TY - JOUR T1 - Association of novel genetic Loci with circulating fibrinogen levels: a genome-wide association study in 6 population-based cohorts. JF - Circ Cardiovasc Genet Y1 - 2009 A1 - Dehghan, Abbas A1 - Yang, Qiong A1 - Peters, Annette A1 - Basu, Saonli A1 - Bis, Joshua C A1 - Rudnicka, Alicja R A1 - Kavousi, Maryam A1 - Chen, Ming-Huei A1 - Baumert, Jens A1 - Lowe, Gordon D O A1 - McKnight, Barbara A1 - Tang, Weihong A1 - de Maat, Moniek A1 - Larson, Martin G A1 - Eyhermendy, Susana A1 - McArdle, Wendy L A1 - Lumley, Thomas A1 - Pankow, James S A1 - Hofman, Albert A1 - Massaro, Joseph M A1 - Rivadeneira, Fernando A1 - Kolz, Melanie A1 - Taylor, Kent D A1 - van Duijn, Cornelia M A1 - Kathiresan, Sekar A1 - Illig, Thomas A1 - Aulchenko, Yurii S A1 - Volcik, Kelly A A1 - Johnson, Andrew D A1 - Uitterlinden, André G A1 - Tofler, Geoffrey H A1 - Gieger, Christian A1 - Psaty, Bruce M A1 - Couper, David J A1 - Boerwinkle, Eric A1 - Koenig, Wolfgang A1 - O'Donnell, Christopher J A1 - Witteman, Jacqueline C A1 - Strachan, David P A1 - Smith, Nicholas L A1 - Folsom, Aaron R KW - Adult KW - Aged KW - Aged, 80 and over KW - Cardiovascular Diseases KW - Cohort Studies KW - European Continental Ancestry Group KW - Female KW - Fibrinogen KW - Genetic Loci KW - Genome-Wide Association Study KW - Humans KW - Male KW - Middle Aged KW - Pedigree KW - Polymorphism, Single Nucleotide KW - Young Adult AB -

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.

VL - 2 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20031576?dopt=Abstract ER - TY - JOUR T1 - Genomewide association studies of stroke. JF - N Engl J Med Y1 - 2009 A1 - Ikram, M Arfan A1 - Seshadri, Sudha A1 - Bis, Joshua C A1 - Fornage, Myriam A1 - DeStefano, Anita L A1 - Aulchenko, Yurii S A1 - Debette, Stephanie A1 - Lumley, Thomas A1 - Folsom, Aaron R A1 - van den Herik, Evita G A1 - Bos, Michiel J A1 - Beiser, Alexa A1 - Cushman, Mary A1 - Launer, Lenore J A1 - Shahar, Eyal A1 - Struchalin, Maksim A1 - Du, Yangchun A1 - Glazer, Nicole L A1 - Rosamond, Wayne D A1 - Rivadeneira, Fernando A1 - Kelly-Hayes, Margaret A1 - Lopez, Oscar L A1 - Coresh, Josef A1 - Hofman, Albert A1 - DeCarli, Charles A1 - Heckbert, Susan R A1 - Koudstaal, Peter J A1 - Yang, Qiong A1 - Smith, Nicholas L A1 - Kase, Carlos S A1 - Rice, Kenneth A1 - Haritunians, Talin A1 - Roks, Gerwin A1 - de Kort, Paul L M A1 - Taylor, Kent D A1 - de Lau, Lonneke M A1 - Oostra, Ben A A1 - Uitterlinden, André G A1 - Rotter, Jerome I A1 - Boerwinkle, Eric A1 - Psaty, Bruce M A1 - Mosley, Thomas H A1 - van Duijn, Cornelia M A1 - Breteler, Monique M B A1 - Longstreth, W T A1 - Wolf, Philip A KW - African Continental Ancestry Group KW - Aged KW - Chromosomes, Human, Pair 12 KW - Cohort Studies KW - European Continental Ancestry Group KW - Female KW - Genetic Markers KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Proportional Hazards Models KW - Risk Factors KW - Stroke AB -

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.

VL - 360 IS - 17 U1 - https://www.ncbi.nlm.nih.gov/pubmed/19369658?dopt=Abstract ER - TY - JOUR T1 - Multiple loci associated with indices of renal function and chronic kidney disease. JF - Nat Genet Y1 - 2009 A1 - Köttgen, Anna A1 - Glazer, Nicole L A1 - Dehghan, Abbas A1 - Hwang, Shih-Jen A1 - Katz, Ronit A1 - Li, Man A1 - Yang, Qiong A1 - Gudnason, Vilmundur A1 - Launer, Lenore J A1 - Harris, Tamara B A1 - Smith, Albert V A1 - Arking, Dan E A1 - Astor, Brad C A1 - Boerwinkle, Eric A1 - Ehret, Georg B A1 - Ruczinski, Ingo A1 - Scharpf, Robert B A1 - Chen, Yii-Der Ida A1 - de Boer, Ian H A1 - Haritunians, Talin A1 - Lumley, Thomas A1 - Sarnak, Mark A1 - Siscovick, David A1 - Benjamin, Emelia J A1 - Levy, Daniel A1 - Upadhyay, Ashish A1 - Aulchenko, Yurii S A1 - Hofman, Albert A1 - Rivadeneira, Fernando A1 - Uitterlinden, André G A1 - van Duijn, Cornelia M A1 - Chasman, Daniel I A1 - Paré, Guillaume A1 - Ridker, Paul M A1 - Kao, W H Linda A1 - Witteman, Jacqueline C A1 - Coresh, Josef A1 - Shlipak, Michael G A1 - Fox, Caroline S KW - Chromosome Mapping KW - Cohort Studies KW - Genetic Variation KW - Genome-Wide Association Study KW - Glomerular Filtration Rate KW - Humans KW - Kidney KW - Kidney Failure, Chronic KW - Meta-Analysis as Topic KW - Mucoproteins KW - Netherlands KW - Polymorphism, Single Nucleotide KW - Prevalence KW - Uromodulin AB -

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.

VL - 41 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/19430482?dopt=Abstract ER - TY - JOUR T1 - Multiple loci influence erythrocyte phenotypes in the CHARGE Consortium. JF - Nat Genet Y1 - 2009 A1 - Ganesh, Santhi K A1 - Zakai, Neil A A1 - van Rooij, Frank J A A1 - Soranzo, Nicole A1 - Smith, Albert V A1 - Nalls, Michael A A1 - Chen, Ming-Huei A1 - Köttgen, Anna A1 - Glazer, Nicole L A1 - Dehghan, Abbas A1 - Kuhnel, Brigitte A1 - Aspelund, Thor A1 - Yang, Qiong A1 - Tanaka, Toshiko A1 - Jaffe, Andrew A1 - Bis, Joshua C M A1 - Verwoert, Germaine C A1 - Teumer, Alexander A1 - Fox, Caroline S A1 - Guralnik, Jack M A1 - Ehret, Georg B A1 - Rice, Kenneth A1 - Felix, Janine F A1 - Rendon, Augusto A1 - Eiriksdottir, Gudny A1 - Levy, Daniel A1 - Patel, Kushang V A1 - Boerwinkle, Eric A1 - Rotter, Jerome I A1 - Hofman, Albert A1 - Sambrook, Jennifer G A1 - Hernandez, Dena G A1 - Zheng, Gang A1 - Bandinelli, Stefania A1 - Singleton, Andrew B A1 - Coresh, Josef A1 - Lumley, Thomas A1 - Uitterlinden, André G A1 - Vangils, Janine M A1 - Launer, Lenore J A1 - Cupples, L Adrienne A1 - Oostra, Ben A A1 - Zwaginga, Jaap-Jan A1 - Ouwehand, Willem H A1 - Thein, Swee-Lay A1 - Meisinger, Christa A1 - Deloukas, Panos A1 - Nauck, Matthias A1 - Spector, Tim D A1 - Gieger, Christian A1 - Gudnason, Vilmundur A1 - van Duijn, Cornelia M A1 - Psaty, Bruce M A1 - Ferrucci, Luigi A1 - Chakravarti, Aravinda A1 - Greinacher, Andreas A1 - O'Donnell, Christopher J A1 - Witteman, Jacqueline C M A1 - Furth, Susan A1 - Cushman, Mary A1 - Harris, Tamara B A1 - Lin, Jing-Ping KW - Blood Pressure KW - Cell Line KW - Cohort Studies KW - Endothelial Cells KW - Erythrocytes KW - Gene Expression KW - Genome, Human KW - Genome-Wide Association Study KW - Humans KW - Hypertension KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci AB -

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.

