %A van Meurs, Joyce B J %A Navarro, Pau %A Rudan, Igor %A Oh, Yeon-Mok %A Redline, Susan %A Jarvis, Deborah L %A Zhao, Jing Hua %A Rantanen, Taina %A O'Connor, George T %A Ripatti, Samuli %A Scott, Rodney J %A Karrasch, Stefan %A Grallert, Harald %A Gaddis, Nathan C %A Starr, John M %A Wijmenga, Cisca %A Minster, Ryan L %A Lederer, David J %A Pekkanen, Juha %A Gyllensten, Ulf %A Campbell, Harry %A Morris, Andrew P %A Gläser, Sven %A Hammond, Christopher J %A Burkart, Kristin M %A Beilby, John %A Kritchevsky, Stephen B %A Gudnason, Vilmundur %A Hancock, Dana B %A Williams, O Dale %A Polasek, Ozren %A Zemunik, Tatijana %A Kolcic, Ivana %A Petrini, Marcy F %A Wjst, Matthias %A Kim, Woo Jin %A Porteous, David J %A Scotland, Generation %A Smith, Blair H %A Viljanen, Anne %A Heliövaara, Markku %A Attia, John R %A Sayers, Ian %A Hampel, Regina %A Gieger, Christian %A Deary, Ian J %A Boezen, H Marike %A Newman, Anne %A Jarvelin, Marjo-Riitta %A Wilson, James F %A Lind, Lars %A Stricker, Bruno H %A Teumer, Alexander %A Spector, Timothy D %A Melén, Erik %A Peters, Marjolein J %A Lange, Leslie A %A Barr, R Graham %A Bracke, Ken R %A Verhamme, Fien M %A Sung, Joohon %A Hiemstra, Pieter S %A Cassano, Patricia A %A Sood, Akshay %A Hayward, Caroline %A Dupuis, Josée %A Hall, Ian P %A Brusselle, Guy G %A Tobin, Martin D %A London, Stephanie J %K Cohort Studies %K Databases, Genetic %K Follow-Up Studies %K Forced Expiratory Volume %K Genetic Loci %K Genetic Predisposition to Disease %K Genome, Human %K Genome-Wide Association Study %K Humans %K Lung Diseases %K Meta-Analysis as Topic %K Polymorphism, Single Nucleotide %K Prognosis %K Quantitative Trait Loci %K Respiratory Function Tests %K Spirometry %K Vital Capacity %X

Forced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 additional individuals of European ancestry. We found six new regions associated at genome-wide significance (P < 5 × 10(-8)) with FVC in or near EFEMP1, BMP6, MIR129-2-HSD17B12, PRDM11, WWOX and KCNJ2. Two loci previously associated with spirometric measures (GSTCD and PTCH1) were related to FVC. Newly implicated regions were followed up in samples from African-American, Korean, Chinese and Hispanic individuals. We detected transcripts for all six newly implicated genes in human lung tissue. The new loci may inform mechanisms involved in lung development and the pathogenesis of restrictive lung disease.

%B Nat Genet %V 46 %P 669-77 %8 2014 Jul %G eng %N 7 %1 http://www.ncbi.nlm.nih.gov/pubmed/24929828?dopt=Abstract %R 10.1038/ng.3011 %0 Journal Article %J Arterioscler Thromb Vasc Biol %D 2014 %T Genome-wide association study for circulating tissue plasminogen activator levels and functional follow-up implicates endothelial STXBP5 and STX2. %A Huang, Jie %A Huffman, Jennifer E %A Yamakuchi, Munekazu %A Yamkauchi, Munekazu %A Trompet, Stella %A Asselbergs, Folkert W %A Sabater-Lleal, Maria %A Trégouët, David-Alexandre %A Chen, Wei-Min %A Smith, Nicholas L %A Kleber, Marcus E %A Shin, So-Youn %A Becker, Diane M %A Tang, Weihong %A Dehghan, Abbas %A Johnson, Andrew D %A Truong, Vinh %A Folkersen, Lasse %A Yang, Qiong %A Oudot-Mellkah, Tiphaine %A Buckley, Brendan M %A Moore, Jason H %A Williams, Frances M K %A Campbell, Harry %A Silbernagel, Günther %A Vitart, Veronique %A Rudan, Igor %A Tofler, Geoffrey H %A Navis, Gerjan J %A DeStefano, Anita %A Wright, Alan F %A Chen, Ming-Huei %A de Craen, Anton J M %A Worrall, Bradford B %A Rudnicka, Alicja R %A Rumley, Ann %A Bookman, Ebony B %A Psaty, Bruce M %A Chen, Fang %A Keene, Keith L %A Franco, Oscar H %A Böhm, Bernhard O %A Uitterlinden, André G %A Carter, Angela M %A Jukema, J Wouter %A Sattar, Naveed %A Bis, Joshua C %A Ikram, Mohammad A %A Sale, Michèle M %A McKnight, Barbara %A Fornage, Myriam %A Ford, Ian %A Taylor, Kent %A Slagboom, P Eline %A McArdle, Wendy L %A Hsu, Fang-Chi %A Franco-Cereceda, Anders %A Goodall, Alison H %A Yanek, Lisa R %A Furie, Karen L %A Cushman, Mary %A Hofman, Albert %A Witteman, Jacqueline C M %A Folsom, Aaron R %A Basu, Saonli %A Matijevic, Nena %A van Gilst, Wiek H %A Wilson, James F %A Westendorp, Rudi G J %A Kathiresan, Sekar %A Reilly, Muredach P %A Tracy, Russell P %A Polasek, Ozren %A Winkelmann, Bernhard R %A Grant, Peter J %A Hillege, Hans L %A Cambien, Francois %A Stott, David J %A Lowe, Gordon D %A Spector, Timothy D %A Meigs, James B %A März, Winfried %A Eriksson, Per %A Becker, Lewis C %A Morange, Pierre-Emmanuel %A Soranzo, Nicole %A Williams, Scott M %A Hayward, Caroline %A van der Harst, Pim %A Hamsten, Anders %A Lowenstein, Charles J %A Strachan, David P %A O'Donnell, Christopher J %K Aged %K Cells, Cultured %K Coronary Artery Disease %K Endothelial Cells %K Europe %K Female %K Gene Expression Regulation %K Gene Silencing %K Genetic Loci %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Male %K Middle Aged %K Nerve Tissue Proteins %K Phenotype %K Polymorphism, Single Nucleotide %K R-SNARE Proteins %K Risk Factors %K Stroke %K Syntaxin 1 %K Tissue Plasminogen Activator %K Transfection %K United States %K Up-Regulation %X

OBJECTIVE: Tissue plasminogen activator (tPA), a serine protease, catalyzes the conversion of plasminogen to plasmin, the major enzyme responsible for endogenous fibrinolysis. In some populations, elevated plasma levels of tPA have been associated with myocardial infarction and other cardiovascular diseases. We conducted a meta-analysis of genome-wide association studies to identify novel correlates of circulating levels of tPA.

APPROACH AND RESULTS: Fourteen cohort studies with tPA measures (N=26 929) contributed to the meta-analysis. Three loci were significantly associated with circulating tPA levels (P<5.0×10(-8)). The first locus is on 6q24.3, with the lead single nucleotide polymorphism (SNP; rs9399599; P=2.9×10(-14)) within STXBP5. The second locus is on 8p11.21. The lead SNP (rs3136739; P=1.3×10(-9)) is intronic to POLB and <200 kb away from the tPA encoding the gene PLAT. We identified a nonsynonymous SNP (rs2020921) in modest linkage disequilibrium with rs3136739 (r(2)=0.50) within exon 5 of PLAT (P=2.0×10(-8)). The third locus is on 12q24.33, with the lead SNP (rs7301826; P=1.0×10(-9)) within intron 7 of STX2. We further found evidence for the association of lead SNPs in STXBP5 and STX2 with expression levels of the respective transcripts. In in vitro cell studies, silencing STXBP5 decreased the release of tPA from vascular endothelial cells, whereas silencing STX2 increased the tPA release. Through an in silico lookup, we found no associations of the 3 lead SNPs with coronary artery disease or stroke.

CONCLUSIONS: We identified 3 loci associated with circulating tPA levels, the PLAT region, STXBP5, and STX2. Our functional studies implicate a novel role for STXBP5 and STX2 in regulating tPA release.

%B Arterioscler Thromb Vasc Biol %V 34 %P 1093-101 %8 2014 May %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/24578379?dopt=Abstract %R 10.1161/ATVBAHA.113.302088 %0 Journal Article %J Circ Cardiovasc Genet %D 2014 %T Genome-wide association study of L-arginine and dimethylarginines reveals novel metabolic pathway for symmetric dimethylarginine. %A Lüneburg, Nicole %A Lieb, Wolfgang %A Zeller, Tanja %A Chen, Ming-Huei %A Maas, Renke %A Carter, Angela M %A Xanthakis, Vanessa %A Glazer, Nicole L %A Schwedhelm, Edzard %A Seshadri, Sudha %A Ikram, Mohammad Arfan %A Longstreth, William T %A Fornage, Myriam %A König, Inke R %A Loley, Christina %A Ojeda, Francisco M %A Schillert, Arne %A Wang, Thomas J %A Sticht, Heinrich %A Kittel, Anja %A König, Jörg %A Benjamin, Emelia J %A Sullivan, Lisa M %A Bernges, Isabel %A Anderssohn, Maike %A Ziegler, Andreas %A Gieger, Christian %A Illig, Thomas %A Meisinger, Christa %A Wichmann, H-Erich %A Wild, Philipp S %A Schunkert, Heribert %A Psaty, Bruce M %A Wiggins, Kerri L %A Heckbert, Susan R %A Smith, Nicholas %A Lackner, Karl %A Lunetta, Kathryn L %A Blankenberg, Stefan %A Erdmann, Jeanette %A Münzel, Thomas %A Grant, Peter J %A Vasan, Ramachandran S %A Böger, Rainer H %K Adult %K Aged %K Amidohydrolases %K Arginine %K Binding Sites %K Cohort Studies %K Female %K Genetic Loci %K Genome-Wide Association Study %K Genotype %K HEK293 Cells %K Humans %K Male %K Mediator Complex %K Middle Aged %K Polymorphism, Single Nucleotide %K Protein Structure, Tertiary %K Risk Factors %K Stroke %K Substrate Specificity %K Transaminases %X

BACKGROUND: Dimethylarginines (DMA) interfere with nitric oxide formation by inhibiting nitric oxide synthase (asymmetrical DMA [ADMA]) and l-arginine uptake into the cell (ADMA and symmetrical DMA [SDMA]). In prospective clinical studies, ADMA has been characterized as a cardiovascular risk marker, whereas SDMA is a novel marker for renal function and associated with all-cause mortality after ischemic stroke. The aim of the current study was to characterize the environmental and genetic contributions to interindividual variability of these biomarkers.

METHODS AND RESULTS: This study comprised a genome-wide association analysis of 3 well-characterized population-based cohorts (Framingham Heart Study [FHS; n=2992], Gutenberg Health Study [GHS; n=4354], and Multinational Monitoring of Trends and Determinants in Cardiovascular Disease Study [MONICA]/Cooperative Health Research in the Augsburg Area, Augsburg, Bavaria, Germany [KORA] F3 [n=581]) and identified replicated loci (DDAH1, MED23, Arg1, and AGXT2) associated with the interindividual variability in ADMA, l-arginine, and SDMA. Experimental in silico and in vitro studies confirmed functional significance of the identified AGXT2 variants. Clinical outcome analysis in 384 patients of the Leeds stroke study demonstrated an association between increased plasma levels of SDMA, AGXT2 variants, and various cardiometabolic risk factors. AGXT2 variants were not associated with poststroke survival in the Leeds study or were they associated with incident stroke in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium.

CONCLUSIONS: These genome-wide association study support the importance of DDAH1 and MED23/Arg1 in regulating ADMA and l-arginine metabolism, respectively, and identify a novel regulatory renal pathway for SDMA by AGXT2. AGXT2 variants might explain part of the pathogenic link between SDMA, renal function, and outcome. An association between AGXT2 variants and stroke is unclear and warrants further investigation.

%B Circ Cardiovasc Genet %V 7 %P 864-72 %8 2014 Dec %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/25245031?dopt=Abstract %R 10.1161/CIRCGENETICS.113.000264 %0 Journal Article %J Circ Cardiovasc Genet %D 2014 %T Genome-wide association study of plasma N6 polyunsaturated fatty acids within the cohorts for heart and aging research in genomic epidemiology consortium. %A Guan, Weihua %A Steffen, Brian T %A Lemaitre, Rozenn N %A Wu, Jason H Y %A Tanaka, Toshiko %A Manichaikul, Ani %A Foy, Millennia %A Rich, Stephen S %A Wang, Lu %A Nettleton, Jennifer A %A Tang, Weihong %A Gu, Xiangjun %A Bandinelli, Stafania %A King, Irena B %A McKnight, Barbara %A Psaty, Bruce M %A Siscovick, David %A Djoussé, Luc %A Chen, Yii-Der Ida %A Ferrucci, Luigi %A Fornage, Myriam %A Mozafarrian, Dariush %A Tsai, Michael Y %A Steffen, Lyn M %K Adult %K Aged %K Aged, 80 and over %K Aging %K Chromosomes, Human, Pair 10 %K Chromosomes, Human, Pair 16 %K Chromosomes, Human, Pair 6 %K Fatty Acid Desaturases %K Fatty Acids, Omega-6 %K Female %K Genome-Wide Association Study %K Genomics %K Heart Diseases %K Humans %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Prospective Studies %K Sequence Analysis, DNA %X

BACKGROUND: Omega6 (n6) polyunsaturated fatty acids (PUFAs) and their metabolites are involved in cell signaling, inflammation, clot formation, and other crucial biological processes. Genetic components, such as variants of fatty acid desaturase (FADS) genes, determine the composition of n6 PUFAs.

METHODS AND RESULTS: To elucidate undiscovered biological pathways that may influence n6 PUFA composition, we conducted genome-wide association studies and meta-analyses of associations of common genetic variants with 6 plasma n6 PUFAs in 8631 white adults (55% women) across 5 prospective studies. Plasma phospholipid or total plasma fatty acids were analyzed by similar gas chromatography techniques. The n6 fatty acids linoleic acid (LA), γ-linolenic acid (GLA), dihomo-GLA, arachidonic acid, and adrenic acid were expressed as percentage of total fatty acids. We performed linear regression with robust SEs to test for single-nucleotide polymorphism-fatty acid associations, with pooling using inverse-variance-weighted meta-analysis. Novel regions were identified on chromosome 10 associated with LA (rs10740118; P=8.1×10(-9); near NRBF2), on chromosome 16 with LA, GLA, dihomo-GLA, and arachidonic acid (rs16966952; P=1.2×10(-15), 5.0×10(-11), 7.6×10(-65), and 2.4×10(-10), respectively; NTAN1), and on chromosome 6 with adrenic acid after adjustment for arachidonic acid (rs3134950; P=2.1×10(-10); AGPAT1). We confirmed previous findings of the FADS cluster on chromosome 11 with LA and arachidonic acid, and further observed novel genome-wide significant association of this cluster with GLA, dihomo-GLA, and adrenic acid (P=2.3×10(-72), 2.6×10(-151), and 6.3×10(-140), respectively).

CONCLUSIONS: Our findings suggest that along with the FADS gene cluster, additional genes may influence n6 PUFA composition.

%B Circ Cardiovasc Genet %V 7 %P 321-331 %8 2014 Jun %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/24823311?dopt=Abstract %R 10.1161/CIRCGENETICS.113.000208 %0 Journal Article %J PLoS Genet %D 2014 %T Identification of novel genetic Loci associated with thyroid peroxidase antibodies and clinical thyroid disease. %A Medici, Marco %A Porcu, Eleonora %A Pistis, Giorgio %A Teumer, Alexander %A Brown, Suzanne J %A Jensen, Richard A %A Rawal, Rajesh %A Roef, Greet L %A Plantinga, Theo S %A Vermeulen, Sita H %A Lahti, Jari %A Simmonds, Matthew J %A Husemoen, Lise Lotte N %A Freathy, Rachel M %A Shields, Beverley M %A Pietzner, Diana %A Nagy, Rebecca %A Broer, Linda %A Chaker, Layal %A Korevaar, Tim I M %A Plia, Maria Grazia %A Sala, Cinzia %A Völker, Uwe %A Richards, J Brent %A Sweep, Fred C %A Gieger, Christian %A Corre, Tanguy %A Kajantie, Eero %A Thuesen, Betina %A Taes, Youri E %A Visser, W Edward %A Hattersley, Andrew T %A Kratzsch, Jürgen %A Hamilton, Alexander %A Li, Wei %A Homuth, Georg %A Lobina, Monia %A Mariotti, Stefano %A Soranzo, Nicole %A Cocca, Massimiliano %A Nauck, Matthias %A Spielhagen, Christin %A Ross, Alec %A Arnold, Alice %A van de Bunt, Martijn %A Liyanarachchi, Sandya %A Heier, Margit %A Grabe, Hans Jörgen %A Masciullo, Corrado %A Galesloot, Tessel E %A Lim, Ee M %A Reischl, Eva %A Leedman, Peter J %A Lai, Sandra %A Delitala, Alessandro %A Bremner, Alexandra P %A Philips, David I W %A Beilby, John P %A Mulas, Antonella %A Vocale, Matteo %A Abecasis, Goncalo %A Forsen, Tom %A James, Alan %A Widen, Elisabeth %A Hui, Jennie %A Prokisch, Holger %A Rietzschel, Ernst E %A Palotie, Aarno %A Feddema, Peter %A Fletcher, Stephen J %A Schramm, Katharina %A Rotter, Jerome I %A Kluttig, Alexander %A Radke, Dörte %A Traglia, Michela %A Surdulescu, Gabriela L %A He, Huiling %A Franklyn, Jayne A %A Tiller, Daniel %A Vaidya, Bijay %A De Meyer, Tim %A Jørgensen, Torben %A Eriksson, Johan G %A O'Leary, Peter C %A Wichmann, Eric %A Hermus, Ad R %A Psaty, Bruce M %A Ittermann, Till %A Hofman, Albert %A Bosi, Emanuele %A Schlessinger, David %A Wallaschofski, Henri %A Pirastu, Nicola %A Aulchenko, Yurii S %A de la Chapelle, Albert %A Netea-Maier, Romana T %A Gough, Stephen C L %A Meyer Zu Schwabedissen, Henriette %A Frayling, Timothy M %A Kaufman, Jean-Marc %A Linneberg, Allan %A Räikkönen, Katri %A Smit, Johannes W A %A Kiemeney, Lambertus A %A Rivadeneira, Fernando %A Uitterlinden, André G %A Walsh, John P %A Meisinger, Christa %A den Heijer, Martin %A Visser, Theo J %A Spector, Timothy D %A Wilson, Scott G %A Völzke, Henry %A Cappola, Anne %A Toniolo, Daniela %A Sanna, Serena %A Naitza, Silvia %A Peeters, Robin P %K Autoantibodies %K Genetic Loci %K Genome-Wide Association Study %K Graves Disease %K Hashimoto Disease %K Humans %K Iodide Peroxidase %K Risk Factors %K Thyroiditis, Autoimmune %K Thyrotropin %X

Autoimmune thyroid diseases (AITD) are common, affecting 2-5% of the general population. Individuals with positive thyroid peroxidase antibodies (TPOAbs) have an increased risk of autoimmune hypothyroidism (Hashimoto's thyroiditis), as well as autoimmune hyperthyroidism (Graves' disease). As the possible causative genes of TPOAbs and AITD remain largely unknown, we performed GWAS meta-analyses in 18,297 individuals for TPOAb-positivity (1769 TPOAb-positives and 16,528 TPOAb-negatives) and in 12,353 individuals for TPOAb serum levels, with replication in 8,990 individuals. Significant associations (P<5×10(-8)) were detected at TPO-rs11675434, ATXN2-rs653178, and BACH2-rs10944479 for TPOAb-positivity, and at TPO-rs11675434, MAGI3-rs1230666, and KALRN-rs2010099 for TPOAb levels. Individual and combined effects (genetic risk scores) of these variants on (subclinical) hypo- and hyperthyroidism, goiter and thyroid cancer were studied. Individuals with a high genetic risk score had, besides an increased risk of TPOAb-positivity (OR: 2.18, 95% CI 1.68-2.81, P = 8.1×10(-8)), a higher risk of increased thyroid-stimulating hormone levels (OR: 1.51, 95% CI 1.26-1.82, P = 2.9×10(-6)), as well as a decreased risk of goiter (OR: 0.77, 95% CI 0.66-0.89, P = 6.5×10(-4)). The MAGI3 and BACH2 variants were associated with an increased risk of hyperthyroidism, which was replicated in an independent cohort of patients with Graves' disease (OR: 1.37, 95% CI 1.22-1.54, P = 1.2×10(-7) and OR: 1.25, 95% CI 1.12-1.39, P = 6.2×10(-5)). The MAGI3 variant was also associated with an increased risk of hypothyroidism (OR: 1.57, 95% CI 1.18-2.10, P = 1.9×10(-3)). This first GWAS meta-analysis for TPOAbs identified five newly associated loci, three of which were also associated with clinical thyroid disease. With these markers we identified a large subgroup in the general population with a substantially increased risk of TPOAbs. The results provide insight into why individuals with thyroid autoimmunity do or do not eventually develop thyroid disease, and these markers may therefore predict which TPOAb-positives are particularly at risk of developing clinical thyroid dysfunction.

%B PLoS Genet %V 10 %P e1004123 %8 2014 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/24586183?dopt=Abstract %R 10.1371/journal.pgen.1004123 %0 Journal Article %J Hum Genet %D 2014 %T Large multiethnic Candidate Gene Study for C-reactive protein levels: identification of a novel association at CD36 in African Americans. %A Ellis, Jaclyn %A Lange, Ethan M %A Li, Jin %A Dupuis, Josée %A Baumert, Jens %A Walston, Jeremy D %A Keating, Brendan J %A Durda, Peter %A Fox, Ervin R %A Palmer, Cameron D %A Meng, Yan A %A Young, Taylor %A Farlow, Deborah N %A Schnabel, Renate B %A Marzi, Carola S %A Larkin, Emma %A Martin, Lisa W %A Bis, Joshua C %A Auer, Paul %A Ramachandran, Vasan S %A Gabriel, Stacey B %A Willis, Monte S %A Pankow, James S %A Papanicolaou, George J %A Rotter, Jerome I %A Ballantyne, Christie M %A Gross, Myron D %A Lettre, Guillaume %A Wilson, James G %A Peters, Ulrike %A Koenig, Wolfgang %A Tracy, Russell P %A Redline, Susan %A Reiner, Alex P %A Benjamin, Emelia J %A Lange, Leslie A %K Adult %K African Americans %K Aged %K Biomarkers %K C-Reactive Protein %K Cardiovascular Diseases %K CD36 Antigens %K Female %K Genetic Loci %K Genetic Predisposition to Disease %K Genetics, Population %K Genome-Wide Association Study %K Humans %K Meta-Analysis as Topic %K Middle Aged %K Polymorphism, Single Nucleotide %K Risk Factors %X

C-reactive protein (CRP) is a heritable biomarker of systemic inflammation and a predictor of cardiovascular disease (CVD). Large-scale genetic association studies for CRP have largely focused on individuals of European descent. We sought to uncover novel genetic variants for CRP in a multiethnic sample using the ITMAT Broad-CARe (IBC) array, a custom 50,000 SNP gene-centric array having dense coverage of over 2,000 candidate CVD genes. We performed analyses on 7,570 African Americans (AA) from the Candidate gene Association Resource (CARe) study and race-combined meta-analyses that included 29,939 additional individuals of European descent from CARe, the Women's Health Initiative (WHI) and KORA studies. We observed array-wide significance (p < 2.2 × 10(-6)) for four loci in AA, three of which have been reported previously in individuals of European descent (IL6R, p = 2.0 × 10(-6); CRP, p = 4.2 × 10(-71); APOE, p = 1.6 × 10(-6)). The fourth significant locus, CD36 (p = 1.6 × 10(-6)), was observed at a functional variant (rs3211938) that is extremely rare in individuals of European descent. We replicated the CD36 finding (p = 1.8 × 10(-5)) in an independent sample of 8,041 AA women from WHI; a meta-analysis combining the CARe and WHI AA results at rs3211938 reached genome-wide significance (p = 1.5 × 10(-10)). In the race-combined meta-analyses, 13 loci reached significance, including ten (CRP, TOMM40/APOE/APOC1, HNF1A, LEPR, GCKR, IL6R, IL1RN, NLRP3, HNF4A and BAZ1B/BCL7B) previously associated with CRP, and one (ARNTL) previously reported to be nominally associated with CRP. Two novel loci were also detected (RPS6KB1, p = 2.0 × 10(-6); CD36, p = 1.4 × 10(-6)). These results highlight both shared and unique genetic risk factors for CRP in AA compared to populations of European descent.

%B Hum Genet %V 133 %P 985-95 %8 2014 Aug %G eng %N 8 %1 http://www.ncbi.nlm.nih.gov/pubmed/24643644?dopt=Abstract %R 10.1007/s00439-014-1439-z %0 Journal Article %J PLoS One %D 2014 %T Large-scale genome-wide association studies and meta-analyses of longitudinal change in adult lung function. %A Tang, Wenbo %A Kowgier, Matthew %A Loth, Daan W %A Soler Artigas, Maria %A Joubert, Bonnie R %A Hodge, Emily %A Gharib, Sina A %A Smith, Albert V %A Ruczinski, Ingo %A Gudnason, Vilmundur %A Mathias, Rasika A %A Harris, Tamara B %A Hansel, Nadia N %A Launer, Lenore J %A Barnes, Kathleen C %A Hansen, Joyanna G %A Albrecht, Eva %A Aldrich, Melinda C %A Allerhand, Michael %A Barr, R Graham %A Brusselle, Guy G %A Couper, David J %A Curjuric, Ivan %A Davies, Gail %A Deary, Ian J %A Dupuis, Josée %A Fall, Tove %A Foy, Millennia %A Franceschini, Nora %A Gao, Wei %A Gläser, Sven %A Gu, Xiangjun %A Hancock, Dana B %A Heinrich, Joachim %A Hofman, Albert %A Imboden, Medea %A Ingelsson, Erik %A James, Alan %A Karrasch, Stefan %A Koch, Beate %A Kritchevsky, Stephen B %A Kumar, Ashish %A Lahousse, Lies %A Li, Guo %A Lind, Lars %A Lindgren, Cecilia %A Liu, Yongmei %A Lohman, Kurt %A Lumley, Thomas %A McArdle, Wendy L %A Meibohm, Bernd %A Morris, Andrew P %A Morrison, Alanna C %A Musk, Bill %A North, Kari E %A Palmer, Lyle J %A Probst-Hensch, Nicole M %A Psaty, Bruce M %A Rivadeneira, Fernando %A Rotter, Jerome I %A Schulz, Holger %A Smith, Lewis J %A Sood, Akshay %A Starr, John M %A Strachan, David P %A Teumer, Alexander %A Uitterlinden, André G %A Völzke, Henry %A Voorman, Arend %A Wain, Louise V %A Wells, Martin T %A Wilk, Jemma B %A Williams, O Dale %A Heckbert, Susan R %A Stricker, Bruno H %A London, Stephanie J %A Fornage, Myriam %A Tobin, Martin D %A O'Connor, George T %A Hall, Ian P %A Cassano, Patricia A %K Adult %K Chromosomes, Human, Pair 11 %K Female %K Gene Expression Regulation %K Genetic Loci %K Genome-Wide Association Study %K Humans %K Longitudinal Studies %K Male %K Respiration %X

BACKGROUND: Genome-wide association studies (GWAS) have identified numerous loci influencing cross-sectional lung function, but less is known about genes influencing longitudinal change in lung function.

METHODS: We performed GWAS of the rate of change in forced expiratory volume in the first second (FEV1) in 14 longitudinal, population-based cohort studies comprising 27,249 adults of European ancestry using linear mixed effects model and combined cohort-specific results using fixed effect meta-analysis to identify novel genetic loci associated with longitudinal change in lung function. Gene expression analyses were subsequently performed for identified genetic loci. As a secondary aim, we estimated the mean rate of decline in FEV1 by smoking pattern, irrespective of genotypes, across these 14 studies using meta-analysis.

RESULTS: The overall meta-analysis produced suggestive evidence for association at the novel IL16/STARD5/TMC3 locus on chromosome 15 (P  =  5.71 × 10(-7)). In addition, meta-analysis using the five cohorts with ≥3 FEV1 measurements per participant identified the novel ME3 locus on chromosome 11 (P  =  2.18 × 10(-8)) at genome-wide significance. Neither locus was associated with FEV1 decline in two additional cohort studies. We confirmed gene expression of IL16, STARD5, and ME3 in multiple lung tissues. Publicly available microarray data confirmed differential expression of all three genes in lung samples from COPD patients compared with controls. Irrespective of genotypes, the combined estimate for FEV1 decline was 26.9, 29.2 and 35.7 mL/year in never, former, and persistent smokers, respectively.

CONCLUSIONS: In this large-scale GWAS, we identified two novel genetic loci in association with the rate of change in FEV1 that harbor candidate genes with biologically plausible functional links to lung function.

%B PLoS One %V 9 %P e100776 %8 2014 %G eng %N 7 %1 http://www.ncbi.nlm.nih.gov/pubmed/24983941?dopt=Abstract %R 10.1371/journal.pone.0100776 %0 Journal Article %J Nat Genet %D 2014 %T Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease. %A Nalls, Mike A %A Pankratz, Nathan %A Lill, Christina M %A Do, Chuong B %A Hernandez, Dena G %A Saad, Mohamad %A DeStefano, Anita L %A Kara, Eleanna %A Bras, Jose %A Sharma, Manu %A Schulte, Claudia %A Keller, Margaux F %A Arepalli, Sampath %A Letson, Christopher %A Edsall, Connor %A Stefansson, Hreinn %A Liu, Xinmin %A Pliner, Hannah %A Lee, Joseph H %A Cheng, Rong %A Ikram, M Arfan %A Ioannidis, John P A %A Hadjigeorgiou, Georgios M %A Bis, Joshua C %A Martinez, Maria %A Perlmutter, Joel S %A Goate, Alison %A Marder, Karen %A Fiske, Brian %A Sutherland, Margaret %A Xiromerisiou, Georgia %A Myers, Richard H %A Clark, Lorraine N %A Stefansson, Kari %A Hardy, John A %A Heutink, Peter %A Chen, Honglei %A Wood, Nicholas W %A Houlden, Henry %A Payami, Haydeh %A Brice, Alexis %A Scott, William K %A Gasser, Thomas %A Bertram, Lars %A Eriksson, Nicholas %A Foroud, Tatiana %A Singleton, Andrew B %K Case-Control Studies %K Genetic Loci %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genotype %K Humans %K Parkinson Disease %K Polymorphism, Single Nucleotide %K Risk Factors %X

We conducted a meta-analysis of Parkinson's disease genome-wide association studies using a common set of 7,893,274 variants across 13,708 cases and 95,282 controls. Twenty-six loci were identified as having genome-wide significant association; these and 6 additional previously reported loci were then tested in an independent set of 5,353 cases and 5,551 controls. Of the 32 tested SNPs, 24 replicated, including 6 newly identified loci. Conditional analyses within loci showed that four loci, including GBA, GAK-DGKQ, SNCA and the HLA region, contain a secondary independent risk variant. In total, we identified and replicated 28 independent risk variants for Parkinson's disease across 24 loci. Although the effect of each individual locus was small, risk profile analysis showed substantial cumulative risk in a comparison of the highest and lowest quintiles of genetic risk (odds ratio (OR) = 3.31, 95% confidence interval (CI) = 2.55-4.30; P = 2 × 10(-16)). We also show six risk loci associated with proximal gene expression or DNA methylation.

%B Nat Genet %V 46 %P 989-93 %8 2014 Sep %G eng %N 9 %1 http://www.ncbi.nlm.nih.gov/pubmed/25064009?dopt=Abstract %R 10.1038/ng.3043 %0 Journal Article %J Neurology %D 2014 %T Meta-analysis in more than 17,900 cases of ischemic stroke reveals a novel association at 12q24.12. %A Kilarski, Laura L %A Achterberg, Sefanja %A Devan, William J %A Traylor, Matthew %A Malik, Rainer %A Lindgren, Arne %A Pare, Guillame %A Sharma, Pankaj %A Slowik, Agniesczka %A Thijs, Vincent %A Walters, Matthew %A Worrall, Bradford B %A Sale, Michèle M %A Algra, Ale %A Kappelle, L Jaap %A Wijmenga, Cisca %A Norrving, Bo %A Sandling, Johanna K %A Rönnblom, Lars %A Goris, An %A Franke, Andre %A Sudlow, Cathie %A Rothwell, Peter M %A Levi, Christopher %A Holliday, Elizabeth G %A Fornage, Myriam %A Psaty, Bruce %A Gretarsdottir, Solveig %A Thorsteinsdottir, Unnar %A Seshadri, Sudha %A Mitchell, Braxton D %A Kittner, Steven %A Clarke, Robert %A Hopewell, Jemma C %A Bis, Joshua C %A Boncoraglio, Giorgio B %A Meschia, James %A Ikram, M Arfan %A Hansen, Bjorn M %A Montaner, Joan %A Thorleifsson, Gudmar %A Stefanson, Kari %A Rosand, Jonathan %A de Bakker, Paul I W %A Farrall, Martin %A Dichgans, Martin %A Markus, Hugh S %A Bevan, Steve %K Brain Ischemia %K Cerebral Hemorrhage %K Chromosomes, Human, Pair 12 %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genotype %K Humans %K Polymorphism, Single Nucleotide %K Risk %K Stroke %X

OBJECTIVES: To perform a genome-wide association study (GWAS) using the Immunochip array in 3,420 cases of ischemic stroke and 6,821 controls, followed by a meta-analysis with data from more than 14,000 additional ischemic stroke cases.

METHODS: Using the Immunochip, we genotyped 3,420 ischemic stroke cases and 6,821 controls. After imputation we meta-analyzed the results with imputed GWAS data from 3,548 cases and 5,972 controls recruited from the ischemic stroke WTCCC2 study, and with summary statistics from a further 8,480 cases and 56,032 controls in the METASTROKE consortium. A final in silico "look-up" of 2 single nucleotide polymorphisms in 2,522 cases and 1,899 controls was performed. Associations were also examined in 1,088 cases with intracerebral hemorrhage and 1,102 controls.

RESULTS: In an overall analysis of 17,970 cases of ischemic stroke and 70,764 controls, we identified a novel association on chromosome 12q24 (rs10744777, odds ratio [OR] 1.10 [1.07-1.13], p = 7.12 × 10(-11)) with ischemic stroke. The association was with all ischemic stroke rather than an individual stroke subtype, with similar effect sizes seen in different stroke subtypes. There was no association with intracerebral hemorrhage (OR 1.03 [0.90-1.17], p = 0.695).

CONCLUSION: Our results show, for the first time, a genetic risk locus associated with ischemic stroke as a whole, rather than in a subtype-specific manner. This finding was not associated with intracerebral hemorrhage.

%B Neurology %V 83 %P 678-85 %8 2014 Aug 19 %G eng %N 8 %1 http://www.ncbi.nlm.nih.gov/pubmed/25031287?dopt=Abstract %R 10.1212/WNL.0000000000000707 %0 Journal Article %J PLoS Genet %D 2014 %T Meta-analysis of genome-wide association studies in African Americans provides insights into the genetic architecture of type 2 diabetes. %A Ng, Maggie C Y %A Shriner, Daniel %A Chen, Brian H %A Li, Jiang %A Chen, Wei-Min %A Guo, Xiuqing %A Liu, Jiankang %A Bielinski, Suzette J %A Yanek, Lisa R %A Nalls, Michael A %A Comeau, Mary E %A Rasmussen-Torvik, Laura J %A Jensen, Richard A %A Evans, Daniel S %A Sun, Yan V %A An, Ping %A Patel, Sanjay R %A Lu, Yingchang %A Long, Jirong %A Armstrong, Loren L %A Wagenknecht, Lynne %A Yang, Lingyao %A Snively, Beverly M %A Palmer, Nicholette D %A Mudgal, Poorva %A Langefeld, Carl D %A Keene, Keith L %A Freedman, Barry I %A Mychaleckyj, Josyf C %A Nayak, Uma %A Raffel, Leslie J %A Goodarzi, Mark O %A Chen, Y-D Ida %A Taylor, Herman A %A Correa, Adolfo %A Sims, Mario %A Couper, David %A Pankow, James S %A Boerwinkle, Eric %A Adeyemo, Adebowale %A Doumatey, Ayo %A Chen, Guanjie %A Mathias, Rasika A %A Vaidya, Dhananjay %A Singleton, Andrew B %A Zonderman, Alan B %A Igo, Robert P %A Sedor, John R %A Kabagambe, Edmond K %A Siscovick, David S %A McKnight, Barbara %A Rice, Kenneth %A Liu, Yongmei %A Hsueh, Wen-Chi %A Zhao, Wei %A Bielak, Lawrence F %A Kraja, Aldi %A Province, Michael A %A Bottinger, Erwin P %A Gottesman, Omri %A Cai, Qiuyin %A Zheng, Wei %A Blot, William J %A Lowe, William L %A Pacheco, Jennifer A %A Crawford, Dana C %A Grundberg, Elin %A Rich, Stephen S %A Hayes, M Geoffrey %A Shu, Xiao-Ou %A Loos, Ruth J F %A Borecki, Ingrid B %A Peyser, Patricia A %A Cummings, Steven R %A Psaty, Bruce M %A Fornage, Myriam %A Iyengar, Sudha K %A Evans, Michele K %A Becker, Diane M %A Kao, W H Linda %A Wilson, James G %A Rotter, Jerome I %A Sale, Michèle M %A Liu, Simin %A Rotimi, Charles N %A Bowden, Donald W %K African Americans %K Diabetes Mellitus, Type 2 %K Genome-Wide Association Study %K HLA-B27 Antigen %K HMGA2 Protein %K Humans %K KCNQ1 Potassium Channel %K Mutant Chimeric Proteins %K Polymorphism, Single Nucleotide %K Transcription Factor 7-Like 2 Protein %X

Type 2 diabetes (T2D) is more prevalent in African Americans than in Europeans. However, little is known about the genetic risk in African Americans despite the recent identification of more than 70 T2D loci primarily by genome-wide association studies (GWAS) in individuals of European ancestry. In order to investigate the genetic architecture of T2D in African Americans, the MEta-analysis of type 2 DIabetes in African Americans (MEDIA) Consortium examined 17 GWAS on T2D comprising 8,284 cases and 15,543 controls in African Americans in stage 1 analysis. Single nucleotide polymorphisms (SNPs) association analysis was conducted in each study under the additive model after adjustment for age, sex, study site, and principal components. Meta-analysis of approximately 2.6 million genotyped and imputed SNPs in all studies was conducted using an inverse variance-weighted fixed effect model. Replications were performed to follow up 21 loci in up to 6,061 cases and 5,483 controls in African Americans, and 8,130 cases and 38,987 controls of European ancestry. We identified three known loci (TCF7L2, HMGA2 and KCNQ1) and two novel loci (HLA-B and INS-IGF2) at genome-wide significance (4.15 × 10(-94) %B PLoS Genet %V 10 %P e1004517 %8 2014 Aug %G eng %N 8 %1 http://www.ncbi.nlm.nih.gov/pubmed/25102180?dopt=Abstract %R 10.1371/journal.pgen.1004517 %0 Journal Article %J Hum Mol Genet %D 2014 %T Meta-analysis of loci associated with age at natural menopause in African-American women. %A Chen, Christina T L %A Liu, Ching-Ti %A Chen, Gary K %A Andrews, Jeanette S %A Arnold, Alice M %A Dreyfus, Jill %A Franceschini, Nora %A Garcia, Melissa E %A Kerr, Kathleen F %A Li, Guo %A Lohman, Kurt K %A Musani, Solomon K %A Nalls, Michael A %A Raffel, Leslie J %A Smith, Jennifer %A Ambrosone, Christine B %A Bandera, Elisa V %A Bernstein, Leslie %A Britton, Angela %A Brzyski, Robert G %A Cappola, Anne %A Carlson, Christopher S %A Couper, David %A Deming, Sandra L %A Goodarzi, Mark O %A Heiss, Gerardo %A John, Esther M %A Lu, Xiaoning %A Le Marchand, Loïc %A Marciante, Kristin %A McKnight, Barbara %A Millikan, Robert %A Nock, Nora L %A Olshan, Andrew F %A Press, Michael F %A Vaiyda, Dhananjay %A Woods, Nancy F %A Taylor, Herman A %A Zhao, Wei %A Zheng, Wei %A Evans, Michele K %A Harris, Tamara B %A Henderson, Brian E %A Kardia, Sharon L R %A Kooperberg, Charles %A Liu, Yongmei %A Mosley, Thomas H %A Psaty, Bruce %A Wellons, Melissa %A Windham, Beverly G %A Zonderman, Alan B %A Cupples, L Adrienne %A Demerath, Ellen W %A Haiman, Christopher %A Murabito, Joanne M %A Rajkovic, Aleksandar %K African Americans %K Age Factors %K Chromosomes, Human %K European Continental Ancestry Group %K Female %K Genetic Loci %K Genetic Variation %K Genome-Wide Association Study %K Humans %K Menopause %K United States %X

Age at menopause marks the end of a woman's reproductive life and its timing associates with risks for cancer, cardiovascular and bone disorders. GWAS and candidate gene studies conducted in women of European ancestry have identified 27 loci associated with age at menopause. The relevance of these loci to women of African ancestry has not been previously studied. We therefore sought to uncover additional menopause loci and investigate the relevance of European menopause loci by performing a GWAS meta-analysis in 6510 women with African ancestry derived from 11 studies across the USA. We did not identify any additional loci significantly associated with age at menopause in African Americans. We replicated the associations between six loci and age at menopause (P-value < 0.05): AMHR2, RHBLD2, PRIM1, HK3/UMC1, BRSK1/TMEM150B and MCM8. In addition, associations of 14 loci are directionally consistent with previous reports. We provide evidence that genetic variants influencing reproductive traits identified in European populations are also important in women of African ancestry residing in USA.

%B Hum Mol Genet %V 23 %P 3327-42 %8 2014 Jun 15 %G eng %N 12 %1 http://www.ncbi.nlm.nih.gov/pubmed/24493794?dopt=Abstract %R 10.1093/hmg/ddu041 %0 Journal Article %J Circ Cardiovasc Genet %D 2014 %T Multiancestral analysis of inflammation-related genetic variants and C-reactive protein in the population architecture using genomics and epidemiology study. %A Kocarnik, Jonathan M %A Pendergrass, Sarah A %A Carty, Cara L %A Pankow, James S %A Schumacher, Fredrick R %A Cheng, Iona %A Durda, Peter %A Ambite, Jose Luis %A Deelman, Ewa %A Cook, Nancy R %A Liu, Simin %A Wactawski-Wende, Jean %A Hutter, Carolyn %A Brown-Gentry, Kristin %A Wilson, Sarah %A Best, Lyle G %A Pankratz, Nathan %A Hong, Ching-Ping %A Cole, Shelley A %A Voruganti, V Saroja %A Bůzková, Petra %A Jorgensen, Neal W %A Jenny, Nancy S %A Wilkens, Lynne R %A Haiman, Christopher A %A Kolonel, Laurence N %A LaCroix, Andrea %A North, Kari %A Jackson, Rebecca %A Le Marchand, Loïc %A Hindorff, Lucia A %A Crawford, Dana C %A Gross, Myron %A Peters, Ulrike %K Adult %K African Continental Ancestry Group %K Aged %K Asian Continental Ancestry Group %K C-Reactive Protein %K Female %K Genetic Variation %K Genome-Wide Association Study %K Hispanic Americans %K Humans %K Indians, North American %K Inflammation %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K United States %K Young Adult %X

BACKGROUND: C-reactive protein (CRP) is a biomarker of inflammation. Genome-wide association studies (GWAS) have identified single-nucleotide polymorphisms (SNPs) associated with CRP concentrations and inflammation-related traits such as cardiovascular disease, type 2 diabetes mellitus, and obesity. We aimed to replicate previous CRP-SNP associations, assess whether these associations generalize to additional race/ethnicity groups, and evaluate inflammation-related SNPs for a potentially pleiotropic association with CRP.

METHODS AND RESULTS: We selected and analyzed 16 CRP-associated and 250 inflammation-related GWAS SNPs among 40 473 African American, American Indian, Asian/Pacific Islander, European American, and Hispanic participants from 7 studies collaborating in the Population Architecture using Genomics and Epidemiology (PAGE) study. Fixed-effect meta-analyses combined study-specific race/ethnicity-stratified linear regression estimates to evaluate the association between each SNP and high-sensitivity CRP. Overall, 18 SNPs in 8 loci were significantly associated with CRP (Bonferroni-corrected P<3.1×10(-3) for replication, P<2.0×10(-4) for pleiotropy): Seven of these were specific to European Americans, while 9 additionally generalized to African Americans (1), Hispanics (5), or both (3); 1 SNP was seen only in African Americans and Hispanics. Two SNPs in the CELSR2/PSRC1/SORT1 locus showed a potentially novel association with CRP: rs599839 (P=2.0×10(-6)) and rs646776 (P=3.1×10(-5)).

CONCLUSIONS: We replicated 16 SNP-CRP associations, 10 of which generalized to African Americans and/or Hispanics. We also identified potentially novel pleiotropic associations with CRP for two SNPs previously associated with coronary artery disease and/or low-density lipoprotein-cholesterol. These findings demonstrate the benefit of evaluating genotype-phenotype associations in multiple race/ethnicity groups and looking for pleiotropic relationships among SNPs previously associated with related phenotypes.

%B Circ Cardiovasc Genet %V 7 %P 178-88 %8 2014 Apr %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/24622110?dopt=Abstract %R 10.1161/CIRCGENETICS.113.000173 %0 Journal Article %J Stroke %D 2014 %T Multilocus genetic risk score associates with ischemic stroke in case-control and prospective cohort studies. %A Malik, Rainer %A Bevan, Steve %A Nalls, Michael A %A Holliday, Elizabeth G %A Devan, William J %A Cheng, Yu-Ching %A Ibrahim-Verbaas, Carla A %A Verhaaren, Benjamin F J %A Bis, Joshua C %A Joon, Aron Y %A de Stefano, Anita L %A Fornage, Myriam %A Psaty, Bruce M %A Ikram, M Arfan %A Launer, Lenore J %A van Duijn, Cornelia M %A Sharma, Pankaj %A Mitchell, Braxton D %A Rosand, Jonathan %A Meschia, James F %A Levi, Christopher %A Rothwell, Peter M %A Sudlow, Cathie %A Markus, Hugh S %A Seshadri, Sudha %A Dichgans, Martin %K Adult %K Aged %K Aged, 80 and over %K Atrial Fibrillation %K Blood Pressure %K Brain Ischemia %K Case-Control Studies %K Cohort Studies %K Coronary Artery Disease %K Female %K Genetic Predisposition to Disease %K Genetic Variation %K Genome-Wide Association Study %K Humans %K Hypertension %K Male %K Middle Aged %K Multilocus Sequence Typing %K Polymorphism, Single Nucleotide %K Population %K Prospective Studies %K Reproducibility of Results %K Risk Assessment %K Risk Factors %K Sex Factors %K Stroke %X

BACKGROUND AND PURPOSE: Genome-wide association studies have revealed multiple common variants associated with known risk factors for ischemic stroke (IS). However, their aggregate effect on risk is uncertain. We aimed to generate a multilocus genetic risk score (GRS) for IS based on genome-wide association studies data from clinical-based samples and to establish its external validity in prospective population-based cohorts.

METHODS: Three thousand five hundred forty-eight clinic-based IS cases and 6399 controls from the Wellcome Trust Case Control Consortium 2 were used for derivation of the GRS. Subjects from the METASTROKE consortium served as a replication sample. The validation sample consisted of 22 751 participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium. We selected variants that had reached genome-wide significance in previous association studies on established risk factors for IS.

RESULTS: A combined GRS for atrial fibrillation, coronary artery disease, hypertension, and systolic blood pressure significantly associated with IS both in the case-control samples and in the prospective population-based studies. Subjects in the top quintile of the combined GRS had >2-fold increased risk of IS compared with subjects in the lowest quintile. Addition of the combined GRS to a simple model based on sex significantly improved the prediction of IS in the combined clinic-based samples but not in the population-based studies, and there was no significant improvement in net reclassification.

CONCLUSIONS: A multilocus GRS based on common variants for established cardiovascular risk factors was significantly associated with IS both in clinic-based samples and in the general population. However, the improvement in clinical risk prediction was found to be small.

%B Stroke %V 45 %P 394-402 %8 2014 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/24436234?dopt=Abstract %R 10.1161/STROKEAHA.113.002938 %0 Journal Article %J Cytokine %D 2014 %T Novel gene variants predict serum levels of the cytokines IL-18 and IL-1ra in older adults. %A Matteini, A M %A Li, J %A Lange, E M %A Tanaka, T %A Lange, L A %A Tracy, R P %A Wang, Y %A Biggs, M L %A Arking, D E %A Fallin, M D %A Chakravarti, A %A Psaty, B M %A Bandinelli, S %A Ferrucci, L %A Reiner, A P %A Walston, J D %K Aged %K Aged, 80 and over %K Calcium-Binding Proteins %K CARD Signaling Adaptor Proteins %K Chromosomes, Human, Pair 2 %K Female %K Genetic Variation %K Genome-Wide Association Study %K Genotype %K Haplotypes %K Humans %K Inflammation %K Interleukin 1 Receptor Antagonist Protein %K Interleukin-18 %K Male %K Polymorphism, Single Nucleotide %X

Activation of inflammatory pathways measured by serum inflammatory markers such as interleukin-18 (IL-18) and interleukin-1 receptor antagonist (IL-1ra) is strongly associated with the progression of chronic disease states in older adults. Given that these serum cytokine levels are in part a heritable trait, genetic variation may predict increased serum levels. Using the Cardiovascular Health Study and InCHIANTI cohorts, a genome-wide association study was performed to identify genetic variants that influence IL-18 and IL-1ra serum levels among older adults. Multiple linear regression models characterized the association between each SNP and log-transformed cytokine values. Tests for multiple independent signals within statistically significant loci were performed using haplotype analysis and regression models conditional on lead SNP in each region. Multiple SNPs were associated with these cytokines with genome-wide significance, including SNPs in the IL-18-BCO gene region of chromosome 2 for IL-18 (top SNP rs2250417, P=1.9×10(-32)) and in the IL-1 gene family region of chromosome 2 for IL-1ra (rs6743376, P=2.3×10(-26)). Haplotype tests and conditional linear regression models showed evidence of multiple independent signals in these regions. Serum IL-18 levels were also associated with a region on chromosome 2 containing the NLRC4 gene (rs12989936, P=2.7×10(-19)). These data characterize multiple robust genetic signals that influence IL-18 and IL-1ra cytokine production. In particular, the signal for serum IL-18 located on chromosome two is novel and potentially important in inflammasome triggered chronic activation of inflammation in older adults. Replication in independent cohorts is an important next step, as well as molecular studies to better understand the role of NLRC4.

%B Cytokine %V 65 %P 10-6 %8 2014 Jan %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/24182552?dopt=Abstract %R 10.1016/j.cyto.2013.10.002 %0 Journal Article %J Nat Commun %D 2014 %T Pharmacogenetic meta-analysis of genome-wide association studies of LDL cholesterol response to statins. %A Postmus, Iris %A Trompet, Stella %A Deshmukh, Harshal A %A Barnes, Michael R %A Li, Xiaohui %A Warren, Helen R %A Chasman, Daniel I %A Zhou, Kaixin %A Arsenault, Benoit J %A Donnelly, Louise A %A Wiggins, Kerri L %A Avery, Christy L %A Griffin, Paula %A Feng, QiPing %A Taylor, Kent D %A Li, Guo %A Evans, Daniel S %A Smith, Albert V %A de Keyser, Catherine E %A Johnson, Andrew D %A de Craen, Anton J M %A Stott, David J %A Buckley, Brendan M %A Ford, Ian %A Westendorp, Rudi G J %A Slagboom, P Eline %A Sattar, Naveed %A Munroe, Patricia B %A Sever, Peter %A Poulter, Neil %A Stanton, Alice %A Shields, Denis C %A O'Brien, Eoin %A Shaw-Hawkins, Sue %A Chen, Y-D Ida %A Nickerson, Deborah A %A Smith, Joshua D %A Dubé, Marie Pierre %A Boekholdt, S Matthijs %A Hovingh, G Kees %A Kastelein, John J P %A McKeigue, Paul M %A Betteridge, John %A Neil, Andrew %A Durrington, Paul N %A Doney, Alex %A Carr, Fiona %A Morris, Andrew %A McCarthy, Mark I %A Groop, Leif %A Ahlqvist, Emma %A Bis, Joshua C %A Rice, Kenneth %A Smith, Nicholas L %A Lumley, Thomas %A Whitsel, Eric A %A Stürmer, Til %A Boerwinkle, Eric %A Ngwa, Julius S %A O'Donnell, Christopher J %A Vasan, Ramachandran S %A Wei, Wei-Qi %A Wilke, Russell A %A Liu, Ching-Ti %A Sun, Fangui %A Guo, Xiuqing %A Heckbert, Susan R %A Post, Wendy %A Sotoodehnia, Nona %A Arnold, Alice M %A Stafford, Jeanette M %A Ding, Jingzhong %A Herrington, David M %A Kritchevsky, Stephen B %A Eiriksdottir, Gudny %A Launer, Leonore J %A Harris, Tamara B %A Chu, Audrey Y %A Giulianini, Franco %A MacFadyen, Jean G %A Barratt, Bryan J %A Nyberg, Fredrik %A Stricker, Bruno H %A Uitterlinden, André G %A Hofman, Albert %A Rivadeneira, Fernando %A Emilsson, Valur %A Franco, Oscar H %A Ridker, Paul M %A Gudnason, Vilmundur %A Liu, Yongmei %A Denny, Joshua C %A Ballantyne, Christie M %A Rotter, Jerome I %A Adrienne Cupples, L %A Psaty, Bruce M %A Palmer, Colin N A %A Tardif, Jean-Claude %A Colhoun, Helen M %A Hitman, Graham %A Krauss, Ronald M %A Wouter Jukema, J %A Caulfield, Mark J %K Cholesterol, LDL %K Genome-Wide Association Study %K Humans %K Hydroxymethylglutaryl-CoA Reductase Inhibitors %K Pharmacogenetics %K Polymorphism, Single Nucleotide %X

Statins effectively lower LDL cholesterol levels in large studies and the observed interindividual response variability may be partially explained by genetic variation. Here we perform a pharmacogenetic meta-analysis of genome-wide association studies (GWAS) in studies addressing the LDL cholesterol response to statins, including up to 18,596 statin-treated subjects. We validate the most promising signals in a further 22,318 statin recipients and identify two loci, SORT1/CELSR2/PSRC1 and SLCO1B1, not previously identified in GWAS. Moreover, we confirm the previously described associations with APOE and LPA. Our findings advance the understanding of the pharmacogenetic architecture of statin response.