VL - 41 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/19862010?dopt=Abstract ER - TY - JOUR T1 - Candidate gene association resource (CARe): design, methods, and proof of concept. JF - Circ Cardiovasc Genet Y1 - 2010 A1 - Musunuru, Kiran A1 - Lettre, Guillaume A1 - Young, Taylor A1 - Farlow, Deborah N A1 - Pirruccello, James P A1 - Ejebe, Kenechi G A1 - Keating, Brendan J A1 - Yang, Qiong A1 - Chen, Ming-Huei A1 - Lapchyk, Nina A1 - Crenshaw, Andrew A1 - Ziaugra, Liuda A1 - Rachupka, Anthony A1 - Benjamin, Emelia J A1 - Cupples, L Adrienne A1 - Fornage, Myriam A1 - Fox, Ervin R A1 - Heckbert, Susan R A1 - Hirschhorn, Joel N A1 - Newton-Cheh, Christopher A1 - Nizzari, Marcia M A1 - Paltoo, Dina N A1 - Papanicolaou, George J A1 - Patel, Sanjay R A1 - Psaty, Bruce M A1 - Rader, Daniel J A1 - Redline, Susan A1 - Rich, Stephen S A1 - Rotter, Jerome I A1 - Taylor, Herman A A1 - Tracy, Russell P A1 - Vasan, Ramachandran S A1 - Wilson, James G A1 - Kathiresan, Sekar A1 - Fabsitz, Richard R A1 - Boerwinkle, Eric A1 - Gabriel, Stacey B KW - African Americans KW - Cholesterol, HDL KW - Cholesterol, LDL KW - Cohort Studies KW - Databases, Genetic KW - European Continental Ancestry Group KW - Genetic Association Studies KW - Genotype KW - Humans KW - Phenotype KW - Pilot Projects KW - Polymorphism, Single Nucleotide KW - Research Design KW - Triglycerides AB -

BACKGROUND: The National Heart, Lung, and Blood Institute's Candidate Gene Association Resource (CARe), a planned cross-cohort analysis of genetic variation in cardiovascular, pulmonary, hematologic, and sleep-related traits, comprises >40,000 participants representing 4 ethnic groups in 9 community-based cohorts. The goals of CARe include the discovery of new variants associated with traits using a candidate gene approach and the discovery of new variants using the genome-wide association mapping approach specifically in African Americans.

METHODS AND RESULTS: CARe has assembled DNA samples for >40,000 individuals self-identified as European American, African American, Hispanic, or Chinese American, with accompanying data on hundreds of phenotypes that have been standardized and deposited in the CARe Phenotype Database. All participants were genotyped for 7 single-nucleotide polymorphisms (SNPs) selected based on prior association evidence. We performed association analyses relating each of these SNPs to lipid traits, stratified by sex and ethnicity, and adjusted for age and age squared. In at least 2 of the ethnic groups, SNPs near CETP, LIPC, and LPL strongly replicated for association with high-density lipoprotein cholesterol concentrations, PCSK9 with low-density lipoprotein cholesterol levels, and LPL and APOA5 with serum triglycerides. Notably, some SNPs showed varying effect sizes and significance of association in different ethnic groups.

CONCLUSIONS: The CARe Pilot Study validates the operational framework for phenotype collection, SNP genotyping, and analytic pipeline of the CARe project and validates the planned candidate gene study of approximately 2000 biological candidate loci in all participants and genome-wide association study in approximately 8000 African American participants. CARe will serve as a valuable resource for the scientific community.

VL - 3 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20400780?dopt=Abstract ER - TY - JOUR T1 - Common genetic variants associate with serum phosphorus concentration. JF - J Am Soc Nephrol Y1 - 2010 A1 - Kestenbaum, Bryan A1 - Glazer, Nicole L A1 - Köttgen, Anna A1 - Felix, Janine F A1 - Hwang, Shih-Jen A1 - Liu, Yongmei A1 - Lohman, Kurt A1 - Kritchevsky, Stephen B A1 - Hausman, Dorothy B A1 - Petersen, Ann-Kristin A1 - Gieger, Christian A1 - Ried, Janina S A1 - Meitinger, Thomas A1 - Strom, Tim M A1 - Wichmann, H Erich A1 - Campbell, Harry A1 - Hayward, Caroline A1 - Rudan, Igor A1 - de Boer, Ian H A1 - Psaty, Bruce M A1 - Rice, Kenneth M A1 - Chen, Yii-Der Ida A1 - Li, Man A1 - Arking, Dan E A1 - Boerwinkle, Eric A1 - Coresh, Josef A1 - Yang, Qiong A1 - Levy, Daniel A1 - van Rooij, Frank J A A1 - Dehghan, Abbas A1 - Rivadeneira, Fernando A1 - Uitterlinden, André G A1 - Hofman, Albert A1 - van Duijn, Cornelia M A1 - Shlipak, Michael G A1 - Kao, W H Linda A1 - Witteman, Jacqueline C M A1 - Siscovick, David S A1 - Fox, Caroline S KW - Adult KW - Aged KW - European Continental Ancestry Group KW - Female KW - Fibroblast Growth Factors KW - Gene Frequency KW - Genetic Loci KW - Genetic Variation KW - Genome-Wide Association Study KW - Humans KW - Kidney KW - Male KW - Middle Aged KW - Phosphorus KW - Polymorphism, Single Nucleotide KW - Receptors, Calcium-Sensing KW - Sex Factors KW - Sodium-Phosphate Cotransporter Proteins, Type IIa AB -

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.

VL - 21 IS - 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20558539?dopt=Abstract ER - TY - JOUR T1 - Common variants in the calcium-sensing receptor gene are associated with total serum calcium levels. JF - Hum Mol Genet Y1 - 2010 A1 - O'Seaghdha, Conall M A1 - Yang, Qiong A1 - Glazer, Nicole L A1 - Leak, Tennille S A1 - Dehghan, Abbas A1 - Smith, Albert V A1 - Kao, W H Linda A1 - Lohman, Kurt A1 - Hwang, Shih-Jen A1 - Johnson, Andrew D A1 - Hofman, Albert A1 - Uitterlinden, André G A1 - Chen, Yii-Der Ida A1 - Brown, Edward M A1 - Siscovick, David S A1 - Harris, Tamara B A1 - Psaty, Bruce M A1 - Coresh, Josef A1 - Gudnason, Vilmundur A1 - Witteman, Jacqueline C A1 - Liu, Yong Mei A1 - Kestenbaum, Bryan R A1 - Fox, Caroline S A1 - Köttgen, Anna KW - Adult KW - Calcium KW - Female KW - Humans KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Receptors, Calcium-Sensing AB -

Serum calcium levels are tightly regulated. We performed genome-wide association studies (GWAS) in population-based studies participating in the CHARGE Consortium to uncover common genetic variations associated with total serum calcium levels. GWAS of serum calcium concentrations was performed in 20 611 individuals of European ancestry for ∼2.5 million genotyped and imputed single-nucleotide polymorphisms (SNPs). The SNP with the lowest P-value was rs17251221 (P = 2.4 * 10(-22), minor allele frequency 14%) in the calcium-sensing receptor gene (CASR). This lead SNP was associated with higher serum calcium levels [0.06 mg/dl (0.015 mmol/l) per copy of the minor G allele] and accounted for 0.54% of the variance in serum calcium concentrations. The identification of variation in CASR that influences serum calcium concentration confirms the results of earlier candidate gene studies. The G allele of rs17251221 was also associated with higher serum magnesium levels (P = 1.2 * 10(-3)), lower serum phosphate levels (P = 2.8 * 10(-7)) and lower bone mineral density at the lumbar spine (P = 0.038), but not the femoral neck. No additional genomic loci contained SNPs associated at genome-wide significance (P < 5 * 10(-8)). These associations resemble clinical characteristics of patients with familial hypocalciuric hypercalcemia, an autosomal-dominant disease arising from rare inactivating mutations in the CASR gene. We conclude that common genetic variation in the CASR gene is associated with similar but milder features in the general population.

VL - 19 IS - 21 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20705733?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association studies of serum magnesium, potassium, and sodium concentrations identify six Loci influencing serum magnesium levels. JF - PLoS Genet Y1 - 2010 A1 - Meyer, Tamra E A1 - Verwoert, Germaine C A1 - Hwang, Shih-Jen A1 - Glazer, Nicole L A1 - Smith, Albert V A1 - van Rooij, Frank J A A1 - Ehret, Georg B A1 - Boerwinkle, Eric A1 - Felix, Janine F A1 - Leak, Tennille S A1 - Harris, Tamara B A1 - Yang, Qiong A1 - Dehghan, Abbas A1 - Aspelund, Thor A1 - Katz, Ronit A1 - Homuth, Georg A1 - Kocher, Thomas A1 - Rettig, Rainer A1 - Ried, Janina S A1 - Gieger, Christian A1 - Prucha, Hanna A1 - Pfeufer, Arne A1 - Meitinger, Thomas A1 - Coresh, Josef A1 - Hofman, Albert A1 - Sarnak, Mark J A1 - Chen, Yii-Der Ida A1 - Uitterlinden, André G A1 - Chakravarti, Aravinda A1 - Psaty, Bruce M A1 - van Duijn, Cornelia M A1 - Kao, W H Linda A1 - Witteman, Jacqueline C M A1 - Gudnason, Vilmundur A1 - Siscovick, David S A1 - Fox, Caroline S A1 - Köttgen, Anna KW - Adult KW - Aged KW - European Continental Ancestry Group KW - Female KW - Genome-Wide Association Study KW - Humans KW - Magnesium KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Potassium KW - Sodium AB -

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.

VL - 6 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20700443?dopt=Abstract ER - TY - JOUR T1 - Multiple genetic loci influence serum urate levels and their relationship with gout and cardiovascular disease risk factors. JF - Circ Cardiovasc Genet Y1 - 2010 A1 - Yang, Qiong A1 - Köttgen, Anna A1 - Dehghan, Abbas A1 - Smith, Albert V A1 - Glazer, Nicole L A1 - Chen, Ming-Huei A1 - Chasman, Daniel I A1 - Aspelund, Thor A1 - Eiriksdottir, Gudny A1 - Harris, Tamara B A1 - Launer, Lenore A1 - Nalls, Michael A1 - Hernandez, Dena A1 - Arking, Dan E A1 - Boerwinkle, Eric A1 - Grove, Megan L A1 - Li, Man A1 - Linda Kao, W H A1 - Chonchol, Michel A1 - Haritunians, Talin A1 - Li, Guo A1 - Lumley, Thomas A1 - Psaty, Bruce M A1 - Shlipak, Michael A1 - Hwang, Shih-Jen A1 - Larson, Martin G A1 - O'Donnell, Christopher J A1 - Upadhyay, Ashish A1 - van Duijn, Cornelia M A1 - Hofman, Albert A1 - Rivadeneira, Fernando A1 - Stricker, Bruno A1 - Uitterlinden, André G A1 - Paré, Guillaume A1 - Parker, Alex N A1 - Ridker, Paul M A1 - Siscovick, David S A1 - Gudnason, Vilmundur A1 - Witteman, Jacqueline C A1 - Fox, Caroline S A1 - Coresh, Josef KW - Cardiovascular Diseases KW - Coronary Disease KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Gout KW - Humans KW - Male KW - Risk Factors KW - Uric Acid AB -

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.

VL - 3 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20884846?dopt=Abstract ER - TY - JOUR T1 - New loci associated with kidney function and chronic kidney disease. JF - Nat Genet Y1 - 2010 A1 - Köttgen, Anna A1 - Pattaro, Cristian A1 - Böger, Carsten A A1 - Fuchsberger, Christian A1 - Olden, Matthias A1 - Glazer, Nicole L A1 - Parsa, Afshin A1 - Gao, Xiaoyi A1 - Yang, Qiong A1 - Smith, Albert V A1 - O'Connell, Jeffrey R A1 - Li, Man A1 - Schmidt, Helena A1 - Tanaka, Toshiko A1 - Isaacs, Aaron A1 - Ketkar, Shamika A1 - Hwang, Shih-Jen A1 - Johnson, Andrew D A1 - Dehghan, Abbas A1 - Teumer, Alexander A1 - Paré, Guillaume A1 - Atkinson, Elizabeth J A1 - Zeller, Tanja A1 - Lohman, Kurt A1 - Cornelis, Marilyn C A1 - Probst-Hensch, Nicole M A1 - Kronenberg, Florian A1 - Tönjes, Anke A1 - Hayward, Caroline A1 - Aspelund, Thor A1 - Eiriksdottir, Gudny A1 - Launer, Lenore J A1 - Harris, Tamara B A1 - Rampersaud, Evadnie A1 - Mitchell, Braxton D A1 - Arking, Dan E A1 - Boerwinkle, Eric A1 - Struchalin, Maksim A1 - Cavalieri, Margherita A1 - Singleton, Andrew A1 - Giallauria, Francesco A1 - Metter, Jeffrey A1 - de Boer, Ian H A1 - Haritunians, Talin A1 - Lumley, Thomas A1 - Siscovick, David A1 - Psaty, Bruce M A1 - Zillikens, M Carola A1 - Oostra, Ben A A1 - Feitosa, Mary A1 - Province, Michael A1 - de Andrade, Mariza A1 - Turner, Stephen T A1 - Schillert, Arne A1 - Ziegler, Andreas A1 - Wild, Philipp S A1 - Schnabel, Renate B A1 - Wilde, Sandra A1 - Munzel, Thomas F A1 - Leak, Tennille S A1 - Illig, Thomas A1 - Klopp, Norman A1 - Meisinger, Christa A1 - Wichmann, H-Erich A1 - Koenig, Wolfgang A1 - Zgaga, Lina A1 - Zemunik, Tatijana A1 - Kolcic, Ivana A1 - Minelli, Cosetta A1 - Hu, Frank B A1 - Johansson, Asa A1 - Igl, Wilmar A1 - Zaboli, Ghazal A1 - Wild, Sarah H A1 - Wright, Alan F A1 - Campbell, Harry A1 - Ellinghaus, David A1 - Schreiber, Stefan A1 - Aulchenko, Yurii S A1 - Felix, Janine F A1 - Rivadeneira, Fernando A1 - Uitterlinden, André G A1 - Hofman, Albert A1 - Imboden, Medea A1 - Nitsch, Dorothea A1 - Brandstätter, Anita A1 - Kollerits, Barbara A1 - Kedenko, Lyudmyla A1 - Mägi, Reedik A1 - Stumvoll, Michael A1 - Kovacs, Peter A1 - Boban, Mladen A1 - Campbell, Susan A1 - Endlich, Karlhans A1 - Völzke, Henry A1 - Kroemer, Heyo K A1 - Nauck, Matthias A1 - Völker, Uwe A1 - Polasek, Ozren A1 - Vitart, Veronique A1 - Badola, Sunita A1 - Parker, Alexander N A1 - Ridker, Paul M A1 - Kardia, Sharon L R A1 - Blankenberg, Stefan A1 - Liu, Yongmei A1 - Curhan, Gary C A1 - Franke, Andre A1 - Rochat, Thierry A1 - Paulweber, Bernhard A1 - Prokopenko, Inga A1 - Wang, Wei A1 - Gudnason, Vilmundur A1 - Shuldiner, Alan R A1 - Coresh, Josef A1 - Schmidt, Reinhold A1 - Ferrucci, Luigi A1 - Shlipak, Michael G A1 - van Duijn, Cornelia M A1 - Borecki, Ingrid A1 - Krämer, Bernhard K A1 - Rudan, Igor A1 - Gyllensten, Ulf A1 - Wilson, James F A1 - Witteman, Jacqueline C A1 - Pramstaller, Peter P A1 - Rettig, Rainer A1 - Hastie, Nick A1 - Chasman, Daniel I A1 - Kao, W H A1 - Heid, Iris M A1 - Fox, Caroline S KW - Cohort Studies KW - Creatinine KW - Cystatin C KW - Diet KW - Europe KW - Genetic Markers KW - Genome-Wide Association Study KW - Glomerular Filtration Rate KW - Humans KW - Kidney KW - Kidney Failure, Chronic KW - Models, Genetic KW - Risk Factors AB -