%B Nat Commun %V 5 %P 5068 %8 2014 Oct 28 %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/25350695?dopt=Abstract %R 10.1038/ncomms6068 %0 Journal Article %J Stroke %D 2014 %T Predicting stroke through genetic risk functions: the CHARGE Risk Score Project. %A Ibrahim-Verbaas, Carla A %A Fornage, Myriam %A Bis, Joshua C %A Choi, Seung Hoan %A Psaty, Bruce M %A Meigs, James B %A Rao, Madhu %A Nalls, Mike %A Fontes, João D %A O'Donnell, Christopher J %A Kathiresan, Sekar %A Ehret, Georg B %A Fox, Caroline S %A Malik, Rainer %A Dichgans, Martin %A Schmidt, Helena %A Lahti, Jari %A Heckbert, Susan R %A Lumley, Thomas %A Rice, Kenneth %A Rotter, Jerome I %A Taylor, Kent D %A Folsom, Aaron R %A Boerwinkle, Eric %A Rosamond, Wayne D %A Shahar, Eyal %A Gottesman, Rebecca F %A Koudstaal, Peter J %A Amin, Najaf %A Wieberdink, Renske G %A Dehghan, Abbas %A Hofman, Albert %A Uitterlinden, André G %A DeStefano, Anita L %A Debette, Stephanie %A Xue, Luting %A Beiser, Alexa %A Wolf, Philip A %A DeCarli, Charles %A Ikram, M Arfan %A Seshadri, Sudha %A Mosley, Thomas H %A Longstreth, W T %A van Duijn, Cornelia M %A Launer, Lenore J %K Age Factors %K Aged %K Aged, 80 and over %K Area Under Curve %K Case-Control Studies %K Cohort Studies %K European Continental Ancestry Group %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genotype %K Humans %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Regression Analysis %K Risk Factors %K ROC Curve %K Sex Factors %K Stroke %X

BACKGROUND AND PURPOSE: Beyond the Framingham Stroke Risk Score, prediction of future stroke may improve with a genetic risk score (GRS) based on single-nucleotide polymorphisms associated with stroke and its risk factors.

METHODS: The study includes 4 population-based cohorts with 2047 first incident strokes from 22,720 initially stroke-free European origin participants aged ≥55 years, who were followed for up to 20 years. GRSs were constructed with 324 single-nucleotide polymorphisms implicated in stroke and 9 risk factors. The association of the GRS to first incident stroke was tested using Cox regression; the GRS predictive properties were assessed with area under the curve statistics comparing the GRS with age and sex, Framingham Stroke Risk Score models, and reclassification statistics. These analyses were performed per cohort and in a meta-analysis of pooled data. Replication was sought in a case-control study of ischemic stroke.

RESULTS: In the meta-analysis, adding the GRS to the Framingham Stroke Risk Score, age and sex model resulted in a significant improvement in discrimination (all stroke: Δjoint area under the curve=0.016, P=2.3×10(-6); ischemic stroke: Δjoint area under the curve=0.021, P=3.7×10(-7)), although the overall area under the curve remained low. In all the studies, there was a highly significantly improved net reclassification index (P<10(-4)).

CONCLUSIONS: The single-nucleotide polymorphisms associated with stroke and its risk factors result only in a small improvement in prediction of future stroke compared with the classical epidemiological risk factors for stroke.

%B Stroke %V 45 %P 403-12 %8 2014 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/24436238?dopt=Abstract %R 10.1161/STROKEAHA.113.003044 %0 Journal Article %J Genet Epidemiol %D 2014 %T A robust method for genome-wide association meta-analysis with the application to circulating insulin-like growth factor I concentrations. %A Wang, Tao %A Zhou, Baiyu %A Guo, Tingwei %A Bidlingmaier, Martin %A Wallaschofski, Henri %A Teumer, Alexander %A Vasan, Ramachandran S %A Kaplan, Robert C %K Computer Simulation %K Genetic Linkage %K Genome %K Genome-Wide Association Study %K Humans %K Insulin-Like Growth Factor I %K Meta-Analysis as Topic %K Models, Genetic %K Polymorphism, Single Nucleotide %K Sample Size %X

Genome-wide association studies (GWAS) offer an excellent opportunity to identify the genetic variants underlying complex human diseases. Successful utilization of this approach requires a large sample size to identify single nucleotide polymorphisms (SNPs) with subtle effects. Meta-analysis is a cost-efficient means to achieve large sample size by combining data from multiple independent GWAS; however, results from studies performed on different populations can be variable due to various reasons, including varied linkage equilibrium structures as well as gene-gene and gene-environment interactions. Nevertheless, one should expect effects of the SNP are more similar between similar populations than those between populations with quite different genetic and environmental backgrounds. Prior information on populations of GWAS is often not considered in current meta-analysis methods, rendering such analyses less optimal for the detecting association. This article describes a test that improves meta-analysis to incorporate variable heterogeneity among populations. The proposed method is remarkably simple in computation and hence can be performed in a rapid fashion in the setting of GWAS. Simulation results demonstrate the validity and higher power of the proposed method over conventional methods in the presence of heterogeneity. As a demonstration, we applied the test to real GWAS data to identify SNPs associated with circulating insulin-like growth factor I concentrations.

%B Genet Epidemiol %V 38 %P 162-71 %8 2014 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/24446417?dopt=Abstract %R 10.1002/gepi.21766 %0 Journal Article %J Circ Cardiovasc Genet %D 2014 %T Sequence variation in TMEM18 in association with body mass index: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study. %A Liu, Ching-Ti %A Young, Kristin L %A Brody, Jennifer A %A Olden, Matthias %A Wojczynski, Mary K %A Heard-Costa, Nancy %A Li, Guo %A Morrison, Alanna C %A Muzny, Donna %A Gibbs, Richard A %A Reid, Jeffrey G %A Shao, Yaming %A Zhou, Yanhua %A Boerwinkle, Eric %A Heiss, Gerardo %A Wagenknecht, Lynne %A McKnight, Barbara %A Borecki, Ingrid B %A Fox, Caroline S %A North, Kari E %A Cupples, L Adrienne %K Adult %K Aged %K Aging %K Body Mass Index %K Cohort Studies %K Female %K Genetic Association Studies %K Genetic Variation %K Genome-Wide Association Study %K Genomics %K Heart Diseases %K Humans %K Male %K Membrane Proteins %K Middle Aged %K Polymorphism, Single Nucleotide %K Sequence Analysis, DNA %K Young Adult %X

BACKGROUND: Genome-wide association studies for body mass index (BMI) previously identified a locus near TMEM18. We conducted targeted sequencing of this region to investigate the role of common, low-frequency, and rare variants influencing BMI.

METHODS AND RESULTS: We sequenced TMEM18 and regions downstream of TMEM18 on chromosome 2 in 3976 individuals of European ancestry from 3 community-based cohorts (Atherosclerosis Risk in Communities, Cardiovascular Health Study, and Framingham Heart Study), including 200 adults selected for high BMI. We examined the association between BMI and variants identified in the region from nucleotide position 586 432 to 677 539 (hg18). Rare variants (minor allele frequency, <1%) were analyzed using a burden test and the sequence kernel association test. Results from the 3 cohort studies were meta-analyzed. We estimate that mean BMI is 0.43 kg/m(2) higher for each copy of the G allele of single-nucleotide polymorphism rs7596758 (minor allele frequency, 29%; P=3.46×10(-4)) using a Bonferroni threshold of P<4.6×10(-4). Analyses conditional on previous genome-wide association study single-nucleotide polymorphisms associated with BMI in the region led to attenuation of this signal and uncovered another independent (r(2)<0.2), statistically significant association, rs186019316 (P=2.11×10(-4)). Both rs186019316 and rs7596758 or proxies are located in transcription factor binding regions. No significant association with rare variants was found in either the exons of TMEM18 or the 3' genome-wide association study region.

CONCLUSIONS: Targeted sequencing around TMEM18 identified 2 novel BMI variants with possible regulatory function.

%B Circ Cardiovasc Genet %V 7 %P 344-9 %8 2014 Jun %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/24951660?dopt=Abstract %R 10.1161/CIRCGENETICS.13.000067 %0 Journal Article %J Circ Cardiovasc Genet %D 2014 %T Sequencing of 2 subclinical atherosclerosis candidate regions in 3669 individuals: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study. %A Bis, Joshua C %A White, Charles C %A Franceschini, Nora %A Brody, Jennifer %A Zhang, Xiaoling %A Muzny, Donna %A Santibanez, Jireh %A Gibbs, Richard %A Liu, Xiaoming %A Lin, Honghuang %A Boerwinkle, Eric %A Psaty, Bruce M %A North, Kari E %A Cupples, L Adrienne %A O'Donnell, Christopher J %K Aged %K Aged, 80 and over %K Aging %K Atherosclerosis %K Class Ib Phosphatidylinositol 3-Kinase %K Cohort Studies %K European Continental Ancestry Group %K Female %K Genetic Variation %K Genome-Wide Association Study %K Genomics %K Humans %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Sequence Analysis, DNA %K Sodium-Phosphate Cotransporter Proteins, Type I %X

BACKGROUND: Atherosclerosis, the precursor to coronary heart disease and stroke, is characterized by an accumulation of fatty cells in the arterial intimal-medial layers. Common carotid intima media thickness (cIMT) and plaque are subclinical atherosclerosis measures that predict cardiovascular disease events. Previously, genome-wide association studies demonstrated evidence for association with cIMT (SLC17A4) and plaque (PIK3CG).

METHODS AND RESULTS: We sequenced 120 kb around SLC17A4 (6p22.2) and 251 kb around PIK3CG (7q22.3) among 3669 European ancestry participants from the Atherosclerosis Risk in Communities (ARIC) study, Cardiovascular Health Study (CHS), and Framingham Heart Study (FHS) in Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Primary analyses focused on 438 common variants (minor allele frequency ≥1%), which were independently meta-analyzed. A 3' untranslated region CCDC71L variant (rs2286149), upstream from PIK3CG, was the most significant finding in cIMT (P=0.00033) and plaque (P=0.0004) analyses. A SLC17A4 intronic variant was also associated with cIMT (P=0.008). Both were in low linkage disequilibrium with the genome-wide association study single nucleotide polymorphisms. Gene-based tests including T1 count and sequence kernel association test for rare variants (minor allele frequency <1%) did not yield statistically significant associations. However, we observed nominal associations for rare variants in CCDC71L and SLC17A3 with cIMT and of the entire 7q22 region with plaque (P=0.05).

CONCLUSIONS: Common and rare variants in PIK3CG and SLC17A4 regions demonstrated modest association with subclinical atherosclerosis traits. Although not conclusive, these findings may help to understand the genetic architecture of regions previously implicated by genome-wide association studies and identify variants within these regions for further investigation in larger samples.

%B Circ Cardiovasc Genet %V 7 %P 359-64 %8 2014 Jun %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/24951662?dopt=Abstract %R 10.1161/CIRCGENETICS.113.000116 %0 Journal Article %J Circ Cardiovasc Genet %D 2014 %T Sequencing of SCN5A identifies rare and common variants associated with cardiac conduction: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. %A Magnani, Jared W %A Brody, Jennifer A %A Prins, Bram P %A Arking, Dan E %A Lin, Honghuang %A Yin, Xiaoyan %A Liu, Ching-Ti %A Morrison, Alanna C %A Zhang, Feng %A Spector, Tim D %A Alonso, Alvaro %A Bis, Joshua C %A Heckbert, Susan R %A Lumley, Thomas %A Sitlani, Colleen M %A Cupples, L Adrienne %A Lubitz, Steven A %A Soliman, Elsayed Z %A Pulit, Sara L %A Newton-Cheh, Christopher %A O'Donnell, Christopher J %A Ellinor, Patrick T %A Benjamin, Emelia J %A Muzny, Donna M %A Gibbs, Richard A %A Santibanez, Jireh %A Taylor, Herman A %A Rotter, Jerome I %A Lange, Leslie A %A Psaty, Bruce M %A Jackson, Rebecca %A Rich, Stephen S %A Boerwinkle, Eric %A Jamshidi, Yalda %A Sotoodehnia, Nona %K Adult %K Aged %K Aged, 80 and over %K Aging %K Cohort Studies %K Female %K Genetic Variation %K Genome-Wide Association Study %K Genomics %K Heart Conduction System %K Heart Diseases %K Humans %K Male %K Middle Aged %K NAV1.5 Voltage-Gated Sodium Channel %K Polymorphism, Single Nucleotide %K Sequence Analysis, DNA %X

BACKGROUND: The cardiac sodium channel SCN5A regulates atrioventricular and ventricular conduction. Genetic variants in this gene are associated with PR and QRS intervals. We sought to characterize further the contribution of rare and common coding variation in SCN5A to cardiac conduction.

METHODS AND RESULTS: In Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study, we performed targeted exonic sequencing of SCN5A (n=3699, European ancestry individuals) and identified 4 common (minor allele frequency >1%) and 157 rare variants. Common and rare SCN5A coding variants were examined for association with PR and QRS intervals through meta-analysis of European ancestry participants from CHARGE, National Heart, Lung, and Blood Institute's Exome Sequencing Project (n=607), and the UK10K (n=1275) and by examining Exome Sequencing Project African ancestry participants (n=972). Rare coding SCN5A variants in aggregate were associated with PR interval in European and African ancestry participants (P=1.3×10(-3)). Three common variants were associated with PR and QRS interval duration among European ancestry participants and one among African ancestry participants. These included 2 well-known missense variants: rs1805124 (H558R) was associated with PR and QRS shortening in European ancestry participants (P=6.25×10(-4) and P=5.2×10(-3), respectively) and rs7626962 (S1102Y) was associated with PR shortening in those of African ancestry (P=2.82×10(-3)). Among European ancestry participants, 2 novel synonymous variants, rs1805126 and rs6599230, were associated with cardiac conduction. Our top signal, rs1805126 was associated with PR and QRS lengthening (P=3.35×10(-7) and P=2.69×10(-4), respectively) and rs6599230 was associated with PR shortening (P=2.67×10(-5)).

CONCLUSIONS: By sequencing SCN5A, we identified novel common and rare coding variants associated with cardiac conduction.

%B Circ Cardiovasc Genet %V 7 %P 365-73 %8 2014 Jun %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/24951663?dopt=Abstract %R 10.1161/CIRCGENETICS.113.000098 %0 Journal Article %J Stroke %D 2014 %T Shared genetic susceptibility to ischemic stroke and coronary artery disease: a genome-wide analysis of common variants. %A Dichgans, Martin %A Malik, Rainer %A König, Inke R %A Rosand, Jonathan %A Clarke, Robert %A Gretarsdottir, Solveig %A Thorleifsson, Gudmar %A Mitchell, Braxton D %A Assimes, Themistocles L %A Levi, Christopher %A O'Donnell, Christopher J %A Fornage, Myriam %A Thorsteinsdottir, Unnur %A Psaty, Bruce M %A Hengstenberg, Christian %A Seshadri, Sudha %A Erdmann, Jeanette %A Bis, Joshua C %A Peters, Annette %A Boncoraglio, Giorgio B %A März, Winfried %A Meschia, James F %A Kathiresan, Sekar %A Ikram, M Arfan %A McPherson, Ruth %A Stefansson, Kari %A Sudlow, Cathie %A Reilly, Muredach P %A Thompson, John R %A Sharma, Pankaj %A Hopewell, Jemma C %A Chambers, John C %A Watkins, Hugh %A Rothwell, Peter M %A Roberts, Robert %A Markus, Hugh S %A Samani, Nilesh J %A Farrall, Martin %A Schunkert, Heribert %K Brain Ischemia %K Coronary Artery Disease %K Data Interpretation, Statistical %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Phenotype %K Polymorphism, Single Nucleotide %K Reproducibility of Results %K Risk Factors %K Stroke %X

BACKGROUND AND PURPOSE: Ischemic stroke (IS) and coronary artery disease (CAD) share several risk factors and each has a substantial heritability. We conducted a genome-wide analysis to evaluate the extent of shared genetic determination of the two diseases.

METHODS: Genome-wide association data were obtained from the METASTROKE, Coronary Artery Disease Genome-wide Replication and Meta-analysis (CARDIoGRAM), and Coronary Artery Disease (C4D) Genetics consortia. We first analyzed common variants reaching a nominal threshold of significance (P<0.01) for CAD for their association with IS and vice versa. We then examined specific overlap across phenotypes for variants that reached a high threshold of significance. Finally, we conducted a joint meta-analysis on the combined phenotype of IS or CAD. Corresponding analyses were performed restricted to the 2167 individuals with the ischemic large artery stroke (LAS) subtype.

RESULTS: Common variants associated with CAD at P<0.01 were associated with a significant excess risk for IS and for LAS and vice versa. Among the 42 known genome-wide significant loci for CAD, 3 and 5 loci were significantly associated with IS and LAS, respectively. In the joint meta-analyses, 15 loci passed genome-wide significance (P<5×10(-8)) for the combined phenotype of IS or CAD and 17 loci passed genome-wide significance for LAS or CAD. Because these loci had prior evidence for genome-wide significance for CAD, we specifically analyzed the respective signals for IS and LAS and found evidence for association at chr12q24/SH2B3 (PIS=1.62×10(-7)) and ABO (PIS=2.6×10(-4)), as well as at HDAC9 (PLAS=2.32×10(-12)), 9p21 (PLAS=3.70×10(-6)), RAI1-PEMT-RASD1 (PLAS=2.69×10(-5)), EDNRA (PLAS=7.29×10(-4)), and CYP17A1-CNNM2-NT5C2 (PLAS=4.9×10(-4)).

CONCLUSIONS: Our results demonstrate substantial overlap in the genetic risk of IS and particularly the LAS subtype with CAD.

%B Stroke %V 45 %P 24-36 %8 2014 Jan %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/24262325?dopt=Abstract %R 10.1161/STROKEAHA.113.002707 %0 Journal Article %J Circ Cardiovasc Genet %D 2014 %T Strategies to design and analyze targeted sequencing data: cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study. %A Lin, Honghuang %A Wang, Min %A Brody, Jennifer A %A Bis, Joshua C %A Dupuis, Josée %A Lumley, Thomas %A McKnight, Barbara %A Rice, Kenneth M %A Sitlani, Colleen M %A Reid, Jeffrey G %A Bressler, Jan %A Liu, Xiaoming %A Davis, Brian C %A Johnson, Andrew D %A O'Donnell, Christopher J %A Kovar, Christie L %A Dinh, Huyen %A Wu, Yuanqing %A Newsham, Irene %A Chen, Han %A Broka, Andi %A DeStefano, Anita L %A Gupta, Mayetri %A Lunetta, Kathryn L %A Liu, Ching-Ti %A White, Charles C %A Xing, Chuanhua %A Zhou, Yanhua %A Benjamin, Emelia J %A Schnabel, Renate B %A Heckbert, Susan R %A Psaty, Bruce M %A Muzny, Donna M %A Cupples, L Adrienne %A Morrison, Alanna C %A Boerwinkle, Eric %K Adult %K Aged %K Aged, 80 and over %K Aging %K Cohort Studies %K Female %K Genetic Variation %K Genome-Wide Association Study %K Genomics %K Heart Diseases %K Humans %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Research Design %K Sequence Analysis, DNA %X

BACKGROUND: Genome-wide association studies have identified thousands of genetic variants that influence a variety of diseases and health-related quantitative traits. However, the causal variants underlying the majority of genetic associations remain unknown. Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study aims to follow up genome-wide association study signals and identify novel associations of the allelic spectrum of identified variants with cardiovascular-related traits.

METHODS AND RESULTS: The study included 4231 participants from 3 CHARGE cohorts: the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, and the Framingham Heart Study. We used a case-cohort design in which we selected both a random sample of participants and participants with extreme phenotypes for each of 14 traits. We sequenced and analyzed 77 genomic loci, which had previously been associated with ≥1 of 14 phenotypes. A total of 52 736 variants were characterized by sequencing and passed our stringent quality control criteria. For common variants (minor allele frequency ≥1%), we performed unweighted regression analyses to obtain P values for associations and weighted regression analyses to obtain effect estimates that accounted for the sampling design. For rare variants, we applied 2 approaches: collapsed aggregate statistics and joint analysis of variants using the sequence kernel association test.

CONCLUSIONS: We sequenced 77 genomic loci in participants from 3 cohorts. We established a set of filters to identify high-quality variants and implemented statistical and bioinformatics strategies to analyze the sequence data and identify potentially functional variants within genome-wide association study loci.

%B Circ Cardiovasc Genet %V 7 %P 335-43 %8 2014 Jun %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/24951659?dopt=Abstract %R 10.1161/CIRCGENETICS.113.000350 %0 Journal Article %J Heart Rhythm %D 2014 %T Targeted sequencing in candidate genes for atrial fibrillation: the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Targeted Sequencing Study. %A Lin, Honghuang %A Sinner, Moritz F %A Brody, Jennifer A %A Arking, Dan E %A Lunetta, Kathryn L %A Rienstra, Michiel %A Lubitz, Steven A %A Magnani, Jared W %A Sotoodehnia, Nona %A McKnight, Barbara %A McManus, David D %A Boerwinkle, Eric %A Psaty, Bruce M %A Rotter, Jerome I %A Bis, Joshua C %A Gibbs, Richard A %A Muzny, Donna %A Kovar, Christie L %A Morrison, Alanna C %A Gupta, Mayetri %A Folsom, Aaron R %A Kääb, Stefan %A Heckbert, Susan R %A Alonso, Alvaro %A Ellinor, Patrick T %A Benjamin, Emelia J %K Aged %K Atrial Fibrillation %K Female %K Genetic Predisposition to Disease %K Genetic Variation %K Genome-Wide Association Study %K Homeodomain Proteins %K Humans %K Linkage Disequilibrium %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Receptors, Interleukin-6 %X

BACKGROUND: Genome-wide association studies (GWAS) have identified common genetic variants that predispose to atrial fibrillation (AF). It is unclear whether rare and low-frequency variants in genes implicated by such GWAS confer additional risk of AF.

OBJECTIVE: To study the association of genetic variants with AF at GWAS top loci.

METHODS: In the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Targeted Sequencing Study, we selected and sequenced 77 target gene regions from GWAS loci of complex diseases or traits, including 4 genes hypothesized to be related to AF (PRRX1, CAV1, CAV2, and ZFHX3). Sequencing was performed in participants with (n = 948) and without (n = 3330) AF from the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Massachusetts General Hospital.

RESULTS: One common variant (rs11265611; P = 1.70 × 10(-6)) intronic to IL6R (interleukin-6 receptor gene) was significantly associated with AF after Bonferroni correction (odds ratio 0.70; 95% confidence interval 0.58-0.85). The variant was not genotyped or imputed by prior GWAS, but it is in linkage disequilibrium (r(2) = .69) with the single-nucleotide polymorphism, with the strongest association with AF so far at this locus (rs4845625). In the rare variant joint analysis, damaging variants within the PRRX1 region showed significant association with AF after Bonferroni correction (P = .01).

CONCLUSIONS: We identified 1 common single-nucleotide polymorphism and 1 gene region that were significantly associated with AF. Future sequencing efforts with larger sample sizes and more comprehensive genome coverage are anticipated to identify additional AF-related variants.

%B Heart Rhythm %V 11 %P 452-7 %8 2014 Mar %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/24239840?dopt=Abstract %R 10.1016/j.hrthm.2013.11.012 %0 Journal Article %J Hum Mol Genet %D 2014 %T Trans-ethnic meta-analysis of white blood cell phenotypes. %A Keller, Margaux F %A Reiner, Alexander P %A Okada, Yukinori %A van Rooij, Frank J A %A Johnson, Andrew D %A Chen, Ming-Huei %A Smith, Albert V %A Morris, Andrew P %A Tanaka, Toshiko %A Ferrucci, Luigi %A Zonderman, Alan B %A Lettre, Guillaume %A Harris, Tamara %A Garcia, Melissa %A Bandinelli, Stefania %A Qayyum, Rehan %A Yanek, Lisa R %A Becker, Diane M %A Becker, Lewis C %A Kooperberg, Charles %A Keating, Brendan %A Reis, Jared %A Tang, Hua %A Boerwinkle, Eric %A Kamatani, Yoichiro %A Matsuda, Koichi %A Kamatani, Naoyuki %A Nakamura, Yusuke %A Kubo, Michiaki %A Liu, Simin %A Dehghan, Abbas %A Felix, Janine F %A Hofman, Albert %A Uitterlinden, André G %A van Duijn, Cornelia M %A Franco, Oscar H %A Longo, Dan L %A Singleton, Andrew B %A Psaty, Bruce M %A Evans, Michelle K %A Cupples, L Adrienne %A Rotter, Jerome I %A O'Donnell, Christopher J %A Takahashi, Atsushi %A Wilson, James G %A Ganesh, Santhi K %A Nalls, Mike A %K African Americans %K Asian Continental Ancestry Group %K Bayes Theorem %K European Continental Ancestry Group %K Genome, Human %K Genome-Wide Association Study %K Genotype %K Humans %K Leukocyte Count %K Leukocytes %K Linkage Disequilibrium %K Phenotype %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %X

White blood cell (WBC) count is a common clinical measure used as a predictor of certain aspects of human health, including immunity and infection status. WBC count is also a complex trait that varies among individuals and ancestry groups. Differences in linkage disequilibrium structure and heterogeneity in allelic effects are expected to play a role in the associations observed between populations. Prior genome-wide association study (GWAS) meta-analyses have identified genomic loci associated with WBC and its subtypes, but much of the heritability of these phenotypes remains unexplained. Using GWAS summary statistics for over 50 000 individuals from three diverse populations (Japanese, African-American and European ancestry), a Bayesian model methodology was employed to account for heterogeneity between ancestry groups. This approach was used to perform a trans-ethnic meta-analysis of total WBC, neutrophil and monocyte counts. Ten previously known associations were replicated and six new loci were identified, including several regions harboring genes related to inflammation and immune cell function. Ninety-five percent credible interval regions were calculated to narrow the association signals and fine-map the putatively causal variants within loci. Finally, a conditional analysis was performed on the most significant SNPs identified by the trans-ethnic meta-analysis (MA), and nine secondary signals within loci previously associated with WBC or its subtypes were identified. This work illustrates the potential of trans-ethnic analysis and ascribes a critical role to multi-ethnic cohorts and consortia in exploring complex phenotypes with respect to variants that lie outside the European-biased GWAS pool.

%B Hum Mol Genet %V 23 %P 6944-60 %8 2014 Dec 20 %G eng %N 25 %1 http://www.ncbi.nlm.nih.gov/pubmed/25096241?dopt=Abstract %R 10.1093/hmg/ddu401 %0 Journal Article %J Am J Hum Genet %D 2014 %T Whole-exome sequencing identifies rare and low-frequency coding variants associated with LDL cholesterol. %A Lange, Leslie A %A Hu, Youna %A Zhang, He %A Xue, Chenyi %A Schmidt, Ellen M %A Tang, Zheng-Zheng %A Bizon, Chris %A Lange, Ethan M %A Smith, Joshua D %A Turner, Emily H %A Jun, Goo %A Kang, Hyun Min %A Peloso, Gina %A Auer, Paul %A Li, Kuo-Ping %A Flannick, Jason %A Zhang, Ji %A Fuchsberger, Christian %A Gaulton, Kyle %A Lindgren, Cecilia %A Locke, Adam %A Manning, Alisa %A Sim, Xueling %A Rivas, Manuel A %A Holmen, Oddgeir L %A Gottesman, Omri %A Lu, Yingchang %A Ruderfer, Douglas %A Stahl, Eli A %A Duan, Qing %A Li, Yun %A Durda, Peter %A Jiao, Shuo %A Isaacs, Aaron %A Hofman, Albert %A Bis, Joshua C %A Correa, Adolfo %A Griswold, Michael E %A Jakobsdottir, Johanna %A Smith, Albert V %A Schreiner, Pamela J %A Feitosa, Mary F %A Zhang, Qunyuan %A Huffman, Jennifer E %A Crosby, Jacy %A Wassel, Christina L %A Do, Ron %A Franceschini, Nora %A Martin, Lisa W %A Robinson, Jennifer G %A Assimes, Themistocles L %A Crosslin, David R %A Rosenthal, Elisabeth A %A Tsai, Michael %A Rieder, Mark J %A Farlow, Deborah N %A Folsom, Aaron R %A Lumley, Thomas %A Fox, Ervin R %A Carlson, Christopher S %A Peters, Ulrike %A Jackson, Rebecca D %A van Duijn, Cornelia M %A Uitterlinden, André G %A Levy, Daniel %A Rotter, Jerome I %A Taylor, Herman A %A Gudnason, Vilmundur %A Siscovick, David S %A Fornage, Myriam %A Borecki, Ingrid B %A Hayward, Caroline %A Rudan, Igor %A Chen, Y Eugene %A Bottinger, Erwin P %A Loos, Ruth J F %A Sætrom, Pål %A Hveem, Kristian %A Boehnke, Michael %A Groop, Leif %A McCarthy, Mark %A Meitinger, Thomas %A Ballantyne, Christie M %A Gabriel, Stacey B %A O'Donnell, Christopher J %A Post, Wendy S %A North, Kari E %A Reiner, Alexander P %A Boerwinkle, Eric %A Psaty, Bruce M %A Altshuler, David %A Kathiresan, Sekar %A Lin, Dan-Yu %A Jarvik, Gail P %A Cupples, L Adrienne %A Kooperberg, Charles %A Wilson, James G %A Nickerson, Deborah A %A Abecasis, Goncalo R %A Rich, Stephen S %A Tracy, Russell P %A Willer, Cristen J %K Adult %K Aged %K Apolipoproteins E %K Cholesterol, LDL %K Cohort Studies %K Dyslipidemias %K Exome %K Female %K Follow-Up Studies %K Gene Frequency %K Genetic Code %K Genome-Wide Association Study %K Genotype %K Humans %K Lipase %K Male %K Middle Aged %K Phenotype %K Polymorphism, Single Nucleotide %K Proprotein Convertase 9 %K Proprotein Convertases %K Receptors, LDL %K Sequence Analysis, DNA %K Serine Endopeptidases %X

Elevated low-density lipoprotein cholesterol (LDL-C) is a treatable, heritable risk factor for cardiovascular disease. Genome-wide association studies (GWASs) have identified 157 variants associated with lipid levels but are not well suited to assess the impact of rare and low-frequency variants. To determine whether rare or low-frequency coding variants are associated with LDL-C, we exome sequenced 2,005 individuals, including 554 individuals selected for extreme LDL-C (>98(th) or <2(nd) percentile). Follow-up analyses included sequencing of 1,302 additional individuals and genotype-based analysis of 52,221 individuals. We observed significant evidence of association between LDL-C and the burden of rare or low-frequency variants in PNPLA5, encoding a phospholipase-domain-containing protein, and both known and previously unidentified variants in PCSK9, LDLR and APOB, three known lipid-related genes. The effect sizes for the burden of rare variants for each associated gene were substantially higher than those observed for individual SNPs identified from GWASs. We replicated the PNPLA5 signal in an independent large-scale sequencing study of 2,084 individuals. In conclusion, this large whole-exome-sequencing study for LDL-C identified a gene not known to be implicated in LDL-C and provides unique insight into the design and analysis of similar experiments.

%B Am J Hum Genet %V 94 %P 233-45 %8 2014 Feb 06 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/24507775?dopt=Abstract %R 10.1016/j.ajhg.2014.01.010 %0 Journal Article %J Neurobiol Aging %D 2015 %T Association of Alzheimer's disease GWAS loci with MRI markers of brain aging. %A Chauhan, Ganesh %A Adams, Hieab H H %A Bis, Joshua C %A Weinstein, Galit %A Yu, Lei %A Töglhofer, Anna Maria %A Smith, Albert Vernon %A van der Lee, Sven J %A Gottesman, Rebecca F %A Thomson, Russell %A Wang, Jing %A Yang, Qiong %A Niessen, Wiro J %A Lopez, Oscar L %A Becker, James T %A Phan, Thanh G %A Beare, Richard J %A Arfanakis, Konstantinos %A Fleischman, Debra %A Vernooij, Meike W %A Mazoyer, Bernard %A Schmidt, Helena %A Srikanth, Velandai %A Knopman, David S %A Jack, Clifford R %A Amouyel, Philippe %A Hofman, Albert %A DeCarli, Charles %A Tzourio, Christophe %A van Duijn, Cornelia M %A Bennett, David A %A Schmidt, Reinhold %A Longstreth, William T %A Mosley, Thomas H %A Fornage, Myriam %A Launer, Lenore J %A Seshadri, Sudha %A Ikram, M Arfan %A Debette, Stephanie %K Aging %K Alleles %K Alzheimer Disease %K Apolipoproteins E %K Brain %K Female %K Genome-Wide Association Study %K Hippocampus %K Humans %K Magnetic Resonance Imaging %K Male %K Organ Size %K Polymorphism, Single Nucleotide %K Risk %K Sialic Acid Binding Ig-like Lectin 3 %X

Whether novel risk variants of Alzheimer's disease (AD) identified through genome-wide association studies also influence magnetic resonance imaging-based intermediate phenotypes of AD in the general population is unclear. We studied association of 24 AD risk loci with intracranial volume, total brain volume, hippocampal volume (HV), white matter hyperintensity burden, and brain infarcts in a meta-analysis of genetic association studies from large population-based samples (N = 8175-11,550). In single-SNP based tests, AD risk allele of APOE (rs2075650) was associated with smaller HV (p = 0.0054) and CD33 (rs3865444) with smaller intracranial volume (p = 0.0058). In gene-based tests, there was associations of HLA-DRB1 with total brain volume (p = 0.0006) and BIN1 with HV (p = 0.00089). A weighted AD genetic risk score was associated with smaller HV (beta ± SE = -0.047 ± 0.013, p = 0.00041), even after excluding the APOE locus (p = 0.029). However, only association of AD genetic risk score with HV, including APOE, was significant after multiple testing correction (including number of independent phenotypes tested). These results suggest that novel AD genetic risk variants may contribute to structural brain aging in nondemented older community persons.

%B Neurobiol Aging %V 36 %P 1765.e7-16 %8 2015 Apr %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/25670335?dopt=Abstract %R 10.1016/j.neurobiolaging.2014.12.028 %0 Journal Article %J Hum Mol Genet %D 2015 %T Association of exome sequences with plasma C-reactive protein levels in >9000 participants. %A Schick, Ursula M %A Auer, Paul L %A Bis, Joshua C %A Lin, Honghuang %A Wei, Peng %A Pankratz, Nathan %A Lange, Leslie A %A Brody, Jennifer %A Stitziel, Nathan O %A Kim, Daniel S %A Carlson, Christopher S %A Fornage, Myriam %A Haessler, Jeffery %A Hsu, Li %A Jackson, Rebecca D %A Kooperberg, Charles %A Leal, Suzanne M %A Psaty, Bruce M %A Boerwinkle, Eric %A Tracy, Russell %A Ardissino, Diego %A Shah, Svati %A Willer, Cristen %A Loos, Ruth %A Melander, Olle %A McPherson, Ruth %A Hovingh, Kees %A Reilly, Muredach %A Watkins, Hugh %A Girelli, Domenico %A Fontanillas, Pierre %A Chasman, Daniel I %A Gabriel, Stacey B %A Gibbs, Richard %A Nickerson, Deborah A %A Kathiresan, Sekar %A Peters, Ulrike %A Dupuis, Josée %A Wilson, James G %A Rich, Stephen S %A Morrison, Alanna C %A Benjamin, Emelia J %A Gross, Myron D %A Reiner, Alex P %K Adult %K African Americans %K C-Reactive Protein %K Cardiovascular Diseases %K Cohort Studies %K European Continental Ancestry Group %K Exome %K Female %K Gene Frequency %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Hepatocyte Nuclear Factor 1-alpha %K Humans %K Male %K Plasma %K Polymorphism, Single Nucleotide %K Receptors, Interleukin-6 %K Risk Factors %X

C-reactive protein (CRP) concentration is a heritable systemic marker of inflammation that is associated with cardiovascular disease risk. Genome-wide association studies have identified CRP-associated common variants associated in ∼25 genes. Our aims were to apply exome sequencing to (1) assess whether the candidate loci contain rare coding variants associated with CRP levels and (2) perform an exome-wide search for rare variants in novel genes associated with CRP levels. We exome-sequenced 6050 European-Americans (EAs) and 3109 African-Americans (AAs) from the NHLBI-ESP and the CHARGE consortia, and performed association tests of sequence data with measured CRP levels. In single-variant tests across candidate loci, a novel rare (minor allele frequency = 0.16%) CRP-coding variant (rs77832441-A; p.Thr59Met) was associated with 53% lower mean CRP levels (P = 2.9 × 10(-6)). We replicated the association of rs77832441 in an exome array analysis of 11 414 EAs (P = 3.0 × 10(-15)). Despite a strong effect on CRP levels, rs77832441 was not associated with inflammation-related phenotypes including coronary heart disease. We also found evidence for an AA-specific association of APOE-ε2 rs7214 with higher CRP levels. At the exome-wide significance level (P < 5.0 × 10(-8)), we confirmed associations for reported common variants of HNF1A, CRP, IL6R and TOMM40-APOE. In gene-based tests, a burden of rare/lower frequency variation in CRP in EAs (P ≤ 6.8 × 10(-4)) and in retinoic acid receptor-related orphan receptor α (RORA) in AAs (P = 1.7 × 10(-3)) were associated with CRP levels at the candidate gene level (P < 2.0 × 10(-3)). This inquiry did not elucidate novel genes, but instead demonstrated that variants distributed across the allele frequency spectrum within candidate genes contribute to CRP levels.

%B Hum Mol Genet %V 24 %P 559-71 %8 2015 Jan 15 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/25187575?dopt=Abstract %R 10.1093/hmg/ddu450 %0 Journal Article %J Am J Clin Nutr %D 2015 %T Consumption of meat is associated with higher fasting glucose and insulin concentrations regardless of glucose and insulin genetic risk scores: a meta-analysis of 50,345 Caucasians. %A Fretts, Amanda M %A Follis, Jack L %A Nettleton, Jennifer A %A Lemaitre, Rozenn N %A Ngwa, Julius S %A Wojczynski, Mary K %A Kalafati, Ioanna Panagiota %A Varga, Tibor V %A Frazier-Wood, Alexis C %A Houston, Denise K %A Lahti, Jari %A Ericson, Ulrika %A van den Hooven, Edith H %A Mikkilä, Vera %A Kiefte-de Jong, Jessica C %A Mozaffarian, Dariush %A Rice, Kenneth %A Renstrom, Frida %A North, Kari E %A McKeown, Nicola M %A Feitosa, Mary F %A Kanoni, Stavroula %A Smith, Caren E %A Garcia, Melissa E %A Tiainen, Anna-Maija %A Sonestedt, Emily %A Manichaikul, Ani %A van Rooij, Frank J A %A Dimitriou, Maria %A Raitakari, Olli %A Pankow, James S %A Djoussé, Luc %A Province, Michael A %A Hu, Frank B %A Lai, Chao-Qiang %A Keller, Margaux F %A Perälä, Mia-Maria %A Rotter, Jerome I %A Hofman, Albert %A Graff, Misa %A Kähönen, Mika %A Mukamal, Kenneth %A Johansson, Ingegerd %A Ordovas, Jose M %A Liu, Yongmei %A Männistö, Satu %A Uitterlinden, André G %A Deloukas, Panos %A Seppälä, Ilkka %A Psaty, Bruce M %A Cupples, L Adrienne %A Borecki, Ingrid B %A Franks, Paul W %A Arnett, Donna K %A Nalls, Mike A %A Eriksson, Johan G %A Orho-Melander, Marju %A Franco, Oscar H %A Lehtimäki, Terho %A Dedoussis, George V %A Meigs, James B %A Siscovick, David S %K Blood Glucose %K Cohort Studies %K Genetic Association Studies %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Hyperglycemia %K Hyperinsulinism %K Insulin %K Insulin Resistance %K Insulin-Secreting Cells %K Meat %K Meat Products %K Middle Aged %K Polymorphism, Single Nucleotide %K Risk Factors %X

BACKGROUND: Recent studies suggest that meat intake is associated with diabetes-related phenotypes. However, whether the associations of meat intake and glucose and insulin homeostasis are modified by genes related to glucose and insulin is unknown.

OBJECTIVE: We investigated the associations of meat intake and the interaction of meat with genotype on fasting glucose and insulin concentrations in Caucasians free of diabetes mellitus.

DESIGN: Fourteen studies that are part of the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium participated in the analysis. Data were provided for up to 50,345 participants. Using linear regression within studies and a fixed-effects meta-analysis across studies, we examined 1) the associations of processed meat and unprocessed red meat intake with fasting glucose and insulin concentrations; and 2) the interactions of processed meat and unprocessed red meat with genetic risk score related to fasting glucose or insulin resistance on fasting glucose and insulin concentrations.

RESULTS: Processed meat was associated with higher fasting glucose, and unprocessed red meat was associated with both higher fasting glucose and fasting insulin concentrations after adjustment for potential confounders [not including body mass index (BMI)]. For every additional 50-g serving of processed meat per day, fasting glucose was 0.021 mmol/L (95% CI: 0.011, 0.030 mmol/L) higher. Every additional 100-g serving of unprocessed red meat per day was associated with a 0.037-mmol/L (95% CI: 0.023, 0.051-mmol/L) higher fasting glucose concentration and a 0.049-ln-pmol/L (95% CI: 0.035, 0.063-ln-pmol/L) higher fasting insulin concentration. After additional adjustment for BMI, observed associations were attenuated and no longer statistically significant. The association of processed meat and fasting insulin did not reach statistical significance after correction for multiple comparisons. Observed associations were not modified by genetic loci known to influence fasting glucose or insulin resistance.

CONCLUSION: The association of higher fasting glucose and insulin concentrations with meat consumption was not modified by an index of glucose- and insulin-related single-nucleotide polymorphisms. Six of the participating studies are registered at clinicaltrials.gov as NCT0000513 (Atherosclerosis Risk in Communities), NCT00149435 (Cardiovascular Health Study), NCT00005136 (Family Heart Study), NCT00005121 (Framingham Heart Study), NCT00083369 (Genetics of Lipid Lowering Drugs and Diet Network), and NCT00005487 (Multi-Ethnic Study of Atherosclerosis).

%B Am J Clin Nutr %V 102 %P 1266-78 %8 2015 Nov %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/26354543?dopt=Abstract %R 10.3945/ajcn.114.101238 %0 Journal Article %J Alzheimers Dement %D 2015 %T Convergent genetic and expression data implicate immunity in Alzheimer's disease. %K Algorithms %K Alzheimer Disease %K Brain %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Polymorphism, Single Nucleotide %X

BACKGROUND: Late-onset Alzheimer's disease (AD) is heritable with 20 genes showing genome-wide association in the International Genomics of Alzheimer's Project (IGAP). To identify the biology underlying the disease, we extended these genetic data in a pathway analysis.

METHODS: The ALIGATOR and GSEA algorithms were used in the IGAP data to identify associated functional pathways and correlated gene expression networks in human brain.

RESULTS: ALIGATOR identified an excess of curated biological pathways showing enrichment of association. Enriched areas of biology included the immune response (P = 3.27 × 10(-12) after multiple testing correction for pathways), regulation of endocytosis (P = 1.31 × 10(-11)), cholesterol transport (P = 2.96 × 10(-9)), and proteasome-ubiquitin activity (P = 1.34 × 10(-6)). Correlated gene expression analysis identified four significant network modules, all related to the immune response (corrected P = .002-.05).

CONCLUSIONS: The immune response, regulation of endocytosis, cholesterol transport, and protein ubiquitination represent prime targets for AD therapeutics.

%B Alzheimers Dement %V 11 %P 658-71 %8 2015 Jun %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/25533204?dopt=Abstract %R 10.1016/j.jalz.2014.05.1757 %0 Journal Article %J J Med Genet %D 2015 %T DCAF4, a novel gene associated with leucocyte telomere length. %A Mangino, Massimo %A Christiansen, Lene %A Stone, Rivka %A Hunt, Steven C %A Horvath, Kent %A Eisenberg, Dan T A %A Kimura, Masayuki %A Petersen, Inge %A Kark, Jeremy D %A Herbig, Utz %A Reiner, Alex P %A Benetos, Athanase %A Codd, Veryan %A Nyholt, Dale R %A Sinnreich, Ronit %A Christensen, Kaare %A Nassar, Hisham %A Hwang, Shih-Jen %A Levy, Daniel %A Bataille, Veronique %A Fitzpatrick, Annette L %A Chen, Wei %A Berenson, Gerald S %A Samani, Nilesh J %A Martin, Nicholas G %A Tishkoff, Sarah %A Schork, Nicholas J %A Kyvik, Kirsten Ohm %A Dalgård, Christine %A Spector, Timothy D %A Aviv, Abraham %K Alleles %K Carrier Proteins %K Gene Expression Regulation %K Genome-Wide Association Study %K Humans %K Leukocytes %K Melanoma %K Risk Factors %K Telomere %K Telomere Homeostasis %X

BACKGROUND: Leucocyte telomere length (LTL), which is fashioned by multiple genes, has been linked to a host of human diseases, including sporadic melanoma. A number of genes associated with LTL have already been identified through genome-wide association studies. The main aim of this study was to establish whether DCAF4 (DDB1 and CUL4-associated factor 4) is associated with LTL. In addition, using ingenuity pathway analysis (IPA), we examined whether LTL-associated genes in the general population might partially explain the inherently longer LTL in patients with sporadic melanoma, the risk for which is increased with ultraviolet radiation (UVR).

RESULTS: Genome-wide association (GWA) meta-analysis and de novo genotyping of 20 022 individuals revealed a novel association (p=6.4×10(-10)) between LTL and rs2535913, which lies within DCAF4. Notably, eQTL analysis showed that rs2535913 is associated with decline in DCAF4 expressions in both lymphoblastoid cells and sun-exposed skin (p=4.1×10(-3) and 2×10(-3), respectively). Moreover, IPA revealed that LTL-associated genes, derived from GWA meta-analysis (N=9190), are over-represented among genes engaged in melanoma pathways. Meeting increasingly stringent p value thresholds (p<0.05, <0.01, <0.005, <0.001) in the LTL-GWA meta-analysis, these genes were jointly over-represented for melanoma at p values ranging from 1.97×10(-169) to 3.42×10(-24).

CONCLUSIONS: We uncovered a new locus associated with LTL in the general population. We also provided preliminary findings that suggest a link of LTL through genetic mechanisms with UVR and melanoma in the general population.

%B J Med Genet %V 52 %P 157-62 %8 2015 Mar %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/25624462?dopt=Abstract %R 10.1136/jmedgenet-2014-102681 %0 Journal Article %J PLoS One %D 2015 %T Drug-Gene Interactions of Antihypertensive Medications and Risk of Incident Cardiovascular Disease: A Pharmacogenomics Study from the CHARGE Consortium. %A Bis, Joshua C %A Sitlani, Colleen %A Irvin, Ryan %A Avery, Christy L %A Smith, Albert Vernon %A Sun, Fangui %A Evans, Daniel S %A Musani, Solomon K %A Li, Xiaohui %A Trompet, Stella %A Krijthe, Bouwe P %A Harris, Tamara B %A Quibrera, P Miguel %A Brody, Jennifer A %A Demissie, Serkalem %A Davis, Barry R %A Wiggins, Kerri L %A Tranah, Gregory J %A Lange, Leslie A %A Sotoodehnia, Nona %A Stott, David J %A Franco, Oscar H %A Launer, Lenore J %A Stürmer, Til %A Taylor, Kent D %A Cupples, L Adrienne %A Eckfeldt, John H %A Smith, Nicholas L %A Liu, Yongmei %A Wilson, James G %A Heckbert, Susan R %A Buckley, Brendan M %A Ikram, M Arfan %A Boerwinkle, Eric %A Chen, Yii-Der Ida %A de Craen, Anton J M %A Uitterlinden, André G %A Rotter, Jerome I %A Ford, Ian %A Hofman, Albert %A Sattar, Naveed %A Slagboom, P Eline %A Westendorp, Rudi G J %A Gudnason, Vilmundur %A Vasan, Ramachandran S %A Lumley, Thomas %A Cummings, Steven R %A Taylor, Herman A %A Post, Wendy %A Jukema, J Wouter %A Stricker, Bruno H %A Whitsel, Eric A %A Psaty, Bruce M %A Arnett, Donna %K African Americans %K Aged %K Antihypertensive Agents %K Cardiovascular Diseases %K European Continental Ancestry Group %K Female %K Genome-Wide Association Study %K Humans %K Hypertension %K Incidence %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Treatment Outcome %X

BACKGROUND: Hypertension is a major risk factor for a spectrum of cardiovascular diseases (CVD), including myocardial infarction, sudden death, and stroke. In the US, over 65 million people have high blood pressure and a large proportion of these individuals are prescribed antihypertensive medications. Although large long-term clinical trials conducted in the last several decades have identified a number of effective antihypertensive treatments that reduce the risk of future clinical complications, responses to therapy and protection from cardiovascular events vary among individuals.

METHODS: Using a genome-wide association study among 21,267 participants with pharmaceutically treated hypertension, we explored the hypothesis that genetic variants might influence or modify the effectiveness of common antihypertensive therapies on the risk of major cardiovascular outcomes. The classes of drug treatments included angiotensin-converting enzyme inhibitors, beta-blockers, calcium channel blockers, and diuretics. In the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, each study performed array-based genome-wide genotyping, imputed to HapMap Phase II reference panels, and used additive genetic models in proportional hazards or logistic regression models to evaluate drug-gene interactions for each of four therapeutic drug classes. We used meta-analysis to combine study-specific interaction estimates for approximately 2 million single nucleotide polymorphisms (SNPs) in a discovery analysis among 15,375 European Ancestry participants (3,527 CVD cases) with targeted follow-up in a case-only study of 1,751 European Ancestry GenHAT participants as well as among 4,141 African-Americans (1,267 CVD cases).

RESULTS: Although drug-SNP interactions were biologically plausible, exposures and outcomes were well measured, and power was sufficient to detect modest interactions, we did not identify any statistically significant interactions from the four antihypertensive therapy meta-analyses (Pinteraction > 5.0×10-8). Similarly, findings were null for meta-analyses restricted to 66 SNPs with significant main effects on coronary artery disease or blood pressure from large published genome-wide association studies (Pinteraction ≥ 0.01). Our results suggest that there are no major pharmacogenetic influences of common SNPs on the relationship between blood pressure medications and the risk of incident CVD.

%B PLoS One %V 10 %P e0140496 %8 2015 %G eng %N 10 %1 http://www.ncbi.nlm.nih.gov/pubmed/26516778?dopt=Abstract %R 10.1371/journal.pone.0140496 %0 Journal Article %J Hum Mol Genet %D 2015 %T Gene × dietary pattern interactions in obesity: analysis of up to 68 317 adults of European ancestry. %A Nettleton, Jennifer A %A Follis, Jack L %A Ngwa, Julius S %A Smith, Caren E %A Ahmad, Shafqat %A Tanaka, Toshiko %A Wojczynski, Mary K %A Voortman, Trudy %A Lemaitre, Rozenn N %A Kristiansson, Kati %A Nuotio, Marja-Liisa %A Houston, Denise K %A Perälä, Mia-Maria %A Qi, Qibin %A Sonestedt, Emily %A Manichaikul, Ani %A Kanoni, Stavroula %A Ganna, Andrea %A Mikkilä, Vera %A North, Kari E %A Siscovick, David S %A Harald, Kennet %A McKeown, Nicola M %A Johansson, Ingegerd %A Rissanen, Harri %A Liu, Yongmei %A Lahti, Jari %A Hu, Frank B %A Bandinelli, Stefania %A Rukh, Gull %A Rich, Stephen %A Booij, Lisanne %A Dmitriou, Maria %A Ax, Erika %A Raitakari, Olli %A Mukamal, Kenneth %A Männistö, Satu %A Hallmans, Göran %A Jula, Antti %A Ericson, Ulrika %A Jacobs, David R %A van Rooij, Frank J A %A Deloukas, Panos %A Sjogren, Per %A Kähönen, Mika %A Djoussé, Luc %A Perola, Markus %A Barroso, Inês %A Hofman, Albert %A Stirrups, Kathleen %A Viikari, Jorma %A Uitterlinden, André G %A Kalafati, Ioanna P %A Franco, Oscar H %A Mozaffarian, Dariush %A Salomaa, Veikko %A Borecki, Ingrid B %A Knekt, Paul %A Kritchevsky, Stephen B %A Eriksson, Johan G %A Dedoussis, George V %A Qi, Lu %A Ferrucci, Luigi %A Orho-Melander, Marju %A Zillikens, M Carola %A Ingelsson, Erik %A Lehtimäki, Terho %A Renstrom, Frida %A Cupples, L Adrienne %A Loos, Ruth J F %A Franks, Paul W %K Adult %K Body Mass Index %K Case-Control Studies %K Diet, Western %K Epistasis, Genetic %K European Continental Ancestry Group %K Female %K Genetic Loci %K Genome-Wide Association Study %K Humans %K Male %K Obesity %K Polymorphism, Single Nucleotide %X

Obesity is highly heritable. Genetic variants showing robust associations with obesity traits have been identified through genome-wide association studies. We investigated whether a composite score representing healthy diet modifies associations of these variants with obesity traits. Totally, 32 body mass index (BMI)- and 14 waist-hip ratio (WHR)-associated single nucleotide polymorphisms were genotyped, and genetic risk scores (GRS) were calculated in 18 cohorts of European ancestry (n = 68 317). Diet score was calculated based on self-reported intakes of whole grains, fish, fruits, vegetables, nuts/seeds (favorable) and red/processed meats, sweets, sugar-sweetened beverages and fried potatoes (unfavorable). Multivariable adjusted, linear regression within each cohort followed by inverse variance-weighted, fixed-effects meta-analysis was used to characterize: (a) associations of each GRS with BMI and BMI-adjusted WHR and (b) diet score modification of genetic associations with BMI and BMI-adjusted WHR. Nominally significant interactions (P = 0.006-0.04) were observed between the diet score and WHR-GRS (but not BMI-GRS), two WHR loci (GRB14 rs10195252; LYPLAL1 rs4846567) and two BMI loci (LRRN6C rs10968576; MTIF3 rs4771122), for the respective BMI-adjusted WHR or BMI outcomes. Although the magnitudes of these select interactions were small, our data indicated that associations between genetic predisposition and obesity traits were stronger with a healthier diet. Our findings generate interesting hypotheses; however, experimental and functional studies are needed to determine their clinical relevance.