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.

VL - 42 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20383146?dopt=Abstract ER - TY - JOUR T1 - 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. JF - Circulation Y1 - 2010 A1 - Smith, Nicholas L A1 - Chen, Ming-Huei A1 - Dehghan, Abbas A1 - Strachan, David P A1 - Basu, Saonli A1 - Soranzo, Nicole A1 - Hayward, Caroline A1 - Rudan, Igor A1 - Sabater-Lleal, Maria A1 - Bis, Joshua C A1 - de Maat, Moniek P M A1 - Rumley, Ann A1 - Kong, Xiaoxiao A1 - Yang, Qiong A1 - Williams, Frances M K A1 - Vitart, Veronique A1 - Campbell, Harry A1 - Mälarstig, Anders A1 - Wiggins, Kerri L A1 - van Duijn, Cornelia M A1 - McArdle, Wendy L A1 - Pankow, James S A1 - Johnson, Andrew D A1 - Silveira, Angela A1 - McKnight, Barbara A1 - Uitterlinden, André G A1 - Aleksic, Nena A1 - Meigs, James B A1 - Peters, Annette A1 - Koenig, Wolfgang A1 - Cushman, Mary A1 - Kathiresan, Sekar A1 - Rotter, Jerome I A1 - Bovill, Edwin G A1 - Hofman, Albert A1 - Boerwinkle, Eric A1 - Tofler, Geoffrey H A1 - Peden, John F A1 - Psaty, Bruce M A1 - Leebeek, Frank A1 - Folsom, Aaron R A1 - Larson, Martin G A1 - Spector, Timothy D A1 - Wright, Alan F A1 - Wilson, James F A1 - Hamsten, Anders A1 - Lumley, Thomas A1 - Witteman, Jacqueline C M A1 - Tang, Weihong A1 - O'Donnell, Christopher J KW - Adult KW - Factor VII KW - Factor VIII KW - Female KW - Genome-Wide Association Study KW - Hemostasis KW - Humans KW - Male KW - Middle Aged KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Thrombosis KW - von Willebrand Factor AB -

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.

VL - 121 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20231535?dopt=Abstract ER - TY - JOUR T1 - Association of eGFR-Related Loci Identified by GWAS with Incident CKD and ESRD. JF - PLoS Genet Y1 - 2011 A1 - Böger, Carsten A A1 - Gorski, Mathias A1 - Li, Man A1 - Hoffmann, Michael M A1 - Huang, Chunmei A1 - Yang, Qiong A1 - Teumer, Alexander A1 - Krane, Vera A1 - O'Seaghdha, Conall M A1 - Kutalik, Zoltán A1 - Wichmann, H-Erich A1 - Haak, Thomas A1 - Boes, Eva A1 - Coassin, Stefan A1 - Coresh, Josef A1 - Kollerits, Barbara A1 - Haun, Margot A1 - Paulweber, Bernhard A1 - Köttgen, Anna A1 - Li, Guo A1 - Shlipak, Michael G A1 - Powe, Neil A1 - Hwang, Shih-Jen A1 - Dehghan, Abbas A1 - Rivadeneira, Fernando A1 - Uitterlinden, Andre A1 - Hofman, Albert A1 - Beckmann, Jacques S A1 - Krämer, Bernhard K A1 - Witteman, Jacqueline A1 - Bochud, Murielle A1 - Siscovick, David A1 - Rettig, Rainer A1 - Kronenberg, Florian A1 - Wanner, Christoph A1 - Thadhani, Ravi I A1 - Heid, Iris M A1 - Fox, Caroline S A1 - Kao, W H KW - Adaptor Proteins, Signal Transducing KW - Adult KW - Aged KW - Chronic Disease KW - Creatinine KW - European Continental Ancestry Group KW - Female KW - Follow-Up Studies KW - Genetic Association Studies KW - Humans KW - Kidney Diseases KW - Kidney Failure, Chronic KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Receptor, Epidermal Growth Factor KW - Uromodulin AB -

Family studies suggest a genetic component to the etiology of chronic kidney disease (CKD) and end stage renal disease (ESRD). Previously, we identified 16 loci for eGFR in genome-wide association studies, but the associations of these single nucleotide polymorphisms (SNPs) for incident CKD or ESRD are unknown. We thus investigated the association of these loci with incident CKD in 26,308 individuals of European ancestry free of CKD at baseline drawn from eight population-based cohorts followed for a median of 7.2 years (including 2,122 incident CKD cases defined as eGFR <60ml/min/1.73m(2) at follow-up) and with ESRD in four case-control studies in subjects of European ancestry (3,775 cases, 4,577 controls). SNPs at 11 of the 16 loci (UMOD, PRKAG2, ANXA9, DAB2, SHROOM3, DACH1, STC1, SLC34A1, ALMS1/NAT8, UBE2Q2, and GCKR) were associated with incident CKD; p-values ranged from p = 4.1e-9 in UMOD to p = 0.03 in GCKR. After adjusting for baseline eGFR, six of these loci remained significantly associated with incident CKD (UMOD, PRKAG2, ANXA9, DAB2, DACH1, and STC1). SNPs in UMOD (OR = 0.92, p = 0.04) and GCKR (OR = 0.93, p = 0.03) were nominally associated with ESRD. In summary, the majority of eGFR-related loci are either associated or show a strong trend towards association with incident CKD, but have modest associations with ESRD in individuals of European descent. Additional work is required to characterize the association of genetic determinants of CKD and ESRD at different stages of disease progression.