%B Hum Mol Genet %V 24 %P 4728-38 %8 2015 Aug 15 %G eng %N 16 %1 http://www.ncbi.nlm.nih.gov/pubmed/25994509?dopt=Abstract %R 10.1093/hmg/ddv186 %0 Journal Article %J Am J Hematol %D 2015 %T Gene-centric approach identifies new and known loci for FVIII activity and VWF antigen levels in European Americans and African Americans. %A Tang, Weihong %A Cushman, Mary %A Green, David %A Rich, Stephen S %A Lange, Leslie A %A Yang, Qiong %A Tracy, Russell P %A Tofler, Geoffrey H %A Basu, Saonli %A Wilson, James G %A Keating, Brendan J %A Weng, Lu-Chen %A Taylor, Herman A %A Jacobs, David R %A Delaney, Joseph A %A Palmer, Cameron D %A Young, Taylor %A Pankow, James S %A O'Donnell, Christopher J %A Smith, Nicholas L %A Reiner, Alexander P %A Folsom, Aaron R %K Adult %K African Americans %K Aged %K European Continental Ancestry Group %K Factor VIII %K Female %K Genetic Loci %K Genome-Wide Association Study %K Humans %K Male %K Methionine Adenosyltransferase %K Middle Aged %K Polymorphism, Single Nucleotide %K Venous Thromboembolism %K von Willebrand Factor %X

Coagulation factor VIII and von Willebrand factor (VWF) are key proteins in procoagulant activation. Higher FVIII coagulant activity (FVIII :C) and VWF antigen (VWF :Ag) are risk factors for cardiovascular disease and venous thromboembolism. Beyond associations with ABO blood group, genetic determinants of FVIII and VWF are not well understood, especially in non European-American populations. We performed a genetic association study of FVIII :C and VWF:Ag that assessed 50,000 gene-centric single nucleotide polymorphisms (SNPs) in 18,556 European Americans (EAs) and 5,047 African Americans (AAs) from five population-based cohorts. Previously unreported associations for FVIII :C were identified in both AAs and EAs with KNG1 (most significantly associated SNP rs710446, Ile581Thr, Ile581Thr, P = 5.10 × 10(-7) in EAs and P = 3.88 × 10(-3) in AAs) and VWF rs7962217 (Gly2705Arg,P = 6.30 × 10(-9) in EAs and P = 2.98 × 10(-2) in AAs. Significant associations for FVIII :C were also observed with F8/TMLHE region SNP rs12557310 in EAs (P = 8.02 × 10(-10) ), with VWF rs1800380 in AAs (P = 5.62 × 10(-11) ), and with MAT1A rs2236568 in AAs (P51.69 × 10(-6) ). We replicated previously reported associations of FVIII :C and VWF :Ag with the ABO blood group, VWF rs1063856(Thr789Ala), rs216321 (Ala852Gln), and VWF rs2229446 (Arg2185Gln). Findings from this study expand our understanding of genetic influences for FVIII :C and VWF :Ag in both EAs and AAs.

%B Am J Hematol %V 90 %P 534-40 %8 2015 Jun %G eng %N 6 %R 10.1002/ajh.24005 %0 Journal Article %J Stat Med %D 2015 %T Generalized estimating equations for genome-wide association studies using longitudinal phenotype data. %A Sitlani, Colleen M %A Rice, Kenneth M %A Lumley, Thomas %A McKnight, Barbara %A Cupples, L Adrienne %A Avery, Christy L %A Noordam, Raymond %A Stricker, Bruno H C %A Whitsel, Eric A %A Psaty, Bruce M %K Aged %K Aging %K Cardiovascular Diseases %K Cohort Studies %K Computer Simulation %K Cross-Sectional Studies %K Epidemiologic Research Design %K Gene-Environment Interaction %K Genetic Variation %K Genome, Human %K Genome-Wide Association Study %K Humans %K Longitudinal Studies %K Meta-Analysis as Topic %K Models, Genetic %K Pharmacogenetics %K Risk Assessment %K United States %X

Many longitudinal cohort studies have both genome-wide measures of genetic variation and repeated measures of phenotypes and environmental exposures. Genome-wide association study analyses have typically used only cross-sectional data to evaluate quantitative phenotypes and binary traits. Incorporation of repeated measures may increase power to detect associations, but also requires specialized analysis methods. Here, we discuss one such method-generalized estimating equations (GEE)-in the contexts of analysis of main effects of rare genetic variants and analysis of gene-environment interactions. We illustrate the potential for increased power using GEE analyses instead of cross-sectional analyses. We also address challenges that arise, such as the need for small-sample corrections when the minor allele frequency of a genetic variant and/or the prevalence of an environmental exposure is low. To illustrate methods for detection of gene-drug interactions on a genome-wide scale, using repeated measures data, we conduct single-study analyses and meta-analyses across studies in three large cohort studies participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium-the Atherosclerosis Risk in Communities study, the Cardiovascular Health Study, and the Rotterdam Study.

%B Stat Med %V 34 %P 118-30 %8 2015 Jan 15 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/25297442?dopt=Abstract %R 10.1002/sim.6323 %0 Journal Article %J Stroke %D 2015 %T Genes from a translational analysis support a multifactorial nature of white matter hyperintensities. %A Lopez, Lorna M %A Hill, W David %A Harris, Sarah E %A Valdes Hernandez, Maria %A Munoz Maniega, Susana %A Bastin, Mark E %A Bailey, Emma %A Smith, Colin %A McBride, Martin %A McClure, John %A Graham, Delyth %A Dominiczak, Anna %A Yang, Qiong %A Fornage, Myriam %A Ikram, M Arfan %A Debette, Stephanie %A Launer, Lenore %A Bis, Joshua C %A Schmidt, Reinhold %A Seshadri, Sudha %A Porteous, David J %A Starr, John %A Deary, Ian J %A Wardlaw, Joanna M %K Aged %K Alzheimer Disease %K Animals %K Brain %K Causality %K Dementia %K Female %K Genome-Wide Association Study %K Humans %K Leukoencephalopathies %K Male %K Polymorphism, Single Nucleotide %K Rats %K Rats, Inbred SHR %K Rats, Wistar %K Risk Factors %K Translational Medical Research %K White Matter %X

BACKGROUND AND PURPOSE: White matter hyperintensities (WMH) of presumed vascular origin increase the risk of stroke and dementia. Despite strong WMH heritability, few gene associations have been identified. Relevant experimental models may be informative.

METHODS: We tested the associations between genes that were differentially expressed in brains of young spontaneously hypertensive stroke-prone rats and human WMH (using volume and visual score) in 621 subjects from the Lothian Birth Cohort 1936 (LBC1936). We then attempted replication in 9361 subjects from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE). We also tested the subjects from LBC1936 for previous genome-wide WMH associations found in subjects from CHARGE.

RESULTS: Of 126 spontaneously hypertensive stroke-prone rat genes, 10 were nominally associated with WMH volume or score in subjects from LBC1936, of which 5 (AFP, ALB, GNAI1, RBM8a, and MRPL18) were associated with both WMH volume and score (P<0.05); 2 of the 10 (XPNPEP1, P=6.7×10(-5); FARP1, P=0.024) plus another spontaneously hypertensive stroke-prone rat gene (USMG5, P=0.00014), on chromosomes 10, 13, and 10 respectively, were associated with WMH in subjects from CHARGE. Gene set enrichment showed significant associations for downregulated spontaneously hypertensive stroke-prone rat genes with WMH in humans. In subjects from LBC1936, we replicated CHARGE's genome-wide WMH associations on chromosomes 17 (TRIM65 and TRIM47) and, for the first time, 1 (PMF1).

CONCLUSIONS: Despite not passing multiple testing thresholds individually, these genes collectively are relevant to known WMH associations, proposed WMH mechanisms, or dementia: associations with Alzheimer's disease, late-life depression, ATP production, osmotic regulation, neurodevelopmental abnormalities, and cognitive impairment. If replicated further, they suggest a multifactorial nature for WMH and argue for more consideration of vascular contributions to dementia.

%B Stroke %V 46 %P 341-7 %8 2015 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/25586835?dopt=Abstract %R 10.1161/STROKEAHA.114.007649 %0 Journal Article %J Mol Psychiatry %D 2015 %T Genetic contributions to variation in general cognitive function: a meta-analysis of genome-wide association studies in the CHARGE consortium (N=53949). %A Davies, G %A Armstrong, N %A Bis, J C %A Bressler, J %A Chouraki, V %A Giddaluru, S %A Hofer, E %A Ibrahim-Verbaas, C A %A Kirin, M %A Lahti, J %A van der Lee, S J %A Le Hellard, S %A Liu, T %A Marioni, R E %A Oldmeadow, C %A Postmus, I %A Smith, A V %A Smith, J A %A Thalamuthu, A %A Thomson, R %A Vitart, V %A Wang, J %A Yu, L %A Zgaga, L %A Zhao, W %A Boxall, R %A Harris, S E %A Hill, W D %A Liewald, D C %A Luciano, M %A Adams, H %A Ames, D %A Amin, N %A Amouyel, P %A Assareh, A A %A Au, R %A Becker, J T %A Beiser, A %A Berr, C %A Bertram, L %A Boerwinkle, E %A Buckley, B M %A Campbell, H %A Corley, J %A De Jager, P L %A Dufouil, C %A Eriksson, J G %A Espeseth, T %A Faul, J D %A Ford, I %A Gottesman, R F %A Griswold, M E %A Gudnason, V %A Harris, T B %A Heiss, G %A Hofman, A %A Holliday, E G %A Huffman, J %A Kardia, S L R %A Kochan, N %A Knopman, D S %A Kwok, J B %A Lambert, J-C %A Lee, T %A Li, G %A Li, S-C %A Loitfelder, M %A Lopez, O L %A Lundervold, A J %A Lundqvist, A %A Mather, K A %A Mirza, S S %A Nyberg, L %A Oostra, B A %A Palotie, A %A Papenberg, G %A Pattie, A %A Petrovic, K %A Polasek, O %A Psaty, B M %A Redmond, P %A Reppermund, S %A Rotter, J I %A Schmidt, H %A Schuur, M %A Schofield, P W %A Scott, R J %A Steen, V M %A Stott, D J %A van Swieten, J C %A Taylor, K D %A Trollor, J %A Trompet, S %A Uitterlinden, A G %A Weinstein, G %A Widen, E %A Windham, B G %A Jukema, J W %A Wright, A F %A Wright, M J %A Yang, Q %A Amieva, H %A Attia, J R %A Bennett, D A %A Brodaty, H %A de Craen, A J M %A Hayward, C %A Ikram, M A %A Lindenberger, U %A Nilsson, L-G %A Porteous, D J %A Räikkönen, K %A Reinvang, I %A Rudan, I %A Sachdev, P S %A Schmidt, R %A Schofield, P R %A Srikanth, V %A Starr, J M %A Turner, S T %A Weir, D R %A Wilson, J F %A van Duijn, C %A Launer, L %A Fitzpatrick, A L %A Seshadri, S %A Mosley, T H %A Deary, I J %K Aged %K Aged, 80 and over %K Atherosclerosis %K Cognition %K Cognition Disorders %K Cohort Studies %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K HMGN1 Protein %K Humans %K Male %K Middle Aged %K Neuropsychological Tests %K Phenotype %K Polymorphism, Single Nucleotide %K Scotland %X

General cognitive function is substantially heritable across the human life course from adolescence to old age. We investigated the genetic contribution to variation in this important, health- and well-being-related trait in middle-aged and older adults. We conducted a meta-analysis of genome-wide association studies of 31 cohorts (N=53,949) in which the participants had undertaken multiple, diverse cognitive tests. A general cognitive function phenotype was tested for, and created in each cohort by principal component analysis. We report 13 genome-wide significant single-nucleotide polymorphism (SNP) associations in three genomic regions, 6q16.1, 14q12 and 19q13.32 (best SNP and closest gene, respectively: rs10457441, P=3.93 × 10(-9), MIR2113; rs17522122, P=2.55 × 10(-8), AKAP6; rs10119, P=5.67 × 10(-9), APOE/TOMM40). We report one gene-based significant association with the HMGN1 gene located on chromosome 21 (P=1 × 10(-6)). These genes have previously been associated with neuropsychiatric phenotypes. Meta-analysis results are consistent with a polygenic model of inheritance. To estimate SNP-based heritability, the genome-wide complex trait analysis procedure was applied to two large cohorts, the Atherosclerosis Risk in Communities Study (N=6617) and the Health and Retirement Study (N=5976). The proportion of phenotypic variation accounted for by all genotyped common SNPs was 29% (s.e.=5%) and 28% (s.e.=7%), respectively. Using polygenic prediction analysis, ~1.2% of the variance in general cognitive function was predicted in the Generation Scotland cohort (N=5487; P=1.5 × 10(-17)). In hypothesis-driven tests, there was significant association between general cognitive function and four genes previously associated with Alzheimer's disease: TOMM40, APOE, ABCG1 and MEF2C.

%B Mol Psychiatry %V 20 %P 183-92 %8 2015 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/25644384?dopt=Abstract %R 10.1038/mp.2014.188 %0 Journal Article %J J Lipid Res %D 2015 %T Genetic loci associated with circulating levels of very long-chain saturated fatty acids. %A Lemaitre, Rozenn N %A King, Irena B %A Kabagambe, Edmond K %A Wu, Jason H Y %A McKnight, Barbara %A Manichaikul, Ani %A Guan, Weihua %A Sun, Qi %A Chasman, Daniel I %A Foy, Millennia %A Wang, Lu %A Zhu, Jingwen %A Siscovick, David S %A Tsai, Michael Y %A Arnett, Donna K %A Psaty, Bruce M %A Djoussé, Luc %A Chen, Yii-der I %A Tang, Weihong %A Weng, Lu-Chen %A Wu, Hongyu %A Jensen, Majken K %A Chu, Audrey Y %A Jacobs, David R %A Rich, Stephen S %A Mozaffarian, Dariush %A Steffen, Lyn %A Rimm, Eric B %A Hu, Frank B %A Ridker, Paul M %A Fornage, Myriam %A Friedlander, Yechiel %K Cohort Studies %K Fatty Acids %K Genetic Loci %K Genetic Variation %K Genome-Wide Association Study %K Humans %X

Very long-chain saturated fatty acids (VLSFAs) are saturated fatty acids with 20 or more carbons. In contrast to the more abundant saturated fatty acids, such as palmitic acid, there is growing evidence that circulating VLSFAs may have beneficial biological properties. Whether genetic factors influence circulating levels of VLSFAs is not known. We investigated the association of common genetic variation with plasma phospholipid/erythrocyte levels of three VLSFAs by performing genome-wide association studies in seven population-based cohorts comprising 10,129 subjects of European ancestry. We observed associations of circulating VLSFA concentrations with common variants in two genes, serine palmitoyl-transferase long-chain base subunit 3 (SPTLC3), a gene involved in the rate-limiting step of de novo sphingolipid synthesis, and ceramide synthase 4 (CERS4). The SPTLC3 variant at rs680379 was associated with higher arachidic acid (20:0 , P = 5.81 × 10(-13)). The CERS4 variant at rs2100944 was associated with higher levels of 20:0 (P = 2.65 × 10(-40)) and in analyses that adjusted for 20:0, with lower levels of behenic acid (P = 4.22 × 10(-26)) and lignoceric acid (P = 3.20 × 10(-21)). These novel associations suggest an inter-relationship of circulating VLSFAs and sphingolipid synthesis.

%B J Lipid Res %V 56 %P 176-84 %8 2015 Jan %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/25378659?dopt=Abstract %R 10.1194/jlr.M052456 %0 Journal Article %J Stroke %D 2015 %T Genetic overlap between diagnostic subtypes of ischemic stroke. %A Holliday, Elizabeth G %A Traylor, Matthew %A Malik, Rainer %A Bevan, Steve %A Falcone, Guido %A Hopewell, Jemma C %A Cheng, Yu-Ching %A Cotlarciuc, Ioana %A Bis, Joshua C %A Boerwinkle, Eric %A Boncoraglio, Giorgio B %A Clarke, Robert %A Cole, John W %A Fornage, Myriam %A Furie, Karen L %A Ikram, M Arfan %A Jannes, Jim %A Kittner, Steven J %A Lincz, Lisa F %A Maguire, Jane M %A Meschia, James F %A Mosley, Thomas H %A Nalls, Mike A %A Oldmeadow, Christopher %A Parati, Eugenio A %A Psaty, Bruce M %A Rothwell, Peter M %A Seshadri, Sudha %A Scott, Rodney J %A Sharma, Pankaj %A Sudlow, Cathie %A Wiggins, Kerri L %A Worrall, Bradford B %A Rosand, Jonathan %A Mitchell, Braxton D %A Dichgans, Martin %A Markus, Hugh S %A Levi, Christopher %A Attia, John %A Wray, Naomi R %K Alleles %K Atherosclerosis %K Cerebral Small Vessel Diseases %K Cohort Studies %K Data Interpretation, Statistical %K Embolism %K Genome-Wide Association Study %K Genotype %K Humans %K Ischemia %K Linear Models %K Meta-Analysis as Topic %K Phenotype %K Polymorphism, Single Nucleotide %K Stroke %X

BACKGROUND AND PURPOSE: Despite moderate heritability, the phenotypic heterogeneity of ischemic stroke has hampered gene discovery, motivating analyses of diagnostic subtypes with reduced sample sizes. We assessed evidence for a shared genetic basis among the 3 major subtypes: large artery atherosclerosis (LAA), cardioembolism, and small vessel disease (SVD), to inform potential cross-subtype analyses.

METHODS: Analyses used genome-wide summary data for 12 389 ischemic stroke cases (including 2167 LAA, 2405 cardioembolism, and 1854 SVD) and 62 004 controls from the Metastroke consortium. For 4561 cases and 7094 controls, individual-level genotype data were also available. Genetic correlations between subtypes were estimated using linear mixed models and polygenic profile scores. Meta-analysis of a combined LAA-SVD phenotype (4021 cases and 51 976 controls) was performed to identify shared risk alleles.

RESULTS: High genetic correlation was identified between LAA and SVD using linear mixed models (rg=0.96, SE=0.47, P=9×10(-4)) and profile scores (rg=0.72; 95% confidence interval, 0.52-0.93). Between LAA and cardioembolism and SVD and cardioembolism, correlation was moderate using linear mixed models but not significantly different from zero for profile scoring. Joint meta-analysis of LAA and SVD identified strong association (P=1×10(-7)) for single nucleotide polymorphisms near the opioid receptor μ1 (OPRM1) gene.

CONCLUSIONS: Our results suggest that LAA and SVD, which have been hitherto treated as genetically distinct, may share a substantial genetic component. Combined analyses of LAA and SVD may increase power to identify small-effect alleles influencing shared pathophysiological processes.

%B Stroke %V 46 %P 615-9 %8 2015 Mar %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/25613305?dopt=Abstract %R 10.1161/STROKEAHA.114.007930 %0 Journal Article %J J Gerontol A Biol Sci Med Sci %D 2015 %T Genome-Wide Association Study and Linkage Analysis of the Healthy Aging Index. %A Minster, Ryan L %A Sanders, Jason L %A Singh, Jatinder %A Kammerer, Candace M %A Barmada, M Michael %A Matteini, Amy M %A Zhang, Qunyuan %A Wojczynski, Mary K %A Daw, E Warwick %A Brody, Jennifer A %A Arnold, Alice M %A Lunetta, Kathryn L %A Murabito, Joanne M %A Christensen, Kaare %A Perls, Thomas T %A Province, Michael A %A Newman, Anne B %K Aging %K Apolipoproteins E %K Forkhead Transcription Factors %K Genetic Linkage %K Genome-Wide Association Study %K Humans %K Longevity %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %X

BACKGROUND: The Healthy Aging Index (HAI) is a tool for measuring the extent of health and disease across multiple systems.

METHODS: We conducted a genome-wide association study and a genome-wide linkage analysis to map quantitative trait loci associated with the HAI and a modified HAI weighted for mortality risk in 3,140 individuals selected for familial longevity from the Long Life Family Study. The genome-wide association study used the Long Life Family Study as the discovery cohort and individuals from the Cardiovascular Health Study and the Framingham Heart Study as replication cohorts.

RESULTS: There were no genome-wide significant findings from the genome-wide association study; however, several single-nucleotide polymorphisms near ZNF704 on chromosome 8q21.13 were suggestively associated with the HAI in the Long Life Family Study (p < 10(-) (6)) and nominally replicated in the Cardiovascular Health Study and Framingham Heart Study. Linkage results revealed significant evidence (log-odds score = 3.36) for a quantitative trait locus for mortality-optimized HAI in women on chromosome 9p24-p23. However, results of fine-mapping studies did not implicate any specific candidate genes within this region of interest.

CONCLUSIONS: ZNF704 may be a potential candidate gene for studies of the genetic underpinnings of longevity.

%B J Gerontol A Biol Sci Med Sci %V 70 %P 1003-8 %8 2015 Aug %G ENG %N 8 %1 http://www.ncbi.nlm.nih.gov/pubmed/25758594?dopt=Abstract %R 10.1093/gerona/glv006 %0 Journal Article %J Mol Psychiatry %D 2015 %T Genome-wide meta-analysis identifies six novel loci associated with habitual coffee consumption. %A Cornelis, M C %A Byrne, E M %A Esko, T %A Nalls, M A %A Ganna, A %A Paynter, N %A Monda, K L %A Amin, N %A Fischer, K %A Renstrom, F %A Ngwa, J S %A Huikari, V %A Cavadino, A %A Nolte, I M %A Teumer, A %A Yu, K %A Marques-Vidal, P %A Rawal, R %A Manichaikul, A %A Wojczynski, M K %A Vink, J M %A Zhao, J H %A Burlutsky, G %A Lahti, J %A Mikkilä, V %A Lemaitre, R N %A Eriksson, J %A Musani, S K %A Tanaka, T %A Geller, F %A Luan, J %A Hui, J %A Mägi, R %A Dimitriou, M %A Garcia, M E %A Ho, W-K %A Wright, M J %A Rose, L M %A Magnusson, P K E %A Pedersen, N L %A Couper, D %A Oostra, B A %A Hofman, A %A Ikram, M A %A Tiemeier, H W %A Uitterlinden, A G %A van Rooij, F J A %A Barroso, I %A Johansson, I %A Xue, L %A Kaakinen, M %A Milani, L %A Power, C %A Snieder, H %A Stolk, R P %A Baumeister, S E %A Biffar, R %A Gu, F %A Bastardot, F %A Kutalik, Z %A Jacobs, D R %A Forouhi, N G %A Mihailov, E %A Lind, L %A Lindgren, C %A Michaëlsson, K %A Morris, A %A Jensen, M %A Khaw, K-T %A Luben, R N %A Wang, J J %A Männistö, S %A Perälä, M-M %A Kähönen, M %A Lehtimäki, T %A Viikari, J %A Mozaffarian, D %A Mukamal, K %A Psaty, B M %A Döring, A %A Heath, A C %A Montgomery, G W %A Dahmen, N %A Carithers, T %A Tucker, K L %A Ferrucci, L %A Boyd, H A %A Melbye, M %A Treur, J L %A Mellström, D %A Hottenga, J J %A Prokopenko, I %A Tönjes, A %A Deloukas, P %A Kanoni, S %A Lorentzon, M %A Houston, D K %A Liu, Y %A Danesh, J %A Rasheed, A %A Mason, M A %A Zonderman, A B %A Franke, L %A Kristal, B S %A Karjalainen, J %A Reed, D R %A Westra, H-J %A Evans, M K %A Saleheen, D %A Harris, T B %A Dedoussis, G %A Curhan, G %A Stumvoll, M %A Beilby, J %A Pasquale, L R %A Feenstra, B %A Bandinelli, S %A Ordovás, J M %A Chan, A T %A Peters, U %A Ohlsson, C %A Gieger, C %A Martin, N G %A Waldenberger, M %A Siscovick, D S %A Raitakari, O %A Eriksson, J G %A Mitchell, P %A Hunter, D J %A Kraft, P %A Rimm, E B %A Boomsma, D I %A Borecki, I B %A Loos, R J F %A Wareham, N J %A Vollenweider, P %A Caporaso, N %A Grabe, H J %A Neuhouser, M L %A Wolffenbuttel, B H R %A Hu, F B %A Hypponen, E %A Järvelin, M-R %A Cupples, L A %A Franks, P W %A Ridker, P M %A van Duijn, C M %A Heiss, G %A Metspalu, A %A North, K E %A Ingelsson, E %A Nettleton, J A %A van Dam, R M %A Chasman, D I %K Adaptor Proteins, Signal Transducing %K Basic Helix-Loop-Helix Leucine Zipper Transcription Factors %K Brain-Derived Neurotrophic Factor %K Coffea %K Cytochrome P-450 CYP1A2 %K Food Habits %K Genome-Wide Association Study %K Humans %K Phenotype %K Polymorphism, Single Nucleotide %X

Coffee, a major dietary source of caffeine, is among the most widely consumed beverages in the world and has received considerable attention regarding health risks and benefits. We conducted a genome-wide (GW) meta-analysis of predominately regular-type coffee consumption (cups per day) among up to 91,462 coffee consumers of European ancestry with top single-nucleotide polymorphisms (SNPs) followed-up in ~30 062 and 7964 coffee consumers of European and African-American ancestry, respectively. Studies from both stages were combined in a trans-ethnic meta-analysis. Confirmed loci were examined for putative functional and biological relevance. Eight loci, including six novel loci, met GW significance (log10Bayes factor (BF)>5.64) with per-allele effect sizes of 0.03-0.14 cups per day. Six are located in or near genes potentially involved in pharmacokinetics (ABCG2, AHR, POR and CYP1A2) and pharmacodynamics (BDNF and SLC6A4) of caffeine. Two map to GCKR and MLXIPL genes related to metabolic traits but lacking known roles in coffee consumption. Enhancer and promoter histone marks populate the regions of many confirmed loci and several potential regulatory SNPs are highly correlated with the lead SNP of each. SNP alleles near GCKR, MLXIPL, BDNF and CYP1A2 that were associated with higher coffee consumption have previously been associated with smoking initiation, higher adiposity and fasting insulin and glucose but lower blood pressure and favorable lipid, inflammatory and liver enzyme profiles (P<5 × 10(-8)).Our genetic findings among European and African-American adults reinforce the role of caffeine in mediating habitual coffee consumption and may point to molecular mechanisms underlying inter-individual variability in pharmacological and health effects of coffee.

%B Mol Psychiatry %V 20 %P 647-56 %8 2015 May %G ENG %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/25288136?dopt=Abstract %R 10.1038/mp.2014.107 %0 Journal Article %J Biol Psychiatry %D 2015 %T Genome-wide studies of verbal declarative memory in nondemented older people: the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium. %A Debette, Stephanie %A Ibrahim Verbaas, Carla A %A Bressler, Jan %A Schuur, Maaike %A Smith, Albert %A Bis, Joshua C %A Davies, Gail %A Wolf, Christiane %A Gudnason, Vilmundur %A Chibnik, Lori B %A Yang, Qiong %A DeStefano, Anita L %A de Quervain, Dominique J F %A Srikanth, Velandai %A Lahti, Jari %A Grabe, Hans J %A Smith, Jennifer A %A Priebe, Lutz %A Yu, Lei %A Karbalai, Nazanin %A Hayward, Caroline %A Wilson, James F %A Campbell, Harry %A Petrovic, Katja %A Fornage, Myriam %A Chauhan, Ganesh %A Yeo, Robin %A Boxall, Ruth %A Becker, James %A Stegle, Oliver %A Mather, Karen A %A Chouraki, Vincent %A Sun, Qi %A Rose, Lynda M %A Resnick, Susan %A Oldmeadow, Christopher %A Kirin, Mirna %A Wright, Alan F %A Jonsdottir, Maria K %A Au, Rhoda %A Becker, Albert %A Amin, Najaf %A Nalls, Mike A %A Turner, Stephen T %A Kardia, Sharon L R %A Oostra, Ben %A Windham, Gwen %A Coker, Laura H %A Zhao, Wei %A Knopman, David S %A Heiss, Gerardo %A Griswold, Michael E %A Gottesman, Rebecca F %A Vitart, Veronique %A Hastie, Nicholas D %A Zgaga, Lina %A Rudan, Igor %A Polasek, Ozren %A Holliday, Elizabeth G %A Schofield, Peter %A Choi, Seung Hoan %A Tanaka, Toshiko %A An, Yang %A Perry, Rodney T %A Kennedy, Richard E %A Sale, Michèle M %A Wang, Jing %A Wadley, Virginia G %A Liewald, David C %A Ridker, Paul M %A Gow, Alan J %A Pattie, Alison %A Starr, John M %A Porteous, David %A Liu, Xuan %A Thomson, Russell %A Armstrong, Nicola J %A Eiriksdottir, Gudny %A Assareh, Arezoo A %A Kochan, Nicole A %A Widen, Elisabeth %A Palotie, Aarno %A Hsieh, Yi-Chen %A Eriksson, Johan G %A Vogler, Christian %A van Swieten, John C %A Shulman, Joshua M %A Beiser, Alexa %A Rotter, Jerome %A Schmidt, Carsten O %A Hoffmann, Wolfgang %A Nöthen, Markus M %A Ferrucci, Luigi %A Attia, John %A Uitterlinden, André G %A Amouyel, Philippe %A Dartigues, Jean-François %A Amieva, Hélène %A Räikkönen, Katri %A Garcia, Melissa %A Wolf, Philip A %A Hofman, Albert %A Longstreth, W T %A Psaty, Bruce M %A Boerwinkle, Eric %A DeJager, Philip L %A Sachdev, Perminder S %A Schmidt, Reinhold %A Breteler, Monique M B %A Teumer, Alexander %A Lopez, Oscar L %A Cichon, Sven %A Chasman, Daniel I %A Grodstein, Francine %A Müller-Myhsok, Bertram %A Tzourio, Christophe %A Papassotiropoulos, Andreas %A Bennett, David A %A Ikram, M Arfan %A Deary, Ian J %A van Duijn, Cornelia M %A Launer, Lenore %A Fitzpatrick, Annette L %A Seshadri, Sudha %A Mosley, Thomas H %K Aged %K Aged, 80 and over %K Aging %K Apolipoproteins E %K Claudin-5 %K Cohort Studies %K Female %K Genome-Wide Association Study %K Genotype %K Humans %K Male %K Memory Disorders %K Middle Aged %K Polymorphism, Single Nucleotide %K Proteins %K Proteoglycans %K Regression Analysis %K Sulfotransferases %K Verbal Learning %X

BACKGROUND: Memory performance in older persons can reflect genetic influences on cognitive function and dementing processes. We aimed to identify genetic contributions to verbal declarative memory in a community setting.

METHODS: We conducted genome-wide association studies for paragraph or word list delayed recall in 19 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, comprising 29,076 dementia- and stroke-free individuals of European descent, aged ≥45 years. Replication of suggestive associations (p < 5 × 10(-6)) was sought in 10,617 participants of European descent, 3811 African-Americans, and 1561 young adults.

RESULTS: rs4420638, near APOE, was associated with poorer delayed recall performance in discovery (p = 5.57 × 10(-10)) and replication cohorts (p = 5.65 × 10(-8)). This association was stronger for paragraph than word list delayed recall and in the oldest persons. Two associations with specific tests, in subsets of the total sample, reached genome-wide significance in combined analyses of discovery and replication (rs11074779 [HS3ST4], p = 3.11 × 10(-8), and rs6813517 [SPOCK3], p = 2.58 × 10(-8)) near genes involved in immune response. A genetic score combining 58 independent suggestive memory risk variants was associated with increasing Alzheimer disease pathology in 725 autopsy samples. Association of memory risk loci with gene expression in 138 human hippocampus samples showed cis-associations with WDR48 and CLDN5, both related to ubiquitin metabolism.

CONCLUSIONS: This largest study to date exploring the genetics of memory function in ~40,000 older individuals revealed genome-wide associations and suggested an involvement of immune and ubiquitin pathways.

%B Biol Psychiatry %V 77 %P 749-63 %8 2015 Apr 15 %G eng %N 8 %1 http://www.ncbi.nlm.nih.gov/pubmed/25648963?dopt=Abstract %R 10.1016/j.biopsych.2014.08.027 %0 Journal Article %J J Gerontol A Biol Sci Med Sci %D 2015 %T GWAS of longevity in CHARGE consortium confirms APOE and FOXO3 candidacy. %A Broer, Linda %A Buchman, Aron S %A Deelen, Joris %A Evans, Daniel S %A Faul, Jessica D %A Lunetta, Kathryn L %A Sebastiani, Paola %A Smith, Jennifer A %A Smith, Albert V %A Tanaka, Toshiko %A Yu, Lei %A Arnold, Alice M %A Aspelund, Thor %A Benjamin, Emelia J %A De Jager, Philip L %A Eirkisdottir, Gudny %A Evans, Denis A %A Garcia, Melissa E %A Hofman, Albert %A Kaplan, Robert C %A Kardia, Sharon L R %A Kiel, Douglas P %A Oostra, Ben A %A Orwoll, Eric S %A Parimi, Neeta %A Psaty, Bruce M %A Rivadeneira, Fernando %A Rotter, Jerome I %A Seshadri, Sudha %A Singleton, Andrew %A Tiemeier, Henning %A Uitterlinden, André G %A Zhao, Wei %A Bandinelli, Stefania %A Bennett, David A %A Ferrucci, Luigi %A Gudnason, Vilmundur %A Harris, Tamara B %A Karasik, David %A Launer, Lenore J %A Perls, Thomas T %A Slagboom, P Eline %A Tranah, Gregory J %A Weir, David R %A Newman, Anne B %A van Duijn, Cornelia M %A Murabito, Joanne M %K Aged %K Aged, 80 and over %K Apolipoproteins E %K Cell Adhesion Molecules %K Cohort Studies %K Female %K Forkhead Box Protein O3 %K Forkhead Transcription Factors %K Genome-Wide Association Study %K Humans %K Longevity %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Receptors, Kainic Acid %X

BACKGROUND: The genetic contribution to longevity in humans has been estimated to range from 15% to 25%. Only two genes, APOE and FOXO3, have shown association with longevity in multiple independent studies.

METHODS: We conducted a meta-analysis of genome-wide association studies including 6,036 longevity cases, age ≥90 years, and 3,757 controls that died between ages 55 and 80 years. We additionally attempted to replicate earlier identified single nucleotide polymorphism (SNP) associations with longevity.

RESULTS: In our meta-analysis, we found suggestive evidence for the association of SNPs near CADM2 (odds ratio [OR] = 0.81; p value = 9.66 × 10(-7)) and GRIK2 (odds ratio = 1.24; p value = 5.09 × 10(-8)) with longevity. When attempting to replicate findings earlier identified in genome-wide association studies, only the APOE locus consistently replicated. In an additional look-up of the candidate gene FOXO3, we found that an earlier identified variant shows a highly significant association with longevity when including published data with our meta-analysis (odds ratio = 1.17; p value = 1.85×10(-10)).

CONCLUSIONS: We did not identify new genome-wide significant associations with longevity and did not replicate earlier findings except for APOE and FOXO3. Our inability to find new associations with survival to ages ≥90 years because longevity represents multiple complex traits with heterogeneous genetic underpinnings, or alternatively, that longevity may be regulated by rare variants that are not captured by standard genome-wide genotyping and imputation of common variants.

%B J Gerontol A Biol Sci Med Sci %V 70 %P 110-8 %8 2015 Jan %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/25199915?dopt=Abstract %R 10.1093/gerona/glu166 %0 Journal Article %J Hum Mol Genet %D 2015 %T Integrative pathway genomics of lung function and airflow obstruction. %A Gharib, Sina A %A Loth, Daan W %A Soler Artigas, Maria %A Birkland, Timothy P %A Wilk, Jemma B %A Wain, Louise V %A Brody, Jennifer A %A Obeidat, Ma'en %A Hancock, Dana B %A Tang, Wenbo %A Rawal, Rajesh %A Boezen, H Marike %A Imboden, Medea %A Huffman, Jennifer E %A Lahousse, Lies %A Alves, Alexessander C %A Manichaikul, Ani %A Hui, Jennie %A Morrison, Alanna C %A Ramasamy, Adaikalavan %A Smith, Albert Vernon %A Gudnason, Vilmundur %A Surakka, Ida %A Vitart, Veronique %A Evans, David M %A Strachan, David P %A Deary, Ian J %A Hofman, Albert %A Gläser, Sven %A Wilson, James F %A North, Kari E %A Zhao, Jing Hua %A Heckbert, Susan R %A Jarvis, Deborah L %A Probst-Hensch, Nicole %A Schulz, Holger %A Barr, R Graham %A Jarvelin, Marjo-Riitta %A O'Connor, George T %A Kähönen, Mika %A Cassano, Patricia A %A Hysi, Pirro G %A Dupuis, Josée %A Hayward, Caroline %A Psaty, Bruce M %A Hall, Ian P %A Parks, William C %A Tobin, Martin D %A London, Stephanie J %K Airway Obstruction %K Animals %K Cell Proliferation %K European Continental Ancestry Group %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genomics %K Humans %K Immune System %K Lung %K Male %K Metabolic Networks and Pathways %K Mice %K Phenotype %K Polymorphism, Single Nucleotide %K Signal Transduction %X

Chronic respiratory disorders are important contributors to the global burden of disease. Genome-wide association studies (GWASs) of lung function measures have identified several trait-associated loci, but explain only a modest portion of the phenotypic variability. We postulated that integrating pathway-based methods with GWASs of pulmonary function and airflow obstruction would identify a broader repertoire of genes and processes influencing these traits. We performed two independent GWASs of lung function and applied gene set enrichment analysis to one of the studies and validated the results using the second GWAS. We identified 131 significantly enriched gene sets associated with lung function and clustered them into larger biological modules involved in diverse processes including development, immunity, cell signaling, proliferation and arachidonic acid. We found that enrichment of gene sets was not driven by GWAS-significant variants or loci, but instead by those with less stringent association P-values. Next, we applied pathway enrichment analysis to a meta-analyzed GWAS of airflow obstruction. We identified several biologic modules that functionally overlapped with those associated with pulmonary function. However, differences were also noted, including enrichment of extracellular matrix (ECM) processes specifically in the airflow obstruction study. Network analysis of the ECM module implicated a candidate gene, matrix metalloproteinase 10 (MMP10), as a putative disease target. We used a knockout mouse model to functionally validate MMP10's role in influencing lung's susceptibility to cigarette smoke-induced emphysema. By integrating pathway analysis with population-based genomics, we unraveled biologic processes underlying pulmonary function traits and identified a candidate gene for obstructive lung disease.

%B Hum Mol Genet %V 24 %P 6836-48 %8 2015 Dec 1 %G eng %N 23 %1 http://www.ncbi.nlm.nih.gov/pubmed/26395457?dopt=Abstract %R 10.1093/hmg/ddv378 %0 Journal Article %J Am J Hum Genet %D 2015 %T Meta-analysis of 65,734 individuals identifies TSPAN15 and SLC44A2 as two susceptibility loci for venous thromboembolism. %A Germain, Marine %A Chasman, Daniel I %A de Haan, Hugoline %A Tang, Weihong %A Lindström, Sara %A Weng, Lu-Chen %A de Andrade, Mariza %A de Visser, Marieke C H %A Wiggins, Kerri L %A Suchon, Pierre %A Saut, Noémie %A Smadja, David M %A Le Gal, Grégoire %A van Hylckama Vlieg, Astrid %A Di Narzo, Antonio %A Hao, Ke %A Nelson, Christopher P %A Rocanin-Arjo, Ares %A Folkersen, Lasse %A Monajemi, Ramin %A Rose, Lynda M %A Brody, Jennifer A %A Slagboom, Eline %A Aïssi, Dylan %A Gagnon, France %A Deleuze, Jean-Francois %A Deloukas, Panos %A Tzourio, Christophe %A Dartigues, Jean-François %A Berr, Claudine %A Taylor, Kent D %A Civelek, Mete %A Eriksson, Per %A Psaty, Bruce M %A Houwing-Duitermaat, Jeanine %A Goodall, Alison H %A Cambien, Francois %A Kraft, Peter %A Amouyel, Philippe %A Samani, Nilesh J %A Basu, Saonli %A Ridker, Paul M %A Rosendaal, Frits R %A Kabrhel, Christopher %A Folsom, Aaron R %A Heit, John %A Reitsma, Pieter H %A Trégouët, David-Alexandre %A Smith, Nicholas L %A Morange, Pierre-Emmanuel %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genotype %K Humans %K Membrane Glycoproteins %K Membrane Transport Proteins %K Odds Ratio %K Tetraspanins %K Venous Thromboembolism %X

Venous thromboembolism (VTE), the third leading cause of cardiovascular mortality, is a complex thrombotic disorder with environmental and genetic determinants. Although several genetic variants have been found associated with VTE, they explain a minor proportion of VTE risk in cases. We undertook a meta-analysis of genome-wide association studies (GWASs) to identify additional VTE susceptibility genes. Twelve GWASs totaling 7,507 VTE case subjects and 52,632 control subjects formed our discovery stage where 6,751,884 SNPs were tested for association with VTE. Nine loci reached the genome-wide significance level of 5 × 10(-8) including six already known to associate with VTE (ABO, F2, F5, F11, FGG, and PROCR) and three unsuspected loci. SNPs mapping to these latter were selected for replication in three independent case-control studies totaling 3,009 VTE-affected individuals and 2,586 control subjects. This strategy led to the identification and replication of two VTE-associated loci, TSPAN15 and SLC44A2, with lead risk alleles associated with odds ratio for disease of 1.31 (p = 1.67 × 10(-16)) and 1.21 (p = 2.75 × 10(-15)), respectively. The lead SNP at the TSPAN15 locus is the intronic rs78707713 and the lead SLC44A2 SNP is the non-synonymous rs2288904 previously shown to associate with transfusion-related acute lung injury. We further showed that these two variants did not associate with known hemostatic plasma markers. TSPAN15 and SLC44A2 do not belong to conventional pathways for thrombosis and have not been associated to other cardiovascular diseases nor related quantitative biomarkers. Our findings uncovered unexpected actors of VTE etiology and pave the way for novel mechanistic concepts of VTE pathophysiology.

%B Am J Hum Genet %V 96 %P 532-42 %8 2015 Apr 2 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/25772935?dopt=Abstract %R 10.1016/j.ajhg.2015.01.019 %0 Journal Article %J Stroke %D 2015 %T Meta-Analysis of Genome-Wide Association Studies Identifies Genetic Risk Factors for Stroke in African Americans. %A Carty, Cara L %A Keene, Keith L %A Cheng, Yu-Ching %A Meschia, James F %A Chen, Wei-Min %A Nalls, Mike %A Bis, Joshua C %A Kittner, Steven J %A Rich, Stephen S %A Tajuddin, Salman %A Zonderman, Alan B %A Evans, Michele K %A Langefeld, Carl D %A Gottesman, Rebecca %A Mosley, Thomas H %A Shahar, Eyal %A Woo, Daniel %A Yaffe, Kristine %A Liu, Yongmei %A Sale, Michèle M %A Dichgans, Martin %A Malik, Rainer %A Longstreth, W T %A Mitchell, Braxton D %A Psaty, Bruce M %A Kooperberg, Charles %A Reiner, Alexander %A Worrall, Bradford B %A Fornage, Myriam %K African Americans %K Case-Control Studies %K Cohort Studies %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Polymorphism, Single Nucleotide %K Risk Factors %K Stroke %X

BACKGROUND AND PURPOSE: The majority of genome-wide association studies (GWAS) of stroke have focused on European-ancestry populations; however, none has been conducted in African Americans, despite the disproportionately high burden of stroke in this population. The Consortium of Minority Population Genome-Wide Association Studies of Stroke (COMPASS) was established to identify stroke susceptibility loci in minority populations.

METHODS: Using METAL, we conducted meta-analyses of GWAS in 14 746 African Americans (1365 ischemic and 1592 total stroke cases) from COMPASS, and tested genetic variants with P<10(-6) for validation in METASTROKE, a consortium of ischemic stroke genetic studies in European-ancestry populations. We also evaluated stroke loci previously identified in European-ancestry populations.

RESULTS: The 15q21.3 locus linked with lipid levels and hypertension was associated with total stroke (rs4471613; P=3.9×10(-8)) in African Americans. Nominal associations (P<10(-6)) for total or ischemic stroke were observed for 18 variants in or near genes implicated in cell cycle/mRNA presplicing (PTPRG, CDC5L), platelet function (HPS4), blood-brain barrier permeability (CLDN17), immune response (ELTD1, WDFY4, and IL1F10-IL1RN), and histone modification (HDAC9). Two of these loci achieved nominal significance in METASTROKE: 5q35.2 (P=0.03), and 1p31.1 (P=0.018). Four of 7 previously reported ischemic stroke loci (PITX2, HDAC9, CDKN2A/CDKN2B, and ZFHX3) were nominally associated (P<0.05) with stroke in COMPASS.

CONCLUSIONS: We identified a novel genetic variant associated with total stroke in African Americans and found that ischemic stroke loci identified in European-ancestry populations may also be relevant for African Americans. Our findings support investigation of diverse populations to identify and characterize genetic risk factors, and the importance of shared genetic risk across populations.

%B Stroke %V 46 %P 2063-8 %8 2015 Aug %G eng %N 8 %1 http://www.ncbi.nlm.nih.gov/pubmed/26089329?dopt=Abstract %R 10.1161/STROKEAHA.115.009044 %0 Journal Article %J Circ Cardiovasc Genet %D 2015 %T Multiethnic genome-wide association study of cerebral white matter hyperintensities on MRI. %A Verhaaren, Benjamin F J %A Debette, Stephanie %A Bis, Joshua C %A Smith, Jennifer A %A Ikram, M Kamran %A Adams, Hieab H %A Beecham, Ashley H %A Rajan, Kumar B %A Lopez, Lorna M %A Barral, Sandra %A van Buchem, Mark A %A van der Grond, Jeroen %A Smith, Albert V %A Hegenscheid, Katrin %A Aggarwal, Neelum T %A de Andrade, Mariza %A Atkinson, Elizabeth J %A Beekman, Marian %A Beiser, Alexa S %A Blanton, Susan H %A Boerwinkle, Eric %A Brickman, Adam M %A Bryan, R Nick %A Chauhan, Ganesh %A Chen, Christopher P L H %A Chouraki, Vincent %A de Craen, Anton J M %A Crivello, Fabrice %A Deary, Ian J %A Deelen, Joris %A De Jager, Philip L %A Dufouil, Carole %A Elkind, Mitchell S V %A Evans, Denis A %A Freudenberger, Paul %A Gottesman, Rebecca F %A Guðnason, Vilmundur %A Habes, Mohamad %A Heckbert, Susan R %A Heiss, Gerardo %A Hilal, Saima %A Hofer, Edith %A Hofman, Albert %A Ibrahim-Verbaas, Carla A %A Knopman, David S %A Lewis, Cora E %A Liao, Jiemin %A Liewald, David C M %A Luciano, Michelle %A van der Lugt, Aad %A Martinez, Oliver O %A Mayeux, Richard %A Mazoyer, Bernard %A Nalls, Mike %A Nauck, Matthias %A Niessen, Wiro J %A Oostra, Ben A %A Psaty, Bruce M %A Rice, Kenneth M %A Rotter, Jerome I %A von Sarnowski, Bettina %A Schmidt, Helena %A Schreiner, Pamela J %A Schuur, Maaike %A Sidney, Stephen S %A Sigurdsson, Sigurdur %A Slagboom, P Eline %A Stott, David J M %A van Swieten, John C %A Teumer, Alexander %A Töglhofer, Anna Maria %A Traylor, Matthew %A Trompet, Stella %A Turner, Stephen T %A Tzourio, Christophe %A Uh, Hae-Won %A Uitterlinden, André G %A Vernooij, Meike W %A Wang, Jing J %A Wong, Tien Y %A Wardlaw, Joanna M %A Windham, B Gwen %A Wittfeld, Katharina %A Wolf, Christiane %A Wright, Clinton B %A Yang, Qiong %A Zhao, Wei %A Zijdenbos, Alex %A Jukema, J Wouter %A Sacco, Ralph L %A Kardia, Sharon L R %A Amouyel, Philippe %A Mosley, Thomas H %A Longstreth, W T %A DeCarli, Charles C %A van Duijn, Cornelia M %A Schmidt, Reinhold %A Launer, Lenore J %A Grabe, Hans J %A Seshadri, Sudha S %A Ikram, M Arfan %A Fornage, Myriam %K Aged %K Aged, 80 and over %K Chromosomes, Human %K Continental Population Groups %K Female %K Genetic Loci %K Genome-Wide Association Study %K Humans %K Male %K Meta-Analysis as Topic %K Middle Aged %K Models, Genetic %K Stroke %K White Matter %X

BACKGROUND: The burden of cerebral white matter hyperintensities (WMH) is associated with an increased risk of stroke, dementia, and death. WMH are highly heritable, but their genetic underpinnings are incompletely characterized. To identify novel genetic variants influencing WMH burden, we conducted a meta-analysis of multiethnic genome-wide association studies.

METHODS AND RESULTS: We included 21 079 middle-aged to elderly individuals from 29 population-based cohorts, who were free of dementia and stroke and were of European (n=17 936), African (n=1943), Hispanic (n=795), and Asian (n=405) descent. WMH burden was quantified on MRI either by a validated automated segmentation method or a validated visual grading scale. Genotype data in each study were imputed to the 1000 Genomes reference. Within each ethnic group, we investigated the relationship between each single-nucleotide polymorphism and WMH burden using a linear regression model adjusted for age, sex, intracranial volume, and principal components of ancestry. A meta-analysis was conducted for each ethnicity separately and for the combined sample. In the European descent samples, we confirmed a previously known locus on chr17q25 (P=2.7×10(-19)) and identified novel loci on chr10q24 (P=1.6×10(-9)) and chr2p21 (P=4.4×10(-8)). In the multiethnic meta-analysis, we identified 2 additional loci, on chr1q22 (P=2.0×10(-8)) and chr2p16 (P=1.5×10(-8)). The novel loci contained genes that have been implicated in Alzheimer disease (chr2p21 and chr10q24), intracerebral hemorrhage (chr1q22), neuroinflammatory diseases (chr2p21), and glioma (chr10q24 and chr2p16).

CONCLUSIONS: We identified 4 novel genetic loci that implicate inflammatory and glial proliferative pathways in the development of WMH in addition to previously proposed ischemic mechanisms.

%B Circ Cardiovasc Genet %V 8 %P 398-409 %8 2015 Apr %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/25663218?dopt=Abstract %R 10.1161/CIRCGENETICS.114.000858 %0 Journal Article %J Mol Psychiatry %D 2015 %T Novel loci associated with usual sleep duration: the CHARGE Consortium Genome-Wide Association Study. %A Gottlieb, D J %A Hek, K %A Chen, T-H %A Watson, N F %A Eiriksdottir, G %A Byrne, E M %A Cornelis, M %A Warby, S C %A Bandinelli, S %A Cherkas, L %A Evans, D S %A Grabe, H J %A Lahti, J %A Li, M %A Lehtimäki, T %A Lumley, T %A Marciante, K D %A Pérusse, L %A Psaty, B M %A Robbins, J %A Tranah, G J %A Vink, J M %A Wilk, J B %A Stafford, J M %A Bellis, C %A Biffar, R %A Bouchard, C %A Cade, B %A Curhan, G C %A Eriksson, J G %A Ewert, R %A Ferrucci, L %A Fülöp, T %A Gehrman, P R %A Goodloe, R %A Harris, T B %A Heath, A C %A Hernandez, D %A Hofman, A %A Hottenga, J-J %A Hunter, D J %A Jensen, M K %A Johnson, A D %A Kähönen, M %A Kao, L %A Kraft, P %A Larkin, E K %A Lauderdale, D S %A Luik, A I %A Medici, M %A Montgomery, G W %A Palotie, A %A Patel, S R %A Pistis, G %A Porcu, E %A Quaye, L %A Raitakari, O %A Redline, S %A Rimm, E B %A Rotter, J I %A Smith, A V %A Spector, T D %A Teumer, A %A Uitterlinden, A G %A Vohl, M-C %A Widen, E %A Willemsen, G %A Young, T %A Zhang, X %A Liu, Y %A Blangero, J %A Boomsma, D I %A Gudnason, V %A Hu, F %A Mangino, M %A Martin, N G %A O'Connor, G T %A Stone, K L %A Tanaka, T %A Viikari, J %A Gharib, S A %A Punjabi, N M %A Räikkönen, K %A Völzke, H %A Mignot, E %A Tiemeier, H %K Adult %K African Americans %K Aged %K Dyssomnias %K European Continental Ancestry Group %K Female %K Genetic Association Studies %K Genome-Wide Association Study %K Humans %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Self Report %K Sleep %X

Usual sleep duration is a heritable trait correlated with psychiatric morbidity, cardiometabolic disease and mortality, although little is known about the genetic variants influencing this trait. A genome-wide association study (GWAS) of usual sleep duration was conducted using 18 population-based cohorts totaling 47 180 individuals of European ancestry. Genome-wide significant association was identified at two loci. The strongest is located on chromosome 2, in an intergenic region 35- to 80-kb upstream from the thyroid-specific transcription factor PAX8 (lowest P=1.1 × 10(-9)). This finding was replicated in an African-American sample of 4771 individuals (lowest P=9.3 × 10(-4)). The strongest combined association was at rs1823125 (P=1.5 × 10(-10), minor allele frequency 0.26 in the discovery sample, 0.12 in the replication sample), with each copy of the minor allele associated with a sleep duration 3.1 min longer per night. The alleles associated with longer sleep duration were associated in previous GWAS with a more favorable metabolic profile and a lower risk of attention deficit hyperactivity disorder. Understanding the mechanisms underlying these associations may help elucidate biological mechanisms influencing sleep duration and its association with psychiatric, metabolic and cardiovascular disease.

%B Mol Psychiatry %V 20 %P 1232-9 %8 2015 Oct %G eng %N 10 %1 http://www.ncbi.nlm.nih.gov/pubmed/25469926?dopt=Abstract %R 10.1038/mp.2014.133 %0 Journal Article %J Arterioscler Thromb Vasc Biol %D 2015 %T Plasma Levels of Soluble Interleukin-2 Receptor α: Associations With Clinical Cardiovascular Events and Genome-Wide Association Scan. %A Durda, Peter %A Sabourin, Jeremy %A Lange, Ethan M %A Nalls, Mike A %A Mychaleckyj, Josyf C %A Jenny, Nancy Swords %A Li, Jin %A Walston, Jeremy %A Harris, Tamara B %A Psaty, Bruce M %A Valdar, William %A Liu, Yongmei %A Cushman, Mary %A Reiner, Alex P %A Tracy, Russell P %A Lange, Leslie A %K Adult %K African Americans %K Age Distribution %K Aged %K Cardiovascular Diseases %K Cohort Studies %K Coronary Artery Disease %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Incidence %K Interleukin-2 Receptor alpha Subunit %K Kaplan-Meier Estimate %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Proportional Hazards Models %K Prospective Studies %K Risk Assessment %K Sex Distribution %K Survival Analysis %X

OBJECTIVE: Interleukin (IL) -2 receptor subunit α regulates lymphocyte activation, which plays an important role in atherosclerosis. Associations between soluble IL-2Rα (sIL-2Rα) and cardiovascular disease (CVD) have not been widely studied and little is known about the genetic determinants of sIL-2Rα levels.