VL - 7 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21980298?dopt=Abstract ER - TY - JOUR T1 - Association of genomic loci from a cardiovascular gene SNP array with fibrinogen levels in European Americans and African-Americans from six cohort studies: the Candidate Gene Association Resource (CARe). JF - Blood Y1 - 2011 A1 - Wassel, Christina L A1 - Lange, Leslie A A1 - Keating, Brendan J A1 - Taylor, Kira C A1 - Johnson, Andrew D A1 - Palmer, Cameron A1 - Ho, Lindsey A A1 - Smith, Nicholas L A1 - Lange, Ethan M A1 - Li, Yun A1 - Yang, Qiong A1 - Delaney, Joseph A A1 - Tang, Weihong A1 - Tofler, Geoffrey A1 - Redline, Susan A1 - Taylor, Herman A A1 - Wilson, James G A1 - Tracy, Russell P A1 - Jacobs, David R A1 - Folsom, Aaron R A1 - Green, David A1 - O'Donnell, Christopher J A1 - Reiner, Alexander P KW - Adult KW - African Americans KW - Aged KW - Cardiovascular Diseases KW - Cohort Studies KW - European Continental Ancestry Group KW - Female KW - Fibrinogen KW - Genetic Predisposition to Disease KW - Haplotypes KW - Humans KW - Male KW - Middle Aged KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Risk Factors AB -

Several common genomic loci, involving various immunity- and metabolism-related genes, have been associated with plasma fibrinogen in European Americans (EAs). The genetic determinants of fibrinogen in African Americans (AAs) are poorly characterized. Using a vascular gene-centric array in 23,634 EA and 6657 AA participants from 6 studies comprising the Candidate Gene Association Resource project, we examined the association of 47,539 common and lower frequency variants with fibrinogen concentration. We identified a rare Pro265Leu variant in FGB (rs6054) associated with lower fibrinogen. Common fibrinogen gene single nucleotide polymorphisms (FGB rs1800787 and FGG rs2066861) significantly associated with fibrinogen in EAs were prevalent in AAs and showed consistent associations. Several fibrinogen locus single nucleotide polymorphism associated with lower fibrinogen were exclusive to AAs; these include a newly reported association with FGA rs10050257. For IL6R, IL1RN, and NLRP3 inflammatory gene loci, associations with fibrinogen were concordant between EAs and AAs, but not at other loci (CPS1, PCCB, and SCL22A5-IRF1). The association of FGG rs2066861 with fibrinogen differed according to assay type used to measure fibrinogen. Further characterization of common and lower-frequency genetic variants that contribute to interpopulation differences in fibrinogen phenotype may help refine our understanding of the contribution of hemostasis and inflammation to atherothrombotic risk.

VL - 117 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20978265?dopt=Abstract ER - TY - JOUR T1 - CUBN is a gene locus for albuminuria. JF - J Am Soc Nephrol Y1 - 2011 A1 - Böger, Carsten A A1 - Chen, Ming-Huei A1 - Tin, Adrienne A1 - Olden, Matthias A1 - Köttgen, Anna A1 - de Boer, Ian H A1 - Fuchsberger, Christian A1 - O'Seaghdha, Conall M A1 - Pattaro, Cristian A1 - Teumer, Alexander A1 - Liu, Ching-Ti A1 - Glazer, Nicole L A1 - Li, Man A1 - O'Connell, Jeffrey R A1 - Tanaka, Toshiko A1 - Peralta, Carmen A A1 - Kutalik, Zoltán A1 - Luan, Jian'an A1 - Zhao, Jing Hua A1 - Hwang, Shih-Jen A1 - Akylbekova, Ermeg A1 - Kramer, Holly A1 - van der Harst, Pim A1 - Smith, Albert V A1 - Lohman, Kurt A1 - de Andrade, Mariza A1 - Hayward, Caroline A1 - Kollerits, Barbara A1 - Tönjes, Anke A1 - Aspelund, Thor A1 - Ingelsson, Erik A1 - Eiriksdottir, Gudny A1 - Launer, Lenore J A1 - Harris, Tamara B A1 - Shuldiner, Alan R A1 - Mitchell, Braxton D A1 - Arking, Dan E A1 - Franceschini, Nora A1 - Boerwinkle, Eric A1 - Egan, Josephine A1 - Hernandez, Dena A1 - Reilly, Muredach A1 - Townsend, Raymond R A1 - Lumley, Thomas A1 - Siscovick, David S A1 - Psaty, Bruce M A1 - Kestenbaum, Bryan A1 - Haritunians, Talin A1 - Bergmann, Sven A1 - Vollenweider, Peter A1 - Waeber, Gérard A1 - Mooser, Vincent A1 - Waterworth, Dawn A1 - Johnson, Andrew D A1 - Florez, Jose C A1 - Meigs, James B A1 - Lu, Xiaoning A1 - Turner, Stephen T A1 - Atkinson, Elizabeth J A1 - Leak, Tennille S A1 - Aasarød, Knut A1 - Skorpen, Frank A1 - Syvänen, Ann-Christine A1 - Illig, Thomas A1 - Baumert, Jens A1 - Koenig, Wolfgang A1 - Krämer, Bernhard K A1 - Devuyst, Olivier A1 - Mychaleckyj, Josyf C A1 - Minelli, Cosetta A1 - Bakker, Stephan J L A1 - Kedenko, Lyudmyla A1 - Paulweber, Bernhard A1 - Coassin, Stefan A1 - Endlich, Karlhans A1 - Kroemer, Heyo K A1 - Biffar, Reiner A1 - Stracke, Sylvia A1 - Völzke, Henry A1 - Stumvoll, Michael A1 - Mägi, Reedik A1 - Campbell, Harry A1 - Vitart, Veronique A1 - Hastie, Nicholas D A1 - Gudnason, Vilmundur A1 - Kardia, Sharon L R A1 - Liu, Yongmei A1 - Polasek, Ozren A1 - Curhan, Gary A1 - Kronenberg, Florian A1 - Prokopenko, Inga A1 - Rudan, Igor A1 - Arnlöv, Johan A1 - Hallan, Stein A1 - Navis, Gerjan A1 - Parsa, Afshin A1 - Ferrucci, Luigi A1 - Coresh, Josef A1 - Shlipak, Michael G A1 - Bull, Shelley B A1 - Paterson, Nicholas J A1 - Wichmann, H-Erich A1 - Wareham, Nicholas J A1 - Loos, Ruth J F A1 - Rotter, Jerome I A1 - Pramstaller, Peter P A1 - Cupples, L Adrienne A1 - Beckmann, Jacques S A1 - Yang, Qiong A1 - Heid, Iris M A1 - Rettig, Rainer A1 - Dreisbach, Albert W A1 - Bochud, Murielle A1 - Fox, Caroline S A1 - Kao, W H L KW - African Continental Ancestry Group KW - Albuminuria KW - European Continental Ancestry Group KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Humans KW - Mutation, Missense KW - Receptors, Cell Surface AB -

Identification of genetic risk factors for albuminuria may alter strategies for early prevention of CKD progression, particularly among patients with diabetes. Little is known about the influence of common genetic variants on albuminuria in both general and diabetic populations. We performed a meta-analysis of data from 63,153 individuals of European ancestry with genotype information from genome-wide association studies (CKDGen Consortium) and from a large candidate gene study (CARe Consortium) to identify susceptibility loci for the quantitative trait urinary albumin-to-creatinine ratio (UACR) and the clinical diagnosis microalbuminuria. We identified an association between a missense variant (I2984V) in the CUBN gene, which encodes cubilin, and both UACR (P = 1.1 × 10(-11)) and microalbuminuria (P = 0.001). We observed similar associations among 6981 African Americans in the CARe Consortium. The associations between this variant and both UACR and microalbuminuria were significant in individuals of European ancestry regardless of diabetes status. Finally, this variant associated with a 41% increased risk for the development of persistent microalbuminuria during 20 years of follow-up among 1304 participants with type 1 diabetes in the prospective DCCT/EDIC Study. In summary, we identified a missense CUBN variant that associates with levels of albuminuria in both the general population and in individuals with diabetes.