APPROACH AND RESULTS: We measured baseline levels of sIL-2Rα in 4408 European American (EA) and 766 African American (AA) adults from the Cardiovascular Health Study (CHS) and examined associations with baseline CVD risk factors, subclinical CVD, and incident CVD events. We also performed a genome-wide association study for sIL-2Rα in CHS (2964 EAs and 683 AAs) and further combined CHS EA results with those from two other EA cohorts in a meta-analysis (n=4464 EAs). In age, sex- and race- adjusted models, sIL-2Rα was positively associated with current smoking, type 2 diabetes mellitus, hypertension, insulin, waist circumference, C-reactive protein, IL-6, fibrinogen, internal carotid wall thickness, all-cause mortality, CVD mortality, and incident CVD, stroke, and heart failure. When adjusted for baseline CVD risk factors and subclinical CVD, associations with all-cause mortality, CVD mortality, and heart failure remained significant in both EAs and AAs. In the EA genome-wide association study analysis, we observed 52 single-nucleotide polymorphisms in the chromosome 10p15-14 region, which contains IL2RA, IL15RA, and RMB17, that reached genome-wide significance (P<5×10(-8)). The most significant single-nucleotide polymorphism was rs7911500 (P=1.31×10(-75)). The EA meta-analysis results were highly consistent with CHS-only results. No single-nucleotide polymorphisms reached statistical significance in the AAs.

CONCLUSIONS: These results support a role for sIL-2Rα in atherosclerosis and provide evidence for multiple-associated single-nucleotide polymorphisms at chromosome 10p15-14.

%B Arterioscler Thromb Vasc Biol %V 35 %P 2246-53 %8 2015 Oct %G eng %N 10 %1 http://www.ncbi.nlm.nih.gov/pubmed/26293465?dopt=Abstract %R 10.1161/ATVBAHA.115.305289 %0 Journal Article %J JAMA Neurol %D 2015 %T Rare and Coding Region Genetic Variants Associated With Risk of Ischemic Stroke: The NHLBI Exome Sequence Project. %A Auer, Paul L %A Nalls, Mike %A Meschia, James F %A Worrall, Bradford B %A Longstreth, W T %A Seshadri, Sudha %A Kooperberg, Charles %A Burger, Kathleen M %A Carlson, Christopher S %A Carty, Cara L %A Chen, Wei-Min %A Cupples, L Adrienne %A DeStefano, Anita L %A Fornage, Myriam %A Hardy, John %A Hsu, Li %A Jackson, Rebecca D %A Jarvik, Gail P %A Kim, Daniel S %A Lakshminarayan, Kamakshi %A Lange, Leslie A %A Manichaikul, Ani %A Quinlan, Aaron R %A Singleton, Andrew B %A Thornton, Timothy A %A Nickerson, Deborah A %A Peters, Ulrike %A Rich, Stephen S %K Aged %K Brain Ischemia %K Exome %K Female %K Genetic Predisposition to Disease %K Genetic Variation %K Genome-Wide Association Study %K Humans %K Male %K Middle Aged %K Muscle Proteins %K National Heart, Lung, and Blood Institute (U.S.) %K Nuclear Proteins %K Open Reading Frames %K Palmitoyl-CoA Hydrolase %K Stroke %K United States %X

IMPORTANCE: Stroke is the second leading cause of death and the third leading cause of years of life lost. Genetic factors contribute to stroke prevalence, and candidate gene and genome-wide association studies (GWAS) have identified variants associated with ischemic stroke risk. These variants often have small effects without obvious biological significance. Exome sequencing may discover predicted protein-altering variants with a potentially large effect on ischemic stroke risk.

OBJECTIVE: To investigate the contribution of rare and common genetic variants to ischemic stroke risk by targeting the protein-coding regions of the human genome.

DESIGN, SETTING, AND PARTICIPANTS: The National Heart, Lung, and Blood Institute (NHLBI) Exome Sequencing Project (ESP) analyzed approximately 6000 participants from numerous cohorts of European and African ancestry. For discovery, 365 cases of ischemic stroke (small-vessel and large-vessel subtypes) and 809 European ancestry controls were sequenced; for replication, 47 affected sibpairs concordant for stroke subtype and an African American case-control series were sequenced, with 1672 cases and 4509 European ancestry controls genotyped. The ESP's exome sequencing and genotyping started on January 1, 2010, and continued through June 30, 2012. Analyses were conducted on the full data set between July 12, 2012, and July 13, 2013.

MAIN OUTCOMES AND MEASURES: Discovery of new variants or genes contributing to ischemic stroke risk and subtype (primary analysis) and determination of support for protein-coding variants contributing to risk in previously published candidate genes (secondary analysis).

RESULTS: We identified 2 novel genes associated with an increased risk of ischemic stroke: a protein-coding variant in PDE4DIP (rs1778155; odds ratio, 2.15; P = 2.63 × 10(-8)) with an intracellular signal transduction mechanism and in ACOT4 (rs35724886; odds ratio, 2.04; P = 1.24 × 10(-7)) with a fatty acid metabolism; confirmation of PDE4DIP was observed in affected sibpair families with large-vessel stroke subtype and in African Americans. Replication of protein-coding variants in candidate genes was observed for 2 previously reported GWAS associations: ZFHX3 (cardioembolic stroke) and ABCA1 (large-vessel stroke).

CONCLUSIONS AND RELEVANCE: Exome sequencing discovered 2 novel genes and mechanisms, PDE4DIP and ACOT4, associated with increased risk for ischemic stroke. In addition, ZFHX3 and ABCA1 were discovered to have protein-coding variants associated with ischemic stroke. These results suggest that genetic variation in novel pathways contributes to ischemic stroke risk and serves as a target for prediction, prevention, and therapy.

%B JAMA Neurol %V 72 %P 781-8 %8 2015 Jul %G eng %N 7 %1 http://www.ncbi.nlm.nih.gov/pubmed/25961151?dopt=Abstract %R 10.1001/jamaneurol.2015.0582 %0 Journal Article %J Neurology %D 2015 %T Shared genetic basis for migraine and ischemic stroke: A genome-wide analysis of common variants. %A Malik, Rainer %A Freilinger, Tobias %A Winsvold, Bendik S %A Anttila, Verneri %A Vander Heiden, Jason %A Traylor, Matthew %A de Vries, Boukje %A Holliday, Elizabeth G %A Terwindt, Gisela M %A Sturm, Jonathan %A Bis, Joshua C %A Hopewell, Jemma C %A Ferrari, Michel D %A Rannikmae, Kristiina %A Wessman, Maija %A Kallela, Mikko %A Kubisch, Christian %A Fornage, Myriam %A Meschia, James F %A Lehtimäki, Terho %A Sudlow, Cathie %A Clarke, Robert %A Chasman, Daniel I %A Mitchell, Braxton D %A Maguire, Jane %A Kaprio, Jaakko %A Farrall, Martin %A Raitakari, Olli T %A Kurth, Tobias %A Ikram, M Arfan %A Reiner, Alex P %A Longstreth, W T %A Rothwell, Peter M %A Strachan, David P %A Sharma, Pankaj %A Seshadri, Sudha %A Quaye, Lydia %A Cherkas, Lynn %A Schürks, Markus %A Rosand, Jonathan %A Ligthart, Lannie %A Boncoraglio, Giorgio B %A Davey Smith, George %A van Duijn, Cornelia M %A Stefansson, Kari %A Worrall, Bradford B %A Nyholt, Dale R %A Markus, Hugh S %A van den Maagdenberg, Arn M J M %A Cotsapas, Chris %A Zwart, John A %A Palotie, Aarno %A Dichgans, Martin %K Brain Ischemia %K Genome-Wide Association Study %K Humans %K Migraine with Aura %K Migraine without Aura %K Stroke %X

OBJECTIVE: To quantify genetic overlap between migraine and ischemic stroke (IS) with respect to common genetic variation.

METHODS: We applied 4 different approaches to large-scale meta-analyses of genome-wide data on migraine (23,285 cases and 95,425 controls) and IS (12,389 cases and 62,004 controls). First, we queried known genome-wide significant loci for both disorders, looking for potential overlap of signals. We then analyzed the overall shared genetic load using polygenic scores and estimated the genetic correlation between disease subtypes using data derived from these models. We further interrogated genomic regions of shared risk using analysis of covariance patterns between the 2 phenotypes using cross-phenotype spatial mapping.

RESULTS: We found substantial genetic overlap between migraine and IS using all 4 approaches. Migraine without aura (MO) showed much stronger overlap with IS and its subtypes than migraine with aura (MA). The strongest overlap existed between MO and large artery stroke (LAS; p = 6.4 × 10(-28) for the LAS polygenic score in MO) and between MO and cardioembolic stroke (CE; p = 2.7 × 10(-20) for the CE score in MO).

CONCLUSIONS: Our findings indicate shared genetic susceptibility to migraine and IS, with a particularly strong overlap between MO and both LAS and CE pointing towards shared mechanisms. Our observations on MA are consistent with a limited role of common genetic variants in this subtype.

%B Neurology %V 84 %P 2132-45 %8 2015 May 26 %G eng %N 21 %1 http://www.ncbi.nlm.nih.gov/pubmed/25934857?dopt=Abstract %R 10.1212/WNL.0000000000001606 %0 Journal Article %J Stroke %D 2015 %T White Matter Lesion Progression: Genome-Wide Search for Genetic Influences. %A Hofer, Edith %A Cavalieri, Margherita %A Bis, Joshua C %A DeCarli, Charles %A Fornage, Myriam %A Sigurdsson, Sigurdur %A Srikanth, Velandai %A Trompet, Stella %A Verhaaren, Benjamin F J %A Wolf, Christiane %A Yang, Qiong %A Adams, Hieab H H %A Amouyel, Philippe %A Beiser, Alexa %A Buckley, Brendan M %A Callisaya, Michele %A Chauhan, Ganesh %A de Craen, Anton J M %A Dufouil, Carole %A van Duijn, Cornelia M %A Ford, Ian %A Freudenberger, Paul %A Gottesman, Rebecca F %A Gudnason, Vilmundur %A Heiss, Gerardo %A Hofman, Albert %A Lumley, Thomas %A Martinez, Oliver %A Mazoyer, Bernard %A Moran, Chris %A Niessen, Wiro J %A Phan, Thanh %A Psaty, Bruce M %A Satizabal, Claudia L %A Sattar, Naveed %A Schilling, Sabrina %A Shibata, Dean K %A Slagboom, P Eline %A Smith, Albert %A Stott, David J %A Taylor, Kent D %A Thomson, Russell %A Töglhofer, Anna M %A Tzourio, Christophe %A van Buchem, Mark %A Wang, Jing %A Westendorp, Rudi G J %A Windham, B Gwen %A Vernooij, Meike W %A Zijdenbos, Alex %A Beare, Richard %A Debette, Stephanie %A Ikram, M Arfan %A Jukema, J Wouter %A Launer, Lenore J %A Longstreth, W T %A Mosley, Thomas H %A Seshadri, Sudha %A Schmidt, Helena %A Schmidt, Reinhold %K Adult %K Aged %K Cohort Studies %K Disease Progression %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Leukoencephalopathies %K Male %K Middle Aged %K Prospective Studies %K White Matter %X

BACKGROUND AND PURPOSE: White matter lesion (WML) progression on magnetic resonance imaging is related to cognitive decline and stroke, but its determinants besides baseline WML burden are largely unknown. Here, we estimated heritability of WML progression, and sought common genetic variants associated with WML progression in elderly participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium.

METHODS: Heritability of WML progression was calculated in the Framingham Heart Study. The genome-wide association study included 7773 elderly participants from 10 cohorts. To assess the relative contribution of genetic factors to progression of WML, we compared in 7 cohorts risk models including demographics, vascular risk factors plus single-nucleotide polymorphisms that have been shown to be associated cross-sectionally with WML in the current and previous association studies.

RESULTS: A total of 1085 subjects showed WML progression. The heritability estimate for WML progression was low at 6.5%, and no single-nucleotide polymorphisms achieved genome-wide significance (P<5×10(-8)). Four loci were suggestive (P<1×10(-5)) of an association with WML progression: 10q24.32 (rs10883817, P=1.46×10(-6)); 12q13.13 (rs4761974, P=8.71×10(-7)); 20p12.1 (rs6135309, P=3.69×10(-6)); and 4p15.31 (rs7664442, P=2.26×10(-6)). Variants that have been previously related to WML explained only 0.8% to 11.7% more of the variance in WML progression than age, vascular risk factors, and baseline WML burden.

CONCLUSIONS: Common genetic factors contribute little to the progression of age-related WML in middle-aged and older adults. Future research on determinants of WML progression should focus more on environmental, lifestyle, or host-related biological factors.

%B Stroke %V 46 %P 3048-57 %8 2015 Nov %G eng %N 11 %1 http://www.ncbi.nlm.nih.gov/pubmed/26451028?dopt=Abstract %R 10.1161/STROKEAHA.115.009252 %0 Journal Article %J Stroke %D 2016 %T Genome-Wide Association Analysis of Young-Onset Stroke Identifies a Locus on Chromosome 10q25 Near HABP2. %A Cheng, Yu-Ching %A Stanne, Tara M %A Giese, Anne-Katrin %A Ho, Weang Kee %A Traylor, Matthew %A Amouyel, Philippe %A Holliday, Elizabeth G %A Malik, Rainer %A Xu, Huichun %A Kittner, Steven J %A Cole, John W %A O'Connell, Jeffrey R %A Danesh, John %A Rasheed, Asif %A Zhao, Wei %A Engelter, Stefan %A Grond-Ginsbach, Caspar %A Kamatani, Yoichiro %A Lathrop, Mark %A Leys, Didier %A Thijs, Vincent %A Metso, Tiina M %A Tatlisumak, Turgut %A Pezzini, Alessandro %A Parati, Eugenio A %A Norrving, Bo %A Bevan, Steve %A Rothwell, Peter M %A Sudlow, Cathie %A Slowik, Agnieszka %A Lindgren, Arne %A Walters, Matthew R %A Jannes, Jim %A Shen, Jess %A Crosslin, David %A Doheny, Kimberly %A Laurie, Cathy C %A Kanse, Sandip M %A Bis, Joshua C %A Fornage, Myriam %A Mosley, Thomas H %A Hopewell, Jemma C %A Strauch, Konstantin %A Müller-Nurasyid, Martina %A Gieger, Christian %A Waldenberger, Melanie %A Peters, Annette %A Meisinger, Christine %A Ikram, M Arfan %A Longstreth, W T %A Meschia, James F %A Seshadri, Sudha %A Sharma, Pankaj %A Worrall, Bradford %A Jern, Christina %A Levi, Christopher %A Dichgans, Martin %A Boncoraglio, Giorgio B %A Markus, Hugh S %A Debette, Stephanie %A Rolfs, Arndt %A Saleheen, Danish %A Mitchell, Braxton D %K Adult %K African Continental Ancestry Group %K Age of Onset %K Aged %K Asian Continental Ancestry Group %K Brain Ischemia %K Chromosomes, Human, Pair 10 %K Computer Simulation %K DNA, Intergenic %K European Continental Ancestry Group %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Male %K Middle Aged %K Odds Ratio %K Polymorphism, Single Nucleotide %K Serine Endopeptidases %K Stroke %X

BACKGROUND AND PURPOSE: Although a genetic contribution to ischemic stroke is well recognized, only a handful of stroke loci have been identified by large-scale genetic association studies to date. Hypothesizing that genetic effects might be stronger for early- versus late-onset stroke, we conducted a 2-stage meta-analysis of genome-wide association studies, focusing on stroke cases with an age of onset <60 years.

METHODS: The discovery stage of our genome-wide association studies included 4505 cases and 21 968 controls of European, South-Asian, and African ancestry, drawn from 6 studies. In Stage 2, we selected the lead genetic variants at loci with association P<5×10(-6) and performed in silico association analyses in an independent sample of ≤1003 cases and 7745 controls.

RESULTS: One stroke susceptibility locus at 10q25 reached genome-wide significance in the combined analysis of all samples from the discovery and follow-up stages (rs11196288; odds ratio =1.41; P=9.5×10(-9)). The associated locus is in an intergenic region between TCF7L2 and HABP2. In a further analysis in an independent sample, we found that 2 single nucleotide polymorphisms in high linkage disequilibrium with rs11196288 were significantly associated with total plasma factor VII-activating protease levels, a product of HABP2.

CONCLUSIONS: HABP2, which encodes an extracellular serine protease involved in coagulation, fibrinolysis, and inflammatory pathways, may be a genetic susceptibility locus for early-onset stroke.

%B Stroke %V 47 %P 307-16 %8 2016 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26732560?dopt=Abstract %R 10.1161/STROKEAHA.115.011328 %0 Journal Article %J PLoS One %D 2016 %T Genome-Wide Association Study for Incident Myocardial Infarction and Coronary Heart Disease in Prospective Cohort Studies: The CHARGE Consortium. %A Dehghan, Abbas %A Bis, Joshua C %A White, Charles C %A Smith, Albert Vernon %A Morrison, Alanna C %A Cupples, L Adrienne %A Trompet, Stella %A Chasman, Daniel I %A Lumley, Thomas %A Völker, Uwe %A Buckley, Brendan M %A Ding, Jingzhong %A Jensen, Majken K %A Folsom, Aaron R %A Kritchevsky, Stephen B %A Girman, Cynthia J %A Ford, Ian %A Dörr, Marcus %A Salomaa, Veikko %A Uitterlinden, André G %A Eiriksdottir, Gudny %A Vasan, Ramachandran S %A Franceschini, Nora %A Carty, Cara L %A Virtamo, Jarmo %A Demissie, Serkalem %A Amouyel, Philippe %A Arveiler, Dominique %A Heckbert, Susan R %A Ferrieres, Jean %A Ducimetiere, Pierre %A Smith, Nicholas L %A Wang, Ying A %A Siscovick, David S %A Rice, Kenneth M %A Wiklund, Per-Gunnar %A Taylor, Kent D %A Evans, Alun %A Kee, Frank %A Rotter, Jerome I %A Karvanen, Juha %A Kuulasmaa, Kari %A Heiss, Gerardo %A Kraft, Peter %A Launer, Lenore J %A Hofman, Albert %A Markus, Marcello R P %A Rose, Lynda M %A Silander, Kaisa %A Wagner, Peter %A Benjamin, Emelia J %A Lohman, Kurt %A Stott, David J %A Rivadeneira, Fernando %A Harris, Tamara B %A Levy, Daniel %A Liu, Yongmei %A Rimm, Eric B %A Jukema, J Wouter %A Völzke, Henry %A Ridker, Paul M %A Blankenberg, Stefan %A Franco, Oscar H %A Gudnason, Vilmundur %A Psaty, Bruce M %A Boerwinkle, Eric %A O'Donnell, Christopher J %K Aged %K Cohort Studies %K Cooperative Behavior %K Coronary Artery Disease %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Male %K Middle Aged %K Myocardial Infarction %K Polymorphism, Single Nucleotide %K Prospective Studies %X

BACKGROUND: Data are limited on genome-wide association studies (GWAS) for incident coronary heart disease (CHD). Moreover, it is not known whether genetic variants identified to date also associate with risk of CHD in a prospective setting.

METHODS: We performed a two-stage GWAS analysis of incident myocardial infarction (MI) and CHD in a total of 64,297 individuals (including 3898 MI cases, 5465 CHD cases). SNPs that passed an arbitrary threshold of 5×10-6 in Stage I were taken to Stage II for further discovery. Furthermore, in an analysis of prognosis, we studied whether known SNPs from former GWAS were associated with total mortality in individuals who experienced MI during follow-up.

RESULTS: In Stage I 15 loci passed the threshold of 5×10-6; 8 loci for MI and 8 loci for CHD, for which one locus overlapped and none were reported in previous GWAS meta-analyses. We took 60 SNPs representing these 15 loci to Stage II of discovery. Four SNPs near QKI showed nominally significant association with MI (p-value<8.8×10-3) and three exceeded the genome-wide significance threshold when Stage I and Stage II results were combined (top SNP rs6941513: p = 6.2×10-9). Despite excellent power, the 9p21 locus SNP (rs1333049) was only modestly associated with MI (HR = 1.09, p-value = 0.02) and marginally with CHD (HR = 1.06, p-value = 0.08). Among an inception cohort of those who experienced MI during follow-up, the risk allele of rs1333049 was associated with a decreased risk of subsequent mortality (HR = 0.90, p-value = 3.2×10-3).

CONCLUSIONS: QKI represents a novel locus that may serve as a predictor of incident CHD in prospective studies. The association of the 9p21 locus both with increased risk of first myocardial infarction and longer survival after MI highlights the importance of study design in investigating genetic determinants of complex disorders.

%B PLoS One %V 11 %P e0144997 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26950853?dopt=Abstract %R 10.1371/journal.pone.0144997 %0 Journal Article %J Mol Psychiatry %D 2016 %T A novel Alzheimer disease locus located near the gene encoding tau protein. %A Jun, G %A Ibrahim-Verbaas, C A %A Vronskaya, M %A Lambert, J-C %A Chung, J %A Naj, A C %A Kunkle, B W %A Wang, L-S %A Bis, J C %A Bellenguez, C %A Harold, D %A Lunetta, K L %A DeStefano, A L %A Grenier-Boley, B %A Sims, R %A Beecham, G W %A Smith, A V %A Chouraki, V %A Hamilton-Nelson, K L %A Ikram, M A %A Fiévet, N %A Denning, N %A Martin, E R %A Schmidt, H %A Kamatani, Y %A Dunstan, M L %A Valladares, O %A Laza, A R %A Zelenika, D %A Ramirez, A %A Foroud, T M %A Choi, S-H %A Boland, A %A Becker, T %A Kukull, W A %A van der Lee, S J %A Pasquier, F %A Cruchaga, C %A Beekly, D %A Fitzpatrick, A L %A Hanon, O %A Gill, M %A Barber, R %A Gudnason, V %A Campion, D %A Love, S %A Bennett, D A %A Amin, N %A Berr, C %A Tsolaki, Magda %A Buxbaum, J D %A Lopez, O L %A Deramecourt, V %A Fox, N C %A Cantwell, L B %A Tárraga, L %A Dufouil, C %A Hardy, J %A Crane, P K %A Eiriksdottir, G %A Hannequin, D %A Clarke, R %A Evans, D %A Mosley, T H %A Letenneur, L %A Brayne, C %A Maier, W %A De Jager, P %A Emilsson, V %A Dartigues, J-F %A Hampel, H %A Kamboh, M I %A de Bruijn, R F A G %A Tzourio, C %A Pastor, P %A Larson, E B %A Rotter, J I %A O'Donovan, M C %A Montine, T J %A Nalls, M A %A Mead, S %A Reiman, E M %A Jonsson, P V %A Holmes, C %A St George-Hyslop, P H %A Boada, M %A Passmore, P %A Wendland, J R %A Schmidt, R %A Morgan, K %A Winslow, A R %A Powell, J F %A Carasquillo, M %A Younkin, S G %A Jakobsdóttir, J %A Kauwe, J S K %A Wilhelmsen, K C %A Rujescu, D %A Nöthen, M M %A Hofman, A %A Jones, L %A Haines, J L %A Psaty, B M %A Van Broeckhoven, C %A Holmans, P %A Launer, L J %A Mayeux, R %A Lathrop, M %A Goate, A M %A Escott-Price, V %A Seshadri, S %A Pericak-Vance, M A %A Amouyel, P %A Williams, J %A van Duijn, C M %A Schellenberg, G D %A Farrer, L A %K Alzheimer Disease %K Apolipoprotein E4 %K Chromosomes, Human, Pair 17 %K Genome-Wide Association Study %K Humans %K Polymorphism, Single Nucleotide %K tau Proteins %X

APOE ɛ4, the most significant genetic risk factor for Alzheimer disease (AD), may mask effects of other loci. We re-analyzed genome-wide association study (GWAS) data from the International Genomics of Alzheimer's Project (IGAP) Consortium in APOE ɛ4+ (10 352 cases and 9207 controls) and APOE ɛ4- (7184 cases and 26 968 controls) subgroups as well as in the total sample testing for interaction between a single-nucleotide polymorphism (SNP) and APOE ɛ4 status. Suggestive associations (P<1 × 10(-4)) in stage 1 were evaluated in an independent sample (stage 2) containing 4203 subjects (APOE ɛ4+: 1250 cases and 536 controls; APOE ɛ4-: 718 cases and 1699 controls). Among APOE ɛ4- subjects, novel genome-wide significant (GWS) association was observed with 17 SNPs (all between KANSL1 and LRRC37A on chromosome 17 near MAPT) in a meta-analysis of the stage 1 and stage 2 data sets (best SNP, rs2732703, P=5·8 × 10(-9)). Conditional analysis revealed that rs2732703 accounted for association signals in the entire 100-kilobase region that includes MAPT. Except for previously identified AD loci showing stronger association in APOE ɛ4+ subjects (CR1 and CLU) or APOE ɛ4- subjects (MS4A6A/MS4A4A/MS4A6E), no other SNPs were significantly associated with AD in a specific APOE genotype subgroup. In addition, the finding in the stage 1 sample that AD risk is significantly influenced by the interaction of APOE with rs1595014 in TMEM106B (P=1·6 × 10(-7)) is noteworthy, because TMEM106B variants have previously been associated with risk of frontotemporal dementia. Expression quantitative trait locus analysis revealed that rs113986870, one of the GWS SNPs near rs2732703, is significantly associated with four KANSL1 probes that target transcription of the first translated exon and an untranslated exon in hippocampus (P ⩽ 1.3 × 10(-8)), frontal cortex (P ⩽ 1.3 × 10(-9)) and temporal cortex (P⩽1.2 × 10(-11)). Rs113986870 is also strongly associated with a MAPT probe that targets transcription of alternatively spliced exon 3 in frontal cortex (P=9.2 × 10(-6)) and temporal cortex (P=2.6 × 10(-6)). Our APOE-stratified GWAS is the first to show GWS association for AD with SNPs in the chromosome 17q21.31 region. Replication of this finding in independent samples is needed to verify that SNPs in this region have significantly stronger effects on AD risk in persons lacking APOE ɛ4 compared with persons carrying this allele, and if this is found to hold, further examination of this region and studies aimed at deciphering the mechanism(s) are warranted.

%B Mol Psychiatry %V 21 %P 108-17 %8 2016 Jan %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/25778476?dopt=Abstract %R 10.1038/mp.2015.23 %0 Journal Article %J Nat Commun %D 2016 %T A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape. %A Ried, Janina S %A Jeff M, Janina %A Chu, Audrey Y %A Bragg-Gresham, Jennifer L %A van Dongen, Jenny %A Huffman, Jennifer E %A Ahluwalia, Tarunveer S %A Cadby, Gemma %A Eklund, Niina %A Eriksson, Joel %A Esko, Tõnu %A Feitosa, Mary F %A Goel, Anuj %A Gorski, Mathias %A Hayward, Caroline %A Heard-Costa, Nancy L %A Jackson, Anne U %A Jokinen, Eero %A Kanoni, Stavroula %A Kristiansson, Kati %A Kutalik, Zoltán %A Lahti, Jari %A Luan, Jian'an %A Mägi, Reedik %A Mahajan, Anubha %A Mangino, Massimo %A Medina-Gómez, Carolina %A Monda, Keri L %A Nolte, Ilja M %A Perusse, Louis %A Prokopenko, Inga %A Qi, Lu %A Rose, Lynda M %A Salvi, Erika %A Smith, Megan T %A Snieder, Harold %A Stančáková, Alena %A Ju Sung, Yun %A Tachmazidou, Ioanna %A Teumer, Alexander %A Thorleifsson, Gudmar %A van der Harst, Pim %A Walker, Ryan W %A Wang, Sophie R %A Wild, Sarah H %A Willems, Sara M %A Wong, Andrew %A Zhang, Weihua %A Albrecht, Eva %A Couto Alves, Alexessander %A Bakker, Stephan J L %A Barlassina, Cristina %A Bartz, Traci M %A Beilby, John %A Bellis, Claire %A Bergman, Richard N %A Bergmann, Sven %A Blangero, John %A Blüher, Matthias %A Boerwinkle, Eric %A Bonnycastle, Lori L %A Bornstein, Stefan R %A Bruinenberg, Marcel %A Campbell, Harry %A Chen, Yii-Der Ida %A Chiang, Charleston W K %A Chines, Peter S %A Collins, Francis S %A Cucca, Fracensco %A Cupples, L Adrienne %A D'Avila, Francesca %A de Geus, Eco J C %A Dedoussis, George %A Dimitriou, Maria %A Döring, Angela %A Eriksson, Johan G %A Farmaki, Aliki-Eleni %A Farrall, Martin %A Ferreira, Teresa %A Fischer, Krista %A Forouhi, Nita G %A Friedrich, Nele %A Gjesing, Anette Prior %A Glorioso, Nicola %A Graff, Mariaelisa %A Grallert, Harald %A Grarup, Niels %A Gräßler, Jürgen %A Grewal, Jagvir %A Hamsten, Anders %A Harder, Marie Neergaard %A Hartman, Catharina A %A Hassinen, Maija %A Hastie, Nicholas %A Hattersley, Andrew Tym %A Havulinna, Aki S %A Heliövaara, Markku %A Hillege, Hans %A Hofman, Albert %A Holmen, Oddgeir %A Homuth, Georg %A Hottenga, Jouke-Jan %A Hui, Jennie %A Husemoen, Lise Lotte %A Hysi, Pirro G %A Isaacs, Aaron %A Ittermann, Till %A Jalilzadeh, Shapour %A James, Alan L %A Jørgensen, Torben %A Jousilahti, Pekka %A Jula, Antti %A Marie Justesen, Johanne %A Justice, Anne E %A Kähönen, Mika %A Karaleftheri, Maria %A Tee Khaw, Kay %A Keinanen-Kiukaanniemi, Sirkka M %A Kinnunen, Leena %A Knekt, Paul B %A Koistinen, Heikki A %A Kolcic, Ivana %A Kooner, Ishminder K %A Koskinen, Seppo %A Kovacs, Peter %A Kyriakou, Theodosios %A Laitinen, Tomi %A Langenberg, Claudia %A Lewin, Alexandra M %A Lichtner, Peter %A Lindgren, Cecilia M %A Lindström, Jaana %A Linneberg, Allan %A Lorbeer, Roberto %A Lorentzon, Mattias %A Luben, Robert %A Lyssenko, Valeriya %A Männistö, Satu %A Manunta, Paolo %A Leach, Irene Mateo %A McArdle, Wendy L %A McKnight, Barbara %A Mohlke, Karen L %A Mihailov, Evelin %A Milani, Lili %A Mills, Rebecca %A Montasser, May E %A Morris, Andrew P %A Müller, Gabriele %A Musk, Arthur W %A Narisu, Narisu %A Ong, Ken K %A Oostra, Ben A %A Osmond, Clive %A Palotie, Aarno %A Pankow, James S %A Paternoster, Lavinia %A Penninx, Brenda W %A Pichler, Irene %A Pilia, Maria G %A Polasek, Ozren %A Pramstaller, Peter P %A Raitakari, Olli T %A Rankinen, Tuomo %A Rao, D C %A Rayner, Nigel W %A Ribel-Madsen, Rasmus %A Rice, Treva K %A Richards, Marcus %A Ridker, Paul M %A Rivadeneira, Fernando %A Ryan, Kathy A %A Sanna, Serena %A Sarzynski, Mark A %A Scholtens, Salome %A Scott, Robert A %A Sebert, Sylvain %A Southam, Lorraine %A Sparsø, Thomas Hempel %A Steinthorsdottir, Valgerdur %A Stirrups, Kathleen %A Stolk, Ronald P %A Strauch, Konstantin %A Stringham, Heather M %A Swertz, Morris A %A Swift, Amy J %A Tönjes, Anke %A Tsafantakis, Emmanouil %A van der Most, Peter J %A van Vliet-Ostaptchouk, Jana V %A Vandenput, Liesbeth %A Vartiainen, Erkki %A Venturini, Cristina %A Verweij, Niek %A Viikari, Jorma S %A Vitart, Veronique %A Vohl, Marie-Claude %A Vonk, Judith M %A Waeber, Gérard %A Widen, Elisabeth %A Willemsen, Gonneke %A Wilsgaard, Tom %A Winkler, Thomas W %A Wright, Alan F %A Yerges-Armstrong, Laura M %A Hua Zhao, Jing %A Zillikens, M Carola %A Boomsma, Dorret I %A Bouchard, Claude %A Chambers, John C %A Chasman, Daniel I %A Cusi, Daniele %A Gansevoort, Ron T %A Gieger, Christian %A Hansen, Torben %A Hicks, Andrew A %A Hu, Frank %A Hveem, Kristian %A Jarvelin, Marjo-Riitta %A Kajantie, Eero %A Kooner, Jaspal S %A Kuh, Diana %A Kuusisto, Johanna %A Laakso, Markku %A Lakka, Timo A %A Lehtimäki, Terho %A Metspalu, Andres %A Njølstad, Inger %A Ohlsson, Claes %A Oldehinkel, Albertine J %A Palmer, Lyle J %A Pedersen, Oluf %A Perola, Markus %A Peters, Annette %A Psaty, Bruce M %A Puolijoki, Hannu %A Rauramaa, Rainer %A Rudan, Igor %A Salomaa, Veikko %A Schwarz, Peter E H %A Shudiner, Alan R %A Smit, Jan H %A Sørensen, Thorkild I A %A Spector, Timothy D %A Stefansson, Kari %A Stumvoll, Michael %A Tremblay, Angelo %A Tuomilehto, Jaakko %A Uitterlinden, André G %A Uusitupa, Matti %A Völker, Uwe %A Vollenweider, Peter %A Wareham, Nicholas J %A Watkins, Hugh %A Wilson, James F %A Zeggini, Eleftheria %A Abecasis, Goncalo R %A Boehnke, Michael %A Borecki, Ingrid B %A Deloukas, Panos %A van Duijn, Cornelia M %A Fox, Caroline %A Groop, Leif C %A Heid, Iris M %A Hunter, David J %A Kaplan, Robert C %A McCarthy, Mark I %A North, Kari E %A O'Connell, Jeffrey R %A Schlessinger, David %A Thorsteinsdottir, Unnur %A Strachan, David P %A Frayling, Timothy %A Hirschhorn, Joel N %A Müller-Nurasyid, Martina %A Loos, Ruth J F %K Anthropometry %K Body Size %K Genome-Wide Association Study %K Genotype %K Humans %K Models, Genetic %K Principal Component Analysis %X

Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways.

%B Nat Commun %V 7 %P 13357 %8 2016 11 23 %G eng %R 10.1038/ncomms13357 %0 Journal Article %J Hum Mol Genet %D 2016 %T Twenty-eight genetic loci associated with ST-T-wave amplitudes of the electrocardiogram. %A Verweij, Niek %A Mateo Leach, Irene %A Isaacs, Aaron %A Arking, Dan E %A Bis, Joshua C %A Pers, Tune H %A van den Berg, Marten E %A Lyytikäinen, Leo-Pekka %A Barnett, Phil %A Wang, Xinchen %A Soliman, Elsayed Z %A van Duijn, Cornelia M %A Kähönen, Mika %A van Veldhuisen, Dirk J %A Kors, Jan A %A Raitakari, Olli T %A Silva, Claudia T %A Lehtimäki, Terho %A Hillege, Hans L %A Hirschhorn, Joel N %A Boyer, Laurie A %A van Gilst, Wiek H %A Alonso, Alvaro %A Sotoodehnia, Nona %A Eijgelsheim, Mark %A de Boer, Rudolf A %A de Bakker, Paul I W %A Franke, Lude %A van der Harst, Pim %K Adaptor Proteins, Signal Transducing %K Arrhythmias, Cardiac %K Basic Helix-Loop-Helix Transcription Factors %K Brugada Syndrome %K Cardiac Conduction System Disease %K Death, Sudden, Cardiac %K Electrocardiography %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Heart Conduction System %K Humans %K Male %K NAV1.5 Voltage-Gated Sodium Channel %K Polymorphism, Single Nucleotide %K Repressor Proteins %K Shab Potassium Channels %K Shal Potassium Channels %X

The ST-segment and adjacent T-wave (ST-T wave) amplitudes of the electrocardiogram are quantitative characteristics of cardiac repolarization. Repolarization abnormalities have been linked to ventricular arrhythmias and sudden cardiac death. We performed the first genome-wide association meta-analysis of ST-T-wave amplitudes in up to 37 977 individuals identifying 71 robust genotype-phenotype associations clustered within 28 independent loci. Fifty-four genes were prioritized as candidates underlying the phenotypes, including genes with established roles in the cardiac repolarization phase (SCN5A/SCN10A, KCND3, KCNB1, NOS1AP and HEY2) and others with as yet undefined cardiac function. These associations may provide insights in the spatiotemporal contribution of genetic variation influencing cardiac repolarization and provide novel leads for future functional follow-up.

%B Hum Mol Genet %V 25 %P 2093-2103 %8 2016 05 15 %G eng %N 10 %R 10.1093/hmg/ddw058 %0 Journal Article %J Hum Genet %D 2017 %T Assessing the causal relationship between obesity and venous thromboembolism through a Mendelian Randomization study. %A Lindström, Sara %A Germain, Marine %A Crous-Bou, Marta %A Smith, Erin N %A Morange, Pierre-Emmanuel %A van Hylckama Vlieg, Astrid %A de Haan, Hugoline G %A Chasman, Daniel %A Ridker, Paul %A Brody, Jennifer %A de Andrade, Mariza %A Heit, John A %A Tang, Weihong %A DeVivo, Immaculata %A Grodstein, Francine %A Smith, Nicholas L %A Tregouet, David %A Kabrhel, Christopher %K Adult %K Body Mass Index %K Case-Control Studies %K European Continental Ancestry Group %K Female %K Genome-Wide Association Study %K Humans %K Incidence %K Logistic Models %K Male %K Mendelian Randomization Analysis %K Obesity %K Polymorphism, Single Nucleotide %K Proportional Hazards Models %K Venous Thromboembolism %X

Observational studies have shown an association between obesity and venous thromboembolism (VTE) but it is not known if observed associations are causal, due to reverse causation or confounding bias. We conducted a Mendelian Randomization study of body mass index (BMI) and VTE. We identified 95 single nucleotide polymorphisms (SNPs) that have been previously associated with BMI and assessed the association between genetically predicted high BMI and VTE leveraging data from a previously conducted GWAS within the INVENT consortium comprising a total of 7507 VTE cases and 52,632 controls of European ancestry. Five BMI SNPs were associated with VTE at P < 0.05, with the strongest association seen for the FTO SNP rs1558902 (OR 1.07, 95% CI 1.02-1.12, P = 0.005). In addition, we observed a significant association between genetically predicted BMI and VTE (OR = 1.59, 95% CI 1.30-1.93 per standard deviation increase in BMI, P = 5.8 × 10). Our study provides evidence for a causal relationship between high BMI and risk of VTE. Reducing obesity levels will likely result in lower incidence in VTE.

%B Hum Genet %V 136 %P 897-902 %8 2017 07 %G eng %N 7 %R 10.1007/s00439-017-1811-x %0 Journal Article %J JAMA Oncol %D 2017 %T Association Between Telomere Length and Risk of Cancer and Non-Neoplastic Diseases: A Mendelian Randomization Study. %A Haycock, Philip C %A Burgess, Stephen %A Nounu, Aayah %A Zheng, Jie %A Okoli, George N %A Bowden, Jack %A Wade, Kaitlin Hazel %A Timpson, Nicholas J %A Evans, David M %A Willeit, Peter %A Aviv, Abraham %A Gaunt, Tom R %A Hemani, Gibran %A Mangino, Massimo %A Ellis, Hayley Patricia %A Kurian, Kathreena M %A Pooley, Karen A %A Eeles, Rosalind A %A Lee, Jeffrey E %A Fang, Shenying %A Chen, Wei V %A Law, Matthew H %A Bowdler, Lisa M %A Iles, Mark M %A Yang, Qiong %A Worrall, Bradford B %A Markus, Hugh Stephen %A Hung, Rayjean J %A Amos, Chris I %A Spurdle, Amanda B %A Thompson, Deborah J %A O'Mara, Tracy A %A Wolpin, Brian %A Amundadottir, Laufey %A Stolzenberg-Solomon, Rachael %A Trichopoulou, Antonia %A Onland-Moret, N Charlotte %A Lund, Eiliv %A Duell, Eric J %A Canzian, Federico %A Severi, Gianluca %A Overvad, Kim %A Gunter, Marc J %A Tumino, Rosario %A Svenson, Ulrika %A van Rij, Andre %A Baas, Annette F %A Bown, Matthew J %A Samani, Nilesh J %A van t'Hof, Femke N G %A Tromp, Gerard %A Jones, Gregory T %A Kuivaniemi, Helena %A Elmore, James R %A Johansson, Mattias %A Mckay, James %A Scelo, Ghislaine %A Carreras-Torres, Robert %A Gaborieau, Valerie %A Brennan, Paul %A Bracci, Paige M %A Neale, Rachel E %A Olson, Sara H %A Gallinger, Steven %A Li, Donghui %A Petersen, Gloria M %A Risch, Harvey A %A Klein, Alison P %A Han, Jiali %A Abnet, Christian C %A Freedman, Neal D %A Taylor, Philip R %A Maris, John M %A Aben, Katja K %A Kiemeney, Lambertus A %A Vermeulen, Sita H %A Wiencke, John K %A Walsh, Kyle M %A Wrensch, Margaret %A Rice, Terri %A Turnbull, Clare %A Litchfield, Kevin %A Paternoster, Lavinia %A Standl, Marie %A Abecasis, Goncalo R %A SanGiovanni, John Paul %A Li, Yong %A Mijatovic, Vladan %A Sapkota, Yadav %A Low, Siew-Kee %A Zondervan, Krina T %A Montgomery, Grant W %A Nyholt, Dale R %A van Heel, David A %A Hunt, Karen %A Arking, Dan E %A Ashar, Foram N %A Sotoodehnia, Nona %A Woo, Daniel %A Rosand, Jonathan %A Comeau, Mary E %A Brown, W Mark %A Silverman, Edwin K %A Hokanson, John E %A Cho, Michael H %A Hui, Jennie %A Ferreira, Manuel A %A Thompson, Philip J %A Morrison, Alanna C %A Felix, Janine F %A Smith, Nicholas L %A Christiano, Angela M %A Petukhova, Lynn %A Betz, Regina C %A Fan, Xing %A Zhang, Xuejun %A Zhu, Caihong %A Langefeld, Carl D %A Thompson, Susan D %A Wang, Feijie %A Lin, Xu %A Schwartz, David A %A Fingerlin, Tasha %A Rotter, Jerome I %A Cotch, Mary Frances %A Jensen, Richard A %A Munz, Matthias %A Dommisch, Henrik %A Schaefer, Arne S %A Han, Fang %A Ollila, Hanna M %A Hillary, Ryan P %A Albagha, Omar %A Ralston, Stuart H %A Zeng, Chenjie %A Zheng, Wei %A Shu, Xiao-Ou %A Reis, Andre %A Uebe, Steffen %A Hüffmeier, Ulrike %A Kawamura, Yoshiya %A Otowa, Takeshi %A Sasaki, Tsukasa %A Hibberd, Martin Lloyd %A Davila, Sonia %A Xie, Gang %A Siminovitch, Katherine %A Bei, Jin-Xin %A Zeng, Yi-Xin %A Försti, Asta %A Chen, Bowang %A Landi, Stefano %A Franke, Andre %A Fischer, Annegret %A Ellinghaus, David %A Flores, Carlos %A Noth, Imre %A Ma, Shwu-Fan %A Foo, Jia Nee %A Liu, Jianjun %A Kim, Jong-Won %A Cox, David G %A Delattre, Olivier %A Mirabeau, Olivier %A Skibola, Christine F %A Tang, Clara S %A Garcia-Barcelo, Merce %A Chang, Kai-Ping %A Su, Wen-Hui %A Chang, Yu-Sun %A Martin, Nicholas G %A Gordon, Scott %A Wade, Tracey D %A Lee, Chaeyoung %A Kubo, Michiaki %A Cha, Pei-Chieng %A Nakamura, Yusuke %A Levy, Daniel %A Kimura, Masayuki %A Hwang, Shih-Jen %A Hunt, Steven %A Spector, Tim %A Soranzo, Nicole %A Manichaikul, Ani W %A Barr, R Graham %A Kahali, Bratati %A Speliotes, Elizabeth %A Yerges-Armstrong, Laura M %A Cheng, Ching-Yu %A Jonas, Jost B %A Wong, Tien Yin %A Fogh, Isabella %A Lin, Kuang %A Powell, John F %A Rice, Kenneth %A Relton, Caroline L %A Martin, Richard M %A Davey Smith, George %K Adult %K Aged %K Aged, 80 and over %K Cardiovascular Diseases %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Germ-Line Mutation %K Humans %K Male %K Mendelian Randomization Analysis %K Middle Aged %K Neoplasms %K Polymorphism, Single Nucleotide %K Risk Assessment %K Telomere %K Telomere Homeostasis %X

Importance: The causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain owing to the susceptibility of observational studies to confounding and reverse causation.

Objective: To conduct a Mendelian randomization study, using germline genetic variants as instrumental variables, to appraise the causal relevance of telomere length for risk of cancer and non-neoplastic diseases.

Data Sources: Genomewide association studies (GWAS) published up to January 15, 2015.

Study Selection: GWAS of noncommunicable diseases that assayed germline genetic variation and did not select cohort or control participants on the basis of preexisting diseases. Of 163 GWAS of noncommunicable diseases identified, summary data from 103 were available.

Data Extraction and Synthesis: Summary association statistics for single nucleotide polymorphisms (SNPs) that are strongly associated with telomere length in the general population.

Main Outcomes and Measures: Odds ratios (ORs) and 95% confidence intervals (CIs) for disease per standard deviation (SD) higher telomere length due to germline genetic variation.

Results: Summary data were available for 35 cancers and 48 non-neoplastic diseases, corresponding to 420 081 cases (median cases, 2526 per disease) and 1 093 105 controls (median, 6789 per disease). Increased telomere length due to germline genetic variation was generally associated with increased risk for site-specific cancers. The strongest associations (ORs [95% CIs] per 1-SD change in genetically increased telomere length) were observed for glioma, 5.27 (3.15-8.81); serous low-malignant-potential ovarian cancer, 4.35 (2.39-7.94); lung adenocarcinoma, 3.19 (2.40-4.22); neuroblastoma, 2.98 (1.92-4.62); bladder cancer, 2.19 (1.32-3.66); melanoma, 1.87 (1.55-2.26); testicular cancer, 1.76 (1.02-3.04); kidney cancer, 1.55 (1.08-2.23); and endometrial cancer, 1.31 (1.07-1.61). Associations were stronger for rarer cancers and at tissue sites with lower rates of stem cell division. There was generally little evidence of association between genetically increased telomere length and risk of psychiatric, autoimmune, inflammatory, diabetic, and other non-neoplastic diseases, except for coronary heart disease (OR, 0.78 [95% CI, 0.67-0.90]), abdominal aortic aneurysm (OR, 0.63 [95% CI, 0.49-0.81]), celiac disease (OR, 0.42 [95% CI, 0.28-0.61]) and interstitial lung disease (OR, 0.09 [95% CI, 0.05-0.15]).

Conclusions and Relevance: It is likely that longer telomeres increase risk for several cancers but reduce risk for some non-neoplastic diseases, including cardiovascular diseases.

%B JAMA Oncol %V 3 %P 636-651 %8 2017 May 01 %G eng %N 5 %R 10.1001/jamaoncol.2016.5945 %0 Journal Article %J Am J Hum Genet %D 2017 %T DNA Methylation Analysis Identifies Loci for Blood Pressure Regulation. %A Richard, Melissa A %A Huan, Tianxiao %A Ligthart, Symen %A Gondalia, Rahul %A Jhun, Min A %A Brody, Jennifer A %A Irvin, Marguerite R %A Marioni, Riccardo %A Shen, Jincheng %A Tsai, Pei-Chien %A Montasser, May E %A Jia, Yucheng %A Syme, Catriona %A Salfati, Elias L %A Boerwinkle, Eric %A Guan, Weihua %A Mosley, Thomas H %A Bressler, Jan %A Morrison, Alanna C %A Liu, Chunyu %A Mendelson, Michael M %A Uitterlinden, André G %A van Meurs, Joyce B %A Franco, Oscar H %A Zhang, Guosheng %A Li, Yun %A Stewart, James D %A Bis, Joshua C %A Psaty, Bruce M %A Chen, Yii-Der Ida %A Kardia, Sharon L R %A Zhao, Wei %A Turner, Stephen T %A Absher, Devin %A Aslibekyan, Stella %A Starr, John M %A McRae, Allan F %A Hou, Lifang %A Just, Allan C %A Schwartz, Joel D %A Vokonas, Pantel S %A Menni, Cristina %A Spector, Tim D %A Shuldiner, Alan %A Damcott, Coleen M %A Rotter, Jerome I %A Palmas, Walter %A Liu, Yongmei %A Paus, Tomáš %A Horvath, Steve %A O'Connell, Jeffrey R %A Guo, Xiuqing %A Pausova, Zdenka %A Assimes, Themistocles L %A Sotoodehnia, Nona %A Smith, Jennifer A %A Arnett, Donna K %A Deary, Ian J %A Baccarelli, Andrea A %A Bell, Jordana T %A Whitsel, Eric %A Dehghan, Abbas %A Levy, Daniel %A Fornage, Myriam %K Aged %K Blood Pressure %K CpG Islands %K Cross-Sectional Studies %K DNA Methylation %K Epigenesis, Genetic %K Genetic Variation %K Genome-Wide Association Study %K Humans %K Mendelian Randomization Analysis %K Middle Aged %K Nerve Tissue Proteins %K Quantitative Trait Loci %K Tetraspanins %X

Genome-wide association studies have identified hundreds of genetic variants associated with blood pressure (BP), but sequence variation accounts for a small fraction of the phenotypic variance. Epigenetic changes may alter the expression of genes involved in BP regulation and explain part of the missing heritability. We therefore conducted a two-stage meta-analysis of the cross-sectional associations of systolic and diastolic BP with blood-derived genome-wide DNA methylation measured on the Infinium HumanMethylation450 BeadChip in 17,010 individuals of European, African American, and Hispanic ancestry. Of 31 discovery-stage cytosine-phosphate-guanine (CpG) dinucleotides, 13 replicated after Bonferroni correction (discovery: N = 9,828, p < 1.0 × 10-7; replication: N = 7,182, p < 1.6 × 10-3). The replicated methylation sites are heritable (h2 > 30%) and independent of known BP genetic variants, explaining an additional 1.4% and 2.0% of the interindividual variation in systolic and diastolic BP, respectively. Bidirectional Mendelian randomization among up to 4,513 individuals of European ancestry from 4 cohorts suggested that methylation at cg08035323 (TAF1B-YWHAQ) influences BP, while BP influences methylation at cg00533891 (ZMIZ1), cg00574958 (CPT1A), and cg02711608 (SLC1A5). Gene expression analyses further identified six genes (TSPAN2, SLC7A11, UNC93B1, CPT1A, PTMS, and LPCAT3) with evidence of triangular associations between methylation, gene expression, and BP. Additional integrative Mendelian randomization analyses of gene expression and DNA methylation suggested that the expression of TSPAN2 is a putative mediator of association between DNA methylation at cg23999170 and BP. These findings suggest that heritable DNA methylation plays a role in regulating BP independently of previously known genetic variants.

%B Am J Hum Genet %V 101 %P 888-902 %8 2017 Dec 07 %G eng %N 6 %R 10.1016/j.ajhg.2017.09.028 %0 Journal Article %J Circ Cardiovasc Genet %D 2017 %T Fifteen Genetic Loci Associated With the Electrocardiographic P Wave. %A Christophersen, Ingrid E %A Magnani, Jared W %A Yin, Xiaoyan %A Barnard, John %A Weng, Lu-Chen %A Arking, Dan E %A Niemeijer, Maartje N %A Lubitz, Steven A %A Avery, Christy L %A Duan, Qing %A Felix, Stephan B %A Bis, Joshua C %A Kerr, Kathleen F %A Isaacs, Aaron %A Müller-Nurasyid, Martina %A Müller, Christian %A North, Kari E %A Reiner, Alex P %A Tinker, Lesley F %A Kors, Jan A %A Teumer, Alexander %A Petersmann, Astrid %A Sinner, Moritz F %A Bůzková, Petra %A Smith, Jonathan D %A Van Wagoner, David R %A Völker, Uwe %A Waldenberger, Melanie %A Peters, Annette %A Meitinger, Thomas %A Limacher, Marian C %A Wilhelmsen, Kirk C %A Psaty, Bruce M %A Hofman, Albert %A Uitterlinden, Andre %A Krijthe, Bouwe P %A Zhang, Zhu-Ming %A Schnabel, Renate B %A Kääb, Stefan %A van Duijn, Cornelia %A Rotter, Jerome I %A Sotoodehnia, Nona %A Dörr, Marcus %A Li, Yun %A Chung, Mina K %A Soliman, Elsayed Z %A Alonso, Alvaro %A Whitsel, Eric A %A Stricker, Bruno H %A Benjamin, Emelia J %A Heckbert, Susan R %A Ellinor, Patrick T %K Arrhythmias, Cardiac %K Caveolin 1 %K Caveolin 2 %K Electrocardiography %K Genetic Loci %K Genome-Wide Association Study %K Genotype %K Heart Atria %K Humans %K NAV1.5 Voltage-Gated Sodium Channel %K NAV1.8 Voltage-Gated Sodium Channel %K T-Box Domain Proteins %X

BACKGROUND: The P wave on an ECG is a measure of atrial electric function, and its characteristics may serve as predictors for atrial arrhythmias. Increased mean P-wave duration and P-wave terminal force traditionally have been used as markers for left atrial enlargement, and both have been associated with increased risk of atrial fibrillation. Here, we explore the genetic basis of P-wave morphology through meta-analysis of genome-wide association study results for P-wave duration and P-wave terminal force from 12 cohort studies.

METHODS AND RESULTS: We included 44 456 individuals, of which 6778 (16%) were of African ancestry. Genotyping, imputation, and genome-wide association study were performed at each study site. Summary-level results were meta-analyzed centrally using inverse-variance weighting. In meta-analyses of P-wave duration, we identified 6 significant (P<5×10-8) novel loci and replicated a prior association with SCN10A. We identified 3 loci at SCN5A, TBX5, and CAV1/CAV2 that were jointly associated with the PR interval, PR segment, and P-wave duration. We identified 6 novel loci in meta-analysis of P-wave terminal force. Four of the identified genetic loci were significantly associated with gene expression in 329 left atrial samples. Finally, we observed that some of the loci associated with the P wave were linked to overall atrial conduction, whereas others identified distinct phases of atrial conduction.

CONCLUSIONS: We have identified 6 novel genetic loci associated with P-wave duration and 6 novel loci associated with P-wave terminal force. Future studies of these loci may aid in identifying new targets for drugs that may modify atrial conduction or treat atrial arrhythmias.

%B Circ Cardiovasc Genet %V 10 %8 2017 Aug %G eng %N 4 %R 10.1161/CIRCGENETICS.116.001667 %0 Journal Article %J Diabetes %D 2017 %T Genetically Determined Plasma Lipid Levels and Risk of Diabetic Retinopathy: A Mendelian Randomization Study. %A Sobrin, Lucia %A Chong, Yong He %A Fan, Qiao %A Gan, Alfred %A Stanwyck, Lynn K %A Kaidonis, Georgia %A Craig, Jamie E %A Kim, Jihye %A Liao, Wen-Ling %A Huang, Yu-Chuen %A Lee, Wen-Jane %A Hung, Yi-Jen %A Guo, Xiuqing %A Hai, Yang %A Ipp, Eli %A Pollack, Samuela %A Hancock, Heather %A Price, Alkes %A Penman, Alan %A Mitchell, Paul %A Liew, Gerald %A Smith, Albert V %A Gudnason, Vilmundur %A Tan, Gavin %A Klein, Barbara E K %A Kuo, Jane %A Li, Xiaohui %A Christiansen, Mark W %A Psaty, Bruce M %A Sandow, Kevin %A Jensen, Richard A %A Klein, Ronald %A Cotch, Mary Frances %A Wang, Jie Jin %A Jia, Yucheng %A Chen, Ching J %A Chen, Yii-Der Ida %A Rotter, Jerome I %A Tsai, Fuu-Jen %A Hanis, Craig L %A Burdon, Kathryn P %A Wong, Tien Yin %A Cheng, Ching-Yu %K Aged %K Diabetic Retinopathy %K Female %K Genome-Wide Association Study %K Humans %K Lipids %K Male %K Mendelian Randomization Analysis %K Middle Aged %K Polymorphism, Single Nucleotide %K Risk %X

Results from observational studies examining dyslipidemia as a risk factor for diabetic retinopathy (DR) have been inconsistent. We evaluated the causal relationship between plasma lipids and DR using a Mendelian randomization approach. We pooled genome-wide association studies summary statistics from 18 studies for two DR phenotypes: any DR (N = 2,969 case and 4,096 control subjects) and severe DR (N = 1,277 case and 3,980 control subjects). Previously identified lipid-associated single nucleotide polymorphisms served as instrumental variables. Meta-analysis to combine the Mendelian randomization estimates from different cohorts was conducted. There was no statistically significant change in odds ratios of having any DR or severe DR for any of the lipid fractions in the primary analysis that used single nucleotide polymorphisms that did not have a pleiotropic effect on another lipid fraction. Similarly, there was no significant association in the Caucasian and Chinese subgroup analyses. This study did not show evidence of a causal role of the four lipid fractions on DR. However, the study had limited power to detect odds ratios less than 1.23 per SD in genetically induced increase in plasma lipid levels, thus we cannot exclude that causal relationships with more modest effect sizes exist.

%B Diabetes %V 66 %P 3130-3141 %8 2017 12 %G eng %N 12 %R 10.2337/db17-0398 %0 Journal Article %J PLoS One %D 2017 %T Genome-wide association meta-analysis of fish and EPA+DHA consumption in 17 US and European cohorts. %A Mozaffarian, Dariush %A Dashti, Hassan S %A Wojczynski, Mary K %A Chu, Audrey Y %A Nettleton, Jennifer A %A Männistö, Satu %A Kristiansson, Kati %A Reedik, Mägi %A Lahti, Jari %A Houston, Denise K %A Cornelis, Marilyn C %A van Rooij, Frank J A %A Dimitriou, Maria %A Kanoni, Stavroula %A Mikkilä, Vera %A Steffen, Lyn M %A de Oliveira Otto, Marcia C %A Qi, Lu %A Psaty, Bruce %A Djoussé, Luc %A Rotter, Jerome I %A Harald, Kennet %A Perola, Markus %A Rissanen, Harri %A Jula, Antti %A Krista, Fischer %A Mihailov, Evelin %A Feitosa, Mary F %A Ngwa, Julius S %A Xue, Luting %A Jacques, Paul F %A Perälä, Mia-Maria %A Palotie, Aarno %A Liu, Yongmei %A Nalls, Nike A %A Ferrucci, Luigi %A Hernandez, Dena %A Manichaikul, Ani %A Tsai, Michael Y %A Kiefte-de Jong, Jessica C %A Hofman, Albert %A Uitterlinden, André G %A Rallidis, Loukianos %A Ridker, Paul M %A Rose, Lynda M %A Buring, Julie E %A Lehtimäki, Terho %A Kähönen, Mika %A Viikari, Jorma %A Lemaitre, Rozenn %A Salomaa, Veikko %A Knekt, Paul %A Metspalu, Andres %A Borecki, Ingrid B %A Cupples, L Adrienne %A Eriksson, Johan G %A Kritchevsky, Stephen B %A Bandinelli, Stefania %A Siscovick, David %A Franco, Oscar H %A Deloukas, Panos %A Dedoussis, George %A Chasman, Daniel I %A Raitakari, Olli %A Tanaka, Toshiko %K Adult %K Aged %K Cohort Studies %K Docosahexaenoic Acids %K Eicosapentaenoic Acid %K Europe %K European Continental Ancestry Group %K Female %K Genome-Wide Association Study %K Humans %K Male %K Middle Aged %K Seafood %K United States %X

BACKGROUND: Regular fish and omega-3 consumption may have several health benefits and are recommended by major dietary guidelines. Yet, their intakes remain remarkably variable both within and across populations, which could partly owe to genetic influences.

OBJECTIVE: To identify common genetic variants that influence fish and dietary eicosapentaenoic acid plus docosahexaenoic acid (EPA+DHA) consumption.

DESIGN: We conducted genome-wide association (GWA) meta-analysis of fish (n = 86,467) and EPA+DHA (n = 62,265) consumption in 17 cohorts of European descent from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium Nutrition Working Group. Results from cohort-specific GWA analyses (additive model) for fish and EPA+DHA consumption were adjusted for age, sex, energy intake, and population stratification, and meta-analyzed separately using fixed-effect meta-analysis with inverse variance weights (METAL software). Additionally, heritability was estimated in 2 cohorts.

RESULTS: Heritability estimates for fish and EPA+DHA consumption ranged from 0.13-0.24 and 0.12-0.22, respectively. A significant GWA for fish intake was observed for rs9502823 on chromosome 6: each copy of the minor allele (FreqA = 0.015) was associated with 0.029 servings/day (~1 serving/month) lower fish consumption (P = 1.96x10-8). No significant association was observed for EPA+DHA, although rs7206790 in the obesity-associated FTO gene was among top hits (P = 8.18x10-7). Post-hoc calculations demonstrated 95% statistical power to detect a genetic variant associated with effect size of 0.05% for fish and 0.08% for EPA+DHA.

CONCLUSIONS: These novel findings suggest that non-genetic personal and environmental factors are principal determinants of the remarkable variation in fish consumption, representing modifiable targets for increasing intakes among all individuals. Genes underlying the signal at rs72838923 and mechanisms for the association warrant further investigation.

%B PLoS One %V 12 %P e0186456 %8 2017 %G eng %N 12 %R 10.1371/journal.pone.0186456 %0 Journal Article %J Circ Cardiovasc Genet %D 2017 %T Genome-Wide Association Study Meta-Analysis of Long-Term Average Blood Pressure in East Asians. %A Li, Changwei %A Kim, Yun Kyoung %A Dorajoo, Rajkumar %A Li, Huaixing %A Lee, I-Te %A Cheng, Ching-Yu %A He, Meian %A Sheu, Wayne H-H %A Guo, Xiuqing %A Ganesh, Santhi K %A He, Jiang %A Lee, Juyoung %A Liu, Jianjun %A Hu, Yao %A Rao, Dabeeru C %A Tsai, Fuu-Jen %A Koh, Jia Yu %A Hu, Hua %A Liang, Kae-Woei %A Palmas, Walter %A Hixson, James E %A Han, Sohee %A Teo, Yik-Ying %A Wang, Yiqin %A Chen, Jing %A Lu, Chieh Hsiang %A Zheng, Yingfeng %A Gui, Lixuan %A Lee, Wen-Jane %A Yao, Jie %A Gu, Dongfeng %A Han, Bok-Ghee %A Sim, Xueling %A Sun, Liang %A Zhao, Jinying %A Chen, Chien-Hsiun %A Kumari, Neelam %A He, Yunfeng %A Taylor, Kent D %A Raffel, Leslie J %A Moon, Sanghoon %A Rotter, Jerome I %A Ida Chen, Yii-Der %A Wu, Tangchun %A Wong, Tien Yin %A Wu, Jer-Yuarn %A Lin, Xu %A Tai, E-Shyong %A Kim, Bong-Jo %A Kelly, Tanika N %K Asian Continental Ancestry Group %K Blood Pressure %K Far East %K Female %K Genetic Loci %K Genome-Wide Association Study %K Humans %K Male %K Phenotype %K Polymorphism, Single Nucleotide %X

BACKGROUND: Genome-wide single marker and gene-based meta-analyses of long-term average (LTA) blood pressure (BP) phenotypes may reveal novel findings for BP.

METHODS AND RESULTS: We conducted genome-wide analysis among 18 422 East Asian participants (stage 1) followed by replication study of ≤46 629 participants of European ancestry (stage 2). Significant single-nucleotide polymorphisms and genes were determined by a P<5.0×10-8 and 2.5×10-6, respectively, in joint analyses of stage-1 and stage-2 data. We identified 1 novel ARL3 variant, rs4919669 at 10q24.32, influencing LTA systolic BP (stage-1 P=5.03×10-8, stage-2 P=8.64×10-3, joint P=2.63×10-8) and mean arterial pressure (stage-1 P=3.59×10-9, stage-2 P=2.35×10-2, joint P=2.64×10-8). Three previously reported BP loci (WBP1L, NT5C2, and ATP2B1) were also identified for all BP phenotypes. Gene-based analysis provided the first robust evidence for association of KCNJ11 with LTA systolic BP (stage-1 P=8.55×10-6, stage-2 P=1.62×10-5, joint P=3.28×10-9) and mean arterial pressure (stage-1 P=9.19×10-7, stage-2 P=9.69×10-5, joint P=2.15×10-9) phenotypes. Fourteen genes (TMEM180, ACTR1A, SUFU, ARL3, SFXN2, WBP1L, CYP17A1, C10orf32, C10orf32-ASMT, AS3MT, CNNM2, and NT5C2 at 10q24.32; ATP2B1 at 12q21.33; and NCR3LG1 at 11p15.1) implicated by previous genome-wide association study meta-analyses were also identified. Among the loci identified by the previous genome-wide association study meta-analysis of LTA BP, we transethnically replicated associations of the KCNK3 marker rs1275988 at 2p23.3 with LTA systolic BP and mean arterial pressure phenotypes (P=1.27×10-4 and 3.30×10-4, respectively).

CONCLUSIONS: We identified 1 novel variant and 1 novel gene and present the first direct evidence of relevance of the KCNK3 locus for LTA BP among East Asians.

%B Circ Cardiovasc Genet %V 10 %P e001527 %8 2017 Apr %G eng %N 2 %R 10.1161/CIRCGENETICS.116.001527 %0 Journal Article %J PLoS Med %D 2017 %T Impact of common genetic determinants of Hemoglobin A1c on type 2 diabetes risk and diagnosis in ancestrally diverse populations: A transethnic genome-wide meta-analysis. %A Wheeler, Eleanor %A Leong, Aaron %A Liu, Ching-Ti %A Hivert, Marie-France %A Strawbridge, Rona J %A Podmore, Clara %A Li, Man %A Yao, Jie %A Sim, Xueling %A Hong, Jaeyoung %A Chu, Audrey Y %A Zhang, Weihua %A Wang, Xu %A Chen, Peng %A Maruthur, Nisa M %A Porneala, Bianca C %A Sharp, Stephen J %A Jia, Yucheng %A Kabagambe, Edmond K %A Chang, Li-Ching %A Chen, Wei-Min %A Elks, Cathy E %A Evans, Daniel S %A Fan, Qiao %A Giulianini, Franco %A Go, Min Jin %A Hottenga, Jouke-Jan %A Hu, Yao %A Jackson, Anne U %A Kanoni, Stavroula %A Kim, Young Jin %A Kleber, Marcus E %A Ladenvall, Claes %A Lecoeur, Cécile %A Lim, Sing-Hui %A Lu, Yingchang %A Mahajan, Anubha %A Marzi, Carola %A Nalls, Mike A %A Navarro, Pau %A Nolte, Ilja M %A Rose, Lynda M %A Rybin, Denis V %A Sanna, Serena %A Shi, Yuan %A Stram, Daniel O %A Takeuchi, Fumihiko %A Tan, Shu Pei %A van der Most, Peter J %A van Vliet-Ostaptchouk, Jana V %A Wong, Andrew %A Yengo, Loic %A Zhao, Wanting %A Goel, Anuj %A Martinez Larrad, Maria Teresa %A Radke, Dörte %A Salo, Perttu %A Tanaka, Toshiko %A van Iperen, Erik P A %A Abecasis, Goncalo %A Afaq, Saima %A Alizadeh, Behrooz Z %A Bertoni, Alain G %A Bonnefond, Amélie %A Böttcher, Yvonne %A Bottinger, Erwin P %A Campbell, Harry %A Carlson, Olga D %A Chen, Chien-Hsiun %A Cho, Yoon Shin %A Garvey, W Timothy %A Gieger, Christian %A Goodarzi, Mark O %A Grallert, Harald %A Hamsten, Anders %A Hartman, Catharina A %A Herder, Christian %A Hsiung, Chao Agnes %A Huang, Jie %A Igase, Michiya %A Isono, Masato %A Katsuya, Tomohiro %A Khor, Chiea-Chuen %A Kiess, Wieland %A Kohara, Katsuhiko %A Kovacs, Peter %A Lee, Juyoung %A Lee, Wen-Jane %A Lehne, Benjamin %A Li, Huaixing %A Liu, Jianjun %A Lobbens, Stephane %A Luan, Jian'an %A Lyssenko, Valeriya %A Meitinger, Thomas %A Miki, Tetsuro %A Miljkovic, Iva %A Moon, Sanghoon %A Mulas, Antonella %A Müller, Gabriele %A Müller-Nurasyid, Martina %A Nagaraja, Ramaiah %A Nauck, Matthias %A Pankow, James S %A Polasek, Ozren %A Prokopenko, Inga %A Ramos, Paula S %A Rasmussen-Torvik, Laura %A Rathmann, Wolfgang %A Rich, Stephen S %A Robertson, Neil R %A Roden, Michael %A Roussel, Ronan %A Rudan, Igor %A Scott, Robert A %A Scott, William R %A Sennblad, Bengt %A Siscovick, David S %A Strauch, Konstantin %A Sun, Liang %A Swertz, Morris %A Tajuddin, Salman M %A Taylor, Kent D %A Teo, Yik-Ying %A Tham, Yih Chung %A Tönjes, Anke %A Wareham, Nicholas J %A Willemsen, Gonneke %A Wilsgaard, Tom %A Hingorani, Aroon D %A Egan, Josephine %A Ferrucci, Luigi %A Hovingh, G Kees %A Jula, Antti %A Kivimaki, Mika %A Kumari, Meena %A Njølstad, Inger %A Palmer, Colin N A %A Serrano Ríos, Manuel %A Stumvoll, Michael %A Watkins, Hugh %A Aung, Tin %A Blüher, Matthias %A Boehnke, Michael %A Boomsma, Dorret I %A Bornstein, Stefan R %A Chambers, John C %A Chasman, Daniel I %A Chen, Yii-Der Ida %A Chen, Yduan-Tsong %A Cheng, Ching-Yu %A Cucca, Francesco %A de Geus, Eco J C %A Deloukas, Panos %A Evans, Michele K %A Fornage, Myriam %A Friedlander, Yechiel %A Froguel, Philippe %A Groop, Leif %A Gross, Myron D %A Harris, Tamara B %A Hayward, Caroline %A Heng, Chew-Kiat %A Ingelsson, Erik %A Kato, Norihiro %A Kim, Bong-Jo %A Koh, Woon-Puay %A Kooner, Jaspal S %A Körner, Antje %A Kuh, Diana %A Kuusisto, Johanna %A Laakso, Markku %A Lin, Xu %A Liu, Yongmei %A Loos, Ruth J F %A Magnusson, Patrik K E %A März, Winfried %A McCarthy, Mark I %A Oldehinkel, Albertine J %A Ong, Ken K %A Pedersen, Nancy L %A Pereira, Mark A %A Peters, Annette %A Ridker, Paul M %A Sabanayagam, Charumathi %A Sale, Michele %A Saleheen, Danish %A Saltevo, Juha %A Schwarz, Peter Eh %A Sheu, Wayne H H %A Snieder, Harold %A Spector, Timothy D %A Tabara, Yasuharu %A Tuomilehto, Jaakko %A van Dam, Rob M %A Wilson, James G %A Wilson, James F %A Wolffenbuttel, Bruce H R %A Wong, Tien Yin %A Wu, Jer-Yuarn %A Yuan, Jian-Min %A Zonderman, Alan B %A Soranzo, Nicole %A Guo, Xiuqing %A Roberts, David J %A Florez, Jose C %A Sladek, Robert %A Dupuis, Josée %A Morris, Andrew P %A Tai, E-Shyong %A Selvin, Elizabeth %A Rotter, Jerome I %A Langenberg, Claudia %A Barroso, Inês %A Meigs, James B %K Diabetes Mellitus, Type 2 %K Genetic Variation %K Genome-Wide Association Study %K Glycated Hemoglobin A %K Humans %K Phenotype %K Risk %X

BACKGROUND: Glycated hemoglobin (HbA1c) is used to diagnose type 2 diabetes (T2D) and assess glycemic control in patients with diabetes. Previous genome-wide association studies (GWAS) have identified 18 HbA1c-associated genetic variants. These variants proved to be classifiable by their likely biological action as erythrocytic (also associated with erythrocyte traits) or glycemic (associated with other glucose-related traits). In this study, we tested the hypotheses that, in a very large scale GWAS, we would identify more genetic variants associated with HbA1c and that HbA1c variants implicated in erythrocytic biology would affect the diagnostic accuracy of HbA1c. We therefore expanded the number of HbA1c-associated loci and tested the effect of genetic risk-scores comprised of erythrocytic or glycemic variants on incident diabetes prediction and on prevalent diabetes screening performance. Throughout this multiancestry study, we kept a focus on interancestry differences in HbA1c genetics performance that might influence race-ancestry differences in health outcomes.

METHODS & FINDINGS: Using genome-wide association meta-analyses in up to 159,940 individuals from 82 cohorts of European, African, East Asian, and South Asian ancestry, we identified 60 common genetic variants associated with HbA1c. We classified variants as implicated in glycemic, erythrocytic, or unclassified biology and tested whether additive genetic scores of erythrocytic variants (GS-E) or glycemic variants (GS-G) were associated with higher T2D incidence in multiethnic longitudinal cohorts (N = 33,241). Nineteen glycemic and 22 erythrocytic variants were associated with HbA1c at genome-wide significance. GS-G was associated with higher T2D risk (incidence OR = 1.05, 95% CI 1.04-1.06, per HbA1c-raising allele, p = 3 × 10-29); whereas GS-E was not (OR = 1.00, 95% CI 0.99-1.01, p = 0.60). In Europeans and Asians, erythrocytic variants in aggregate had only modest effects on the diagnostic accuracy of HbA1c. Yet, in African Americans, the X-linked G6PD G202A variant (T-allele frequency 11%) was associated with an absolute decrease in HbA1c of 0.81%-units (95% CI 0.66-0.96) per allele in hemizygous men, and 0.68%-units (95% CI 0.38-0.97) in homozygous women. The G6PD variant may cause approximately 2% (N = 0.65 million, 95% CI 0.55-0.74) of African American adults with T2D to remain undiagnosed when screened with HbA1c. Limitations include the smaller sample sizes for non-European ancestries and the inability to classify approximately one-third of the variants. Further studies in large multiethnic cohorts with HbA1c, glycemic, and erythrocytic traits are required to better determine the biological action of the unclassified variants.

CONCLUSIONS: As G6PD deficiency can be clinically silent until illness strikes, we recommend investigation of the possible benefits of screening for the G6PD genotype along with using HbA1c to diagnose T2D in populations of African ancestry or groups where G6PD deficiency is common. Screening with direct glucose measurements, or genetically-informed HbA1c diagnostic thresholds in people with G6PD deficiency, may be required to avoid missed or delayed diagnoses.

%B PLoS Med %V 14 %P e1002383 %8 2017 Sep %G eng %N 9 %R 10.1371/journal.pmed.1002383 %0 Journal Article %J Am J Hum Genet %D 2017 %T Low-Frequency Synonymous Coding Variation in CYP2R1 Has Large Effects on Vitamin D Levels and Risk of Multiple Sclerosis. %A Manousaki, Despoina %A Dudding, Tom %A Haworth, Simon %A Hsu, Yi-Hsiang %A Liu, Ching-Ti %A Medina-Gómez, Carolina %A Voortman, Trudy %A van der Velde, Nathalie %A Melhus, Håkan %A Robinson-Cohen, Cassianne %A Cousminer, Diana L %A Nethander, Maria %A Vandenput, Liesbeth %A Noordam, Raymond %A Forgetta, Vincenzo %A Greenwood, Celia M T %A Biggs, Mary L %A Psaty, Bruce M %A Rotter, Jerome I %A Zemel, Babette S %A Mitchell, Jonathan A %A Taylor, Bruce %A Lorentzon, Mattias %A Karlsson, Magnus %A Jaddoe, Vincent V W %A Tiemeier, Henning %A Campos-Obando, Natalia %A Franco, Oscar H %A Utterlinden, Andre G %A Broer, Linda %A van Schoor, Natasja M %A Ham, Annelies C %A Ikram, M Arfan %A Karasik, David %A de Mutsert, Renée %A Rosendaal, Frits R %A den Heijer, Martin %A Wang, Thomas J %A Lind, Lars %A Orwoll, Eric S %A Mook-Kanamori, Dennis O %A Michaëlsson, Karl %A Kestenbaum, Bryan %A Ohlsson, Claes %A Mellström, Dan %A de Groot, Lisette C P G M %A Grant, Struan F A %A Kiel, Douglas P %A Zillikens, M Carola %A Rivadeneira, Fernando %A Sawcer, Stephen %A Timpson, Nicholas J %A Richards, J Brent %K Cholestanetriol 26-Monooxygenase %K Cytochrome P450 Family 2 %K Gene Frequency %K Genetic Predisposition to Disease %K Genome, Human %K Genome-Wide Association Study %K Humans %K Multiple Sclerosis %K Polymorphism, Single Nucleotide %K Risk Factors %K Vitamin D %K Vitamin D Deficiency %X

Vitamin D insufficiency is common, correctable, and influenced by genetic factors, and it has been associated with risk of several diseases. We sought to identify low-frequency genetic variants that strongly increase the risk of vitamin D insufficiency and tested their effect on risk of multiple sclerosis, a disease influenced by low vitamin D concentrations. We used whole-genome sequencing data from 2,619 individuals through the UK10K program and deep-imputation data from 39,655 individuals genotyped genome-wide. Meta-analysis of the summary statistics from 19 cohorts identified in CYP2R1 the low-frequency (minor allele frequency = 2.5%) synonymous coding variant g.14900931G>A (p.Asp120Asp) (rs117913124[A]), which conferred a large effect on 25-hydroxyvitamin D (25OHD) levels (-0.43 SD of standardized natural log-transformed 25OHD per A allele; p value = 1.5 × 10(-88)). The effect on 25OHD was four times larger and independent of the effect of a previously described common variant near CYP2R1. By analyzing 8,711 individuals, we showed that heterozygote carriers of this low-frequency variant have an increased risk of vitamin D insufficiency (odds ratio [OR] = 2.2, 95% confidence interval [CI] = 1.78-2.78, p = 1.26 × 10(-12)). Individuals carrying one copy of this variant also had increased odds of multiple sclerosis (OR = 1.4, 95% CI = 1.19-1.64, p = 2.63 × 10(-5)) in a sample of 5,927 case and 5,599 control subjects. In conclusion, we describe a low-frequency CYP2R1 coding variant that exerts the largest effect upon 25OHD levels identified to date in the general European population and implicates vitamin D in the etiology of multiple sclerosis.

%B Am J Hum Genet %V 101 %P 227-238 %8 2017 Aug 03 %G eng %N 2 %R 10.1016/j.ajhg.2017.06.014 %0 Journal Article %J J Cardiovasc Transl Res %D 2017 %T Phenotype-Specific Association of Single-Nucleotide Polymorphisms with Heart Failure and Preserved Ejection Fraction: a Genome-Wide Association Analysis of the Cardiovascular Health Study. %A Kao, David P %A Stevens, Laura M %A Hinterberg, Michael A %A Görg, Carsten %K Aged %K Computational Biology %K Databases, Genetic %K European Continental Ancestry Group %K Female %K Gene Expression Profiling %K Genetic Markers %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Heart Failure %K Humans %K Male %K Oligonucleotide Array Sequence Analysis %K Phenotype %K Polymorphism, Single Nucleotide %K Predictive Value of Tests %K Prognosis %K Proteoglycans %K Receptors, Transforming Growth Factor beta %K Risk Assessment %K Risk Factors %K Stroke Volume %K United States %X

Little is known about genetics of heart failure with preserved ejection fraction (HFpEF) in part because of the many comorbidities in this population. To identify single-nucleotide polymorphisms (SNPs) associated with HFpEF, we analyzed phenotypic and genotypic data from the Cardiovascular Health Study, which profiled patients using a 50,000 SNP array. Results were explored using novel SNP- and gene-centric tools. We performed analyses to determine whether some SNPs were relevant only in certain phenotypes. Among 3804 patients, 7 clinical factors and 9 SNPs were significantly associated with HFpEF; the most notable of which was rs6996224, a SNP associated with transforming growth factor-beta receptor 3. Most SNPs were associated with HFpEF only in the absence of a clinical predictor. Significant SNPs represented genes involved in myocyte proliferation, transforming growth factor-beta/erbB signaling, and extracellular matrix formation. These findings suggest that genetic factors may be more important in some phenotypes than others.

%B J Cardiovasc Transl Res %V 10 %P 285-294 %8 2017 Jun %G eng %N 3 %R 10.1007/s12265-017-9729-1 %0 Journal Article %J PLoS Genet %D 2017 %T Rare coding variants pinpoint genes that control human hematological traits. %A Mousas, Abdou %A Ntritsos, Georgios %A Chen, Ming-Huei %A Song, Ci %A Huffman, Jennifer E %A Tzoulaki, Ioanna %A Elliott, Paul %A Psaty, Bruce M %A Auer, Paul L %A Johnson, Andrew D %A Evangelou, Evangelos %A Lettre, Guillaume %A Reiner, Alexander P %K Asthma %K Databases, Genetic %K Endometriosis %K Female %K Fibrin Fibrinogen Degradation Products %K Gene Frequency %K Genetic Loci %K Genome, Human %K Genome-Wide Association Study %K Humans %K Interleukin-33 %K Linear Models %K Logistic Models %K Male %K Mutation, Missense %K Phenotype %K Plasminogen %K Platelet Count %K Polymorphism, Single Nucleotide %K Principal Component Analysis %K Protein Splicing %K Rhinitis, Allergic %K Sequence Analysis, DNA %X

The identification of rare coding or splice site variants remains the most straightforward strategy to link genes with human phenotypes. Here, we analyzed the association between 137,086 rare (minor allele frequency (MAF) <1%) coding or splice site variants and 15 hematological traits in up to 308,572 participants. We found 56 such rare coding or splice site variants at P<5x10-8, including 31 that are associated with a blood-cell phenotype for the first time. All but one of these 31 new independent variants map to loci previously implicated in hematopoiesis by genome-wide association studies (GWAS). This includes a rare splice acceptor variant (rs146597587, MAF = 0.5%) in interleukin 33 (IL33) associated with reduced eosinophil count (P = 2.4x10-23), and lower risk of asthma (P = 2.6x10-7, odds ratio [95% confidence interval] = 0.56 [0.45-0.70]) and allergic rhinitis (P = 4.2x10-4, odds ratio = 0.55 [0.39-0.76]). The single new locus identified in our study is defined by a rare p.Arg172Gly missense variant (rs145535174, MAF = 0.05%) in plasminogen (PLG) associated with increased platelet count (P = 6.8x10-9), and decreased D-dimer concentration (P = 0.018) and platelet reactivity (P<0.03). Finally, our results indicate that searching for rare coding or splice site variants in very large sample sizes can help prioritize causal genes at many GWAS loci associated with complex human diseases and traits.

%B PLoS Genet %V 13 %P e1006925 %8 2017 Aug %G eng %N 8 %R 10.1371/journal.pgen.1006925 %0 Journal Article %J PLoS Genet %D 2017 %T Single-trait and multi-trait genome-wide association analyses identify novel loci for blood pressure in African-ancestry populations. %A Liang, Jingjing %A Le, Thu H %A Edwards, Digna R Velez %A Tayo, Bamidele O %A Gaulton, Kyle J %A Smith, Jennifer A %A Lu, Yingchang %A Jensen, Richard A %A Chen, Guanjie %A Yanek, Lisa R %A Schwander, Karen %A Tajuddin, Salman M %A Sofer, Tamar %A Kim, Wonji %A Kayima, James %A McKenzie, Colin A %A Fox, Ervin %A Nalls, Michael A %A Young, J Hunter %A Sun, Yan V %A Lane, Jacqueline M %A Cechova, Sylvia %A Zhou, Jie %A Tang, Hua %A Fornage, Myriam %A Musani, Solomon K %A Wang, Heming %A Lee, Juyoung %A Adeyemo, Adebowale %A Dreisbach, Albert W %A Forrester, Terrence %A Chu, Pei-Lun %A Cappola, Anne %A Evans, Michele K %A Morrison, Alanna C %A Martin, Lisa W %A Wiggins, Kerri L %A Hui, Qin %A Zhao, Wei %A Jackson, Rebecca D %A Ware, Erin B %A Faul, Jessica D %A Reiner, Alex P %A Bray, Michael %A Denny, Joshua C %A Mosley, Thomas H %A Palmas, Walter %A Guo, Xiuqing %A Papanicolaou, George J %A Penman, Alan D %A Polak, Joseph F %A Rice, Kenneth %A Taylor, Ken D %A Boerwinkle, Eric %A Bottinger, Erwin P %A Liu, Kiang %A Risch, Neil %A Hunt, Steven C %A Kooperberg, Charles %A Zonderman, Alan B %A Laurie, Cathy C %A Becker, Diane M %A Cai, Jianwen %A Loos, Ruth J F %A Psaty, Bruce M %A Weir, David R %A Kardia, Sharon L R %A Arnett, Donna K %A Won, Sungho %A Edwards, Todd L %A Redline, Susan %A Cooper, Richard S %A Rao, D C %A Rotter, Jerome I %A Rotimi, Charles %A Levy, Daniel %A Chakravarti, Aravinda %A Zhu, Xiaofeng %A Franceschini, Nora %K African Americans %K Animals %K Basic Helix-Loop-Helix Transcription Factors %K Blood Pressure %K Cadherins %K Case-Control Studies %K Female %K Genetic Loci %K Genome-Wide Association Study %K Humans %K Hypertension %K Male %K Membrane Proteins %K Mice %K Multifactorial Inheritance %K Polymorphism, Single Nucleotide %X

Hypertension is a leading cause of global disease, mortality, and disability. While individuals of African descent suffer a disproportionate burden of hypertension and its complications, they have been underrepresented in genetic studies. To identify novel susceptibility loci for blood pressure and hypertension in people of African ancestry, we performed both single and multiple-trait genome-wide association analyses. We analyzed 21 genome-wide association studies comprised of 31,968 individuals of African ancestry, and validated our results with additional 54,395 individuals from multi-ethnic studies. These analyses identified nine loci with eleven independent variants which reached genome-wide significance (P < 1.25×10-8) for either systolic and diastolic blood pressure, hypertension, or for combined traits. Single-trait analyses identified two loci (TARID/TCF21 and LLPH/TMBIM4) and multiple-trait analyses identified one novel locus (FRMD3) for blood pressure. At these three loci, as well as at GRP20/CDH17, associated variants had alleles common only in African-ancestry populations. Functional annotation showed enrichment for genes expressed in immune and kidney cells, as well as in heart and vascular cells/tissues. Experiments driven by these findings and using angiotensin-II induced hypertension in mice showed altered kidney mRNA expression of six genes, suggesting their potential role in hypertension. Our study provides new evidence for genes related to hypertension susceptibility, and the need to study African-ancestry populations in order to identify biologic factors contributing to hypertension.

%B PLoS Genet %V 13 %P e1006728 %8 2017 May %G eng %N 5 %R 10.1371/journal.pgen.1006728 %0 Journal Article %J Alzheimers Dement %D 2017 %T Systems biology approach to late-onset Alzheimer's disease genome-wide association study identifies novel candidate genes validated using brain expression data and Caenorhabditis elegans experiments. %A Mukherjee, Shubhabrata %A Russell, Joshua C %A Carr, Daniel T %A Burgess, Jeremy D %A Allen, Mariet %A Serie, Daniel J %A Boehme, Kevin L %A Kauwe, John S K %A Naj, Adam C %A Fardo, David W %A Dickson, Dennis W %A Montine, Thomas J %A Ertekin-Taner, Nilufer %A Kaeberlein, Matt R %A Crane, Paul K %K Alzheimer Disease %K Amyloid beta-Peptides %K Amyloid beta-Protein Precursor %K Animals %K Animals, Genetically Modified %K Antigens, Neoplasm %K Caenorhabditis elegans %K Disease Models, Animal %K Early Growth Response Protein 1 %K Female %K Gene Expression Regulation %K Genome-Wide Association Study %K Heparin-binding EGF-like Growth Factor %K Humans %K Male %K Membrane Transport Proteins %K Mitochondrial ADP, ATP Translocases %K NADH Dehydrogenase %K Polymorphism, Single Nucleotide %K Protein Interaction Maps %K RNA Interference %K Systems Biology %K Temporal Lobe %X

INTRODUCTION: We sought to determine whether a systems biology approach may identify novel late-onset Alzheimer's disease (LOAD) loci.

METHODS: We performed gene-wide association analyses and integrated results with human protein-protein interaction data using network analyses. We performed functional validation on novel genes using a transgenic Caenorhabditis elegans Aβ proteotoxicity model and evaluated novel genes using brain expression data from people with LOAD and other neurodegenerative conditions.

RESULTS: We identified 13 novel candidate LOAD genes outside chromosome 19. Of those, RNA interference knockdowns of the C. elegans orthologs of UBC, NDUFS3, EGR1, and ATP5H were associated with Aβ toxicity, and NDUFS3, SLC25A11, ATP5H, and APP were differentially expressed in the temporal cortex.

DISCUSSION: Network analyses identified novel LOAD candidate genes. We demonstrated a functional role for four of these in a C. elegans model and found enrichment of differentially expressed genes in the temporal cortex.

%B Alzheimers Dement %V 13 %P 1133-1142 %8 2017 Oct %G eng %N 10 %R 10.1016/j.jalz.2017.01.016 %0 Journal Article %J PLoS One %D 2018 %T Genome-wide association meta-analysis of circulating odd-numbered chain saturated fatty acids: Results from the CHARGE Consortium. %A de Oliveira Otto, Marcia C %A Lemaitre, Rozenn N %A Sun, Qi %A King, Irena B %A Wu, Jason H Y %A Manichaikul, Ani %A Rich, Stephen S %A Tsai, Michael Y %A Chen, Y D %A Fornage, Myriam %A Weihua, Guan %A Aslibekyan, Stella %A Irvin, Marguerite R %A Kabagambe, Edmond K %A Arnett, Donna K %A Jensen, Majken K %A McKnight, Barbara %A Psaty, Bruce M %A Steffen, Lyn M %A Smith, Caren E %A Riserus, Ulf %A Lind, Lars %A Hu, Frank B %A Rimm, Eric B %A Siscovick, David S %A Mozaffarian, Dariush %K Fatty Acids %K Genome-Wide Association Study %K Humans %K Introns %K Lactase %K Myosins %K Polymorphism, Single Nucleotide %K Sphingomyelins %K Sphingosine N-Acyltransferase %K Tumor Suppressor Proteins %X

BACKGROUND: Odd-numbered chain saturated fatty acids (OCSFA) have been associated with potential health benefits. Although some OCSFA (e.g., C15:0 and C17:0) are found in meats and dairy products, sources and metabolism of C19:0 and C23:0 are relatively unknown, and the influence of non-dietary determinants, including genetic factors, on circulating levels of OCSFA is not established.

OBJECTIVE: To elucidate the biological processes that influence circulating levels of OCSFA by investigating associations between genetic variation and OCSFA.

DESIGN: We performed a meta-analysis of genome-wide association studies (GWAS) of plasma phospholipid/erythrocyte levels of C15:0, C17:0, C19:0, and C23:0 among 11,494 individuals of European descent. We also investigated relationships between specific single nucleotide polymorphisms (SNPs) in the lactase (LCT) gene, associated with adult-onset lactase intolerance, with circulating levels of dairy-derived OCSFA, and evaluated associations of candidate sphingolipid genes with C23:0 levels.

RESULTS: We found no genome-wide significant evidence that common genetic variation is associated with circulating levels of C15:0 or C23:0. In two cohorts with available data, we identified one intronic SNP (rs13361131) in myosin X gene (MYO10) associated with C17:0 level (P = 1.37×10-8), and two intronic SNP (rs12874278 and rs17363566) in deleted in lymphocytic leukemia 1 (DLEU1) region associated with C19:0 level (P = 7.07×10-9). In contrast, when using a candidate-gene approach, we found evidence that three SNPs in LCT (rs11884924, rs16832067, and rs3816088) are associated with circulating C17:0 level (adjusted P = 4×10-2). In addition, nine SNPs in the ceramide synthase 4 (CERS4) region were associated with circulating C23:0 levels (adjusted P<5×10-2).

CONCLUSIONS: Our findings suggest that circulating levels of OCSFA may be predominantly influenced by non-genetic factors. SNPs associated with C17:0 level in the LCT gene may reflect genetic influence in dairy consumption or in metabolism of dairy foods. SNPs associated with C23:0 may reflect a role of genetic factors in the synthesis of sphingomyelin.

%B PLoS One %V 13 %P e0196951 %8 2018 %G eng %N 5 %R 10.1371/journal.pone.0196951 %0 Journal Article %J Nat Commun %D 2018 %T GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes. %A Franceschini, Nora %A Giambartolomei, Claudia %A de Vries, Paul S %A Finan, Chris %A Bis, Joshua C %A Huntley, Rachael P %A Lovering, Ruth C %A Tajuddin, Salman M %A Winkler, Thomas W %A Graff, Misa %A Kavousi, Maryam %A Dale, Caroline %A Smith, Albert V %A Hofer, Edith %A van Leeuwen, Elisabeth M %A Nolte, Ilja M %A Lu, Lingyi %A Scholz, Markus %A Sargurupremraj, Muralidharan %A Pitkänen, Niina %A Franzén, Oscar %A Joshi, Peter K %A Noordam, Raymond %A Marioni, Riccardo E %A Hwang, Shih-Jen %A Musani, Solomon K %A Schminke, Ulf %A Palmas, Walter %A Isaacs, Aaron %A Correa, Adolfo %A Zonderman, Alan B %A Hofman, Albert %A Teumer, Alexander %A Cox, Amanda J %A Uitterlinden, André G %A Wong, Andrew %A Smit, Andries J %A Newman, Anne B %A Britton, Annie %A Ruusalepp, Arno %A Sennblad, Bengt %A Hedblad, Bo %A Pasaniuc, Bogdan %A Penninx, Brenda W %A Langefeld, Carl D %A Wassel, Christina L %A Tzourio, Christophe %A Fava, Cristiano %A Baldassarre, Damiano %A O'Leary, Daniel H %A Teupser, Daniel %A Kuh, Diana %A Tremoli, Elena %A Mannarino, Elmo %A Grossi, Enzo %A Boerwinkle, Eric %A Schadt, Eric E %A Ingelsson, Erik %A Veglia, Fabrizio %A Rivadeneira, Fernando %A Beutner, Frank %A Chauhan, Ganesh %A Heiss, Gerardo %A Snieder, Harold %A Campbell, Harry %A Völzke, Henry %A Markus, Hugh S %A Deary, Ian J %A Jukema, J Wouter %A de Graaf, Jacqueline %A Price, Jacqueline %A Pott, Janne %A Hopewell, Jemma C %A Liang, Jingjing %A Thiery, Joachim %A Engmann, Jorgen %A Gertow, Karl %A Rice, Kenneth %A Taylor, Kent D %A Dhana, Klodian %A Kiemeney, Lambertus A L M %A Lind, Lars %A Raffield, Laura M %A Launer, Lenore J %A Holdt, Lesca M %A Dörr, Marcus %A Dichgans, Martin %A Traylor, Matthew %A Sitzer, Matthias %A Kumari, Meena %A Kivimaki, Mika %A Nalls, Mike A %A Melander, Olle %A Raitakari, Olli %A Franco, Oscar H %A Rueda-Ochoa, Oscar L %A Roussos, Panos %A Whincup, Peter H %A Amouyel, Philippe %A Giral, Philippe %A Anugu, Pramod %A Wong, Quenna %A Malik, Rainer %A Rauramaa, Rainer %A Burkhardt, Ralph %A Hardy, Rebecca %A Schmidt, Reinhold %A de Mutsert, Renée %A Morris, Richard W %A Strawbridge, Rona J %A Wannamethee, S Goya %A Hägg, Sara %A Shah, Sonia %A McLachlan, Stela %A Trompet, Stella %A Seshadri, Sudha %A Kurl, Sudhir %A Heckbert, Susan R %A Ring, Susan %A Harris, Tamara B %A Lehtimäki, Terho %A Galesloot, Tessel E %A Shah, Tina %A de Faire, Ulf %A Plagnol, Vincent %A Rosamond, Wayne D %A Post, Wendy %A Zhu, Xiaofeng %A Zhang, Xiaoling %A Guo, Xiuqing %A Saba, Yasaman %A Dehghan, Abbas %A Seldenrijk, Adrie %A Morrison, Alanna C %A Hamsten, Anders %A Psaty, Bruce M %A van Duijn, Cornelia M %A Lawlor, Deborah A %A Mook-Kanamori, Dennis O %A Bowden, Donald W %A Schmidt, Helena %A Wilson, James F %A Wilson, James G %A Rotter, Jerome I %A Wardlaw, Joanna M %A Deanfield, John %A Halcox, Julian %A Lyytikäinen, Leo-Pekka %A Loeffler, Markus %A Evans, Michele K %A Debette, Stephanie %A Humphries, Steve E %A Völker, Uwe %A Gudnason, Vilmundur %A Hingorani, Aroon D %A Björkegren, Johan L M %A Casas, Juan P %A O'Donnell, Christopher J %K ADAMTS9 Protein %K Amino Acid Oxidoreductases %K Carotid Intima-Media Thickness %K Coronary Disease %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Lod Score %K Plaque, Atherosclerotic %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %K Risk Factors %X

Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans.

%B Nat Commun %V 9 %P 5141 %8 2018 12 03 %G eng %N 1 %R 10.1038/s41467-018-07340-5 %0 Journal Article %J Aging (Albany NY) %D 2018 %T Strong impact of natural-selection-free heterogeneity in genetics of age-related phenotypes. %A Kulminski, Alexander M %A Huang, Jian %A Loika, Yury %A Arbeev, Konstantin G %A Bagley, Olivia %A Yashkin, Arseniy %A Duan, Matt %A Culminskaya, Irina %K Aging %K Computational Biology %K Gene Expression Regulation %K Genome-Wide Association Study %K Genotype %K Humans %K Polymorphism, Single Nucleotide %X

A conceptual difficulty in genetics of age-related phenotypes that make individuals vulnerable to disease in post-reproductive life is genetic heterogeneity attributed to an undefined role of evolution in establishing their molecular mechanisms. Here, we performed univariate and pleiotropic genome-wide meta-analyses of 20 age-related phenotypes leveraging longitudinal information in a sample of 33,431 individuals and dealing with the natural-selection-free genetic heterogeneity. We identified 142 non-proxy single nucleotide polymorphisms (SNPs) with phenotype-specific (18 SNPs) and pleiotropic (124 SNPs) associations at genome-wide level. Univariate meta-analysis identified two novel (11.1%) and replicated 16 SNPs whereas pleiotropic meta-analysis identified 115 novel (92.7%) and nine replicated SNPs. Pleiotropic associations for most novel (93.9%) and all replicated SNPs were strongly impacted by the natural-selection-free genetic heterogeneity in its unconventional form of antagonistic heterogeneity, implying antagonistic directions of genetic effects for directly correlated phenotypes. Our results show that the common genome-wide approach is well adapted to handle homogeneous univariate associations within Mendelian framework whereas most associations with age-related phenotypes are more complex and well beyond that framework. Dissecting the natural-selection-free genetic heterogeneity is critical for gaining insights into genetics of age-related phenotypes and has substantial and unexplored yet potential for improving efficiency of genome-wide analysis.

%B Aging (Albany NY) %V 10 %P 492-514 %8 2018 03 29 %G eng %N 3 %R 10.18632/aging.101407 %0 Journal Article %J PLoS Genet %D 2019 %T Associations of variants In the hexokinase 1 and interleukin 18 receptor regions with oxyhemoglobin saturation during sleep. %A Cade, Brian E %A Chen, Han %A Stilp, Adrienne M %A Louie, Tin %A Ancoli-Israel, Sonia %A Arens, Raanan %A Barfield, Richard %A Below, Jennifer E %A Cai, Jianwen %A Conomos, Matthew P %A Evans, Daniel S %A Frazier-Wood, Alexis C %A Gharib, Sina A %A Gleason, Kevin J %A Gottlieb, Daniel J %A Hillman, David R %A Johnson, W Craig %A Lederer, David J %A Lee, Jiwon %A Loredo, Jose S %A Mei, Hao %A Mukherjee, Sutapa %A Patel, Sanjay R %A Post, Wendy S %A Purcell, Shaun M %A Ramos, Alberto R %A Reid, Kathryn J %A Rice, Ken %A Shah, Neomi A %A Sofer, Tamar %A Taylor, Kent D %A Thornton, Timothy A %A Wang, Heming %A Yaffe, Kristine %A Zee, Phyllis C %A Hanis, Craig L %A Palmer, Lyle J %A Rotter, Jerome I %A Stone, Katie L %A Tranah, Gregory J %A Wilson, James G %A Sunyaev, Shamil R %A Laurie, Cathy C %A Zhu, Xiaofeng %A Saxena, Richa %A Lin, Xihong %A Redline, Susan %K Adolescent %K Adult %K Aged %K Aged, 80 and over %K Cell Adhesion Molecules, Neuronal %K Computational Biology %K Extracellular Matrix Proteins %K Female %K Gene Regulatory Networks %K Genetic Variation %K Genome-Wide Association Study %K Hexokinase %K Humans %K Hypoxia %K Interleukin-18 Receptor alpha Subunit %K Male %K Middle Aged %K Nerve Tissue Proteins %K NLR Family, Pyrin Domain-Containing 3 Protein %K Oxygen %K Oxyhemoglobins %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %K Serine Endopeptidases %K Sleep %K Sleep Apnea Syndromes %K Young Adult %X

Sleep disordered breathing (SDB)-related overnight hypoxemia is associated with cardiometabolic disease and other comorbidities. Understanding the genetic bases for variations in nocturnal hypoxemia may help understand mechanisms influencing oxygenation and SDB-related mortality. We conducted genome-wide association tests across 10 cohorts and 4 populations to identify genetic variants associated with three correlated measures of overnight oxyhemoglobin saturation: average and minimum oxyhemoglobin saturation during sleep and the percent of sleep with oxyhemoglobin saturation under 90%. The discovery sample consisted of 8,326 individuals. Variants with p < 1 × 10(-6) were analyzed in a replication group of 14,410 individuals. We identified 3 significantly associated regions, including 2 regions in multi-ethnic analyses (2q12, 10q22). SNPs in the 2q12 region associated with minimum SpO2 (rs78136548 p = 2.70 × 10(-10)). SNPs at 10q22 were associated with all three traits including average SpO2 (rs72805692 p = 4.58 × 10(-8)). SNPs in both regions were associated in over 20,000 individuals and are supported by prior associations or functional evidence. Four additional significant regions were detected in secondary sex-stratified and combined discovery and replication analyses, including a region overlapping Reelin, a known marker of respiratory complex neurons.These are the first genome-wide significant findings reported for oxyhemoglobin saturation during sleep, a phenotype of high clinical interest. Our replicated associations with HK1 and IL18R1 suggest that variants in inflammatory pathways, such as the biologically-plausible NLRP3 inflammasome, may contribute to nocturnal hypoxemia.

%B PLoS Genet %V 15 %P e1007739 %8 2019 04 %G eng %N 4 %R 10.1371/journal.pgen.1007739 %0 Journal Article %J Circulation %D 2019 %T Blood Leukocyte DNA Methylation Predicts Risk of Future Myocardial Infarction and Coronary Heart Disease. %A Agha, Golareh %A Mendelson, Michael M %A Ward-Caviness, Cavin K %A Joehanes, Roby %A Huan, Tianxiao %A Gondalia, Rahul %A Salfati, Elias %A Brody, Jennifer A %A Fiorito, Giovanni %A Bressler, Jan %A Chen, Brian H %A Ligthart, Symen %A Guarrera, Simonetta %A Colicino, Elena %A Just, Allan C %A Wahl, Simone %A Gieger, Christian %A Vandiver, Amy R %A Tanaka, Toshiko %A Hernandez, Dena G %A Pilling, Luke C %A Singleton, Andrew B %A Sacerdote, Carlotta %A Krogh, Vittorio %A Panico, Salvatore %A Tumino, Rosario %A Li, Yun %A Zhang, Guosheng %A Stewart, James D %A Floyd, James S %A Wiggins, Kerri L %A Rotter, Jerome I %A Multhaup, Michael %A Bakulski, Kelly %A Horvath, Steven %A Tsao, Philip S %A Absher, Devin M %A Vokonas, Pantel %A Hirschhorn, Joel %A Fallin, M Daniele %A Liu, Chunyu %A Bandinelli, Stefania %A Boerwinkle, Eric %A Dehghan, Abbas %A Schwartz, Joel D %A Psaty, Bruce M %A Feinberg, Andrew P %A Hou, Lifang %A Ferrucci, Luigi %A Sotoodehnia, Nona %A Matullo, Giuseppe %A Peters, Annette %A Fornage, Myriam %A Assimes, Themistocles L %A Whitsel, Eric A %A Levy, Daniel %A Baccarelli, Andrea A %K Adult %K Aged %K Cohort Studies %K Coronary Disease %K CpG Islands %K DNA Methylation %K Europe %K Female %K Genome-Wide Association Study %K Humans %K Incidence %K Leukocytes %K Male %K Middle Aged %K Myocardial Infarction %K Population Groups %K Prognosis %K Prospective Studies %K Risk %K United States %X

BACKGROUND: DNA methylation is implicated in coronary heart disease (CHD), but current evidence is based on small, cross-sectional studies. We examined blood DNA methylation in relation to incident CHD across multiple prospective cohorts.

METHODS: Nine population-based cohorts from the United States and Europe profiled epigenome-wide blood leukocyte DNA methylation using the Illumina Infinium 450k microarray, and prospectively ascertained CHD events including coronary insufficiency/unstable angina, recognized myocardial infarction, coronary revascularization, and coronary death. Cohorts conducted race-specific analyses adjusted for age, sex, smoking, education, body mass index, blood cell type proportions, and technical variables. We conducted fixed-effect meta-analyses across cohorts.

RESULTS: Among 11 461 individuals (mean age 64 years, 67% women, 35% African American) free of CHD at baseline, 1895 developed CHD during a mean follow-up of 11.2 years. Methylation levels at 52 CpG (cytosine-phosphate-guanine) sites were associated with incident CHD or myocardial infarction (false discovery rate<0.05). These CpGs map to genes with key roles in calcium regulation (ATP2B2, CASR, GUCA1B, HPCAL1), and genes identified in genome- and epigenome-wide studies of serum calcium (CASR), serum calcium-related risk of CHD (CASR), coronary artery calcified plaque (PTPRN2), and kidney function (CDH23, HPCAL1), among others. Mendelian randomization analyses supported a causal effect of DNA methylation on incident CHD; these CpGs map to active regulatory regions proximal to long non-coding RNA transcripts.

CONCLUSION: Methylation of blood-derived DNA is associated with risk of future CHD across diverse populations and may serve as an informative tool for gaining further insight on the development of CHD.