VL - 22 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21355061?dopt=Abstract ER - TY - JOUR T1 - Enhanced statistical tests for GWAS in admixed populations: assessment using African Americans from CARe and a Breast Cancer Consortium. JF - PLoS Genet Y1 - 2011 A1 - Pasaniuc, Bogdan A1 - Zaitlen, Noah A1 - Lettre, Guillaume A1 - Chen, Gary K A1 - Tandon, Arti A1 - Kao, W H Linda A1 - Ruczinski, Ingo A1 - Fornage, Myriam A1 - Siscovick, David S A1 - Zhu, Xiaofeng A1 - Larkin, Emma A1 - Lange, Leslie A A1 - Cupples, L Adrienne A1 - Yang, Qiong A1 - Akylbekova, Ermeg L A1 - Musani, Solomon K A1 - Divers, Jasmin A1 - Mychaleckyj, Joe A1 - Li, Mingyao A1 - Papanicolaou, George J A1 - Millikan, Robert C A1 - Ambrosone, Christine B A1 - John, Esther M A1 - Bernstein, Leslie A1 - Zheng, Wei A1 - Hu, Jennifer J A1 - Ziegler, Regina G A1 - Nyante, Sarah J A1 - Bandera, Elisa V A1 - Ingles, Sue A A1 - Press, Michael F A1 - Chanock, Stephen J A1 - Deming, Sandra L A1 - Rodriguez-Gil, Jorge L A1 - Palmer, Cameron D A1 - Buxbaum, Sarah A1 - Ekunwe, Lynette A1 - Hirschhorn, Joel N A1 - Henderson, Brian E A1 - Myers, Simon A1 - Haiman, Christopher A A1 - Reich, David A1 - Patterson, Nick A1 - Wilson, James G A1 - Price, Alkes L KW - African Americans KW - Algorithms KW - Breast Neoplasms KW - Chromosome Mapping KW - Coronary Disease KW - Diabetes Mellitus, Type 2 KW - Female KW - Gene Frequency KW - Genetic Variation KW - Genetics, Population KW - Genome, Human KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Linkage Disequilibrium KW - Male KW - Odds Ratio KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Principal Component Analysis KW - Receptor, Fibroblast Growth Factor, Type 2 KW - Software AB -

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.

VL - 7 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21541012?dopt=Abstract ER - TY - JOUR T1 - Genetic predictors of fibrin D-dimer levels in healthy adults. JF - Circulation Y1 - 2011 A1 - Smith, Nicholas L A1 - Huffman, Jennifer E A1 - Strachan, David P A1 - Huang, Jie A1 - Dehghan, Abbas A1 - Trompet, Stella A1 - Lopez, Lorna M A1 - Shin, So-Youn A1 - Baumert, Jens A1 - Vitart, Veronique A1 - Bis, Joshua C A1 - Wild, Sarah H A1 - Rumley, Ann A1 - Yang, Qiong A1 - Uitterlinden, André G A1 - Stott, David J A1 - Davies, Gail A1 - Carter, Angela M A1 - Thorand, Barbara A1 - Polasek, Ozren A1 - McKnight, Barbara A1 - Campbell, Harry A1 - Rudnicka, Alicja R A1 - Chen, Ming-Huei A1 - Buckley, Brendan M A1 - Harris, Sarah E A1 - Peters, Annette A1 - Pulanic, Drazen A1 - Lumley, Thomas A1 - de Craen, Anton J M A1 - Liewald, David C A1 - Gieger, Christian A1 - Campbell, Susan A1 - Ford, Ian A1 - Gow, Alan J A1 - Luciano, Michelle A1 - Porteous, David J A1 - Guo, Xiuqing A1 - Sattar, Naveed A1 - Tenesa, Albert A1 - Cushman, Mary A1 - Slagboom, P Eline A1 - Visscher, Peter M A1 - Spector, Tim D A1 - Illig, Thomas A1 - Rudan, Igor A1 - Bovill, Edwin G A1 - Wright, Alan F A1 - McArdle, Wendy L A1 - Tofler, Geoffrey A1 - Hofman, Albert A1 - Westendorp, Rudi G J A1 - Starr, John M A1 - Grant, Peter J A1 - Karakas, Mahir A1 - Hastie, Nicholas D A1 - Psaty, Bruce M A1 - Wilson, James F A1 - Lowe, Gordon D O A1 - O'Donnell, Christopher J A1 - Witteman, Jacqueline C M A1 - Jukema, J Wouter A1 - Deary, Ian J A1 - Soranzo, Nicole A1 - Koenig, Wolfgang A1 - Hayward, Caroline KW - Adult KW - Aged KW - Blood Coagulation KW - European Continental Ancestry Group KW - Factor V KW - Female KW - Fibrin Fibrinogen Degradation Products KW - Fibrinogen KW - Genetic Testing KW - Genome-Wide Association Study KW - Humans KW - Male KW - Middle Aged KW - Reference Values KW - Thromboplastin AB -

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.

VL - 123 IS - 17 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21502573?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association studies of cerebral white matter lesion burden: the CHARGE consortium. JF - Ann Neurol Y1 - 2011 A1 - Fornage, Myriam A1 - Debette, Stephanie A1 - Bis, Joshua C A1 - Schmidt, Helena A1 - Ikram, M Arfan A1 - Dufouil, Carole A1 - Sigurdsson, Sigurdur A1 - Lumley, Thomas A1 - DeStefano, Anita L A1 - Fazekas, Franz A1 - Vrooman, Henri A A1 - Shibata, Dean K A1 - Maillard, Pauline A1 - Zijdenbos, Alex A1 - Smith, Albert V A1 - Gudnason, Haukur A1 - de Boer, Renske A1 - Cushman, Mary A1 - Mazoyer, Bernard A1 - Heiss, Gerardo A1 - Vernooij, Meike W A1 - Enzinger, Christian A1 - Glazer, Nicole L A1 - Beiser, Alexa A1 - Knopman, David S A1 - Cavalieri, Margherita A1 - Niessen, Wiro J A1 - Harris, Tamara B A1 - Petrovic, Katja A1 - Lopez, Oscar L A1 - Au, Rhoda A1 - Lambert, Jean-Charles A1 - Hofman, Albert A1 - Gottesman, Rebecca F A1 - Garcia, Melissa A1 - Heckbert, Susan R A1 - Atwood, Larry D A1 - Catellier, Diane J A1 - Uitterlinden, André G A1 - Yang, Qiong A1 - Smith, Nicholas L A1 - Aspelund, Thor A1 - Romero, Jose R A1 - Rice, Kenneth A1 - Taylor, Kent D A1 - Nalls, Michael A A1 - Rotter, Jerome I A1 - Sharrett, Richey A1 - van Duijn, Cornelia M A1 - Amouyel, Philippe A1 - Wolf, Philip A A1 - Gudnason, Vilmundur A1 - van der Lugt, Aad A1 - Boerwinkle, Eric A1 - Psaty, Bruce M A1 - Seshadri, Sudha A1 - Tzourio, Christophe A1 - Breteler, Monique M B A1 - Mosley, Thomas H A1 - Schmidt, Reinhold A1 - Longstreth, W T A1 - DeCarli, Charles A1 - Launer, Lenore J KW - Aged KW - Aged, 80 and over KW - Cerebral Cortex KW - Chromosomes, Human, Pair 17 KW - Cognition Disorders KW - Cohort Studies KW - European Continental Ancestry Group KW - Female KW - Gene Frequency KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Leukoencephalopathies KW - Magnetic Resonance Imaging KW - Male KW - Middle Aged KW - Movement Disorders KW - Nerve Fibers, Myelinated KW - Polymorphism, Single Nucleotide KW - Residence Characteristics KW - RNA, Messenger AB -

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.

VL - 69 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21681796?dopt=Abstract ER - TY - JOUR T1 - 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. JF - Hum Mol Genet Y1 - 2011 A1 - Tin, Adrienne A1 - Woodward, Owen M A1 - Kao, Wen Hong Linda A1 - Liu, Ching-Ti A1 - Lu, Xiaoning A1 - Nalls, Michael A A1 - Shriner, Daniel A1 - Semmo, Mariam A1 - Akylbekova, Ermeg L A1 - Wyatt, Sharon B A1 - Hwang, Shih-Jen A1 - Yang, Qiong A1 - Zonderman, Alan B A1 - Adeyemo, Adebowale A A1 - Palmer, Cameron A1 - Meng, Yan A1 - Reilly, Muredach A1 - Shlipak, Michael G A1 - Siscovick, David A1 - Evans, Michele K A1 - Rotimi, Charles N A1 - Flessner, Michael F A1 - Köttgen, Michael A1 - Cupples, L Adrienne A1 - Fox, Caroline S A1 - Köttgen, Anna KW - Adult KW - African Americans KW - Aged KW - Animals KW - CHO Cells KW - Cricetinae KW - European Continental Ancestry Group KW - Female KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Genotype KW - Gout KW - Humans KW - Loss of Heterozygosity KW - Male KW - Middle Aged KW - Organic Anion Transporters KW - Organic Cation Transport Proteins KW - Polymorphism, Single Nucleotide KW - Uric Acid KW - Young Adult AB -

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.