%B Circulation %V 140 %P 645-657 %8 2019 08 20 %G eng %N 8 %R 10.1161/CIRCULATIONAHA.118.039357 %0 Journal Article %J Nat Genet %D 2019 %T A catalog of genetic loci associated with kidney function from analyses of a million individuals. %A Wuttke, Matthias %A Li, Yong %A Li, Man %A Sieber, Karsten B %A Feitosa, Mary F %A Gorski, Mathias %A Tin, Adrienne %A Wang, Lihua %A Chu, Audrey Y %A Hoppmann, Anselm %A Kirsten, Holger %A Giri, Ayush %A Chai, Jin-Fang %A Sveinbjornsson, Gardar %A Tayo, Bamidele O %A Nutile, Teresa %A Fuchsberger, Christian %A Marten, Jonathan %A Cocca, Massimiliano %A Ghasemi, Sahar %A Xu, Yizhe %A Horn, Katrin %A Noce, Damia %A van der Most, Peter J %A Sedaghat, Sanaz %A Yu, Zhi %A Akiyama, Masato %A Afaq, Saima %A Ahluwalia, Tarunveer S %A Almgren, Peter %A Amin, Najaf %A Arnlöv, Johan %A Bakker, Stephan J L %A Bansal, Nisha %A Baptista, Daniela %A Bergmann, Sven %A Biggs, Mary L %A Biino, Ginevra %A Boehnke, Michael %A Boerwinkle, Eric %A Boissel, Mathilde %A Bottinger, Erwin P %A Boutin, Thibaud S %A Brenner, Hermann %A Brumat, Marco %A Burkhardt, Ralph %A Butterworth, Adam S %A Campana, Eric %A Campbell, Archie %A Campbell, Harry %A Canouil, Mickaël %A Carroll, Robert J %A Catamo, Eulalia %A Chambers, John C %A Chee, Miao-Ling %A Chee, Miao-Li %A Chen, Xu %A Cheng, Ching-Yu %A Cheng, Yurong %A Christensen, Kaare %A Cifkova, Renata %A Ciullo, Marina %A Concas, Maria Pina %A Cook, James P %A Coresh, Josef %A Corre, Tanguy %A Sala, Cinzia Felicita %A Cusi, Daniele %A Danesh, John %A Daw, E Warwick %A de Borst, Martin H %A De Grandi, Alessandro %A de Mutsert, Renée %A de Vries, Aiko P J %A Degenhardt, Frauke %A Delgado, Graciela %A Demirkan, Ayse %A Di Angelantonio, Emanuele %A Dittrich, Katalin %A Divers, Jasmin %A Dorajoo, Rajkumar %A Eckardt, Kai-Uwe %A Ehret, Georg %A Elliott, Paul %A Endlich, Karlhans %A Evans, Michele K %A Felix, Janine F %A Foo, Valencia Hui Xian %A Franco, Oscar H %A Franke, Andre %A Freedman, Barry I %A Freitag-Wolf, Sandra %A Friedlander, Yechiel %A Froguel, Philippe %A Gansevoort, Ron T %A Gao, He %A Gasparini, Paolo %A Gaziano, J Michael %A Giedraitis, Vilmantas %A Gieger, Christian %A Girotto, Giorgia %A Giulianini, Franco %A Gögele, Martin %A Gordon, Scott D %A Gudbjartsson, Daniel F %A Gudnason, Vilmundur %A Haller, Toomas %A Hamet, Pavel %A Harris, Tamara B %A Hartman, Catharina A %A Hayward, Caroline %A Hellwege, Jacklyn N %A Heng, Chew-Kiat %A Hicks, Andrew A %A Hofer, Edith %A Huang, Wei %A Hutri-Kähönen, Nina %A Hwang, Shih-Jen %A Ikram, M Arfan %A Indridason, Olafur S %A Ingelsson, Erik %A Ising, Marcus %A Jaddoe, Vincent W V %A Jakobsdottir, Johanna %A Jonas, Jost B %A Joshi, Peter K %A Josyula, Navya Shilpa %A Jung, Bettina %A Kähönen, Mika %A Kamatani, Yoichiro %A Kammerer, Candace M %A Kanai, Masahiro %A Kastarinen, Mika %A Kerr, Shona M %A Khor, Chiea-Chuen %A Kiess, Wieland %A Kleber, Marcus E %A Koenig, Wolfgang %A Kooner, Jaspal S %A Körner, Antje %A Kovacs, Peter %A Kraja, Aldi T %A Krajcoviechova, Alena %A Kramer, Holly %A Krämer, Bernhard K %A Kronenberg, Florian %A Kubo, Michiaki %A Kuhnel, Brigitte %A Kuokkanen, Mikko %A Kuusisto, Johanna %A La Bianca, Martina %A Laakso, Markku %A Lange, Leslie A %A Langefeld, Carl D %A Lee, Jeannette Jen-Mai %A Lehne, Benjamin %A Lehtimäki, Terho %A Lieb, Wolfgang %A Lim, Su-Chi %A Lind, Lars %A Lindgren, Cecilia M %A Liu, Jun %A Liu, Jianjun %A Loeffler, Markus %A Loos, Ruth J F %A Lucae, Susanne %A Lukas, Mary Ann %A Lyytikäinen, Leo-Pekka %A Mägi, Reedik %A Magnusson, Patrik K E %A Mahajan, Anubha %A Martin, Nicholas G %A Martins, Jade %A März, Winfried %A Mascalzoni, Deborah %A Matsuda, Koichi %A Meisinger, Christa %A Meitinger, Thomas %A Melander, Olle %A Metspalu, Andres %A Mikaelsdottir, Evgenia K %A Milaneschi, Yuri %A Miliku, Kozeta %A Mishra, Pashupati P %A Mohlke, Karen L %A Mononen, Nina %A Montgomery, Grant W %A Mook-Kanamori, Dennis O %A Mychaleckyj, Josyf C %A Nadkarni, Girish N %A Nalls, Mike A %A Nauck, Matthias %A Nikus, Kjell %A Ning, Boting %A Nolte, Ilja M %A Noordam, Raymond %A O'Connell, Jeffrey %A O'Donoghue, Michelle L %A Olafsson, Isleifur %A Oldehinkel, Albertine J %A Orho-Melander, Marju %A Ouwehand, Willem H %A Padmanabhan, Sandosh %A Palmer, Nicholette D %A Palsson, Runolfur %A Penninx, Brenda W J H %A Perls, Thomas %A Perola, Markus %A Pirastu, Mario %A Pirastu, Nicola %A Pistis, Giorgio %A Podgornaia, Anna I %A Polasek, Ozren %A Ponte, Belen %A Porteous, David J %A Poulain, Tanja %A Pramstaller, Peter P %A Preuss, Michael H %A Prins, Bram P %A Province, Michael A %A Rabelink, Ton J %A Raffield, Laura M %A Raitakari, Olli T %A Reilly, Dermot F %A Rettig, Rainer %A Rheinberger, Myriam %A Rice, Kenneth M %A Ridker, Paul M %A Rivadeneira, Fernando %A Rizzi, Federica %A Roberts, David J %A Robino, Antonietta %A Rossing, Peter %A Rudan, Igor %A Rueedi, Rico %A Ruggiero, Daniela %A Ryan, Kathleen A %A Saba, Yasaman %A Sabanayagam, Charumathi %A Salomaa, Veikko %A Salvi, Erika %A Saum, Kai-Uwe %A Schmidt, Helena %A Schmidt, Reinhold %A Schöttker, Ben %A Schulz, Christina-Alexandra %A Schupf, Nicole %A Shaffer, Christian M %A Shi, Yuan %A Smith, Albert V %A Smith, Blair H %A Soranzo, Nicole %A Spracklen, Cassandra N %A Strauch, Konstantin %A Stringham, Heather M %A Stumvoll, Michael %A Svensson, Per O %A Szymczak, Silke %A Tai, E-Shyong %A Tajuddin, Salman M %A Tan, Nicholas Y Q %A Taylor, Kent D %A Teren, Andrej %A Tham, Yih-Chung %A Thiery, Joachim %A Thio, Chris H L %A Thomsen, Hauke %A Thorleifsson, Gudmar %A Toniolo, Daniela %A Tönjes, Anke %A Tremblay, Johanne %A Tzoulaki, Ioanna %A Uitterlinden, André G %A Vaccargiu, Simona %A van Dam, Rob M %A van der Harst, Pim %A van Duijn, Cornelia M %A Velez Edward, Digna R %A Verweij, Niek %A Vogelezang, Suzanne %A Völker, Uwe %A Vollenweider, Peter %A Waeber, Gérard %A Waldenberger, Melanie %A Wallentin, Lars %A Wang, Ya Xing %A Wang, Chaolong %A Waterworth, Dawn M %A Bin Wei, Wen %A White, Harvey %A Whitfield, John B %A Wild, Sarah H %A Wilson, James F %A Wojczynski, Mary K %A Wong, Charlene %A Wong, Tien-Yin %A Xu, Liang %A Yang, Qiong %A Yasuda, Masayuki %A Yerges-Armstrong, Laura M %A Zhang, Weihua %A Zonderman, Alan B %A Rotter, Jerome I %A Bochud, Murielle %A Psaty, Bruce M %A Vitart, Veronique %A Wilson, James G %A Dehghan, Abbas %A Parsa, Afshin %A Chasman, Daniel I %A Ho, Kevin %A Morris, Andrew P %A Devuyst, Olivier %A Akilesh, Shreeram %A Pendergrass, Sarah A %A Sim, Xueling %A Böger, Carsten A %A Okada, Yukinori %A Edwards, Todd L %A Snieder, Harold %A Stefansson, Kari %A Hung, Adriana M %A Heid, Iris M %A Scholz, Markus %A Teumer, Alexander %A Köttgen, Anna %A Pattaro, Cristian %K Chromosome Mapping %K European Continental Ancestry Group %K Genetic Association Studies %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Glomerular Filtration Rate %K Humans %K Inheritance Patterns %K Kidney Function Tests %K Phenotype %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %K Quantitative Trait, Heritable %K Renal Insufficiency, Chronic %K Uromodulin %X

Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through trans-ancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these, 147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.

%B Nat Genet %V 51 %P 957-972 %8 2019 06 %G eng %N 6 %R 10.1038/s41588-019-0407-x %0 Journal Article %J Am J Hypertens %D 2019 %T Genome-Wide Association Study of Apparent Treatment-Resistant Hypertension in the CHARGE Consortium: The CHARGE Pharmacogenetics Working Group. %A Irvin, Marguerite R %A Sitlani, Colleen M %A Floyd, James S %A Psaty, Bruce M %A Bis, Joshua C %A Wiggins, Kerri L %A Whitsel, Eric A %A Stürmer, Til %A Stewart, James %A Raffield, Laura %A Sun, Fangui %A Liu, Ching-Ti %A Xu, Hanfei %A Cupples, Adrienne L %A Tanner, Rikki M %A Rossing, Peter %A Smith, Albert %A Zilhão, Nuno R %A Launer, Lenore J %A Noordam, Raymond %A Rotter, Jerome I %A Yao, Jie %A Li, Xiaohui %A Guo, Xiuqing %A Limdi, Nita %A Sundaresan, Aishwarya %A Lange, Leslie %A Correa, Adolfo %A Stott, David J %A Ford, Ian %A Jukema, J Wouter %A Gudnason, Vilmundur %A Mook-Kanamori, Dennis O %A Trompet, Stella %A Palmas, Walter %A Warren, Helen R %A Hellwege, Jacklyn N %A Giri, Ayush %A O'donnell, Christopher %A Hung, Adriana M %A Edwards, Todd L %A Ahluwalia, Tarunveer S %A Arnett, Donna K %A Avery, Christy L %K Aged %K Antihypertensive Agents %K Black or African American %K Blood Pressure %K Case-Control Studies %K DNA (Cytosine-5-)-Methyltransferases %K DNA Methyltransferase 3A %K DNA-Binding Proteins %K Drug Resistance %K Dystrophin-Associated Proteins %K Europe %K Female %K Genetic Loci %K Genome-Wide Association Study %K Humans %K Hypertension %K Male %K Middle Aged %K Myosin Heavy Chains %K Myosin Type V %K Neuropeptides %K Pharmacogenetics %K Pharmacogenomic Variants %K Polymorphism, Single Nucleotide %K Risk Assessment %K Risk Factors %K Transcription Factors %K United States %K White People %X

BACKGROUND: Only a handful of genetic discovery efforts in apparent treatment-resistant hypertension (aTRH) have been described.

METHODS: We conducted a case-control genome-wide association study of aTRH among persons treated for hypertension, using data from 10 cohorts of European ancestry (EA) and 5 cohorts of African ancestry (AA). Cases were treated with 3 different antihypertensive medication classes and had blood pressure (BP) above goal (systolic BP ≥ 140 mm Hg and/or diastolic BP ≥ 90 mm Hg) or 4 or more medication classes regardless of BP control (nEA = 931, nAA = 228). Both a normotensive control group and a treatment-responsive control group were considered in separate analyses. Normotensive controls were untreated (nEA = 14,210, nAA = 2,480) and had systolic BP/diastolic BP < 140/90 mm Hg. Treatment-responsive controls (nEA = 5,266, nAA = 1,817) had BP at goal (<140/90 mm Hg), while treated with one antihypertensive medication class. Individual cohorts used logistic regression with adjustment for age, sex, study site, and principal components for ancestry to examine the association of single-nucleotide polymorphisms with case-control status. Inverse variance-weighted fixed-effects meta-analyses were carried out using METAL.

RESULTS: The known hypertension locus, CASZ1, was a top finding among EAs (P = 1.1 × 10-8) and in the race-combined analysis (P = 1.5 × 10-9) using the normotensive control group (rs12046278, odds ratio = 0.71 (95% confidence interval: 0.6-0.8)). Single-nucleotide polymorphisms in this locus were robustly replicated in the Million Veterans Program (MVP) study in consideration of a treatment-responsive control group. There were no statistically significant findings for the discovery analyses including treatment-responsive controls.

CONCLUSION: This genomic discovery effort for aTRH identified CASZ1 as an aTRH risk locus.

%B Am J Hypertens %V 32 %P 1146-1153 %8 2019 Nov 15 %G eng %N 12 %R 10.1093/ajh/hpz150 %0 Journal Article %J Clin Pharmacol Ther %D 2019 %T Genomewide Association Study of Statin-Induced Myopathy in Patients Recruited Using the UK Clinical Practice Research Datalink. %A Carr, Daniel F %A Francis, Ben %A Jorgensen, Andrea L %A Zhang, Eunice %A Chinoy, Hector %A Heckbert, Susan R %A Bis, Joshua C %A Brody, Jennifer A %A Floyd, James S %A Psaty, Bruce M %A Molokhia, Mariam %A Lapeyre-Mestre, Maryse %A Conforti, Anita %A Alfirevic, Ana %A van Staa, Tjeerd %A Pirmohamed, Munir %K Adverse Drug Reaction Reporting Systems %K Case-Control Studies %K Databases, Factual %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Hydroxymethylglutaryl-CoA Reductase Inhibitors %K Liver-Specific Organic Anion Transporter 1 %K Muscular Diseases %K Pharmacogenomic Variants %K Polymorphism, Single Nucleotide %K Reproducibility of Results %K Risk Factors %K Severity of Illness Index %K United Kingdom %X

Statins can be associated with myopathy. We have undertaken a genomewide association study (GWAS) to discover and validate genetic risk factors for statin-induced myopathy in a "real-world" setting. One hundred thirty-five patients with statin myopathy recruited via the UK Clinical Practice Research Datalink were genotyped using the Illumina OmniExpress Exome version 1.0 Bead Chip and compared with the Wellcome Trust Case-Control Consortium (n = 2,501). Nominally statistically significant single nucleotide polymorphism (SNP) signals in the GWAS (P < 5 × 10 ) were further evaluated in several independent cohorts (comprising 332 cases and 449 drug-tolerant controls). Only one (rs4149056/c.521C>T in the SLCO1B1 gene) SNP was genomewide significant in the severe myopathy (creatine kinase > 10 × upper limit of normal or rhabdomyolysis) group (P = 2.55 × 10 ; odds ratio 5.15; 95% confidence interval 3.13-8.45). The association with SLCO1B1 was present for several statins and replicated in the independent validation cohorts. The data highlight the role of SLCO1B1 c.521C>T SNP as a replicable genetic risk factor for statin myopathy. No other novel genetic risk factors with a similar effect size were identified.

%B Clin Pharmacol Ther %V 106 %P 1353-1361 %8 2019 12 %G eng %N 6 %R 10.1002/cpt.1557 %0 Journal Article %J Nat Commun %D 2019 %T Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity. %A Kilpeläinen, Tuomas O %A Bentley, Amy R %A Noordam, Raymond %A Sung, Yun Ju %A Schwander, Karen %A Winkler, Thomas W %A Jakupović, Hermina %A Chasman, Daniel I %A Manning, Alisa %A Ntalla, Ioanna %A Aschard, Hugues %A Brown, Michael R %A de Las Fuentes, Lisa %A Franceschini, Nora %A Guo, Xiuqing %A Vojinovic, Dina %A Aslibekyan, Stella %A Feitosa, Mary F %A Kho, Minjung %A Musani, Solomon K %A Richard, Melissa %A Wang, Heming %A Wang, Zhe %A Bartz, Traci M %A Bielak, Lawrence F %A Campbell, Archie %A Dorajoo, Rajkumar %A Fisher, Virginia %A Hartwig, Fernando P %A Horimoto, Andrea R V R %A Li, Changwei %A Lohman, Kurt K %A Marten, Jonathan %A Sim, Xueling %A Smith, Albert V %A Tajuddin, Salman M %A Alver, Maris %A Amini, Marzyeh %A Boissel, Mathilde %A Chai, Jin Fang %A Chen, Xu %A Divers, Jasmin %A Evangelou, Evangelos %A Gao, Chuan %A Graff, Mariaelisa %A Harris, Sarah E %A He, Meian %A Hsu, Fang-Chi %A Jackson, Anne U %A Zhao, Jing Hua %A Kraja, Aldi T %A Kuhnel, Brigitte %A Laguzzi, Federica %A Lyytikäinen, Leo-Pekka %A Nolte, Ilja M %A Rauramaa, Rainer %A Riaz, Muhammad %A Robino, Antonietta %A Rueedi, Rico %A Stringham, Heather M %A Takeuchi, Fumihiko %A van der Most, Peter J %A Varga, Tibor V %A Verweij, Niek %A Ware, Erin B %A Wen, Wanqing %A Li, Xiaoyin %A Yanek, Lisa R %A Amin, Najaf %A Arnett, Donna K %A Boerwinkle, Eric %A Brumat, Marco %A Cade, Brian %A Canouil, Mickaël %A Chen, Yii-Der Ida %A Concas, Maria Pina %A Connell, John %A de Mutsert, Renée %A de Silva, H Janaka %A de Vries, Paul S %A Demirkan, Ayse %A Ding, Jingzhong %A Eaton, Charles B %A Faul, Jessica D %A Friedlander, Yechiel %A Gabriel, Kelley P %A Ghanbari, Mohsen %A Giulianini, Franco %A Gu, Chi Charles %A Gu, Dongfeng %A Harris, Tamara B %A He, Jiang %A Heikkinen, Sami %A Heng, Chew-Kiat %A Hunt, Steven C %A Ikram, M Arfan %A Jonas, Jost B %A Koh, Woon-Puay %A Komulainen, Pirjo %A Krieger, Jose E %A Kritchevsky, Stephen B %A Kutalik, Zoltán %A Kuusisto, Johanna %A Langefeld, Carl D %A Langenberg, Claudia %A Launer, Lenore J %A Leander, Karin %A Lemaitre, Rozenn N %A Lewis, Cora E %A Liang, Jingjing %A Liu, Jianjun %A Mägi, Reedik %A Manichaikul, Ani %A Meitinger, Thomas %A Metspalu, Andres %A Milaneschi, Yuri %A Mohlke, Karen L %A Mosley, Thomas H %A Murray, Alison D %A Nalls, Mike A %A Nang, Ei-Ei Khaing %A Nelson, Christopher P %A Nona, Sotoodehnia %A Norris, Jill M %A Nwuba, Chiamaka Vivian %A O'Connell, Jeff %A Palmer, Nicholette D %A Papanicolau, George J %A Pazoki, Raha %A Pedersen, Nancy L %A Peters, Annette %A Peyser, Patricia A %A Polasek, Ozren %A Porteous, David J %A Poveda, Alaitz %A Raitakari, Olli T %A Rich, Stephen S %A Risch, Neil %A Robinson, Jennifer G %A Rose, Lynda M %A Rudan, Igor %A Schreiner, Pamela J %A Scott, Robert A %A Sidney, Stephen S %A Sims, Mario %A Smith, Jennifer A %A Snieder, Harold %A Sofer, Tamar %A Starr, John M %A Sternfeld, Barbara %A Strauch, Konstantin %A Tang, Hua %A Taylor, Kent D %A Tsai, Michael Y %A Tuomilehto, Jaakko %A Uitterlinden, André G %A van der Ende, M Yldau %A van Heemst, Diana %A Voortman, Trudy %A Waldenberger, Melanie %A Wennberg, Patrik %A Wilson, Gregory %A Xiang, Yong-Bing %A Yao, Jie %A Yu, Caizheng %A Yuan, Jian-Min %A Zhao, Wei %A Zonderman, Alan B %A Becker, Diane M %A Boehnke, Michael %A Bowden, Donald W %A de Faire, Ulf %A Deary, Ian J %A Elliott, Paul %A Esko, Tõnu %A Freedman, Barry I %A Froguel, Philippe %A Gasparini, Paolo %A Gieger, Christian %A Kato, Norihiro %A Laakso, Markku %A Lakka, Timo A %A Lehtimäki, Terho %A Magnusson, Patrik K E %A Oldehinkel, Albertine J %A Penninx, Brenda W J H %A Samani, Nilesh J %A Shu, Xiao-Ou %A van der Harst, Pim %A van Vliet-Ostaptchouk, Jana V %A Vollenweider, Peter %A Wagenknecht, Lynne E %A Wang, Ya X %A Wareham, Nicholas J %A Weir, David R %A Wu, Tangchun %A Zheng, Wei %A Zhu, Xiaofeng %A Evans, Michele K %A Franks, Paul W %A Gudnason, Vilmundur %A Hayward, Caroline %A Horta, Bernardo L %A Kelly, Tanika N %A Liu, Yongmei %A North, Kari E %A Pereira, Alexandre C %A Ridker, Paul M %A Tai, E Shyong %A van Dam, Rob M %A Fox, Ervin R %A Kardia, Sharon L R %A Liu, Ching-Ti %A Mook-Kanamori, Dennis O %A Province, Michael A %A Redline, Susan %A van Duijn, Cornelia M %A Rotter, Jerome I %A Kooperberg, Charles B %A Gauderman, W James %A Psaty, Bruce M %A Rice, Kenneth %A Munroe, Patricia B %A Fornage, Myriam %A Cupples, L Adrienne %A Rotimi, Charles N %A Morrison, Alanna C %A Rao, Dabeeru C %A Loos, Ruth J F %K Adolescent %K Adult %K African Continental Ancestry Group %K Aged %K Aged, 80 and over %K Asian Continental Ancestry Group %K Brazil %K Calcium-Binding Proteins %K Cholesterol %K Cholesterol, HDL %K Cholesterol, LDL %K European Continental Ancestry Group %K Exercise %K Female %K Genetic Loci %K Genome-Wide Association Study %K Genotype %K Hispanic Americans %K Humans %K LIM-Homeodomain Proteins %K Lipid Metabolism %K Lipids %K Male %K Membrane Proteins %K Microtubule-Associated Proteins %K Middle Aged %K Muscle Proteins %K Nerve Tissue Proteins %K Transcription Factors %K Triglycerides %K Young Adult %X

Many genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol-increasing effect of the CNTNAP2 locus. The CLASP1, LHX1, and SNTA1 regions harbor genes linked to muscle function and lipid metabolism. Our results elucidate the role of physical activity interactions in the genetic contribution to blood lipid levels.

%B Nat Commun %V 10 %P 376 %8 2019 01 22 %G eng %N 1 %R 10.1038/s41467-018-08008-w %0 Journal Article %J PLoS Med %D 2019 %T No causal effects of serum urate levels on the risk of chronic kidney disease: A Mendelian randomization study. %A Jordan, Daniel M %A Choi, Hyon K %A Verbanck, Marie %A Topless, Ruth %A Won, Hong-Hee %A Nadkarni, Girish %A Merriman, Tony R %A Do, Ron %K Adult %K Age Factors %K Female %K Genome-Wide Association Study %K Glomerular Filtration Rate %K Humans %K Male %K Mendelian Randomization Analysis %K Renal Insufficiency, Chronic %K Sex Factors %K Uric Acid %K Young Adult %X

BACKGROUND: Studies have shown strong positive associations between serum urate (SU) levels and chronic kidney disease (CKD) risk; however, whether the relation is causal remains uncertain. We evaluate whether genetic data are consistent with a causal impact of SU level on the risk of CKD and estimated glomerular filtration rate (eGFR).

METHODS AND FINDINGS: We used Mendelian randomization (MR) methods to evaluate the presence of a causal effect. We used aggregated genome-wide association data (N = 110,347 for SU, N = 69,374 for gout, N = 133,413 for eGFR, N = 117,165 for CKD), electronic-medical-record-linked UK Biobank data (N = 335,212), and population-based cohorts (N = 13,425), all in individuals of European ancestry, for SU levels and CKD. Our MR analysis showed that SU has a causal effect on neither eGFR level nor CKD risk across all MR analyses (all P > 0.05). These null associations contrasted with our epidemiological association findings from the 4 population-based cohorts (change in eGFR level per 1-mg/dl [59.48 μmol/l] increase in SU: -1.99 ml/min/1.73 m2; 95% CI -2.86 to -1.11; P = 8.08 × 10(-6); odds ratio [OR] for CKD: 1.48; 95% CI 1.32 to 1.65; P = 1.52 × 10(-11)). In contrast, the same MR approaches showed that SU has a causal effect on the risk of gout (OR estimates ranging from 3.41 to 6.04 per 1-mg/dl increase in SU, all P < 10-3), which served as a positive control of our approach. Overall, our MR analysis had >99% power to detect a causal effect of SU level on the risk of CKD of the same magnitude as the observed epidemiological association between SU and CKD. Limitations of this study include the lifelong effect of a genetic perturbation not being the same as an acute perturbation, the inability to study non-European populations, and some sample overlap between the datasets used in the study.

CONCLUSIONS: Evidence from our series of causal inference approaches using genetics does not support a causal effect of SU level on eGFR level or CKD risk. Reducing SU levels is unlikely to reduce the risk of CKD development.

%B PLoS Med %V 16 %P e1002725 %8 2019 01 %G eng %N 1 %R 10.1371/journal.pmed.1002725 %0 Journal Article %J J Neuropathol Exp Neurol %D 2020 %T Alzheimer Disease Pathology-Associated Polymorphism in a Complex Variable Number of Tandem Repeat Region Within the MUC6 Gene, Near the AP2A2 Gene. %A Katsumata, Yuriko %A Fardo, David W %A Bachstetter, Adam D %A Artiushin, Sergey C %A Wang, Wang-Xia %A Wei, Angela %A Brzezinski, Lena J %A Nelson, Bela G %A Huang, Qingwei %A Abner, Erin L %A Anderson, Sonya %A Patel, Indumati %A Shaw, Benjamin C %A Price, Douglas A %A Niedowicz, Dana M %A Wilcock, Donna W %A Jicha, Gregory A %A Neltner, Janna H %A Van Eldik, Linda J %A Estus, Steven %A Nelson, Peter T %K Adaptor Protein Complex 2 %K Adaptor Protein Complex alpha Subunits %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Autopsy %K Cohort Studies %K Female %K Genome-Wide Association Study %K Genotype %K Humans %K Male %K Minisatellite Repeats %K Mucin-6 %K Neurofibrillary Tangles %K Polymorphism, Genetic %K Polymorphism, Single Nucleotide %K TDP-43 Proteinopathies %X

We found evidence of late-onset Alzheimer disease (LOAD)-associated genetic polymorphism within an exon of Mucin 6 (MUC6) and immediately downstream from another gene: Adaptor Related Protein Complex 2 Subunit Alpha 2 (AP2A2). PCR analyses on genomic DNA samples confirmed that the size of the MUC6 variable number tandem repeat (VNTR) region was highly polymorphic. In a cohort of autopsied subjects with quantitative digital pathology data (n = 119), the size of the polymorphic region was associated with the severity of pTau pathology in neocortex. In a separate replication cohort of autopsied subjects (n = 173), more pTau pathology was again observed in subjects with longer VNTR regions (p = 0.031). Unlike MUC6, AP2A2 is highly expressed in human brain. AP2A2 expression was lower in a subset analysis of brain samples from persons with longer versus shorter VNTR regions (p = 0.014 normalizing with AP2B1 expression). Double-label immunofluorescence studies showed that AP2A2 protein often colocalized with neurofibrillary tangles in LOAD but was not colocalized with pTau proteinopathy in progressive supranuclear palsy, or with TDP-43 proteinopathy. In summary, polymorphism in a repeat-rich region near AP2A2 was associated with neocortical pTau proteinopathy (because of the unique repeats, prior genome-wide association studies were probably unable to detect this association), and AP2A2 was often colocalized with neurofibrillary tangles in LOAD.

%B J Neuropathol Exp Neurol %V 79 %P 3-21 %8 2020 01 01 %G eng %N 1 %R 10.1093/jnen/nlz116 %0 Journal Article %J JAMA Ophthalmol %D 2020 %T Association of Genetic Variation With Keratoconus. %A McComish, Bennet J %A Sahebjada, Srujana %A Bykhovskaya, Yelena %A Willoughby, Colin E %A Richardson, Andrea J %A Tenen, Abi %A Charlesworth, Jac C %A Macgregor, Stuart %A Mitchell, Paul %A Lucas, Sionne E M %A Mills, Richard A %A Mackey, David A %A Li, Xiaohui %A Wang, Jie Jin %A Jensen, Richard A %A Rotter, Jerome I %A Taylor, Kent D %A Hewitt, Alex W %A Rabinowitz, Yaron S %A Baird, Paul N %A Craig, Jamie E %A Burdon, Kathryn P %K Adult %K Female %K Fuchs' Endothelial Dystrophy %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Keratoconus %K Lipase %K Logistic Models %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %X

Importance: Keratoconus is a condition in which the cornea progressively thins and protrudes in a conical shape, severely affecting refraction and vision. It is a major indication for corneal transplant. To discover new genetic loci associated with keratoconus and better understand the causative mechanism of this disease, we performed a genome-wide association study on patients with keratoconus.

Objective: To identify genetic susceptibility regions for keratoconus in the human genome.

Design, Setting, and Participants: This study was conducted with data from eye clinics in Australia, the United States, and Northern Ireland. The discovery cohort of individuals with keratoconus and control participants from Australia was genotyped using the Illumina HumanCoreExome single-nucleotide polymorphism array. After quality control and data cleaning, genotypes were imputed against the 1000 Genomes Project reference panel (phase III; version 5), and association analyses were completed using PLINK version 1.90. Single-nucleotide polymorphisms with P < 1.00 × 10-6 were assessed for replication in 3 additional cohorts. Control participants were drawn from the cohorts of the Blue Mountains Eye Study and a previous study of glaucoma. Replication cohorts were from a previous keratoconus genome-wide association study data set from the United States, a cohort of affected and control participants from Australia and Northern Ireland, and a case-control cohort from Victoria, Australia. Data were collected from January 2006 to March 2019.

Main Outcomes and Measures: Associations between keratoconus and 6 252 612 genetic variants were estimated using logistic regression after adjusting for ancestry using the first 3 principal components.

Results: The discovery cohort included 522 affected individuals and 655 control participants, while the replication cohorts included 818 affected individuals (222 from the United States, 331 from Australia and Northern Ireland, and 265 from Victoria, Australia) and 3858 control participants (2927 from the United States, 229 from Australia and Northern Ireland, and 702 from Victoria, Australia). Two novel loci reached genome-wide significance (defined as P < 5.00 × 10-8), with a P value of 7.46 × 10-9 at rs61876744 in patatin-like phospholipase domain-containing 2 gene (PNPLA2) on chromosome 11 and a P value of 6.35 × 10-12 at rs138380, 2.2 kb upstream of casein kinase I isoform epsilon gene (CSNK1E) on chromosome 22. One additional locus was identified with a P value less than 1.00 × 10-6 in mastermind-like transcriptional coactivator 2 (MAML2) on chromosome 11 (P = 3.91 × 10-7). The novel locus in PNPLA2 reached genome-wide significance in an analysis of all 4 cohorts (P = 2.45 × 10-8).

Conclusions and Relevance: In this relatively large keratoconus genome-wide association study, we identified a genome-wide significant locus for keratoconus in the region of PNPLA2 on chromosome 11.

%B JAMA Ophthalmol %V 138 %P 174-181 %8 2020 02 01 %G eng %N 2 %R 10.1001/jamaophthalmol.2019.5293 %0 Journal Article %J Lancet Respir Med %D 2020 %T Chronic obstructive pulmonary disease and related phenotypes: polygenic risk scores in population-based and case-control cohorts. %A Moll, Matthew %A Sakornsakolpat, Phuwanat %A Shrine, Nick %A Hobbs, Brian D %A DeMeo, Dawn L %A John, Catherine %A Guyatt, Anna L %A McGeachie, Michael J %A Gharib, Sina A %A Obeidat, Ma'en %A Lahousse, Lies %A Wijnant, Sara R A %A Brusselle, Guy %A Meyers, Deborah A %A Bleecker, Eugene R %A Li, Xingnan %A Tal-Singer, Ruth %A Manichaikul, Ani %A Rich, Stephen S %A Won, Sungho %A Kim, Woo Jin %A Do, Ah Ra %A Washko, George R %A Barr, R Graham %A Psaty, Bruce M %A Bartz, Traci M %A Hansel, Nadia N %A Barnes, Kathleen %A Hokanson, John E %A Crapo, James D %A Lynch, David %A Bakke, Per %A Gulsvik, Amund %A Hall, Ian P %A Wain, Louise %A Weiss, Scott T %A Silverman, Edwin K %A Dudbridge, Frank %A Tobin, Martin D %A Cho, Michael H %K Adult %K Case-Control Studies %K Cohort Studies %K Female %K Forced Expiratory Volume %K Genome-Wide Association Study %K Humans %K Male %K Middle Aged %K Phenotype %K Pulmonary Disease, Chronic Obstructive %K Risk Factors %K Vital Capacity %X

BACKGROUND: Genetic factors influence chronic obstructive pulmonary disease (COPD) risk, but the individual variants that have been identified have small effects. We hypothesised that a polygenic risk score using additional variants would predict COPD and associated phenotypes.

METHODS: We constructed a polygenic risk score using a genome-wide association study of lung function (FEV and FEV/forced vital capacity [FVC]) from the UK Biobank and SpiroMeta. We tested this polygenic risk score in nine cohorts of multiple ethnicities for an association with moderate-to-severe COPD (defined as FEV/FVC <0·7 and FEV <80% of predicted). Associations were tested using logistic regression models, adjusting for age, sex, height, smoking pack-years, and principal components of genetic ancestry. We assessed predictive performance of models by area under the curve. In a subset of studies, we also studied quantitative and qualitative CT imaging phenotypes that reflect parenchymal and airway pathology, and patterns of reduced lung growth.

FINDINGS: The polygenic risk score was associated with COPD in European (odds ratio [OR] per SD 1·81 [95% CI 1·74-1·88] and non-European (1·42 [1·34-1·51]) populations. Compared with the first decile, the tenth decile of the polygenic risk score was associated with COPD, with an OR of 7·99 (6·56-9·72) in European ancestry and 4·83 (3·45-6·77) in non-European ancestry cohorts. The polygenic risk score was superior to previously described genetic risk scores and, when combined with clinical risk factors (ie, age, sex, and smoking pack-years), showed improved prediction for COPD compared with a model comprising clinical risk factors alone (AUC 0·80 [0·79-0·81] vs 0·76 [0·75-0·76]). The polygenic risk score was associated with CT imaging phenotypes, including wall area percent, quantitative and qualitative measures of emphysema, local histogram emphysema patterns, and destructive emphysema subtypes. The polygenic risk score was associated with a reduced lung growth pattern.

INTERPRETATION: A risk score comprised of genetic variants can identify a small subset of individuals at markedly increased risk for moderate-to-severe COPD, emphysema subtypes associated with cigarette smoking, and patterns of reduced lung growth.

FUNDING: US National Institutes of Health, Wellcome Trust.

%B Lancet Respir Med %V 8 %P 696-708 %8 2020 07 %G eng %N 7 %R 10.1016/S2213-2600(20)30101-6 %0 Journal Article %J PLoS One %D 2020 %T Genetic loci associated with prevalent and incident myocardial infarction and coronary heart disease in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. %A Hahn, Julie %A Fu, Yi-Ping %A Brown, Michael R %A Bis, Joshua C %A de Vries, Paul S %A Feitosa, Mary F %A Yanek, Lisa R %A Weiss, Stefan %A Giulianini, Franco %A Smith, Albert Vernon %A Guo, Xiuqing %A Bartz, Traci M %A Becker, Diane M %A Becker, Lewis C %A Boerwinkle, Eric %A Brody, Jennifer A %A Chen, Yii-Der Ida %A Franco, Oscar H %A Grove, Megan %A Harris, Tamara B %A Hofman, Albert %A Hwang, Shih-Jen %A Kral, Brian G %A Launer, Lenore J %A Markus, Marcello R P %A Rice, Kenneth M %A Rich, Stephen S %A Ridker, Paul M %A Rivadeneira, Fernando %A Rotter, Jerome I %A Sotoodehnia, Nona %A Taylor, Kent D %A Uitterlinden, André G %A Völker, Uwe %A Völzke, Henry %A Yao, Jie %A Chasman, Daniel I %A Dörr, Marcus %A Gudnason, Vilmundur %A Mathias, Rasika A %A Post, Wendy %A Psaty, Bruce M %A Dehghan, Abbas %A O'Donnell, Christopher J %A Morrison, Alanna C %K Aging %K Coronary Artery Disease %K Cross-Sectional Studies %K Europe %K European Continental Ancestry Group %K Genetic Loci %K Genome-Wide Association Study %K Humans %K Myocardial Infarction %K Polymorphism, Single Nucleotide %K Prospective Studies %X

BACKGROUND: Genome-wide association studies have identified multiple genomic loci associated with coronary artery disease, but most are common variants in non-coding regions that provide limited information on causal genes and etiology of the disease. To overcome the limited scope that common variants provide, we focused our investigation on low-frequency and rare sequence variations primarily residing in coding regions of the genome.

METHODS AND RESULTS: Using samples of individuals of European ancestry from ten cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, both cross-sectional and prospective analyses were conducted to examine associations between genetic variants and myocardial infarction (MI), coronary heart disease (CHD), and all-cause mortality following these events. For prevalent events, a total of 27,349 participants of European ancestry, including 1831 prevalent MI cases and 2518 prevalent CHD cases were used. For incident cases, a total of 55,736 participants of European ancestry were included (3,031 incident MI cases and 5,425 incident CHD cases). There were 1,860 all-cause deaths among the 3,751 MI and CHD cases from six cohorts that contributed to the analysis of all-cause mortality. Single variant and gene-based analyses were performed separately in each cohort and then meta-analyzed for each outcome. A low-frequency intronic variant (rs988583) in PLCL1 was significantly associated with prevalent MI (OR = 1.80, 95% confidence interval: 1.43, 2.27; P = 7.12 × 10-7). We conducted gene-based burden tests for genes with a cumulative minor allele count (cMAC) ≥ 5 and variants with minor allele frequency (MAF) < 5%. TMPRSS5 and LDLRAD1 were significantly associated with prevalent MI and CHD, respectively, and RC3H2 and ANGPTL4 were significantly associated with incident MI and CHD, respectively. No loci were significantly associated with all-cause mortality following a MI or CHD event.

CONCLUSION: This study identified one known locus (ANGPTL4) and four new loci (PLCL1, RC3H2, TMPRSS5, and LDLRAD1) associated with cardiovascular disease risk that warrant further investigation.

%B PLoS One %V 15 %P e0230035 %8 2020 %G eng %N 11 %R 10.1371/journal.pone.0230035 %0 Journal Article %J Nat Commun %D 2020 %T Whole genome sequence analysis of pulmonary function and COPD in 19,996 multi-ethnic participants. %A Zhao, Xutong %A Qiao, Dandi %A Yang, Chaojie %A Kasela, Silva %A Kim, Wonji %A Ma, Yanlin %A Shrine, Nick %A Batini, Chiara %A Sofer, Tamar %A Taliun, Sarah A Gagliano %A Sakornsakolpat, Phuwanat %A Balte, Pallavi P %A Prokopenko, Dmitry %A Yu, Bing %A Lange, Leslie A %A Dupuis, Josée %A Cade, Brian E %A Lee, Jiwon %A Gharib, Sina A %A Daya, Michelle %A Laurie, Cecelia A %A Ruczinski, Ingo %A Cupples, L Adrienne %A Loehr, Laura R %A Bartz, Traci M %A Morrison, Alanna C %A Psaty, Bruce M %A Vasan, Ramachandran S %A Wilson, James G %A Taylor, Kent D %A Durda, Peter %A Johnson, W Craig %A Cornell, Elaine %A Guo, Xiuqing %A Liu, Yongmei %A Tracy, Russell P %A Ardlie, Kristin G %A Aguet, Francois %A VanDenBerg, David J %A Papanicolaou, George J %A Rotter, Jerome I %A Barnes, Kathleen C %A Jain, Deepti %A Nickerson, Deborah A %A Muzny, Donna M %A Metcalf, Ginger A %A Doddapaneni, Harshavardhan %A Dugan-Perez, Shannon %A Gupta, Namrata %A Gabriel, Stacey %A Rich, Stephen S %A O'Connor, George T %A Redline, Susan %A Reed, Robert M %A Laurie, Cathy C %A Daviglus, Martha L %A Preudhomme, Liana K %A Burkart, Kristin M %A Kaplan, Robert C %A Wain, Louise V %A Tobin, Martin D %A London, Stephanie J %A Lappalainen, Tuuli %A Oelsner, Elizabeth C %A Abecasis, Goncalo R %A Silverman, Edwin K %A Barr, R Graham %A Cho, Michael H %A Manichaikul, Ani %K Adult %K African Americans %K Aged %K Aged, 80 and over %K Alpha-Ketoglutarate-Dependent Dioxygenase FTO %K Calcium-Binding Proteins %K Feasibility Studies %K Female %K Follow-Up Studies %K Genetic Loci %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Intracellular Signaling Peptides and Proteins %K Lung %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Protein Inhibitors of Activated STAT %K Pulmonary Disease, Chronic Obstructive %K Respiratory Physiological Phenomena %K Small Ubiquitin-Related Modifier Proteins %K Whole Genome Sequencing %X

Chronic obstructive pulmonary disease (COPD), diagnosed by reduced lung function, is a leading cause of morbidity and mortality. We performed whole genome sequence (WGS) analysis of lung function and COPD in a multi-ethnic sample of 11,497 participants from population- and family-based studies, and 8499 individuals from COPD-enriched studies in the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program. We identify at genome-wide significance 10 known GWAS loci and 22 distinct, previously unreported loci, including two common variant signals from stratified analysis of African Americans. Four novel common variants within the regions of PIAS1, RGN (two variants) and FTO show evidence of replication in the UK Biobank (European ancestry n ~ 320,000), while colocalization analyses leveraging multi-omic data from GTEx and TOPMed identify potential molecular mechanisms underlying four of the 22 novel loci. Our study demonstrates the value of performing WGS analyses and multi-omic follow-up in cohorts of diverse ancestry.

%B Nat Commun %V 11 %P 5182 %8 2020 10 14 %G eng %N 1 %R 10.1038/s41467-020-18334-7 %0 Journal Article %J Transl Psychiatry %D 2021 %T Association of low-frequency and rare coding variants with information processing speed. %A Bressler, Jan %A Davies, Gail %A Smith, Albert V %A Saba, Yasaman %A Bis, Joshua C %A Jian, Xueqiu %A Hayward, Caroline %A Yanek, Lisa %A Smith, Jennifer A %A Mirza, Saira S %A Wang, Ruiqi %A Adams, Hieab H H %A Becker, Diane %A Boerwinkle, Eric %A Campbell, Archie %A Cox, Simon R %A Eiriksdottir, Gudny %A Fawns-Ritchie, Chloe %A Gottesman, Rebecca F %A Grove, Megan L %A Guo, Xiuqing %A Hofer, Edith %A Kardia, Sharon L R %A Knol, Maria J %A Koini, Marisa %A Lopez, Oscar L %A Marioni, Riccardo E %A Nyquist, Paul %A Pattie, Alison %A Polasek, Ozren %A Porteous, David J %A Rudan, Igor %A Satizabal, Claudia L %A Schmidt, Helena %A Schmidt, Reinhold %A Sidney, Stephen %A Simino, Jeannette %A Smith, Blair H %A Turner, Stephen T %A van der Lee, Sven J %A Ware, Erin B %A Whitmer, Rachel A %A Yaffe, Kristine %A Yang, Qiong %A Zhao, Wei %A Gudnason, Vilmundur %A Launer, Lenore J %A Fitzpatrick, Annette L %A Psaty, Bruce M %A Fornage, Myriam %A Arfan Ikram, M %A van Duijn, Cornelia M %A Seshadri, Sudha %A Mosley, Thomas H %A Deary, Ian J %K Adult %K Aging %K Cognition %K Genome-Wide Association Study %K Geroscience %K Humans %K Polymorphism, Single Nucleotide %K Ubiquitin-Protein Ligases %X

Measures of information processing speed vary between individuals and decline with age. Studies of aging twins suggest heritability may be as high as 67%. The Illumina HumanExome Bead Chip genotyping array was used to examine the association of rare coding variants with performance on the Digit-Symbol Substitution Test (DSST) in community-dwelling adults participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. DSST scores were available for 30,576 individuals of European ancestry from nine cohorts and for 5758 individuals of African ancestry from four cohorts who were older than 45 years and free of dementia and clinical stroke. Linear regression models adjusted for age and gender were used for analysis of single genetic variants, and the T5, T1, and T01 burden tests that aggregate the number of rare alleles by gene were also applied. Secondary analyses included further adjustment for education. Meta-analyses to combine cohort-specific results were carried out separately for each ancestry group. Variants in RNF19A reached the threshold for statistical significance (p = 2.01 × 10) using the T01 test in individuals of European descent. RNF19A belongs to the class of E3 ubiquitin ligases that confer substrate specificity when proteins are ubiquitinated and targeted for degradation through the 26S proteasome. Variants in SLC22A7 and OR51A7 were suggestively associated with DSST scores after adjustment for education for African-American participants and in the European cohorts, respectively. Further functional characterization of its substrates will be required to confirm the role of RNF19A in cognitive function.

%B Transl Psychiatry %V 11 %P 613 %8 2021 12 04 %G eng %N 1 %R 10.1038/s41398-021-01736-6 %0 Journal Article %J Nat Commun %D 2021 %T Epigenome-wide association study of serum urate reveals insights into urate co-regulation and the SLC2A9 locus. %A Tin, Adrienne %A Schlosser, Pascal %A Matias-Garcia, Pamela R %A Thio, Chris H L %A Joehanes, Roby %A Liu, Hongbo %A Yu, Zhi %A Weihs, Antoine %A Hoppmann, Anselm %A Grundner-Culemann, Franziska %A Min, Josine L %A Kuhns, Victoria L Halperin %A Adeyemo, Adebowale A %A Agyemang, Charles %A Arnlöv, Johan %A Aziz, Nasir A %A Baccarelli, Andrea %A Bochud, Murielle %A Brenner, Hermann %A Bressler, Jan %A Breteler, Monique M B %A Carmeli, Cristian %A Chaker, Layal %A Coresh, Josef %A Corre, Tanguy %A Correa, Adolfo %A Cox, Simon R %A Delgado, Graciela E %A Eckardt, Kai-Uwe %A Ekici, Arif B %A Endlich, Karlhans %A Floyd, James S %A Fraszczyk, Eliza %A Gao, Xu %A Gào, Xīn %A Gelber, Allan C %A Ghanbari, Mohsen %A Ghasemi, Sahar %A Gieger, Christian %A Greenland, Philip %A Grove, Megan L %A Harris, Sarah E %A Hemani, Gibran %A Henneman, Peter %A Herder, Christian %A Horvath, Steve %A Hou, Lifang %A Hurme, Mikko A %A Hwang, Shih-Jen %A Kardia, Sharon L R %A Kasela, Silva %A Kleber, Marcus E %A Koenig, Wolfgang %A Kooner, Jaspal S %A Kronenberg, Florian %A Kuhnel, Brigitte %A Ladd-Acosta, Christine %A Lehtimäki, Terho %A Lind, Lars %A Liu, Dan %A Lloyd-Jones, Donald M %A Lorkowski, Stefan %A Lu, Ake T %A Marioni, Riccardo E %A März, Winfried %A McCartney, Daniel L %A Meeks, Karlijn A C %A Milani, Lili %A Mishra, Pashupati P %A Nauck, Matthias %A Nowak, Christoph %A Peters, Annette %A Prokisch, Holger %A Psaty, Bruce M %A Raitakari, Olli T %A Ratliff, Scott M %A Reiner, Alex P %A Schöttker, Ben %A Schwartz, Joel %A Sedaghat, Sanaz %A Smith, Jennifer A %A Sotoodehnia, Nona %A Stocker, Hannah R %A Stringhini, Silvia %A Sundström, Johan %A Swenson, Brenton R %A van Meurs, Joyce B J %A van Vliet-Ostaptchouk, Jana V %A Venema, Andrea %A Völker, Uwe %A Winkelmann, Juliane %A Wolffenbuttel, Bruce H R %A Zhao, Wei %A Zheng, Yinan %A Loh, Marie %A Snieder, Harold %A Waldenberger, Melanie %A Levy, Daniel %A Akilesh, Shreeram %A Woodward, Owen M %A Susztak, Katalin %A Teumer, Alexander %A Köttgen, Anna %K Amino Acid Transport System y+ %K Cohort Studies %K CpG Islands %K DNA Methylation %K Epigenome %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Glucose Transport Proteins, Facilitative %K Gout %K Humans %K Male %K Uric Acid %X

Elevated serum urate levels, a complex trait and major risk factor for incident gout, are correlated with cardiometabolic traits via incompletely understood mechanisms. DNA methylation in whole blood captures genetic and environmental influences and is assessed in transethnic meta-analysis of epigenome-wide association studies (EWAS) of serum urate (discovery, n = 12,474, replication, n = 5522). The 100 replicated, epigenome-wide significant (p < 1.1E-7) CpGs explain 11.6% of the serum urate variance. At SLC2A9, the serum urate locus with the largest effect in genome-wide association studies (GWAS), five CpGs are associated with SLC2A9 gene expression. Four CpGs at SLC2A9 have significant causal effects on serum urate levels and/or gout, and two of these partly mediate the effects of urate-associated GWAS variants. In other genes, including SLC7A11 and PHGDH, 17 urate-associated CpGs are associated with conditions defining metabolic syndrome, suggesting that these CpGs may represent a blood DNA methylation signature of cardiometabolic risk factors. This study demonstrates that EWAS can provide new insights into GWAS loci and the correlation of serum urate with other complex traits.

%B Nat Commun %V 12 %P 7173 %8 2021 12 09 %G eng %N 1 %R 10.1038/s41467-021-27198-4 %0 Journal Article %J Nat Commun %D 2021 %T Identification of putative causal loci in whole-genome sequencing data via knockoff statistics. %A He, Zihuai %A Liu, Linxi %A Wang, Chen %A Le Guen, Yann %A Lee, Justin %A Gogarten, Stephanie %A Lu, Fred %A Montgomery, Stephen %A Tang, Hua %A Silverman, Edwin K %A Cho, Michael H %A Greicius, Michael %A Ionita-Laza, Iuliana %K Algorithms %K Causality %K Computer Simulation %K Data Interpretation, Statistical %K Datasets as Topic %K Genetic Loci %K Genetic Predisposition to Disease %K Genome, Human %K Genome-Wide Association Study %K Humans %K Linkage Disequilibrium %K Markov Chains %K Models, Genetic %K Polymorphism, Single Nucleotide %K Reproducibility of Results %K Whole Genome Sequencing %X

The analysis of whole-genome sequencing studies is challenging due to the large number of rare variants in noncoding regions and the lack of natural units for testing. We propose a statistical method to detect and localize rare and common risk variants in whole-genome sequencing studies based on a recently developed knockoff framework. It can (1) prioritize causal variants over associations due to linkage disequilibrium thereby improving interpretability; (2) help distinguish the signal due to rare variants from shadow effects of significant common variants nearby; (3) integrate multiple knockoffs for improved power, stability, and reproducibility; and (4) flexibly incorporate state-of-the-art and future association tests to achieve the benefits proposed here. In applications to whole-genome sequencing data from the Alzheimer's Disease Sequencing Project (ADSP) and COPDGene samples from NHLBI Trans-Omics for Precision Medicine (TOPMed) Program we show that our method compared with conventional association tests can lead to substantially more discoveries.

%B Nat Commun %V 12 %P 3152 %8 2021 05 25 %G eng %N 1 %R 10.1038/s41467-021-22889-4 %0 Journal Article %J PLoS Genet %D 2021 %T Rare variants in the endocytic pathway are associated with Alzheimer's disease, its related phenotypes, and functional consequences. %A Zhan, Lingyu %A Li, Jiajin %A Jew, Brandon %A Sul, Jae Hoon %K Alzheimer Disease %K Endocytosis %K Genome-Wide Association Study %K Humans %K Phenotype %K Polymorphism, Single Nucleotide %K Whole Genome Sequencing %X

Late-onset Alzheimer's disease (LOAD) is the most common type of dementia causing irreversible brain damage to the elderly and presents a major public health challenge. Clinical research and genome-wide association studies have suggested a potential contribution of the endocytic pathway to AD, with an emphasis on common loci. However, the contribution of rare variants in this pathway to AD has not been thoroughly investigated. In this study, we focused on the effect of rare variants on AD by first applying a rare-variant gene-set burden analysis using genes in the endocytic pathway on over 3,000 individuals with European ancestry from three large whole-genome sequencing (WGS) studies. We identified significant associations of rare-variant burden within the endocytic pathway with AD, which were successfully replicated in independent datasets. We further demonstrated that this endocytic rare-variant enrichment is associated with neurofibrillary tangles (NFTs) and age-related phenotypes, increasing the risk of obtaining severer brain damage, earlier age-at-onset, and earlier age-of-death. Next, by aggregating rare variants within each gene, we sought to identify single endocytic genes associated with AD and NFTs. Careful examination using NFTs revealed one significantly associated gene, ANKRD13D. To identify functional associations, we integrated bulk RNA-Seq data from over 600 brain tissues and found two endocytic expression genes (eGenes), HLA-A and SLC26A7, that displayed significant influences on their gene expressions. Differential expressions between AD patients and controls of these three identified genes were further examined by incorporating scRNA-Seq data from 48 post-mortem brain samples and demonstrated distinct expression patterns across cell types. Taken together, our results demonstrated strong rare-variant effect in the endocytic pathway on AD risk and progression and functional effect of gene expression alteration in both bulk and single-cell resolution, which may bring more insight and serve as valuable resources for future AD genetic studies, clinical research, and therapeutic targeting.