VL - 20 IS - 20 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21768215?dopt=Abstract ER - TY - JOUR T1 - A genome-wide association study identifies novel loci associated with circulating IGF-I and IGFBP-3. JF - Hum Mol Genet Y1 - 2011 A1 - Kaplan, Robert C A1 - Petersen, Ann-Kristin A1 - Chen, Ming-Huei A1 - Teumer, Alexander A1 - Glazer, Nicole L A1 - Döring, Angela A1 - Lam, Carolyn S P A1 - Friedrich, Nele A1 - Newman, Anne A1 - Müller, Martina A1 - Yang, Qiong A1 - Homuth, Georg A1 - Cappola, Anne A1 - Klopp, Norman A1 - Smith, Holly A1 - Ernst, Florian A1 - Psaty, Bruce M A1 - Wichmann, H-Erich A1 - Sawyer, Douglas B A1 - Biffar, Reiner A1 - Rotter, Jerome I A1 - Gieger, Christian A1 - Sullivan, Lisa S A1 - Völzke, Henry A1 - Rice, Kenneth A1 - Spyroglou, Ariadni A1 - Kroemer, Heyo K A1 - Ida Chen, Y-D A1 - Manolopoulou, Jenny A1 - Nauck, Matthias A1 - Strickler, Howard D A1 - Goodarzi, Mark O A1 - Reincke, Martin A1 - Pollak, Michael N A1 - Bidlingmaier, Martin A1 - Vasan, Ramachandran S A1 - Wallaschofski, Henri KW - Aged KW - Chromosomes, Human, Pair 7 KW - Cohort Studies KW - European Continental Ancestry Group KW - Female KW - Genome-Wide Association Study KW - Humans KW - Insulin-Like Growth Factor Binding Protein 3 KW - Insulin-Like Growth Factor I KW - Male KW - Polymorphism, Single Nucleotide AB -

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.

VL - 20 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21216879?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association and functional follow-up reveals new loci for kidney function. JF - PLoS Genet Y1 - 2012 A1 - Pattaro, Cristian A1 - Köttgen, Anna A1 - Teumer, Alexander A1 - Garnaas, Maija A1 - Böger, Carsten A A1 - Fuchsberger, Christian A1 - Olden, Matthias A1 - Chen, Ming-Huei A1 - Tin, Adrienne A1 - Taliun, Daniel A1 - Li, Man A1 - Gao, Xiaoyi A1 - Gorski, Mathias A1 - Yang, Qiong A1 - Hundertmark, Claudia A1 - Foster, Meredith C A1 - O'Seaghdha, Conall M A1 - Glazer, Nicole A1 - Isaacs, Aaron A1 - Liu, Ching-Ti A1 - Smith, Albert V A1 - O'Connell, Jeffrey R A1 - Struchalin, Maksim A1 - Tanaka, Toshiko A1 - Li, Guo A1 - Johnson, Andrew D A1 - Gierman, Hinco J A1 - Feitosa, Mary A1 - Hwang, Shih-Jen A1 - Atkinson, Elizabeth J A1 - Lohman, Kurt A1 - Cornelis, Marilyn C A1 - Johansson, Asa A1 - Tönjes, Anke A1 - Dehghan, Abbas A1 - Chouraki, Vincent A1 - Holliday, Elizabeth G A1 - Sorice, Rossella A1 - Kutalik, Zoltán A1 - Lehtimäki, Terho A1 - Esko, Tõnu A1 - Deshmukh, Harshal A1 - Ulivi, Sheila A1 - Chu, Audrey Y A1 - Murgia, Federico A1 - Trompet, Stella A1 - Imboden, Medea A1 - Kollerits, Barbara A1 - Pistis, Giorgio A1 - Harris, Tamara B A1 - Launer, Lenore J A1 - Aspelund, Thor A1 - Eiriksdottir, Gudny A1 - Mitchell, Braxton D A1 - Boerwinkle, Eric A1 - Schmidt, Helena A1 - Cavalieri, Margherita A1 - Rao, Madhumathi A1 - Hu, Frank B A1 - Demirkan, Ayse A1 - Oostra, Ben A A1 - de Andrade, Mariza A1 - Turner, Stephen T A1 - Ding, Jingzhong A1 - Andrews, Jeanette S A1 - Freedman, Barry I A1 - Koenig, Wolfgang A1 - Illig, Thomas A1 - Döring, Angela A1 - Wichmann, H-Erich A1 - Kolcic, Ivana A1 - Zemunik, Tatijana A1 - Boban, Mladen A1 - Minelli, Cosetta A1 - Wheeler, Heather E A1 - Igl, Wilmar A1 - Zaboli, Ghazal A1 - Wild, Sarah H A1 - Wright, Alan F A1 - Campbell, Harry A1 - Ellinghaus, David A1 - Nöthlings, Ute A1 - Jacobs, Gunnar A1 - Biffar, Reiner A1 - Endlich, Karlhans A1 - Ernst, Florian A1 - Homuth, Georg A1 - Kroemer, Heyo K A1 - Nauck, Matthias A1 - Stracke, Sylvia A1 - Völker, Uwe A1 - Völzke, Henry A1 - Kovacs, Peter A1 - Stumvoll, Michael A1 - Mägi, Reedik A1 - Hofman, Albert A1 - Uitterlinden, André G A1 - Rivadeneira, Fernando A1 - Aulchenko, Yurii S A1 - Polasek, Ozren A1 - Hastie, Nick A1 - Vitart, Veronique A1 - Helmer, Catherine A1 - Wang, Jie Jin A1 - Ruggiero, Daniela A1 - Bergmann, Sven A1 - Kähönen, Mika A1 - Viikari, Jorma A1 - Nikopensius, Tiit A1 - Province, Michael A1 - Ketkar, Shamika A1 - Colhoun, Helen A1 - Doney, Alex A1 - Robino, Antonietta A1 - Giulianini, Franco A1 - Krämer, Bernhard K A1 - Portas, Laura A1 - Ford, Ian A1 - Buckley, Brendan M A1 - Adam, Martin A1 - Thun, Gian-Andri A1 - Paulweber, Bernhard A1 - Haun, Margot A1 - Sala, Cinzia A1 - Metzger, Marie A1 - Mitchell, Paul A1 - Ciullo, Marina A1 - Kim, Stuart K A1 - Vollenweider, Peter A1 - Raitakari, Olli A1 - Metspalu, Andres A1 - Palmer, Colin A1 - Gasparini, Paolo A1 - Pirastu, Mario A1 - Jukema, J Wouter A1 - Probst-Hensch, Nicole M A1 - Kronenberg, Florian A1 - Toniolo, Daniela A1 - Gudnason, Vilmundur A1 - Shuldiner, Alan R A1 - Coresh, Josef A1 - Schmidt, Reinhold A1 - Ferrucci, Luigi A1 - Siscovick, David S A1 - van Duijn, Cornelia M A1 - Borecki, Ingrid A1 - Kardia, Sharon L R A1 - Liu, Yongmei A1 - Curhan, Gary C A1 - Rudan, Igor A1 - Gyllensten, Ulf A1 - Wilson, James F A1 - Franke, Andre A1 - Pramstaller, Peter P A1 - Rettig, Rainer A1 - Prokopenko, Inga A1 - Witteman, Jacqueline C M A1 - Hayward, Caroline A1 - Ridker, Paul A1 - Parsa, Afshin A1 - Bochud, Murielle A1 - Heid, Iris M A1 - Goessling, Wolfram A1 - Chasman, Daniel I A1 - Kao, W H Linda A1 - Fox, Caroline S KW - African Americans KW - Aged KW - Animals KW - Caspase 9 KW - Cyclin-Dependent Kinases KW - DEAD-box RNA Helicases KW - DNA Helicases KW - European Continental Ancestry Group KW - Female KW - Follow-Up Studies KW - Gene Knockdown Techniques KW - Genome-Wide Association Study KW - Glomerular Filtration Rate KW - Humans KW - Kidney KW - Kidney Failure, Chronic KW - Male KW - Middle Aged KW - Phosphoric Diester Hydrolases KW - Zebrafish AB -

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.