%B PLoS Genet %V 17 %P e1009772 %8 2021 09 %G eng %N 9 %R 10.1371/journal.pgen.1009772 %0 Journal Article %J Am J Hum Genet %D 2021 %T Whole-genome sequencing association analysis of quantitative red blood cell phenotypes: The NHLBI TOPMed program. %A Hu, Yao %A Stilp, Adrienne M %A McHugh, Caitlin P %A Rao, Shuquan %A Jain, Deepti %A Zheng, Xiuwen %A Lane, John %A Méric de Bellefon, Sébastian %A Raffield, Laura M %A Chen, Ming-Huei %A Yanek, Lisa R %A Wheeler, Marsha %A Yao, Yao %A Ren, Chunyan %A Broome, Jai %A Moon, Jee-Young %A de Vries, Paul S %A Hobbs, Brian D %A Sun, Quan %A Surendran, Praveen %A Brody, Jennifer A %A Blackwell, Thomas W %A Choquet, Helene %A Ryan, Kathleen %A Duggirala, Ravindranath %A Heard-Costa, Nancy %A Wang, Zhe %A Chami, Nathalie %A Preuss, Michael H %A Min, Nancy %A Ekunwe, Lynette %A Lange, Leslie A %A Cushman, Mary %A Faraday, Nauder %A Curran, Joanne E %A Almasy, Laura %A Kundu, Kousik %A Smith, Albert V %A Gabriel, Stacey %A Rotter, Jerome I %A Fornage, Myriam %A Lloyd-Jones, Donald M %A Vasan, Ramachandran S %A Smith, Nicholas L %A North, Kari E %A Boerwinkle, Eric %A Becker, Lewis C %A Lewis, Joshua P %A Abecasis, Goncalo R %A Hou, Lifang %A O'Connell, Jeffrey R %A Morrison, Alanna C %A Beaty, Terri H %A Kaplan, Robert %A Correa, Adolfo %A Blangero, John %A Jorgenson, Eric %A Psaty, Bruce M %A Kooperberg, Charles %A Walton, Russell T %A Kleinstiver, Benjamin P %A Tang, Hua %A Loos, Ruth J F %A Soranzo, Nicole %A Butterworth, Adam S %A Nickerson, Debbie %A Rich, Stephen S %A Mitchell, Braxton D %A Johnson, Andrew D %A Auer, Paul L %A Li, Yun %A Mathias, Rasika A %A Lettre, Guillaume %A Pankratz, Nathan %A Laurie, Cathy C %A Laurie, Cecelia A %A Bauer, Daniel E %A Conomos, Matthew P %A Reiner, Alexander P %K Adult %K Aged %K Chromosomes, Human, Pair 16 %K Datasets as Topic %K Erythrocytes %K Female %K Gene Editing %K Genetic Variation %K Genome-Wide Association Study %K HEK293 Cells %K Humans %K Male %K Middle Aged %K National Heart, Lung, and Blood Institute (U.S.) %K Phenotype %K Quality Control %K Reproducibility of Results %K United States %X

Whole-genome sequencing (WGS), a powerful tool for detecting novel coding and non-coding disease-causing variants, has largely been applied to clinical diagnosis of inherited disorders. Here we leveraged WGS data in up to 62,653 ethnically diverse participants from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program and assessed statistical association of variants with seven red blood cell (RBC) quantitative traits. We discovered 14 single variant-RBC trait associations at 12 genomic loci, which have not been reported previously. Several of the RBC trait-variant associations (RPN1, ELL2, MIDN, HBB, HBA1, PIEZO1, and G6PD) were replicated in independent GWAS datasets imputed to the TOPMed reference panel. Most of these discovered variants are rare/low frequency, and several are observed disproportionately among non-European Ancestry (African, Hispanic/Latino, or East Asian) populations. We identified a 3 bp indel p.Lys2169del (g.88717175_88717177TCT[4]) (common only in the Ashkenazi Jewish population) of PIEZO1, a gene responsible for the Mendelian red cell disorder hereditary xerocytosis (MIM: 194380), associated with higher mean corpuscular hemoglobin concentration (MCHC). In stepwise conditional analysis and in gene-based rare variant aggregated association analysis, we identified several of the variants in HBB, HBA1, TMPRSS6, and G6PD that represent the carrier state for known coding, promoter, or splice site loss-of-function variants that cause inherited RBC disorders. Finally, we applied base and nuclease editing to demonstrate that the sentinel variant rs112097551 (nearest gene RPN1) acts through a cis-regulatory element that exerts long-range control of the gene RUVBL1 which is essential for hematopoiesis. Together, these results demonstrate the utility of WGS in ethnically diverse population-based samples and gene editing for expanding knowledge of the genetic architecture of quantitative hematologic traits and suggest a continuum between complex trait and Mendelian red cell disorders.

%B Am J Hum Genet %V 108 %P 874-893 %8 2021 05 06 %G eng %N 5 %R 10.1016/j.ajhg.2021.04.003 %0 Journal Article %J Am J Hum Genet %D 2021 %T Whole-genome sequencing in diverse subjects identifies genetic correlates of leukocyte traits: The NHLBI TOPMed program. %A Mikhaylova, Anna V %A McHugh, Caitlin P %A Polfus, Linda M %A Raffield, Laura M %A Boorgula, Meher Preethi %A Blackwell, Thomas W %A Brody, Jennifer A %A Broome, Jai %A Chami, Nathalie %A Chen, Ming-Huei %A Conomos, Matthew P %A Cox, Corey %A Curran, Joanne E %A Daya, Michelle %A Ekunwe, Lynette %A Glahn, David C %A Heard-Costa, Nancy %A Highland, Heather M %A Hobbs, Brian D %A Ilboudo, Yann %A Jain, Deepti %A Lange, Leslie A %A Miller-Fleming, Tyne W %A Min, Nancy %A Moon, Jee-Young %A Preuss, Michael H %A Rosen, Jonathon %A Ryan, Kathleen %A Smith, Albert V %A Sun, Quan %A Surendran, Praveen %A de Vries, Paul S %A Walter, Klaudia %A Wang, Zhe %A Wheeler, Marsha %A Yanek, Lisa R %A Zhong, Xue %A Abecasis, Goncalo R %A Almasy, Laura %A Barnes, Kathleen C %A Beaty, Terri H %A Becker, Lewis C %A Blangero, John %A Boerwinkle, Eric %A Butterworth, Adam S %A Chavan, Sameer %A Cho, Michael H %A Choquet, Helene %A Correa, Adolfo %A Cox, Nancy %A DeMeo, Dawn L %A Faraday, Nauder %A Fornage, Myriam %A Gerszten, Robert E %A Hou, Lifang %A Johnson, Andrew D %A Jorgenson, Eric %A Kaplan, Robert %A Kooperberg, Charles %A Kundu, Kousik %A Laurie, Cecelia A %A Lettre, Guillaume %A Lewis, Joshua P %A Li, Bingshan %A Li, Yun %A Lloyd-Jones, Donald M %A Loos, Ruth J F %A Manichaikul, Ani %A Meyers, Deborah A %A Mitchell, Braxton D %A Morrison, Alanna C %A Ngo, Debby %A Nickerson, Deborah A %A Nongmaithem, Suraj %A North, Kari E %A O'Connell, Jeffrey R %A Ortega, Victor E %A Pankratz, Nathan %A Perry, James A %A Psaty, Bruce M %A Rich, Stephen S %A Soranzo, Nicole %A Rotter, Jerome I %A Silverman, Edwin K %A Smith, Nicholas L %A Tang, Hua %A Tracy, Russell P %A Thornton, Timothy A %A Vasan, Ramachandran S %A Zein, Joe %A Mathias, Rasika A %A Reiner, Alexander P %A Auer, Paul L %K Asthma %K Biomarkers %K Dermatitis, Atopic %K Genetic Predisposition to Disease %K Genome, Human %K Genome-Wide Association Study %K Humans %K Leukocytes %K National Heart, Lung, and Blood Institute (U.S.) %K Phenotype %K Polymorphism, Single Nucleotide %K Prognosis %K Proteome %K Pulmonary Disease, Chronic Obstructive %K Quantitative Trait Loci %K United Kingdom %K United States %K Whole Genome Sequencing %X

Many common and rare variants associated with hematologic traits have been discovered through imputation on large-scale reference panels. However, the majority of genome-wide association studies (GWASs) have been conducted in Europeans, and determining causal variants has proved challenging. We performed a GWAS of total leukocyte, neutrophil, lymphocyte, monocyte, eosinophil, and basophil counts generated from 109,563,748 variants in the autosomes and the X chromosome in the Trans-Omics for Precision Medicine (TOPMed) program, which included data from 61,802 individuals of diverse ancestry. We discovered and replicated 7 leukocyte trait associations, including (1) the association between a chromosome X, pseudo-autosomal region (PAR), noncoding variant located between cytokine receptor genes (CSF2RA and CLRF2) and lower eosinophil count; and (2) associations between single variants found predominantly among African Americans at the S1PR3 (9q22.1) and HBB (11p15.4) loci and monocyte and lymphocyte counts, respectively. We further provide evidence indicating that the newly discovered eosinophil-lowering chromosome X PAR variant might be associated with reduced susceptibility to common allergic diseases such as atopic dermatitis and asthma. Additionally, we found a burden of very rare FLT3 (13q12.2) variants associated with monocyte counts. Together, these results emphasize the utility of whole-genome sequencing in diverse samples in identifying associations missed by European-ancestry-driven GWASs.

%B Am J Hum Genet %V 108 %P 1836-1851 %8 2021 10 07 %G eng %N 10 %R 10.1016/j.ajhg.2021.08.007 %0 Journal Article %J J Am Heart Assoc %D 2022 %T Circulating Soluble CD163, Associations With Cardiovascular Outcomes and Mortality, and Identification of Genetic Variants in Older Individuals: The Cardiovascular Health Study. %A Durda, Peter %A Raffield, Laura M %A Lange, Ethan M %A Olson, Nels C %A Jenny, Nancy Swords %A Cushman, Mary %A Deichgraeber, Pia %A Grarup, Niels %A Jonsson, Anna %A Hansen, Torben %A Mychaleckyj, Josyf C %A Psaty, Bruce M %A Reiner, Alex P %A Tracy, Russell P %A Lange, Leslie A %K Aged %K Antigens, CD %K Antigens, Differentiation, Myelomonocytic %K Asialoglycoprotein Receptor %K Biomarkers %K Cardiovascular Diseases %K Female %K Genome-Wide Association Study %K Heart Failure %K Humans %K Longitudinal Studies %K Male %X

Background Monocytes/macrophages participate in cardiovascular disease. CD163 (cluster of differentiation 163) is a monocyte/macrophage receptor, and the shed sCD163 (soluble CD163) reflects monocyte/macrophage activation. We examined the association of sCD163 with incident cardiovascular disease events and performed a genome-wide association study to identify sCD163-associated variants. Methods and Results We measured plasma sCD163 in 5214 adults (aged ≥65 years, 58.7% women, 16.2% Black) of the CHS (Cardiovascular Health Study). We used Cox regression models (associations of sCD163 with incident events and mortality); median follow-up was 26 years. Genome-wide association study analyses were stratified on race. Adjusted for age, sex, and race and ethnicity, sCD163 levels were associated with all-cause mortality (hazard ratio [HR], 1.08 [95% CI, 1.04-1.12] per SD increase), cardiovascular disease mortality (HR, 1.15 [95% CI, 1.09-1.21]), incident coronary heart disease (HR, 1.10 [95% CI, 1.04-1.16]), and incident heart failure (HR, 1.18 [95% CI, 1.12-1.25]). When further adjusted (eg, cardiovascular disease risk factors), only incident coronary heart disease lost significance. In European American individuals, genome-wide association studies identified 38 variants on chromosome 2 near (top result rs62165726, =3.3×10),19 variants near chromosome 17 gene (rs55714927, =1.5×10), and 18 variants near chromosome 11 gene . These regions replicated in the European ancestry ADDITION-PRO cohort, a longitudinal cohort study nested in the Danish arm of the Anglo-Danish-Dutch study of Intensive Treatment Intensive Treatment In peOple with screeNdetcted Diabetes in Primary Care. In Black individuals, we identified 9 variants on chromosome 6 (rs3129781 =7.1×10) in the region, and 3 variants (rs115391969 =4.3×10) near the chromosome 16 gene Conclusions Monocyte function, as measured by sCD163, may be predictive of overall and cardiovascular-specific mortality and incident heart failure.

%B J Am Heart Assoc %V 11 %P e024374 %8 2022 Nov %G eng %N 21 %R 10.1161/JAHA.121.024374 %0 Journal Article %J Circulation %D 2022 %T Cross-Ancestry Investigation of Venous Thromboembolism Genomic Predictors. %A Thibord, Florian %A Klarin, Derek %A Brody, Jennifer A %A Chen, Ming-Huei %A Levin, Michael G %A Chasman, Daniel I %A Goode, Ellen L %A Hveem, Kristian %A Teder-Laving, Maris %A Martinez-Perez, Angel %A Aïssi, Dylan %A Daian-Bacq, Delphine %A Ito, Kaoru %A Natarajan, Pradeep %A Lutsey, Pamela L %A Nadkarni, Girish N %A de Vries, Paul S %A Cuellar-Partida, Gabriel %A Wolford, Brooke N %A Pattee, Jack W %A Kooperberg, Charles %A Braekkan, Sigrid K %A Li-Gao, Ruifang %A Saut, Noémie %A Sept, Corriene %A Germain, Marine %A Judy, Renae L %A Wiggins, Kerri L %A Ko, Darae %A O'Donnell, Christopher J %A Taylor, Kent D %A Giulianini, Franco %A de Andrade, Mariza %A Nøst, Therese H %A Boland, Anne %A Empana, Jean-Philippe %A Koyama, Satoshi %A Gilliland, Thomas %A Do, Ron %A Huffman, Jennifer E %A Wang, Xin %A Zhou, Wei %A Manuel Soria, Jose %A Carlos Souto, Juan %A Pankratz, Nathan %A Haessler, Jeffery %A Hindberg, Kristian %A Rosendaal, Frits R %A Turman, Constance %A Olaso, Robert %A Kember, Rachel L %A Bartz, Traci M %A Lynch, Julie A %A Heckbert, Susan R %A Armasu, Sebastian M %A Brumpton, Ben %A Smadja, David M %A Jouven, Xavier %A Komuro, Issei %A Clapham, Katharine R %A Loos, Ruth J F %A Willer, Cristen J %A Sabater-Lleal, Maria %A Pankow, James S %A Reiner, Alexander P %A Morelli, Vania M %A Ridker, Paul M %A Vlieg, Astrid van Hylckama %A Deleuze, Jean-Francois %A Kraft, Peter %A Rader, Daniel J %A Min Lee, Kyung %A Psaty, Bruce M %A Heidi Skogholt, Anne %A Emmerich, Joseph %A Suchon, Pierre %A Rich, Stephen S %A Vy, Ha My T %A Tang, Weihong %A Jackson, Rebecca D %A Hansen, John-Bjarne %A Morange, Pierre-Emmanuel %A Kabrhel, Christopher %A Trégouët, David-Alexandre %A Damrauer, Scott M %A Johnson, Andrew D %A Smith, Nicholas L %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genomics %K Humans %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %K Thrombosis %K Venous Thromboembolism %X

BACKGROUND: Venous thromboembolism (VTE) is a life-threatening vascular event with environmental and genetic determinants. Recent VTE genome-wide association studies (GWAS) meta-analyses involved nearly 30 000 VTE cases and identified up to 40 genetic loci associated with VTE risk, including loci not previously suspected to play a role in hemostasis. The aim of our research was to expand discovery of new genetic loci associated with VTE by using cross-ancestry genomic resources.

METHODS: We present new cross-ancestry meta-analyzed GWAS results involving up to 81 669 VTE cases from 30 studies, with replication of novel loci in independent populations and loci characterization through in silico genomic interrogations.

RESULTS: In our genetic discovery effort that included 55 330 participants with VTE (47 822 European, 6320 African, and 1188 Hispanic ancestry), we identified 48 novel associations, of which 34 were replicated after correction for multiple testing. In our combined discovery-replication analysis (81 669 VTE participants) and ancestry-stratified meta-analyses (European, African, and Hispanic), we identified another 44 novel associations, which are new candidate VTE-associated loci requiring replication. In total, across all GWAS meta-analyses, we identified 135 independent genomic loci significantly associated with VTE risk. A genetic risk score of the significantly associated loci in Europeans identified a 6-fold increase in risk for those in the top 1% of scores compared with those with average scores. We also identified 31 novel transcript associations in transcriptome-wide association studies and 8 novel candidate genes with protein quantitative-trait locus Mendelian randomization analyses. In silico interrogations of hemostasis and hematology traits and a large phenome-wide association analysis of the 135 GWAS loci provided insights to biological pathways contributing to VTE, with some loci contributing to VTE through well-characterized coagulation pathways and others providing new data on the role of hematology traits, particularly platelet function. Many of the replicated loci are outside of known or currently hypothesized pathways to thrombosis.

CONCLUSIONS: Our cross-ancestry GWAS meta-analyses identified new loci associated with VTE. These findings highlight new pathways to thrombosis and provide novel molecules that may be useful in the development of improved antithrombosis treatments.

%B Circulation %V 146 %P 1225-1242 %8 2022 Oct 18 %G eng %N 16 %R 10.1161/CIRCULATIONAHA.122.059675 %0 Journal Article %J Commun Biol %D 2022 %T Differential and shared genetic effects on kidney function between diabetic and non-diabetic individuals. %A Winkler, Thomas W %A Rasheed, Humaira %A Teumer, Alexander %A Gorski, Mathias %A Rowan, Bryce X %A Stanzick, Kira J %A Thomas, Laurent F %A Tin, Adrienne %A Hoppmann, Anselm %A Chu, Audrey Y %A Tayo, Bamidele %A Thio, Chris H L %A Cusi, Daniele %A Chai, Jin-Fang %A Sieber, Karsten B %A Horn, Katrin %A Li, Man %A Scholz, Markus %A Cocca, Massimiliano %A Wuttke, Matthias %A van der Most, Peter J %A Yang, Qiong %A Ghasemi, Sahar %A Nutile, Teresa %A Li, Yong %A Pontali, Giulia %A Günther, Felix %A Dehghan, Abbas %A Correa, Adolfo %A Parsa, Afshin %A Feresin, Agnese %A de Vries, Aiko P J %A Zonderman, Alan B %A Smith, Albert V %A Oldehinkel, Albertine J %A De Grandi, Alessandro %A Rosenkranz, Alexander R %A Franke, Andre %A Teren, Andrej %A Metspalu, Andres %A Hicks, Andrew A %A Morris, Andrew P %A Tönjes, Anke %A Morgan, Anna %A Podgornaia, Anna I %A Peters, Annette %A Körner, Antje %A Mahajan, Anubha %A Campbell, Archie %A Freedman, Barry I %A Spedicati, Beatrice %A Ponte, Belen %A Schöttker, Ben %A Brumpton, Ben %A Banas, Bernhard %A Krämer, Bernhard K %A Jung, Bettina %A Åsvold, Bjørn Olav %A Smith, Blair H %A Ning, Boting %A Penninx, Brenda W J H %A Vanderwerff, Brett R %A Psaty, Bruce M %A Kammerer, Candace M %A Langefeld, Carl D %A Hayward, Caroline %A Spracklen, Cassandra N %A Robinson-Cohen, Cassianne %A Hartman, Catharina A %A Lindgren, Cecilia M %A Wang, Chaolong %A Sabanayagam, Charumathi %A Heng, Chew-Kiat %A Lanzani, Chiara %A Khor, Chiea-Chuen %A Cheng, Ching-Yu %A Fuchsberger, Christian %A Gieger, Christian %A Shaffer, Christian M %A Schulz, Christina-Alexandra %A Willer, Cristen J %A Chasman, Daniel I %A Gudbjartsson, Daniel F %A Ruggiero, Daniela %A Toniolo, Daniela %A Czamara, Darina %A Porteous, David J %A Waterworth, Dawn M %A Mascalzoni, Deborah %A Mook-Kanamori, Dennis O %A Reilly, Dermot F %A Daw, E Warwick %A Hofer, Edith %A Boerwinkle, Eric %A Salvi, Erika %A Bottinger, Erwin P %A Tai, E-Shyong %A Catamo, Eulalia %A Rizzi, Federica %A Guo, Feng %A Rivadeneira, Fernando %A Guilianini, Franco %A Sveinbjornsson, Gardar %A Ehret, Georg %A Waeber, Gérard %A Biino, Ginevra %A Girotto, Giorgia %A Pistis, Giorgio %A Nadkarni, Girish N %A Delgado, Graciela E %A Montgomery, Grant W %A Snieder, Harold %A Campbell, Harry %A White, Harvey D %A Gao, He %A Stringham, Heather M %A Schmidt, Helena %A Li, Hengtong %A Brenner, Hermann %A Holm, Hilma %A Kirsten, Holgen %A Kramer, Holly %A Rudan, Igor %A Nolte, Ilja M %A Tzoulaki, Ioanna %A Olafsson, Isleifur %A Martins, Jade %A Cook, James P %A Wilson, James F %A Halbritter, Jan %A Felix, Janine F %A Divers, Jasmin %A Kooner, Jaspal S %A Lee, Jeannette Jen-Mai %A O'Connell, Jeffrey %A Rotter, Jerome I %A Liu, Jianjun %A Xu, Jie %A Thiery, Joachim %A Arnlöv, Johan %A Kuusisto, Johanna %A Jakobsdottir, Johanna %A Tremblay, Johanne %A Chambers, John C %A Whitfield, John B %A Gaziano, John M %A Marten, Jonathan %A Coresh, Josef %A Jonas, Jost B %A Mychaleckyj, Josyf C %A Christensen, Kaare %A Eckardt, Kai-Uwe %A Mohlke, Karen L %A Endlich, Karlhans %A Dittrich, Katalin %A Ryan, Kathleen A %A Rice, Kenneth M %A Taylor, Kent D %A Ho, Kevin %A Nikus, Kjell %A Matsuda, Koichi %A Strauch, Konstantin %A Miliku, Kozeta %A Hveem, Kristian %A Lind, Lars %A Wallentin, Lars %A Yerges-Armstrong, Laura M %A Raffield, Laura M %A Phillips, Lawrence S %A Launer, Lenore J %A Lyytikäinen, Leo-Pekka %A Lange, Leslie A %A Citterio, Lorena %A Klaric, Lucija %A Ikram, M Arfan %A Ising, Marcus %A Kleber, Marcus E %A Francescatto, Margherita %A Concas, Maria Pina %A Ciullo, Marina %A Piratsu, Mario %A Orho-Melander, Marju %A Laakso, Markku %A Loeffler, Markus %A Perola, Markus %A de Borst, Martin H %A Gögele, Martin %A Bianca, Martina La %A Lukas, Mary Ann %A Feitosa, Mary F %A Biggs, Mary L %A Wojczynski, Mary K %A Kavousi, Maryam %A Kanai, Masahiro %A Akiyama, Masato %A Yasuda, Masayuki %A Nauck, Matthias %A Waldenberger, Melanie %A Chee, Miao-Li %A Chee, Miao-Ling %A Boehnke, Michael %A Preuss, Michael H %A Stumvoll, Michael %A Province, Michael A %A Evans, Michele K %A O'Donoghue, Michelle L %A Kubo, Michiaki %A Kähönen, Mika %A Kastarinen, Mika %A Nalls, Mike A %A Kuokkanen, Mikko %A Ghanbari, Mohsen %A Bochud, Murielle %A Josyula, Navya Shilpa %A Martin, Nicholas G %A Tan, Nicholas Y Q %A Palmer, Nicholette D %A Pirastu, Nicola %A Schupf, Nicole %A Verweij, Niek %A Hutri-Kähönen, Nina %A Mononen, Nina %A Bansal, Nisha %A Devuyst, Olivier %A Melander, Olle %A Raitakari, Olli T %A Polasek, Ozren %A Manunta, Paolo %A Gasparini, Paolo %A Mishra, Pashupati P %A Sulem, Patrick %A Magnusson, Patrik K E %A Elliott, Paul %A Ridker, Paul M %A Hamet, Pavel %A Svensson, Per O %A Joshi, Peter K %A Kovacs, Peter %A Pramstaller, Peter P %A Rossing, Peter %A Vollenweider, Peter %A van der Harst, Pim %A Dorajoo, Rajkumar %A Sim, Ralene Z H %A Burkhardt, Ralph %A Tao, Ran %A Noordam, Raymond %A Mägi, Reedik %A Schmidt, Reinhold %A de Mutsert, Renée %A Rueedi, Rico %A van Dam, Rob M %A Carroll, Robert J %A Gansevoort, Ron T %A Loos, Ruth J F %A Felicita, Sala Cinzia %A Sedaghat, Sanaz %A Padmanabhan, Sandosh %A Freitag-Wolf, Sandra %A Pendergrass, Sarah A %A Graham, Sarah E %A Gordon, Scott D %A Hwang, Shih-Jen %A Kerr, Shona M %A Vaccargiu, Simona %A Patil, Snehal B %A Hallan, Stein %A Bakker, Stephan J L %A Lim, Su-Chi %A Lucae, Susanne %A Vogelezang, Suzanne %A Bergmann, Sven %A Corre, Tanguy %A Ahluwalia, Tarunveer S %A Lehtimäki, Terho %A Boutin, Thibaud S %A Meitinger, Thomas %A Wong, Tien-Yin %A Bergler, Tobias %A Rabelink, Ton J %A Esko, Tõnu %A Haller, Toomas %A Thorsteinsdottir, Unnur %A Völker, Uwe %A Foo, Valencia Hui Xian %A Salomaa, Veikko %A Vitart, Veronique %A Giedraitis, Vilmantas %A Gudnason, Vilmundur %A Jaddoe, Vincent W V %A Huang, Wei %A Zhang, Weihua %A Wei, Wen Bin %A Kiess, Wieland %A März, Winfried %A Koenig, Wolfgang %A Lieb, Wolfgang %A Gào, Xīn %A Sim, Xueling %A Wang, Ya Xing %A Friedlander, Yechiel %A Tham, Yih-Chung %A Kamatani, Yoichiro %A Okada, Yukinori %A Milaneschi, Yuri %A Yu, Zhi %A Stark, Klaus J %A Stefansson, Kari %A Böger, Carsten A %A Hung, Adriana M %A Kronenberg, Florian %A Köttgen, Anna %A Pattaro, Cristian %A Heid, Iris M %K Creatinine %K Diabetes Mellitus %K Diabetic Nephropathies %K Genome-Wide Association Study %K Glomerular Filtration Rate %K Humans %K Kidney %X

Reduced glomerular filtration rate (GFR) can progress to kidney failure. Risk factors include genetics and diabetes mellitus (DM), but little is known about their interaction. We conducted genome-wide association meta-analyses for estimated GFR based on serum creatinine (eGFR), separately for individuals with or without DM (n = 178,691, n = 1,296,113). Our genome-wide searches identified (i) seven eGFR loci with significant DM/noDM-difference, (ii) four additional novel loci with suggestive difference and (iii) 28 further novel loci (including CUBN) by allowing for potential difference. GWAS on eGFR among DM individuals identified 2 known and 27 potentially responsible loci for diabetic kidney disease. Gene prioritization highlighted 18 genes that may inform reno-protective drug development. We highlight the existence of DM-only and noDM-only effects, which can inform about the target group, if respective genes are advanced as drug targets. Largely shared effects suggest that most drug interventions to alter eGFR should be effective in DM and noDM.

%B Commun Biol %V 5 %P 580 %8 2022 Jun 13 %G eng %N 1 %R 10.1038/s42003-022-03448-z %0 Journal Article %J Brief Bioinform %D 2022 %T eSCAN: scan regulatory regions for aggregate association testing using whole-genome sequencing data. %A Yang, Yingxi %A Sun, Quan %A Huang, Le %A Broome, Jai G %A Correa, Adolfo %A Reiner, Alexander %A Raffield, Laura M %A Yang, Yuchen %A Li, Yun %K Genome %K Genome-Wide Association Study %K Genomics %K Regulatory Sequences, Nucleic Acid %K Whole Genome Sequencing %X

Multiple statistical methods for aggregate association testing have been developed for whole-genome sequencing (WGS) data. Many aggregate variants in a given genomic window and ignore existing knowledge to define test regions, resulting in many identified regions not clearly linked to genes, and thus, limiting biological understanding. Functional information from new technologies (such as Hi-C and its derivatives), which can help link enhancers to their effector genes, can be leveraged to predefine variant sets for aggregate testing in WGS data. Here, we propose the eSCAN (scan the enhancers) method for genome-wide assessment of enhancer regions in sequencing studies, combining the advantages of dynamic window selection in SCANG (SCAN the Genome), a previously developed method, with the advantages of incorporating putative regulatory regions from annotation. eSCAN, by searching in putative enhancers, increases statistical power and aids mechanistic interpretation, as demonstrated by extensive simulation studies. We also apply eSCAN for blood cell traits using NHLBI Trans-Omics for Precision Medicine WGS data. Results from real data analysis show that eSCAN is able to capture more significant signals, and these signals are of shorter length (indicating higher resolution fine-mapping capability) and drive association of larger regions detected by other methods.

%B Brief Bioinform %V 23 %8 2022 01 17 %G eng %N 1 %R 10.1093/bib/bbab497 %0 Journal Article %J Nat Methods %D 2022 %T A framework for detecting noncoding rare-variant associations of large-scale whole-genome sequencing studies. %A Li, Zilin %A Li, Xihao %A Zhou, Hufeng %A Gaynor, Sheila M %A Selvaraj, Margaret Sunitha %A Arapoglou, Theodore %A Quick, Corbin %A Liu, Yaowu %A Chen, Han %A Sun, Ryan %A Dey, Rounak %A Arnett, Donna K %A Auer, Paul L %A Bielak, Lawrence F %A Bis, Joshua C %A Blackwell, Thomas W %A Blangero, John %A Boerwinkle, Eric %A Bowden, Donald W %A Brody, Jennifer A %A Cade, Brian E %A Conomos, Matthew P %A Correa, Adolfo %A Cupples, L Adrienne %A Curran, Joanne E %A de Vries, Paul S %A Duggirala, Ravindranath %A Franceschini, Nora %A Freedman, Barry I %A Göring, Harald H H %A Guo, Xiuqing %A Kalyani, Rita R %A Kooperberg, Charles %A Kral, Brian G %A Lange, Leslie A %A Lin, Bridget M %A Manichaikul, Ani %A Manning, Alisa K %A Martin, Lisa W %A Mathias, Rasika A %A Meigs, James B %A Mitchell, Braxton D %A Montasser, May E %A Morrison, Alanna C %A Naseri, Take %A O'Connell, Jeffrey R %A Palmer, Nicholette D %A Peyser, Patricia A %A Psaty, Bruce M %A Raffield, Laura M %A Redline, Susan %A Reiner, Alexander P %A Reupena, Muagututi'a Sefuiva %A Rice, Kenneth M %A Rich, Stephen S %A Smith, Jennifer A %A Taylor, Kent D %A Taub, Margaret A %A Vasan, Ramachandran S %A Weeks, Daniel E %A Wilson, James G %A Yanek, Lisa R %A Zhao, Wei %A Rotter, Jerome I %A Willer, Cristen J %A Natarajan, Pradeep %A Peloso, Gina M %A Lin, Xihong %K Genetic Variation %K Genome %K Genome-Wide Association Study %K Humans %K Phenotype %K Whole Genome Sequencing %X

Large-scale whole-genome sequencing studies have enabled analysis of noncoding rare-variant (RV) associations with complex human diseases and traits. Variant-set analysis is a powerful approach to study RV association. However, existing methods have limited ability in analyzing the noncoding genome. We propose a computationally efficient and robust noncoding RV association detection framework, STAARpipeline, to automatically annotate a whole-genome sequencing study and perform flexible noncoding RV association analysis, including gene-centric analysis and fixed window-based and dynamic window-based non-gene-centric analysis by incorporating variant functional annotations. In gene-centric analysis, STAARpipeline uses STAAR to group noncoding variants based on functional categories of genes and incorporate multiple functional annotations. In non-gene-centric analysis, STAARpipeline uses SCANG-STAAR to incorporate dynamic window sizes and multiple functional annotations. We apply STAARpipeline to identify noncoding RV sets associated with four lipid traits in 21,015 discovery samples from the Trans-Omics for Precision Medicine (TOPMed) program and replicate several of them in an additional 9,123 TOPMed samples. We also analyze five non-lipid TOPMed traits.

%B Nat Methods %V 19 %P 1599-1611 %8 2022 Dec %G eng %N 12 %R 10.1038/s41592-022-01640-x %0 Journal Article %J Circ Res %D 2022 %T Genome Wide Association Studies of Variant-by-Thiazide Interaction on Lipids Identifies a Novel Low-Density Lipoprotein Cholesterol Locus. %A Downie, Carolina G %A Highland, Heather M %A Lee, Moa P %A Raffield, Laura M %A Preuss, Michael %A Whitsel, Eric A %A Psaty, Bruce M %A Sitlani, Colleen M %A Graff, Mariaelisa %A Avery, Christy L %K Cholesterol, HDL %K Cholesterol, LDL %K Diuretics %K Genome-Wide Association Study %K Sodium Chloride Symporter Inhibitors %K Thiazides %K Triglycerides %B Circ Res %V 131 %P 277-279 %8 2022 Jul 22 %G eng %N 3 %R 10.1161/CIRCRESAHA.122.321120 %0 Journal Article %J Nat Med %D 2022 %T Large-scale genome-wide association study of coronary artery disease in genetically diverse populations. %A Tcheandjieu, Catherine %A Zhu, Xiang %A Hilliard, Austin T %A Clarke, Shoa L %A Napolioni, Valerio %A Ma, Shining %A Lee, Kyung Min %A Fang, Huaying %A Chen, Fei %A Lu, Yingchang %A Tsao, Noah L %A Raghavan, Sridharan %A Koyama, Satoshi %A Gorman, Bryan R %A Vujkovic, Marijana %A Klarin, Derek %A Levin, Michael G %A Sinnott-Armstrong, Nasa %A Wojcik, Genevieve L %A Plomondon, Mary E %A Maddox, Thomas M %A Waldo, Stephen W %A Bick, Alexander G %A Pyarajan, Saiju %A Huang, Jie %A Song, Rebecca %A Ho, Yuk-Lam %A Buyske, Steven %A Kooperberg, Charles %A Haessler, Jeffrey %A Loos, Ruth J F %A Do, Ron %A Verbanck, Marie %A Chaudhary, Kumardeep %A North, Kari E %A Avery, Christy L %A Graff, Mariaelisa %A Haiman, Christopher A %A Le Marchand, Loïc %A Wilkens, Lynne R %A Bis, Joshua C %A Leonard, Hampton %A Shen, Botong %A Lange, Leslie A %A Giri, Ayush %A Dikilitas, Ozan %A Kullo, Iftikhar J %A Stanaway, Ian B %A Jarvik, Gail P %A Gordon, Adam S %A Hebbring, Scott %A Namjou, Bahram %A Kaufman, Kenneth M %A Ito, Kaoru %A Ishigaki, Kazuyoshi %A Kamatani, Yoichiro %A Verma, Shefali S %A Ritchie, Marylyn D %A Kember, Rachel L %A Baras, Aris %A Lotta, Luca A %A Kathiresan, Sekar %A Hauser, Elizabeth R %A Miller, Donald R %A Lee, Jennifer S %A Saleheen, Danish %A Reaven, Peter D %A Cho, Kelly %A Gaziano, J Michael %A Natarajan, Pradeep %A Huffman, Jennifer E %A Voight, Benjamin F %A Rader, Daniel J %A Chang, Kyong-Mi %A Lynch, Julie A %A Damrauer, Scott M %A Wilson, Peter W F %A Tang, Hua %A Sun, Yan V %A Tsao, Philip S %A O'Donnell, Christopher J %A Assimes, Themistocles L %K Coronary Artery Disease %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Polymorphism, Single Nucleotide %K Risk Factors %X

We report a genome-wide association study (GWAS) of coronary artery disease (CAD) incorporating nearly a quarter of a million cases, in which existing studies are integrated with data from cohorts of white, Black and Hispanic individuals from the Million Veteran Program. We document near equivalent heritability of CAD across multiple ancestral groups, identify 95 novel loci, including nine on the X chromosome, detect eight loci of genome-wide significance in Black and Hispanic individuals, and demonstrate that two common haplotypes at the 9p21 locus are responsible for risk stratification in all populations except those of African origin, in which these haplotypes are virtually absent. Moreover, in the largest GWAS for angiographically derived coronary atherosclerosis performed to date, we find 15 loci of genome-wide significance that robustly overlap with established loci for clinical CAD. Phenome-wide association analyses of novel loci and polygenic risk scores (PRSs) augment signals related to insulin resistance, extend pleiotropic associations of these loci to include smoking and family history, and precisely document the markedly reduced transferability of existing PRSs to Black individuals. Downstream integrative analyses reinforce the critical roles of vascular endothelial, fibroblast, and smooth muscle cells in CAD susceptibility, but also point to a shared biology between atherosclerosis and oncogenesis. This study highlights the value of diverse populations in further characterizing the genetic architecture of CAD.

%B Nat Med %V 28 %P 1679-1692 %8 2022 08 %G eng %N 8 %R 10.1038/s41591-022-01891-3 %0 Journal Article %J Nat Genet %D 2022 %T Multi-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation. %A Mahajan, Anubha %A Spracklen, Cassandra N %A Zhang, Weihua %A Ng, Maggie C Y %A Petty, Lauren E %A Kitajima, Hidetoshi %A Yu, Grace Z %A Rüeger, Sina %A Speidel, Leo %A Kim, Young Jin %A Horikoshi, Momoko %A Mercader, Josep M %A Taliun, Daniel %A Moon, Sanghoon %A Kwak, Soo-Heon %A Robertson, Neil R %A Rayner, Nigel W %A Loh, Marie %A Kim, Bong-Jo %A Chiou, Joshua %A Miguel-Escalada, Irene %A Della Briotta Parolo, Pietro %A Lin, Kuang %A Bragg, Fiona %A Preuss, Michael H %A Takeuchi, Fumihiko %A Nano, Jana %A Guo, Xiuqing %A Lamri, Amel %A Nakatochi, Masahiro %A Scott, Robert A %A Lee, Jung-Jin %A Huerta-Chagoya, Alicia %A Graff, Mariaelisa %A Chai, Jin-Fang %A Parra, Esteban J %A Yao, Jie %A Bielak, Lawrence F %A Tabara, Yasuharu %A Hai, Yang %A Steinthorsdottir, Valgerdur %A Cook, James P %A Kals, Mart %A Grarup, Niels %A Schmidt, Ellen M %A Pan, Ian %A Sofer, Tamar %A Wuttke, Matthias %A Sarnowski, Chloe %A Gieger, Christian %A Nousome, Darryl %A Trompet, Stella %A Long, Jirong %A Sun, Meng %A Tong, Lin %A Chen, Wei-Min %A Ahmad, Meraj %A Noordam, Raymond %A Lim, Victor J Y %A Tam, Claudia H T %A Joo, Yoonjung Yoonie %A Chen, Chien-Hsiun %A Raffield, Laura M %A Lecoeur, Cécile %A Prins, Bram Peter %A Nicolas, Aude %A Yanek, Lisa R %A Chen, Guanjie %A Jensen, Richard A %A Tajuddin, Salman %A Kabagambe, Edmond K %A An, Ping %A Xiang, Anny H %A Choi, Hyeok Sun %A Cade, Brian E %A Tan, Jingyi %A Flanagan, Jack %A Abaitua, Fernando %A Adair, Linda S %A Adeyemo, Adebowale %A Aguilar-Salinas, Carlos A %A Akiyama, Masato %A Anand, Sonia S %A Bertoni, Alain %A Bian, Zheng %A Bork-Jensen, Jette %A Brandslund, Ivan %A Brody, Jennifer A %A Brummett, Chad M %A Buchanan, Thomas A %A Canouil, Mickaël %A Chan, Juliana C N %A Chang, Li-Ching %A Chee, Miao-Li %A Chen, Ji %A Chen, Shyh-Huei %A Chen, Yuan-Tsong %A Chen, Zhengming %A Chuang, Lee-Ming %A Cushman, Mary %A Das, Swapan K %A de Silva, H Janaka %A Dedoussis, George %A Dimitrov, Latchezar %A Doumatey, Ayo P %A Du, Shufa %A Duan, Qing %A Eckardt, Kai-Uwe %A Emery, Leslie S %A Evans, Daniel S %A Evans, Michele K %A Fischer, Krista %A Floyd, James S %A Ford, Ian %A Fornage, Myriam %A Franco, Oscar H %A Frayling, Timothy M %A Freedman, Barry I %A Fuchsberger, Christian %A Genter, Pauline %A Gerstein, Hertzel C %A Giedraitis, Vilmantas %A González-Villalpando, Clicerio %A Gonzalez-Villalpando, Maria Elena %A Goodarzi, Mark O %A Gordon-Larsen, Penny %A Gorkin, David %A Gross, Myron %A Guo, Yu %A Hackinger, Sophie %A Han, Sohee %A Hattersley, Andrew T %A Herder, Christian %A Howard, Annie-Green %A Hsueh, Willa %A Huang, Mengna %A Huang, Wei %A Hung, Yi-Jen %A Hwang, Mi Yeong %A Hwu, Chii-Min %A Ichihara, Sahoko %A Ikram, Mohammad Arfan %A Ingelsson, Martin %A Islam, Md Tariqul %A Isono, Masato %A Jang, Hye-Mi %A Jasmine, Farzana %A Jiang, Guozhi %A Jonas, Jost B %A Jørgensen, Marit E %A Jørgensen, Torben %A Kamatani, Yoichiro %A Kandeel, Fouad R %A Kasturiratne, Anuradhani %A Katsuya, Tomohiro %A Kaur, Varinderpal %A Kawaguchi, Takahisa %A Keaton, Jacob M %A Kho, Abel N %A Khor, Chiea-Chuen %A Kibriya, Muhammad G %A Kim, Duk-Hwan %A Kohara, Katsuhiko %A Kriebel, Jennifer %A Kronenberg, Florian %A Kuusisto, Johanna %A Läll, Kristi %A Lange, Leslie A %A Lee, Myung-Shik %A Lee, Nanette R %A Leong, Aaron %A Li, Liming %A Li, Yun %A Li-Gao, Ruifang %A Ligthart, Symen %A Lindgren, Cecilia M %A Linneberg, Allan %A Liu, Ching-Ti %A Liu, Jianjun %A Locke, Adam E %A Louie, Tin %A Luan, Jian'an %A Luk, Andrea O %A Luo, Xi %A Lv, Jun %A Lyssenko, Valeriya %A Mamakou, Vasiliki %A Mani, K Radha %A Meitinger, Thomas %A Metspalu, Andres %A Morris, Andrew D %A Nadkarni, Girish N %A Nadler, Jerry L %A Nalls, Michael A %A Nayak, Uma %A Nongmaithem, Suraj S %A Ntalla, Ioanna %A Okada, Yukinori %A Orozco, Lorena %A Patel, Sanjay R %A Pereira, Mark A %A Peters, Annette %A Pirie, Fraser J %A Porneala, Bianca %A Prasad, Gauri %A Preissl, Sebastian %A Rasmussen-Torvik, Laura J %A Reiner, Alexander P %A Roden, Michael %A Rohde, Rebecca %A Roll, Kathryn %A Sabanayagam, Charumathi %A Sander, Maike %A Sandow, Kevin %A Sattar, Naveed %A Schönherr, Sebastian %A Schurmann, Claudia %A Shahriar, Mohammad %A Shi, Jinxiu %A Shin, Dong Mun %A Shriner, Daniel %A Smith, Jennifer A %A So, Wing Yee %A Stančáková, Alena %A Stilp, Adrienne M %A Strauch, Konstantin %A Suzuki, Ken %A Takahashi, Atsushi %A Taylor, Kent D %A Thorand, Barbara %A Thorleifsson, Gudmar %A Thorsteinsdottir, Unnur %A Tomlinson, Brian %A Torres, Jason M %A Tsai, Fuu-Jen %A Tuomilehto, Jaakko %A Tusié-Luna, Teresa %A Udler, Miriam S %A Valladares-Salgado, Adan %A van Dam, Rob M %A van Klinken, Jan B %A Varma, Rohit %A Vujkovic, Marijana %A Wacher-Rodarte, Niels %A Wheeler, Eleanor %A Whitsel, Eric A %A Wickremasinghe, Ananda R %A van Dijk, Ko Willems %A Witte, Daniel R %A Yajnik, Chittaranjan S %A Yamamoto, Ken %A Yamauchi, Toshimasa %A Yengo, Loic %A Yoon, Kyungheon %A Yu, Canqing %A Yuan, Jian-Min %A Yusuf, Salim %A Zhang, Liang %A Zheng, Wei %A Raffel, Leslie J %A Igase, Michiya %A Ipp, Eli %A Redline, Susan %A Cho, Yoon Shin %A Lind, Lars %A Province, Michael A %A Hanis, Craig L %A Peyser, Patricia A %A Ingelsson, Erik %A Zonderman, Alan B %A Psaty, Bruce M %A Wang, Ya-Xing %A Rotimi, Charles N %A Becker, Diane M %A Matsuda, Fumihiko %A Liu, Yongmei %A Zeggini, Eleftheria %A Yokota, Mitsuhiro %A Rich, Stephen S %A Kooperberg, Charles %A Pankow, James S %A Engert, James C %A Chen, Yii-Der Ida %A Froguel, Philippe %A Wilson, James G %A Sheu, Wayne H H %A Kardia, Sharon L R %A Wu, Jer-Yuarn %A Hayes, M Geoffrey %A Ma, Ronald C W %A Wong, Tien-Yin %A Groop, Leif %A Mook-Kanamori, Dennis O %A Chandak, Giriraj R %A Collins, Francis S %A Bharadwaj, Dwaipayan %A Paré, Guillaume %A Sale, Michèle M %A Ahsan, Habibul %A Motala, Ayesha A %A Shu, Xiao-Ou %A Park, Kyong-Soo %A Jukema, J Wouter %A Cruz, Miguel %A McKean-Cowdin, Roberta %A Grallert, Harald %A Cheng, Ching-Yu %A Bottinger, Erwin P %A Dehghan, Abbas %A Tai, E-Shyong %A Dupuis, Josée %A Kato, Norihiro %A Laakso, Markku %A Köttgen, Anna %A Koh, Woon-Puay %A Palmer, Colin N A %A Liu, Simin %A Abecasis, Goncalo %A Kooner, Jaspal S %A Loos, Ruth J F %A North, Kari E %A Haiman, Christopher A %A Florez, Jose C %A Saleheen, Danish %A Hansen, Torben %A Pedersen, Oluf %A Mägi, Reedik %A Langenberg, Claudia %A Wareham, Nicholas J %A Maeda, Shiro %A Kadowaki, Takashi %A Lee, Juyoung %A Millwood, Iona Y %A Walters, Robin G %A Stefansson, Kari %A Myers, Simon R %A Ferrer, Jorge %A Gaulton, Kyle J %A Meigs, James B %A Mohlke, Karen L %A Gloyn, Anna L %A Bowden, Donald W %A Below, Jennifer E %A Chambers, John C %A Sim, Xueling %A Boehnke, Michael %A Rotter, Jerome I %A McCarthy, Mark I %A Morris, Andrew P %K Diabetes Mellitus, Type 2 %K Ethnicity %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Polymorphism, Single Nucleotide %K Risk Factors %X

We assembled an ancestrally diverse collection of genome-wide association studies (GWAS) of type 2 diabetes (T2D) in 180,834 affected individuals and 1,159,055 controls (48.9% non-European descent) through the Diabetes Meta-Analysis of Trans-Ethnic association studies (DIAMANTE) Consortium. Multi-ancestry GWAS meta-analysis identified 237 loci attaining stringent genome-wide significance (P < 5 × 10), which were delineated to 338 distinct association signals. Fine-mapping of these signals was enhanced by the increased sample size and expanded population diversity of the multi-ancestry meta-analysis, which localized 54.4% of T2D associations to a single variant with >50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying the foundations for functional investigations. Multi-ancestry genetic risk scores enhanced transferability of T2D prediction across diverse populations. Our study provides a step toward more effective clinical translation of T2D GWAS to improve global health for all, irrespective of genetic background.

%B Nat Genet %V 54 %P 560-572 %8 2022 May %G eng %N 5 %R 10.1038/s41588-022-01058-3 %0 Journal Article %J Nat Commun %D 2022 %T A multi-ethnic polygenic risk score is associated with hypertension prevalence and progression throughout adulthood. %A Kurniansyah, Nuzulul %A Goodman, Matthew O %A Kelly, Tanika N %A Elfassy, Tali %A Wiggins, Kerri L %A Bis, Joshua C %A Guo, Xiuqing %A Palmas, Walter %A Taylor, Kent D %A Lin, Henry J %A Haessler, Jeffrey %A Gao, Yan %A Shimbo, Daichi %A Smith, Jennifer A %A Yu, Bing %A Feofanova, Elena V %A Smit, Roelof A J %A Wang, Zhe %A Hwang, Shih-Jen %A Liu, Simin %A Wassertheil-Smoller, Sylvia %A Manson, JoAnn E %A Lloyd-Jones, Donald M %A Rich, Stephen S %A Loos, Ruth J F %A Redline, Susan %A Correa, Adolfo %A Kooperberg, Charles %A Fornage, Myriam %A Kaplan, Robert C %A Psaty, Bruce M %A Rotter, Jerome I %A Arnett, Donna K %A Morrison, Alanna C %A Franceschini, Nora %A Levy, Daniel %A Sofer, Tamar %K Adult %K Diabetes Mellitus, Type 2 %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Hypertension %K Multifactorial Inheritance %K Prevalence %K Risk Factors %X

In a multi-stage analysis of 52,436 individuals aged 17-90 across diverse cohorts and biobanks, we train, test, and evaluate a polygenic risk score (PRS) for hypertension risk and progression. The PRS is trained using genome-wide association studies (GWAS) for systolic, diastolic blood pressure, and hypertension, respectively. For each trait, PRS is selected by optimizing the coefficient of variation (CV) across estimated effect sizes from multiple potential PRS using the same GWAS, after which the 3 trait-specific PRSs are combined via an unweighted sum called "PRSsum", forming the HTN-PRS. The HTN-PRS is associated with both prevalent and incident hypertension at 4-6 years of follow up. This association is further confirmed in age-stratified analysis. In an independent biobank of 40,201 individuals, the HTN-PRS is confirmed to be predictive of increased risk for coronary artery disease, ischemic stroke, type 2 diabetes, and chronic kidney disease.

%B Nat Commun %V 13 %P 3549 %8 2022 Jun 21 %G eng %N 1 %R 10.1038/s41467-022-31080-2 %0 Journal Article %J Nat Genet %D 2022 %T New insights into the genetic etiology of Alzheimer's disease and related dementias. %A Bellenguez, Céline %A Küçükali, Fahri %A Jansen, Iris E %A Kleineidam, Luca %A Moreno-Grau, Sonia %A Amin, Najaf %A Naj, Adam C %A Campos-Martin, Rafael %A Grenier-Boley, Benjamin %A Andrade, Victor %A Holmans, Peter A %A Boland, Anne %A Damotte, Vincent %A van der Lee, Sven J %A Costa, Marcos R %A Kuulasmaa, Teemu %A Yang, Qiong %A de Rojas, Itziar %A Bis, Joshua C %A Yaqub, Amber %A Prokic, Ivana %A Chapuis, Julien %A Ahmad, Shahzad %A Giedraitis, Vilmantas %A Aarsland, Dag %A Garcia-Gonzalez, Pablo %A Abdelnour, Carla %A Alarcón-Martín, Emilio %A Alcolea, Daniel %A Alegret, Montserrat %A Alvarez, Ignacio %A Alvarez, Victoria %A Armstrong, Nicola J %A Tsolaki, Anthoula %A Antunez, Carmen %A Appollonio, Ildebrando %A Arcaro, Marina %A Archetti, Silvana %A Pastor, Alfonso Arias %A Arosio, Beatrice %A Athanasiu, Lavinia %A Bailly, Henri %A Banaj, Nerisa %A Baquero, Miquel %A Barral, Sandra %A Beiser, Alexa %A Pastor, Ana Belén %A Below, Jennifer E %A Benchek, Penelope %A Benussi, Luisa %A Berr, Claudine %A Besse, Céline %A Bessi, Valentina %A Binetti, Giuliano %A Bizarro, Alessandra %A Blesa, Rafael %A Boada, Merce %A Boerwinkle, Eric %A Borroni, Barbara %A Boschi, Silvia %A Bossù, Paola %A Bråthen, Geir %A Bressler, Jan %A Bresner, Catherine %A Brodaty, Henry %A Brookes, Keeley J %A Brusco, Luis Ignacio %A Buiza-Rueda, Dolores %A Bûrger, Katharina %A Burholt, Vanessa %A Bush, William S %A Calero, Miguel %A Cantwell, Laura B %A Chene, Geneviève %A Chung, Jaeyoon %A Cuccaro, Michael L %A Carracedo, Angel %A Cecchetti, Roberta %A Cervera-Carles, Laura %A Charbonnier, Camille %A Chen, Hung-Hsin %A Chillotti, Caterina %A Ciccone, Simona %A Claassen, Jurgen A H R %A Clark, Christopher %A Conti, Elisa %A Corma-Gómez, Anaïs %A Costantini, Emanuele %A Custodero, Carlo %A Daian, Delphine %A Dalmasso, Maria Carolina %A Daniele, Antonio %A Dardiotis, Efthimios %A Dartigues, Jean-François %A de Deyn, Peter Paul %A de Paiva Lopes, Katia %A de Witte, Lot D %A Debette, Stephanie %A Deckert, Jürgen %A Del Ser, Teodoro %A Denning, Nicola %A DeStefano, Anita %A Dichgans, Martin %A Diehl-Schmid, Janine %A Diez-Fairen, Monica %A Rossi, Paolo Dionigi %A Djurovic, Srdjan %A Duron, Emmanuelle %A Düzel, Emrah %A Dufouil, Carole %A Eiriksdottir, Gudny %A Engelborghs, Sebastiaan %A Escott-Price, Valentina %A Espinosa, Ana %A Ewers, Michael %A Faber, Kelley M %A Fabrizio, Tagliavini %A Nielsen, Sune Fallgaard %A Fardo, David W %A Farotti, Lucia %A Fenoglio, Chiara %A Fernández-Fuertes, Marta %A Ferrari, Raffaele %A Ferreira, Catarina B %A Ferri, Evelyn %A Fin, Bertrand %A Fischer, Peter %A Fladby, Tormod %A Fließbach, Klaus %A Fongang, Bernard %A Fornage, Myriam %A Fortea, Juan %A Foroud, Tatiana M %A Fostinelli, Silvia %A Fox, Nick C %A Franco-Macías, Emlio %A Bullido, María J %A Frank-García, Ana %A Froelich, Lutz %A Fulton-Howard, Brian %A Galimberti, Daniela %A García-Alberca, Jose Maria %A Garcia-Gonzalez, Pablo %A Garcia-Madrona, Sebastian %A Garcia-Ribas, Guillermo %A Ghidoni, Roberta %A Giegling, Ina %A Giorgio, Giaccone %A Goate, Alison M %A Goldhardt, Oliver %A Gomez-Fonseca, Duber %A González-Perez, Antonio %A Graff, Caroline %A Grande, Giulia %A Green, Emma %A Grimmer, Timo %A Grünblatt, Edna %A Grunin, Michelle %A Gudnason, Vilmundur %A Guetta-Baranes, Tamar %A Haapasalo, Annakaisa %A Hadjigeorgiou, Georgios %A Haines, Jonathan L %A Hamilton-Nelson, Kara L %A Hampel, Harald %A Hanon, Olivier %A Hardy, John %A Hartmann, Annette M %A Hausner, Lucrezia %A Harwood, Janet %A Heilmann-Heimbach, Stefanie %A Helisalmi, Seppo %A Heneka, Michael T %A Hernandez, Isabel %A Herrmann, Martin J %A Hoffmann, Per %A Holmes, Clive %A Holstege, Henne %A Vilas, Raquel Huerto %A Hulsman, Marc %A Humphrey, Jack %A Biessels, Geert Jan %A Jian, Xueqiu %A Johansson, Charlotte %A Jun, Gyungah R %A Kastumata, Yuriko %A Kauwe, John %A Kehoe, Patrick G %A Kilander, Lena %A Ståhlbom, Anne Kinhult %A Kivipelto, Miia %A Koivisto, Anne %A Kornhuber, Johannes %A Kosmidis, Mary H %A Kukull, Walter A %A Kuksa, Pavel P %A Kunkle, Brian W %A Kuzma, Amanda B %A Lage, Carmen %A Laukka, Erika J %A Launer, Lenore %A Lauria, Alessandra %A Lee, Chien-Yueh %A Lehtisalo, Jenni %A Lerch, Ondrej %A Lleo, Alberto %A Longstreth, William %A Lopez, Oscar %A de Munain, Adolfo Lopez %A Love, Seth %A Löwemark, Malin %A Luckcuck, Lauren %A Lunetta, Kathryn L %A Ma, Yiyi %A Macías, Juan %A MacLeod, Catherine A %A Maier, Wolfgang %A Mangialasche, Francesca %A Spallazzi, Marco %A Marquié, Marta %A Marshall, Rachel %A Martin, Eden R %A Montes, Angel Martín %A Rodríguez, Carmen Martínez %A Masullo, Carlo %A Mayeux, Richard %A Mead, Simon %A Mecocci, Patrizia %A Medina, Miguel %A Meggy, Alun %A Mehrabian, Shima %A Mendoza, Silvia %A Menéndez-González, Manuel %A Mir, Pablo %A Moebus, Susanne %A Mol, Merel %A Molina-Porcel, Laura %A Montrreal, Laura %A Morelli, Laura %A Moreno, Fermin %A Morgan, Kevin %A Mosley, Thomas %A Nöthen, Markus M %A Muchnik, Carolina %A Mukherjee, Shubhabrata %A Nacmias, Benedetta %A Ngandu, Tiia %A Nicolas, Gaël %A Nordestgaard, Børge G %A Olaso, Robert %A Orellana, Adelina %A Orsini, Michela %A Ortega, Gemma %A Padovani, Alessandro %A Paolo, Caffarra %A Papenberg, Goran %A Parnetti, Lucilla %A Pasquier, Florence %A Pastor, Pau %A Peloso, Gina %A Pérez-Cordón, Alba %A Pérez-Tur, Jordi %A Pericard, Pierre %A Peters, Oliver %A Pijnenburg, Yolande A L %A Pineda, Juan A %A Piñol-Ripoll, Gerard %A Pisanu, Claudia %A Polak, Thomas %A Popp, Julius %A Posthuma, Danielle %A Priller, Josef %A Puerta, Raquel %A Quenez, Olivier %A Quintela, Inés %A Thomassen, Jesper Qvist %A Rábano, Alberto %A Rainero, Innocenzo %A Rajabli, Farid %A Ramakers, Inez %A Real, Luis M %A Reinders, Marcel J T %A Reitz, Christiane %A Reyes-Dumeyer, Dolly %A Ridge, Perry %A Riedel-Heller, Steffi %A Riederer, Peter %A Roberto, Natalia %A Rodriguez-Rodriguez, Eloy %A Rongve, Arvid %A Allende, Irene Rosas %A Rosende-Roca, Maitée %A Royo, Jose Luis %A Rubino, Elisa %A Rujescu, Dan %A Sáez, María Eugenia %A Sakka, Paraskevi %A Saltvedt, Ingvild %A Sanabria, Ángela %A Sánchez-Arjona, María Bernal %A Sanchez-Garcia, Florentino %A Juan, Pascual Sánchez %A Sánchez-Valle, Raquel %A Sando, Sigrid B %A Sarnowski, Chloe %A Satizabal, Claudia L %A Scamosci, Michela %A Scarmeas, Nikolaos %A Scarpini, Elio %A Scheltens, Philip %A Scherbaum, Norbert %A Scherer, Martin %A Schmid, Matthias %A Schneider, Anja %A Schott, Jonathan M %A Selbæk, Geir %A Seripa, Davide %A Serrano, Manuel %A Sha, Jin %A Shadrin, Alexey A %A Skrobot, Olivia %A Slifer, Susan %A Snijders, Gijsje J L %A Soininen, Hilkka %A Solfrizzi, Vincenzo %A Solomon, Alina %A Song, Yeunjoo %A Sorbi, Sandro %A Sotolongo-Grau, Oscar %A Spalletta, Gianfranco %A Spottke, Annika %A Squassina, Alessio %A Stordal, Eystein %A Tartan, Juan Pablo %A Tarraga, Lluis %A Tesí, Niccolo %A Thalamuthu, Anbupalam %A Thomas, Tegos %A Tosto, Giuseppe %A Traykov, Latchezar %A Tremolizzo, Lucio %A Tybjærg-Hansen, Anne %A Uitterlinden, Andre %A Ullgren, Abbe %A Ulstein, Ingun %A Valero, Sergi %A Valladares, Otto %A Broeckhoven, Christine Van %A Vance, Jeffery %A Vardarajan, Badri N %A van der Lugt, Aad %A Dongen, Jasper Van %A van Rooij, Jeroen %A van Swieten, John %A Vandenberghe, Rik %A Verhey, Frans %A Vidal, Jean-Sébastien %A Vogelgsang, Jonathan %A Vyhnalek, Martin %A Wagner, Michael %A Wallon, David %A Wang, Li-San %A Wang, Ruiqi %A Weinhold, Leonie %A Wiltfang, Jens %A Windle, Gill %A Woods, Bob %A Yannakoulia, Mary %A Zare, Habil %A Zhao, Yi %A Zhang, Xiaoling %A Zhu, Congcong %A Zulaica, Miren %A Farrer, Lindsay A %A Psaty, Bruce M %A Ghanbari, Mohsen %A Raj, Towfique %A Sachdev, Perminder %A Mather, Karen %A Jessen, Frank %A Ikram, M Arfan %A de Mendonça, Alexandre %A Hort, Jakub %A Tsolaki, Magda %A Pericak-Vance, Margaret A %A Amouyel, Philippe %A Williams, Julie %A Frikke-Schmidt, Ruth %A Clarimon, Jordi %A Deleuze, Jean-Francois %A Rossi, Giacomina %A Seshadri, Sudha %A Andreassen, Ole A %A Ingelsson, Martin %A Hiltunen, Mikko %A Sleegers, Kristel %A Schellenberg, Gerard D %A van Duijn, Cornelia M %A Sims, Rebecca %A van der Flier, Wiesje M %A Ruiz, Agustin %A Ramirez, Alfredo %A Lambert, Jean-Charles %K Alzheimer Disease %K Cognitive Dysfunction %K Genome-Wide Association Study %K Humans %K tau Proteins %X

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.

%B Nat Genet %V 54 %P 412-436 %8 2022 Apr %G eng %N 4 %R 10.1038/s41588-022-01024-z %0 Journal Article %J Commun Biol %D 2022 %T Non-linear machine learning models incorporating SNPs and PRS improve polygenic prediction in diverse human populations. %A Elgart, Michael %A Lyons, Genevieve %A Romero-Brufau, Santiago %A Kurniansyah, Nuzulul %A Brody, Jennifer A %A Guo, Xiuqing %A Lin, Henry J %A Raffield, Laura %A Gao, Yan %A Chen, Han %A de Vries, Paul %A Lloyd-Jones, Donald M %A Lange, Leslie A %A Peloso, Gina M %A Fornage, Myriam %A Rotter, Jerome I %A Rich, Stephen S %A Morrison, Alanna C %A Psaty, Bruce M %A Levy, Daniel %A Redline, Susan %A Sofer, Tamar %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Machine Learning %K Multifactorial Inheritance %K Polymorphism, Single Nucleotide %X

Polygenic risk scores (PRS) are commonly used to quantify the inherited susceptibility for a trait, yet they fail to account for non-linear and interaction effects between single nucleotide polymorphisms (SNPs). We address this via a machine learning approach, validated in nine complex phenotypes in a multi-ancestry population. We use an ensemble method of SNP selection followed by gradient boosted trees (XGBoost) to allow for non-linearities and interaction effects. We compare our results to the standard, linear PRS model developed using PRSice, LDpred2, and lassosum2. Combining a PRS as a feature in an XGBoost model results in a relative increase in the percentage variance explained compared to the standard linear PRS model by 22% for height, 27% for HDL cholesterol, 43% for body mass index, 50% for sleep duration, 58% for systolic blood pressure, 64% for total cholesterol, 66% for triglycerides, 77% for LDL cholesterol, and 100% for diastolic blood pressure. Multi-ancestry trained models perform similarly to specific racial/ethnic group trained models and are consistently superior to the standard linear PRS models. This work demonstrates an effective method to account for non-linearities and interaction effects in genetics-based prediction models.

%B Commun Biol %V 5 %P 856 %8 2022 08 22 %G eng %N 1 %R 10.1038/s42003-022-03812-z %0 Journal Article %J Am J Hum Genet %D 2022 %T Rare coding variants in 35 genes associate with circulating lipid levels-A multi-ancestry analysis of 170,000 exomes. %A Hindy, George %A Dornbos, Peter %A Chaffin, Mark D %A Liu, Dajiang J %A Wang, Minxian %A Selvaraj, Margaret Sunitha %A Zhang, David %A Park, Joseph %A Aguilar-Salinas, Carlos A %A Antonacci-Fulton, Lucinda %A Ardissino, Diego %A Arnett, Donna K %A Aslibekyan, Stella %A Atzmon, Gil %A Ballantyne, Christie M %A Barajas-Olmos, Francisco %A Barzilai, Nir %A Becker, Lewis C %A Bielak, Lawrence F %A Bis, Joshua C %A Blangero, John %A Boerwinkle, Eric %A Bonnycastle, Lori L %A Bottinger, Erwin %A Bowden, Donald W %A Bown, Matthew J %A Brody, Jennifer A %A Broome, Jai G %A Burtt, Noel P %A Cade, Brian E %A Centeno-Cruz, Federico %A Chan, Edmund %A Chang, Yi-Cheng %A Chen, Yii-der I %A Cheng, Ching-Yu %A Choi, Won Jung %A Chowdhury, Rajiv %A Contreras-Cubas, Cecilia %A Córdova, Emilio J %A Correa, Adolfo %A Cupples, L Adrienne %A Curran, Joanne E %A Danesh, John %A de Vries, Paul S %A DeFronzo, Ralph A %A Doddapaneni, Harsha %A Duggirala, Ravindranath %A Dutcher, Susan K %A Ellinor, Patrick T %A Emery, Leslie S %A Florez, Jose C %A Fornage, Myriam %A Freedman, Barry I %A Fuster, Valentin %A Garay-Sevilla, Ma Eugenia %A García-Ortiz, Humberto %A Germer, Soren %A Gibbs, Richard A %A Gieger, Christian %A Glaser, Benjamin %A Gonzalez, Clicerio %A Gonzalez-Villalpando, Maria Elena %A Graff, Mariaelisa %A Graham, Sarah E %A Grarup, Niels %A Groop, Leif C %A Guo, Xiuqing %A Gupta, Namrata %A Han, Sohee %A Hanis, Craig L %A Hansen, Torben %A He, Jiang %A Heard-Costa, Nancy L %A Hung, Yi-Jen %A Hwang, Mi Yeong %A Irvin, Marguerite R %A Islas-Andrade, Sergio %A Jarvik, Gail P %A Kang, Hyun Min %A Kardia, Sharon L R %A Kelly, Tanika %A Kenny, Eimear E %A Khan, Alyna T %A Kim, Bong-Jo %A Kim, Ryan W %A Kim, Young Jin %A Koistinen, Heikki A %A Kooperberg, Charles %A Kuusisto, Johanna %A Kwak, Soo Heon %A Laakso, Markku %A Lange, Leslie A %A Lee, Jiwon %A Lee, Juyoung %A Lee, Seonwook %A Lehman, Donna M %A Lemaitre, Rozenn N %A Linneberg, Allan %A Liu, Jianjun %A Loos, Ruth J F %A Lubitz, Steven A %A Lyssenko, Valeriya %A Ma, Ronald C W %A Martin, Lisa Warsinger %A Martínez-Hernández, Angélica %A Mathias, Rasika A %A McGarvey, Stephen T %A McPherson, Ruth %A Meigs, James B %A Meitinger, Thomas %A Melander, Olle %A Mendoza-Caamal, Elvia %A Metcalf, Ginger A %A Mi, Xuenan %A Mohlke, Karen L %A Montasser, May E %A Moon, Jee-Young %A Moreno-Macias, Hortensia %A Morrison, Alanna C %A Muzny, Donna M %A Nelson, Sarah C %A Nilsson, Peter M %A O'Connell, Jeffrey R %A Orho-Melander, Marju %A Orozco, Lorena %A Palmer, Colin N A %A Palmer, Nicholette D %A Park, Cheol Joo %A Park, Kyong Soo %A Pedersen, Oluf %A Peralta, Juan M %A Peyser, Patricia A %A Post, Wendy S %A Preuss, Michael %A Psaty, Bruce M %A Qi, Qibin %A Rao, D C %A Redline, Susan %A Reiner, Alexander P %A Revilla-Monsalve, Cristina %A Rich, Stephen S %A Samani, Nilesh %A Schunkert, Heribert %A Schurmann, Claudia %A Seo, Daekwan %A Seo, Jeong-Sun %A Sim, Xueling %A Sladek, Rob %A Small, Kerrin S %A So, Wing Yee %A Stilp, Adrienne M %A Tai, E Shyong %A Tam, Claudia H T %A Taylor, Kent D %A Teo, Yik Ying %A Thameem, Farook %A Tomlinson, Brian %A Tsai, Michael Y %A Tuomi, Tiinamaija %A Tuomilehto, Jaakko %A Tusié-Luna, Teresa %A Udler, Miriam S %A van Dam, Rob M %A Vasan, Ramachandran S %A Viaud Martinez, Karine A %A Wang, Fei Fei %A Wang, Xuzhi %A Watkins, Hugh %A Weeks, Daniel E %A Wilson, James G %A Witte, Daniel R %A Wong, Tien-Yin %A Yanek, Lisa R %A Kathiresan, Sekar %A Rader, Daniel J %A Rotter, Jerome I %A Boehnke, Michael %A McCarthy, Mark I %A Willer, Cristen J %A Natarajan, Pradeep %A Flannick, Jason A %A Khera, Amit V %A Peloso, Gina M %K Alleles %K Blood Glucose %K Case-Control Studies %K Computational Biology %K Databases, Genetic %K Diabetes Mellitus, Type 2 %K Exome %K Genetic Predisposition to Disease %K Genetic Variation %K Genetics, Population %K Genome-Wide Association Study %K Humans %K Lipid Metabolism %K Lipids %K Liver %K Molecular Sequence Annotation %K Multifactorial Inheritance %K Open Reading Frames %K Phenotype %K Polymorphism, Single Nucleotide %X

Large-scale gene sequencing studies for complex traits have the potential to identify causal genes with therapeutic implications. We performed gene-based association testing of blood lipid levels with rare (minor allele frequency < 1%) predicted damaging coding variation by using sequence data from >170,000 individuals from multiple ancestries: 97,493 European, 30,025 South Asian, 16,507 African, 16,440 Hispanic/Latino, 10,420 East Asian, and 1,182 Samoan. We identified 35 genes associated with circulating lipid levels; some of these genes have not been previously associated with lipid levels when using rare coding variation from population-based samples. We prioritize 32 genes in array-based genome-wide association study (GWAS) loci based on aggregations of rare coding variants; three (EVI5, SH2B3, and PLIN1) had no prior association of rare coding variants with lipid levels. Most of our associated genes showed evidence of association among multiple ancestries. Finally, we observed an enrichment of gene-based associations for low-density lipoprotein cholesterol drug target genes and for genes closest to GWAS index single-nucleotide polymorphisms (SNPs). Our results demonstrate that gene-based associations can be beneficial for drug target development and provide evidence that the gene closest to the array-based GWAS index SNP is often the functional gene for blood lipid levels.

%B Am J Hum Genet %V 109 %P 81-96 %8 2022 01 06 %G eng %N 1 %R 10.1016/j.ajhg.2021.11.021 %0 Journal Article %J Front Endocrinol (Lausanne) %D 2022 %T The Value of Rare Genetic Variation in the Prediction of Common Obesity in European Ancestry Populations. %A Wang, Zhe %A Choi, Shing Wan %A Chami, Nathalie %A Boerwinkle, Eric %A Fornage, Myriam %A Redline, Susan %A Bis, Joshua C %A Brody, Jennifer A %A Psaty, Bruce M %A Kim, Wonji %A McDonald, Merry-Lynn N %A Regan, Elizabeth A %A Silverman, Edwin K %A Liu, Ching-Ti %A Vasan, Ramachandran S %A Kalyani, Rita R %A Mathias, Rasika A %A Yanek, Lisa R %A Arnett, Donna K %A Justice, Anne E %A North, Kari E %A Kaplan, Robert %A Heckbert, Susan R %A de Andrade, Mariza %A Guo, Xiuqing %A Lange, Leslie A %A Rich, Stephen S %A Rotter, Jerome I %A Ellinor, Patrick T %A Lubitz, Steven A %A Blangero, John %A Shoemaker, M Benjamin %A Darbar, Dawood %A Gladwin, Mark T %A Albert, Christine M %A Chasman, Daniel I %A Jackson, Rebecca D %A Kooperberg, Charles %A Reiner, Alexander P %A O'Reilly, Paul F %A Loos, Ruth J F %K Gene Frequency %K Genetic Variation %K Genome-Wide Association Study %K Humans %K Obesity %K Whole Genome Sequencing %X

Polygenic risk scores (PRSs) aggregate the effects of genetic variants across the genome and are used to predict risk of complex diseases, such as obesity. Current PRSs only include common variants (minor allele frequency (MAF) ≥1%), whereas the contribution of rare variants in PRSs to predict disease remains unknown. Here, we examine whether augmenting the standard common variant PRS (PRS) with a rare variant PRS (PRS) improves prediction of obesity. We used genome-wide genotyped and imputed data on 451,145 European-ancestry participants of the UK Biobank, as well as whole exome sequencing (WES) data on 184,385 participants. We performed single variant analyses (for both common and rare variants) and gene-based analyses (for rare variants) for association with BMI (kg/m), obesity (BMI ≥ 30 kg/m), and extreme obesity (BMI ≥ 40 kg/m). We built PRSs and PRSs using a range of methods (Clumping+Thresholding [C+T], PRS-CS, lassosum, gene-burden test). We selected the best-performing PRSs and assessed their performance in 36,757 European-ancestry unrelated participants with whole genome sequencing (WGS) data from the Trans-Omics for Precision Medicine (TOPMed) program. The best-performing PRS explained 10.1% of variation in BMI, and 18.3% and 22.5% of the susceptibility to obesity and extreme obesity, respectively, whereas the best-performing PRS explained 1.49%, and 2.97% and 3.68%, respectively. The PRS was associated with an increased risk of obesity and extreme obesity (OR = 1.37 per SD, = 1.7x10; OR = 1.55 per SD, = 3.8x10), which was attenuated, after adjusting for PRS (OR = 1.08 per SD, = 9.8x10; OR= 1.09 per SD, = 0.02). When PRS and PRS are combined, the increase in explained variance attributed to PRS was small (incremental Nagelkerke R = 0.24% for obesity and 0.51% for extreme obesity). Consistently, combining PRS to PRS provided little improvement to the prediction of obesity (PRS AUC = 0.591; PRS AUC = 0.708; PRS AUC = 0.710). In summary, while rare variants show convincing association with BMI, obesity and extreme obesity, the PRS provides limited improvement over PRS in the prediction of obesity risk, based on these large populations.

%B Front Endocrinol (Lausanne) %V 13 %P 863893 %8 2022 %G eng %R 10.3389/fendo.2022.863893 %0 Journal Article %J Nat Commun %D 2022 %T Whole genome sequencing identifies structural variants contributing to hematologic traits in the NHLBI TOPMed program. %A Wheeler, Marsha M %A Stilp, Adrienne M %A Rao, Shuquan %A Halldorsson, Bjarni V %A Beyter, Doruk %A Wen, Jia %A Mihkaylova, Anna V %A McHugh, Caitlin P %A Lane, John %A Jiang, Min-Zhi %A Raffield, Laura M %A Jun, Goo %A Sedlazeck, Fritz J %A Metcalf, Ginger %A Yao, Yao %A Bis, Joshua B %A Chami, Nathalie %A de Vries, Paul S %A Desai, Pinkal %A Floyd, James S %A Gao, Yan %A Kammers, Kai %A Kim, Wonji %A Moon, Jee-Young %A Ratan, Aakrosh %A Yanek, Lisa R %A Almasy, Laura %A Becker, Lewis C %A Blangero, John %A Cho, Michael H %A Curran, Joanne E %A Fornage, Myriam %A Kaplan, Robert C %A Lewis, Joshua P %A Loos, Ruth J F %A Mitchell, Braxton D %A Morrison, Alanna C %A Preuss, Michael %A Psaty, Bruce M %A Rich, Stephen S %A Rotter, Jerome I %A Tang, Hua %A Tracy, Russell P %A Boerwinkle, Eric %A Abecasis, Goncalo R %A Blackwell, Thomas W %A Smith, Albert V %A Johnson, Andrew D %A Mathias, Rasika A %A Nickerson, Deborah A %A Conomos, Matthew P %A Li, Yun %A Þorsteinsdottir, Unnur %A Magnússon, Magnús K %A Stefansson, Kari %A Pankratz, Nathan D %A Bauer, Daniel E %A Auer, Paul L %A Reiner, Alex P %K Blood Cells %K Genome-Wide Association Study %K Humans %K Whole Genome Sequencing %X

Genome-wide association studies have identified thousands of single nucleotide variants and small indels that contribute to variation in hematologic traits. While structural variants are known to cause rare blood or hematopoietic disorders, the genome-wide contribution of structural variants to quantitative blood cell trait variation is unknown. Here we utilized whole genome sequencing data in ancestrally diverse participants of the NHLBI Trans Omics for Precision Medicine program (N = 50,675) to detect structural variants associated with hematologic traits. Using single variant tests, we assessed the association of common and rare structural variants with red cell-, white cell-, and platelet-related quantitative traits and observed 21 independent signals (12 common and 9 rare) reaching genome-wide significance. The majority of these associations (N = 18) replicated in independent datasets. In genome-editing experiments, we provide evidence that a deletion associated with lower monocyte counts leads to disruption of an S1PR3 monocyte enhancer and decreased S1PR3 expression.

%B Nat Commun %V 13 %P 7592 %8 2022 Dec 08 %G eng %N 1 %R 10.1038/s41467-022-35354-7 %0 Journal Article %J Nature %D 2023 %T Aberrant activation of TCL1A promotes stem cell expansion in clonal haematopoiesis. %A Weinstock, Joshua S %A Gopakumar, Jayakrishnan %A Burugula, Bala Bharathi %A Uddin, Md Mesbah %A Jahn, Nikolaus %A Belk, Julia A %A Bouzid, Hind %A Daniel, Bence %A Miao, Zhuang %A Ly, Nghi %A Mack, Taralynn M %A Luna, Sofia E %A Prothro, Katherine P %A Mitchell, Shaneice R %A Laurie, Cecelia A %A Broome, Jai G %A Taylor, Kent D %A Guo, Xiuqing %A Sinner, Moritz F %A von Falkenhausen, Aenne S %A Kääb, Stefan %A Shuldiner, Alan R %A O'Connell, Jeffrey R %A Lewis, Joshua P %A Boerwinkle, Eric %A Barnes, Kathleen C %A Chami, Nathalie %A Kenny, Eimear E %A Loos, Ruth J F %A Fornage, Myriam %A Hou, Lifang %A Lloyd-Jones, Donald M %A Redline, Susan %A Cade, Brian E %A Psaty, Bruce M %A Bis, Joshua C %A Brody, Jennifer A %A Silverman, Edwin K %A Yun, Jeong H %A Qiao, Dandi %A Palmer, Nicholette D %A Freedman, Barry I %A Bowden, Donald W %A Cho, Michael H %A DeMeo, Dawn L %A Vasan, Ramachandran S %A Yanek, Lisa R %A Becker, Lewis C %A Kardia, Sharon L R %A Peyser, Patricia A %A He, Jiang %A Rienstra, Michiel %A van der Harst, Pim %A Kaplan, Robert %A Heckbert, Susan R %A Smith, Nicholas L %A Wiggins, Kerri L %A Arnett, Donna K %A Irvin, Marguerite R %A Tiwari, Hemant %A Cutler, Michael J %A Knight, Stacey %A Muhlestein, J Brent %A Correa, Adolfo %A Raffield, Laura M %A Gao, Yan %A de Andrade, Mariza %A Rotter, Jerome I %A Rich, Stephen S %A Tracy, Russell P %A Konkle, Barbara A %A Johnsen, Jill M %A Wheeler, Marsha M %A Smith, J Gustav %A Melander, Olle %A Nilsson, Peter M %A Custer, Brian S %A Duggirala, Ravindranath %A Curran, Joanne E %A Blangero, John %A McGarvey, Stephen %A Williams, L Keoki %A Xiao, Shujie %A Yang, Mao %A Gu, C Charles %A Chen, Yii-Der Ida %A Lee, Wen-Jane %A Marcus, Gregory M %A Kane, John P %A Pullinger, Clive R %A Shoemaker, M Benjamin %A Darbar, Dawood %A Roden, Dan M %A Albert, Christine %A Kooperberg, Charles %A Zhou, Ying %A Manson, JoAnn E %A Desai, Pinkal %A Johnson, Andrew D %A Mathias, Rasika A %A Blackwell, Thomas W %A Abecasis, Goncalo R %A Smith, Albert V %A Kang, Hyun M %A Satpathy, Ansuman T %A Natarajan, Pradeep %A Kitzman, Jacob O %A Whitsel, Eric A %A Reiner, Alexander P %A Bick, Alexander G %A Jaiswal, Siddhartha %K Alleles %K Animals %K Clonal Hematopoiesis %K Genome-Wide Association Study %K Hematopoiesis %K Hematopoietic Stem Cells %K Humans %K Mice %K Mutation %K Promoter Regions, Genetic %X

Mutations in a diverse set of driver genes increase the fitness of haematopoietic stem cells (HSCs), leading to clonal haematopoiesis. These lesions are precursors for blood cancers, but the basis of their fitness advantage remains largely unknown, partly owing to a paucity of large cohorts in which the clonal expansion rate has been assessed by longitudinal sampling. Here, to circumvent this limitation, we developed a method to infer the expansion rate from data from a single time point. We applied this method to 5,071 people with clonal haematopoiesis. A genome-wide association study revealed that a common inherited polymorphism in the TCL1A promoter was associated with a slower expansion rate in clonal haematopoiesis overall, but the effect varied by driver gene. Those carrying this protective allele exhibited markedly reduced growth rates or prevalence of clones with driver mutations in TET2, ASXL1, SF3B1 and SRSF2, but this effect was not seen in clones with driver mutations in DNMT3A. TCL1A was not expressed in normal or DNMT3A-mutated HSCs, but the introduction of mutations in TET2 or ASXL1 led to the expression of TCL1A protein and the expansion of HSCs in vitro. The protective allele restricted TCL1A expression and expansion of mutant HSCs, as did experimental knockdown of TCL1A expression. Forced expression of TCL1A promoted the expansion of human HSCs in vitro and mouse HSCs in vivo. Our results indicate that the fitness advantage of several commonly mutated driver genes in clonal haematopoiesis may be mediated by TCL1A activation.

%B Nature %V 616 %P 755-763 %8 2023 Apr %G eng %N 7958 %R 10.1038/s41586-023-05806-1 %0 Journal Article %J Nat Commun %D 2023 %T Evaluating the use of blood pressure polygenic risk scores across race/ethnic background groups. %A Kurniansyah, Nuzulul %A Goodman, Matthew O %A Khan, Alyna T %A Wang, Jiongming %A Feofanova, Elena %A Bis, Joshua C %A Wiggins, Kerri L %A Huffman, Jennifer E %A Kelly, Tanika %A Elfassy, Tali %A Guo, Xiuqing %A Palmas, Walter %A Lin, Henry J %A Hwang, Shih-Jen %A Gao, Yan %A Young, Kendra %A Kinney, Gregory L %A Smith, Jennifer A %A Yu, Bing %A Liu, Simin %A Wassertheil-Smoller, Sylvia %A Manson, JoAnn E %A Zhu, Xiaofeng %A Chen, Yii-Der Ida %A Lee, I-Te %A Gu, C Charles %A Lloyd-Jones, Donald M %A Zöllner, Sebastian %A Fornage, Myriam %A Kooperberg, Charles %A Correa, Adolfo %A Psaty, Bruce M %A Arnett, Donna K %A Isasi, Carmen R %A Rich, Stephen S %A Kaplan, Robert C %A Redline, Susan %A Mitchell, Braxton D %A Franceschini, Nora %A Levy, Daniel %A Rotter, Jerome I %A Morrison, Alanna C %A Sofer, Tamar %K Blood Pressure %K Ethnicity %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Male %K Multifactorial Inheritance %K Population Health %K Risk Factors %X

We assess performance and limitations of polygenic risk scores (PRSs) for multiple blood pressure (BP) phenotypes in diverse population groups. We compare "clumping-and-thresholding" (PRSice2) and LD-based (LDPred2) methods to construct PRSs from each of multiple GWAS, as well as multi-PRS approaches that sum PRSs with and without weights, including PRS-CSx. We use datasets from the MGB Biobank, TOPMed study, UK biobank, and from All of Us to train, assess, and validate PRSs in groups defined by self-reported race/ethnic background (Asian, Black, Hispanic/Latino, and White). For both SBP and DBP, the PRS-CSx based PRS, constructed as a weighted sum of PRSs developed from multiple independent GWAS, perform best across all race/ethnic backgrounds. Stratified analysis in All of Us shows that PRSs are better predictive of BP in females compared to males, individuals without obesity, and middle-aged (40-60 years) compared to older and younger individuals.

%B Nat Commun %V 14 %P 3202 %8 2023 Jun 02 %G eng %N 1 %R 10.1038/s41467-023-38990-9 %0 Journal Article %J Nat Commun %D 2023 %T Genetic architecture of spatial electrical biomarkers for cardiac arrhythmia and relationship with cardiovascular disease. %A Young, William J %A Haessler, Jeffrey %A Benjamins, Jan-Walter %A Repetto, Linda %A Yao, Jie %A Isaacs, Aaron %A Harper, Andrew R %A Ramirez, Julia %A Garnier, Sophie %A Van Duijvenboden, Stefan %A Baldassari, Antoine R %A Concas, Maria Pina %A Duong, ThuyVy %A Foco, Luisa %A Isaksen, Jonas L %A Mei, Hao %A Noordam, Raymond %A Nursyifa, Casia %A Richmond, Anne %A Santolalla, Meddly L %A Sitlani, Colleen M %A Soroush, Negin %A Thériault, Sébastien %A Trompet, Stella %A Aeschbacher, Stefanie %A Ahmadizar, Fariba %A Alonso, Alvaro %A Brody, Jennifer A %A Campbell, Archie %A Correa, Adolfo %A Darbar, Dawood %A De Luca, Antonio %A Deleuze, Jean-Francois %A Ellervik, Christina %A Fuchsberger, Christian %A Goel, Anuj %A Grace, Christopher %A Guo, Xiuqing %A Hansen, Torben %A Heckbert, Susan R %A Jackson, Rebecca D %A Kors, Jan A %A Lima-Costa, Maria Fernanda %A Linneberg, Allan %A Macfarlane, Peter W %A Morrison, Alanna C %A Navarro, Pau %A Porteous, David J %A Pramstaller, Peter P %A Reiner, Alexander P %A Risch, Lorenz %A Schotten, Ulrich %A Shen, Xia %A Sinagra, Gianfranco %A Soliman, Elsayed Z %A Stoll, Monika %A Tarazona-Santos, Eduardo %A Tinker, Andrew %A Trajanoska, Katerina %A Villard, Eric %A Warren, Helen R %A Whitsel, Eric A %A Wiggins, Kerri L %A Arking, Dan E %A Avery, Christy L %A Conen, David %A Girotto, Giorgia %A Grarup, Niels %A Hayward, Caroline %A Jukema, J Wouter %A Mook-Kanamori, Dennis O %A Olesen, Morten Salling %A Padmanabhan, Sandosh %A Psaty, Bruce M %A Pattaro, Cristian %A Ribeiro, Antonio Luiz P %A Rotter, Jerome I %A Stricker, Bruno H %A van der Harst, Pim %A van Duijn, Cornelia M %A Verweij, Niek %A Wilson, James G %A Orini, Michele %A Charron, Philippe %A Watkins, Hugh %A Kooperberg, Charles %A Lin, Henry J %A Wilson, James F %A Kanters, Jørgen K %A Sotoodehnia, Nona %A Mifsud, Borbala %A Lambiase, Pier D %A Tereshchenko, Larisa G %A Munroe, Patricia B %K Arrhythmias, Cardiac %K Atrioventricular Block %K Biomarkers %K Cardiovascular Diseases %K Electrocardiography %K Genome-Wide Association Study %K Humans %K Risk Factors %X

The 3-dimensional spatial and 2-dimensional frontal QRS-T angles are measures derived from the vectorcardiogram. They are independent risk predictors for arrhythmia, but the underlying biology is unknown. Using multi-ancestry genome-wide association studies we identify 61 (58 previously unreported) loci for the spatial QRS-T angle (N = 118,780) and 11 for the frontal QRS-T angle (N = 159,715). Seven out of the 61 spatial QRS-T angle loci have not been reported for other electrocardiographic measures. Enrichments are observed in pathways related to cardiac and vascular development, muscle contraction, and hypertrophy. Pairwise genome-wide association studies with classical ECG traits identify shared genetic influences with PR interval and QRS duration. Phenome-wide scanning indicate associations with atrial fibrillation, atrioventricular block and arterial embolism and genetically determined QRS-T angle measures are associated with fascicular and bundle branch block (and also atrioventricular block for the frontal QRS-T angle). We identify potential biology involved in the QRS-T angle and their genetic relationships with cardiovascular traits and diseases, may inform future research and risk prediction.

%B Nat Commun %V 14 %P 1411 %8 2023 Mar 14 %G eng %N 1 %R 10.1038/s41467-023-36997-w %0 Journal Article %J Nat Genet %D 2023 %T Mosaic chromosomal alterations in blood across ancestries using whole-genome sequencing. %A Jakubek, Yasminka A %A Zhou, Ying %A Stilp, Adrienne %A Bacon, Jason %A Wong, Justin W %A Ozcan, Zuhal %A Arnett, Donna %A Barnes, Kathleen %A Bis, Joshua C %A Boerwinkle, Eric %A Brody, Jennifer A %A Carson, April P %A Chasman, Daniel I %A Chen, Jiawen %A Cho, Michael %A Conomos, Matthew P %A Cox, Nancy %A Doyle, Margaret F %A Fornage, Myriam %A Guo, Xiuqing %A Kardia, Sharon L R %A Lewis, Joshua P %A Loos, Ruth J F %A Ma, Xiaolong %A Machiela, Mitchell J %A Mack, Taralynn M %A Mathias, Rasika A %A Mitchell, Braxton D %A Mychaleckyj, Josyf C %A North, Kari %A Pankratz, Nathan %A Peyser, Patricia A %A Preuss, Michael H %A Psaty, Bruce %A Raffield, Laura M %A Vasan, Ramachandran S %A Redline, Susan %A Rich, Stephen S %A Rotter, Jerome I %A Silverman, Edwin K %A Smith, Jennifer A %A Smith, Aaron P %A Taub, Margaret %A Taylor, Kent D %A Yun, Jeong %A Li, Yun %A Desai, Pinkal %A Bick, Alexander G %A Reiner, Alexander P %A Scheet, Paul %A Auer, Paul L %K Black People %K Genome, Human %K Genome-Wide Association Study %K Hispanic or Latino %K Humans %K Mosaicism %K Precision Medicine %X

Megabase-scale mosaic chromosomal alterations (mCAs) in blood are prognostic markers for a host of human diseases. Here, to gain a better understanding of mCA rates in genetically diverse populations, we analyzed whole-genome sequencing data from 67,390 individuals from the National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine program. We observed higher sensitivity with whole-genome sequencing data, compared with array-based data, in uncovering mCAs at low mutant cell fractions and found that individuals of European ancestry have the highest rates of autosomal mCAs and the lowest rates of chromosome X mCAs, compared with individuals of African or Hispanic ancestry. Although further studies in diverse populations will be needed to replicate our findings, we report three loci associated with loss of chromosome X, associations between autosomal mCAs and rare variants in DCPS, ADM17, PPP1R16B and TET2 and ancestry-specific variants in ATM and MPL with mCAs in cis.

%B Nat Genet %V 55 %P 1912-1919 %8 2023 Nov %G eng %N 11 %R 10.1038/s41588-023-01553-1 %0 Journal Article %J Nat Genet %D 2023 %T Multi-ancestry transcriptome-wide association analyses yield insights into tobacco use biology and drug repurposing. %A Chen, Fang %A Wang, Xingyan %A Jang, Seon-Kyeong %A Quach, Bryan C %A Weissenkampen, J Dylan %A Khunsriraksakul, Chachrit %A Yang, Lina %A Sauteraud, Renan %A Albert, Christine M %A Allred, Nicholette D D %A Arnett, Donna K %A Ashley-Koch, Allison E %A Barnes, Kathleen C %A Barr, R Graham %A Becker, Diane M %A Bielak, Lawrence F %A Bis, Joshua C %A Blangero, John %A Boorgula, Meher Preethi %A Chasman, Daniel I %A Chavan, Sameer %A Chen, Yii-der I %A Chuang, Lee-Ming %A Correa, Adolfo %A Curran, Joanne E %A David, Sean P %A Fuentes, Lisa de Las %A Deka, Ranjan %A Duggirala, Ravindranath %A Faul, Jessica D %A Garrett, Melanie E %A Gharib, Sina A %A Guo, Xiuqing %A Hall, Michael E %A Hawley, Nicola L %A He, Jiang %A Hobbs, Brian D %A Hokanson, John E %A Hsiung, Chao A %A Hwang, Shih-Jen %A Hyde, Thomas M %A Irvin, Marguerite R %A Jaffe, Andrew E %A Johnson, Eric O %A Kaplan, Robert %A Kardia, Sharon L R %A Kaufman, Joel D %A Kelly, Tanika N %A Kleinman, Joel E %A Kooperberg, Charles %A Lee, I-Te %A Levy, Daniel %A Lutz, Sharon M %A Manichaikul, Ani W %A Martin, Lisa W %A Marx, Olivia %A McGarvey, Stephen T %A Minster, Ryan L %A Moll, Matthew %A Moussa, Karine A %A Naseri, Take %A North, Kari E %A Oelsner, Elizabeth C %A Peralta, Juan M %A Peyser, Patricia A %A Psaty, Bruce M %A Rafaels, Nicholas %A Raffield, Laura M %A Reupena, Muagututi'a Sefuiva %A Rich, Stephen S %A Rotter, Jerome I %A Schwartz, David A %A Shadyab, Aladdin H %A Sheu, Wayne H-H %A Sims, Mario %A Smith, Jennifer A %A Sun, Xiao %A Taylor, Kent D %A Telen, Marilyn J %A Watson, Harold %A Weeks, Daniel E %A Weir, David R %A Yanek, Lisa R %A Young, Kendra A %A Young, Kristin L %A Zhao, Wei %A Hancock, Dana B %A Jiang, Bibo %A Vrieze, Scott %A Liu, Dajiang J %K Biology %K Drug Repositioning %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Polymorphism, Single Nucleotide %K Tobacco Use %K Transcriptome %X

Most transcriptome-wide association studies (TWASs) so far focus on European ancestry and lack diversity. To overcome this limitation, we aggregated genome-wide association study (GWAS) summary statistics, whole-genome sequences and expression quantitative trait locus (eQTL) data from diverse ancestries. We developed a new approach, TESLA (multi-ancestry integrative study using an optimal linear combination of association statistics), to integrate an eQTL dataset with a multi-ancestry GWAS. By exploiting shared phenotypic effects between ancestries and accommodating potential effect heterogeneities, TESLA improves power over other TWAS methods. When applied to tobacco use phenotypes, TESLA identified 273 new genes, up to 55% more compared with alternative TWAS methods. These hits and subsequent fine mapping using TESLA point to target genes with biological relevance. In silico drug-repurposing analyses highlight several drugs with known efficacy, including dextromethorphan and galantamine, and new drugs such as muscle relaxants that may be repurposed for treating nicotine addiction.

%B Nat Genet %V 55 %P 291-300 %8 2023 Feb %G eng %N 2 %R 10.1038/s41588-022-01282-x %0 Journal Article %J Nat Genet %D 2023 %T Powerful, scalable and resource-efficient meta-analysis of rare variant associations in large whole genome sequencing studies. %A Li, Xihao %A Quick, Corbin %A Zhou, Hufeng %A Gaynor, Sheila M %A Liu, Yaowu %A Chen, Han %A Selvaraj, Margaret Sunitha %A Sun, Ryan %A Dey, Rounak %A Arnett, Donna K %A Bielak, Lawrence F %A Bis, Joshua C %A Blangero, John %A Boerwinkle, Eric %A Bowden, Donald W %A Brody, Jennifer A %A Cade, Brian E %A Correa, Adolfo %A Cupples, L Adrienne %A Curran, Joanne E %A de Vries, Paul S %A Duggirala, Ravindranath %A Freedman, Barry I %A Göring, Harald H H %A Guo, Xiuqing %A Haessler, Jeffrey %A Kalyani, Rita R %A Kooperberg, Charles %A Kral, Brian G %A Lange, Leslie A %A Manichaikul, Ani %A Martin, Lisa W %A McGarvey, Stephen T %A Mitchell, Braxton D %A Montasser, May E %A Morrison, Alanna C %A Naseri, Take %A O'Connell, Jeffrey R %A Palmer, Nicholette D %A Peyser, Patricia A %A Psaty, Bruce M %A Raffield, Laura M %A Redline, Susan %A Reiner, Alexander P %A Reupena, Muagututi'a Sefuiva %A Rice, Kenneth M %A Rich, Stephen S %A Sitlani, Colleen M %A Smith, Jennifer A %A Taylor, Kent D %A Vasan, Ramachandran S %A Willer, Cristen J %A Wilson, James G %A Yanek, Lisa R %A Zhao, Wei %A Rotter, Jerome I %A Natarajan, Pradeep %A Peloso, Gina M %A Li, Zilin %A Lin, Xihong %K Exome Sequencing %K Genome-Wide Association Study %K Lipids %K Phenotype %K Whole Genome Sequencing %X

Meta-analysis of whole genome sequencing/whole exome sequencing (WGS/WES) studies provides an attractive solution to the problem of collecting large sample sizes for discovering rare variants associated with complex phenotypes. Existing rare variant meta-analysis approaches are not scalable to biobank-scale WGS data. Here we present MetaSTAAR, a powerful and resource-efficient rare variant meta-analysis framework for large-scale WGS/WES studies. MetaSTAAR accounts for relatedness and population structure, can analyze both quantitative and dichotomous traits and boosts the power of rare variant tests by incorporating multiple variant functional annotations. Through meta-analysis of four lipid traits in 30,138 ancestrally diverse samples from 14 studies of the Trans Omics for Precision Medicine (TOPMed) Program, we show that MetaSTAAR performs rare variant meta-analysis at scale and produces results comparable to using pooled data. Additionally, we identified several conditionally significant rare variant associations with lipid traits. We further demonstrate that MetaSTAAR is scalable to biobank-scale cohorts through meta-analysis of TOPMed WGS data and UK Biobank WES data of ~200,000 samples.

%B Nat Genet %V 55 %P 154-164 %8 2023 Jan %G eng %N 1 %R 10.1038/s41588-022-01225-6 %0 Journal Article %J Nat Commun %D 2023 %T Whole-Genome Sequencing Analysis of Human Metabolome in Multi-Ethnic Populations. %A Feofanova, Elena V %A Brown, Michael R %A Alkis, Taryn %A Manuel, Astrid M %A Li, Xihao %A Tahir, Usman A %A Li, Zilin %A Mendez, Kevin M %A Kelly, Rachel S %A Qi, Qibin %A Chen, Han %A Larson, Martin G %A Lemaitre, Rozenn N %A Morrison, Alanna C %A Grieser, Charles %A Wong, Kari E %A Gersztern, Robert E %A Zhao, Zhongming %A Lasky-Su, Jessica %A Yu, Bing %K Ethnicity %K Genome-Wide Association Study %K Humans %K Metabolome %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %X

Circulating metabolite levels may reflect the state of the human organism in health and disease, however, the genetic architecture of metabolites is not fully understood. We have performed a whole-genome sequencing association analysis of both common and rare variants in up to 11,840 multi-ethnic participants from five studies with up to 1666 circulating metabolites. We have discovered 1985 novel variant-metabolite associations, and validated 761 locus-metabolite associations reported previously. Seventy-nine novel variant-metabolite associations have been replicated, including three genetic loci located on the X chromosome that have demonstrated its involvement in metabolic regulation. Gene-based analysis have provided further support for seven metabolite-replicated loci pairs and their biologically plausible genes. Among those novel replicated variant-metabolite pairs, follow-up analyses have revealed that 26 metabolites have colocalized with 21 tissues, seven metabolite-disease outcome associations have been putatively causal, and 7 metabolites might be regulated by plasma protein levels. Our results have depicted the genetic contribution to circulating metabolite levels, providing additional insights into understanding human disease.

%B Nat Commun %V 14 %P 3111 %8 2023 May 30 %G eng %N 1 %R 10.1038/s41467-023-38800-2 %0 Journal Article %J Alzheimers Res Ther %D 2024 %T Multi-omics and pathway analyses of genome-wide associations implicate regulation and immunity in verbal declarative memory performance. %A Mei, Hao %A Simino, Jeannette %A Li, Lianna %A Jiang, Fan %A Bis, Joshua C %A Davies, Gail %A Hill, W David %A Xia, Charley %A Gudnason, Vilmundur %A Yang, Qiong %A Lahti, Jari %A Smith, Jennifer A %A Kirin, Mirna %A De Jager, Philip %A Armstrong, Nicola J %A Ghanbari, Mohsen %A Kolcic, Ivana %A Moran, Christopher %A Teumer, Alexander %A Sargurupremraj, Murali %A Mahmud, Shamsed %A Fornage, Myriam %A Zhao, Wei %A Satizabal, Claudia L %A Polasek, Ozren %A Räikkönen, Katri %A Liewald, David C %A Homuth, Georg %A Callisaya, Michele %A Mather, Karen A %A Windham, B Gwen %A Zemunik, Tatijana %A Palotie, Aarno %A Pattie, Alison %A van der Auwera, Sandra %A Thalamuthu, Anbupalam %A Knopman, David S %A Rudan, Igor %A Starr, John M %A Wittfeld, Katharina %A Kochan, Nicole A %A Griswold, Michael E %A Vitart, Veronique %A Brodaty, Henry %A Gottesman, Rebecca %A Cox, Simon R %A Psaty, Bruce M %A Boerwinkle, Eric %A Chasman, Daniel I %A Grodstein, Francine %A Sachdev, Perminder S %A Srikanth, Velandai %A Hayward, Caroline %A Wilson, James F %A Eriksson, Johan G %A Kardia, Sharon L R %A Grabe, Hans J %A Bennett, David A %A Ikram, M Arfan %A Deary, Ian J %A van Duijn, Cornelia M %A Launer, Lenore %A Fitzpatrick, Annette L %A Seshadri, Sudha %A Bressler, Jan %A Debette, Stephanie %A Mosley, Thomas H %K Aged %K Cognition %K Genome-Wide Association Study %K Humans %K Memory %K MicroRNAs %K Multiomics %K Polymorphism, Single Nucleotide %X

BACKGROUND: Uncovering the functional relevance underlying verbal declarative memory (VDM) genome-wide association study (GWAS) results may facilitate the development of interventions to reduce age-related memory decline and dementia.

METHODS: We performed multi-omics and pathway enrichment analyses of paragraph (PAR-dr) and word list (WL-dr) delayed recall GWAS from 29,076 older non-demented individuals of European descent. We assessed the relationship between single-variant associations and expression quantitative trait loci (eQTLs) in 44 tissues and methylation quantitative trait loci (meQTLs) in the hippocampus. We determined the relationship between gene associations and transcript levels in 53 tissues, annotation as immune genes, and regulation by transcription factors (TFs) and microRNAs. To identify significant pathways, gene set enrichment was tested in each cohort and meta-analyzed across cohorts. Analyses of differential expression in brain tissues were conducted for pathway component genes.

RESULTS: The single-variant associations of VDM showed significant linkage disequilibrium (LD) with eQTLs across all tissues and meQTLs within the hippocampus. Stronger WL-dr gene associations correlated with reduced expression in four brain tissues, including the hippocampus. More robust PAR-dr and/or WL-dr gene associations were intricately linked with immunity and were influenced by 31 TFs and 2 microRNAs. Six pathways, including type I diabetes, exhibited significant associations with both PAR-dr and WL-dr. These pathways included fifteen MHC genes intricately linked to VDM performance, showing diverse expression patterns based on cognitive status in brain tissues.

CONCLUSIONS: VDM genetic associations influence expression regulation via eQTLs and meQTLs. The involvement of TFs, microRNAs, MHC genes, and immune-related pathways contributes to VDM performance in older individuals.

%B Alzheimers Res Ther %V 16 %P 14 %8 2024 Jan 20 %G eng %N 1 %R 10.1186/s13195-023-01376-6 %0 Journal Article %J Nat Commun %D 2024 %T X-chromosome and kidney function: evidence from a multi-trait genetic analysis of 908,697 individuals reveals sex-specific and sex-differential findings in genes regulated by androgen response elements. %A Scholz, Markus %A Horn, Katrin %A Pott, Janne %A Wuttke, Matthias %A Kühnapfel, Andreas %A Nasr, M Kamal %A Kirsten, Holger %A Li, Yong %A Hoppmann, Anselm %A Gorski, Mathias %A Ghasemi, Sahar %A Li, Man %A Tin, Adrienne %A Chai, Jin-Fang %A Cocca, Massimiliano %A Wang, Judy %A Nutile, Teresa %A Akiyama, Masato %A Åsvold, Bjørn Olav %A Bansal, Nisha %A Biggs, Mary L %A Boutin, Thibaud %A Brenner, Hermann %A Brumpton, Ben %A Burkhardt, Ralph %A Cai, Jianwen %A Campbell, Archie %A Campbell, Harry %A Chalmers, John %A Chasman, Daniel I %A Chee, Miao Ling %A Chee, Miao Li %A Chen, Xu %A Cheng, Ching-Yu %A Cifkova, Renata %A Daviglus, Martha %A Delgado, Graciela %A Dittrich, Katalin %A Edwards, Todd L %A Endlich, Karlhans %A Michael Gaziano, J %A Giri, Ayush %A Giulianini, Franco %A Gordon, Scott D %A Gudbjartsson, Daniel F %A Hallan, Stein %A Hamet, Pavel %A Hartman, Catharina A %A Hayward, Caroline %A Heid, Iris M %A Hellwege, Jacklyn N %A Holleczek, Bernd %A Holm, Hilma %A Hutri-Kähönen, Nina %A Hveem, Kristian %A Isermann, Berend %A Jonas, Jost B %A Joshi, Peter K %A Kamatani, Yoichiro %A Kanai, Masahiro %A Kastarinen, Mika %A Khor, Chiea Chuen %A Kiess, Wieland %A Kleber, Marcus E %A Körner, Antje %A Kovacs, Peter %A Krajcoviechova, Alena %A Kramer, Holly %A Krämer, Bernhard K %A Kuokkanen, Mikko %A Kähönen, Mika %A Lange, Leslie A %A Lash, James P %A Lehtimäki, Terho %A Li, Hengtong %A Lin, Bridget M %A Liu, Jianjun %A Loeffler, Markus %A Lyytikäinen, Leo-Pekka %A Magnusson, Patrik K E %A Martin, Nicholas G %A Matsuda, Koichi %A Milaneschi, Yuri %A Mishra, Pashupati P %A Mononen, Nina %A Montgomery, Grant W %A Mook-Kanamori, Dennis O %A Mychaleckyj, Josyf C %A März, Winfried %A Nauck, Matthias %A Nikus, Kjell %A Nolte, Ilja M %A Noordam, Raymond %A Okada, Yukinori %A Olafsson, Isleifur %A Oldehinkel, Albertine J %A Penninx, Brenda W J H %A Perola, Markus %A Pirastu, Nicola %A Polasek, Ozren %A Porteous, David J %A Poulain, Tanja %A Psaty, Bruce M %A Rabelink, Ton J %A Raffield, Laura M %A Raitakari, Olli T %A Rasheed, Humaira %A Reilly, Dermot F %A Rice, Kenneth M %A Richmond, Anne %A Ridker, Paul M %A Rotter, Jerome I %A Rudan, Igor %A Sabanayagam, Charumathi %A Salomaa, Veikko %A Schneiderman, Neil %A Schöttker, Ben %A Sims, Mario %A Snieder, Harold %A Stark, Klaus J %A Stefansson, Kari %A Stocker, Hannah %A Stumvoll, Michael %A Sulem, Patrick %A Sveinbjornsson, Gardar %A Svensson, Per O %A Tai, E-Shyong %A Taylor, Kent D %A Tayo, Bamidele O %A Teren, Andrej %A Tham, Yih-Chung %A Thiery, Joachim %A Thio, Chris H L %A Thomas, Laurent F %A Tremblay, Johanne %A Tönjes, Anke %A van der Most, Peter J %A Vitart, Veronique %A Völker, Uwe %A Wang, Ya Xing %A Wang, Chaolong %A Wei, Wen Bin %A Whitfield, John B %A Wild, Sarah H %A Wilson, James F %A Winkler, Thomas W %A Wong, Tien-Yin %A Woodward, Mark %A Sim, Xueling %A Chu, Audrey Y %A Feitosa, Mary F %A Thorsteinsdottir, Unnur %A Hung, Adriana M %A Teumer, Alexander %A Franceschini, Nora %A Parsa, Afshin %A Köttgen, Anna %A Schlosser, Pascal %A Pattaro, Cristian %K Androgens %K Chromosomes, Human, X %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Kidney %K Male %K Polymorphism, Single Nucleotide %K Response Elements %K Tetraspanins %X

X-chromosomal genetic variants are understudied but can yield valuable insights into sexually dimorphic human traits and diseases. We performed a sex-stratified cross-ancestry X-chromosome-wide association meta-analysis of seven kidney-related traits (n = 908,697), identifying 23 loci genome-wide significantly associated with two of the traits: 7 for uric acid and 16 for estimated glomerular filtration rate (eGFR), including four novel eGFR loci containing the functionally plausible prioritized genes ACSL4, CLDN2, TSPAN6 and the female-specific DRP2. Further, we identified five novel sex-interactions, comprising male-specific effects at FAM9B and AR/EDA2R, and three sex-differential findings with larger genetic effect sizes in males at DCAF12L1 and MST4 and larger effect sizes in females at HPRT1. All prioritized genes in loci showing significant sex-interactions were located next to androgen response elements (ARE). Five ARE genes showed sex-differential expressions. This study contributes new insights into sex-dimorphisms of kidney traits along with new prioritized gene targets for further molecular research.

%B Nat Commun %V 15 %P 586 %8 2024 Jan 18 %G eng %N 1 %R 10.1038/s41467-024-44709-1