VL - 8 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22479191?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association study for circulating levels of PAI-1 provides novel insights into its regulation. JF - Blood Y1 - 2012 A1 - Huang, Jie A1 - Sabater-Lleal, Maria A1 - Asselbergs, Folkert W A1 - Tregouet, David A1 - Shin, So-Youn A1 - Ding, Jingzhong A1 - Baumert, Jens A1 - Oudot-Mellakh, Tiphaine A1 - Folkersen, Lasse A1 - Johnson, Andrew D A1 - Smith, Nicholas L A1 - Williams, Scott M A1 - Ikram, Mohammad A A1 - Kleber, Marcus E A1 - Becker, Diane M A1 - Truong, Vinh A1 - Mychaleckyj, Josyf C A1 - Tang, Weihong A1 - Yang, Qiong A1 - Sennblad, Bengt A1 - Moore, Jason H A1 - Williams, Frances M K A1 - Dehghan, Abbas A1 - Silbernagel, Günther A1 - Schrijvers, Elisabeth M C A1 - Smith, Shelly A1 - Karakas, Mahir A1 - Tofler, Geoffrey H A1 - Silveira, Angela A1 - Navis, Gerjan J A1 - Lohman, Kurt A1 - Chen, Ming-Huei A1 - Peters, Annette A1 - Goel, Anuj A1 - Hopewell, Jemma C A1 - Chambers, John C A1 - Saleheen, Danish A1 - Lundmark, Per A1 - Psaty, Bruce M A1 - Strawbridge, Rona J A1 - Boehm, Bernhard O A1 - Carter, Angela M A1 - Meisinger, Christa A1 - Peden, John F A1 - Bis, Joshua C A1 - McKnight, Barbara A1 - Ohrvik, John A1 - Taylor, Kent A1 - Franzosi, Maria Grazia A1 - Seedorf, Udo A1 - Collins, Rory A1 - Franco-Cereceda, Anders A1 - Syvänen, Ann-Christine A1 - Goodall, Alison H A1 - Yanek, Lisa R A1 - Cushman, Mary A1 - Müller-Nurasyid, Martina A1 - Folsom, Aaron R A1 - Basu, Saonli A1 - Matijevic, Nena A1 - van Gilst, Wiek H A1 - Kooner, Jaspal S A1 - Hofman, Albert A1 - Danesh, John A1 - Clarke, Robert A1 - Meigs, James B A1 - Kathiresan, Sekar A1 - Reilly, Muredach P A1 - Klopp, Norman A1 - Harris, Tamara B A1 - Winkelmann, Bernhard R A1 - Grant, Peter J A1 - Hillege, Hans L A1 - Watkins, Hugh A1 - Spector, Timothy D A1 - Becker, Lewis C A1 - Tracy, Russell P A1 - März, Winfried A1 - Uitterlinden, André G A1 - Eriksson, Per A1 - Cambien, Francois A1 - Morange, Pierre-Emmanuel A1 - Koenig, Wolfgang A1 - Soranzo, Nicole A1 - van der Harst, Pim A1 - Liu, Yongmei A1 - O'Donnell, Christopher J A1 - Hamsten, Anders KW - Adaptor Proteins, Signal Transducing KW - ARNTL Transcription Factors KW - ATPases Associated with Diverse Cellular Activities KW - Cell Line KW - Cell Line, Tumor KW - Cohort Studies KW - Coronary Artery Disease KW - Diabetes Mellitus, Type 2 KW - Gene Expression Profiling KW - Gene Expression Regulation KW - Gene Frequency KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - LIM Domain Proteins KW - Meta-Analysis as Topic KW - Monocytes KW - Mucin-3 KW - Plasminogen Activator Inhibitor 1 KW - Polymorphism, Single Nucleotide KW - PPAR gamma KW - Proteasome Endopeptidase Complex KW - RNA Interference KW - Transcription Factors AB -

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.

VL - 120 IS - 24 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22990020?dopt=Abstract ER - TY - JOUR T1 - Common variants in Mendelian kidney disease genes and their association with renal function. JF - J Am Soc Nephrol Y1 - 2013 A1 - Parsa, Afshin A1 - Fuchsberger, Christian A1 - Köttgen, Anna A1 - O'Seaghdha, Conall M A1 - Pattaro, Cristian A1 - de Andrade, Mariza A1 - Chasman, Daniel I A1 - Teumer, Alexander A1 - Endlich, Karlhans A1 - Olden, Matthias A1 - Chen, Ming-Huei A1 - Tin, Adrienne A1 - Kim, Young J A1 - Taliun, Daniel A1 - Li, Man A1 - Feitosa, Mary A1 - Gorski, Mathias A1 - Yang, Qiong A1 - Hundertmark, Claudia A1 - Foster, Meredith C A1 - Glazer, Nicole A1 - Isaacs, Aaron A1 - Rao, Madhumathi A1 - Smith, Albert V A1 - O'Connell, Jeffrey R A1 - Struchalin, Maksim A1 - Tanaka, Toshiko A1 - Li, Guo A1 - Hwang, Shih-Jen A1 - Atkinson, Elizabeth J A1 - Lohman, Kurt A1 - Cornelis, Marilyn C A1 - Johansson, Asa A1 - Tönjes, Anke A1 - Dehghan, Abbas A1 - Couraki, Vincent A1 - Holliday, Elizabeth G A1 - Sorice, Rossella A1 - Kutalik, Zoltán A1 - Lehtimäki, Terho A1 - Esko, Tõnu A1 - Deshmukh, Harshal A1 - Ulivi, Sheila A1 - Chu, Audrey Y A1 - Murgia, Federico A1 - Trompet, Stella A1 - Imboden, Medea A1 - Kollerits, Barbara A1 - Pistis, Giorgio A1 - Harris, Tamara B A1 - Launer, Lenore J A1 - Aspelund, Thor A1 - Eiriksdottir, Gudny A1 - Mitchell, Braxton D A1 - Boerwinkle, Eric A1 - Schmidt, Helena A1 - Hofer, Edith A1 - Hu, Frank A1 - Demirkan, Ayse A1 - Oostra, Ben A A1 - Turner, Stephen T A1 - Ding, Jingzhong A1 - Andrews, Jeanette S A1 - Freedman, Barry I A1 - Giulianini, Franco A1 - Koenig, Wolfgang A1 - Illig, Thomas A1 - Döring, Angela A1 - Wichmann, H-Erich A1 - Zgaga, Lina A1 - Zemunik, Tatijana A1 - Boban, Mladen A1 - Minelli, Cosetta A1 - Wheeler, Heather E A1 - Igl, Wilmar A1 - Zaboli, Ghazal A1 - Wild, Sarah H A1 - Wright, Alan F A1 - Campbell, Harry A1 - Ellinghaus, David A1 - Nöthlings, Ute A1 - Jacobs, Gunnar A1 - Biffar, Reiner A1 - Ernst, Florian A1 - Homuth, Georg A1 - Kroemer, Heyo K A1 - Nauck, Matthias A1 - Stracke, Sylvia A1 - Völker, Uwe A1 - Völzke, Henry A1 - Kovacs, Peter A1 - Stumvoll, Michael A1 - Mägi, Reedik A1 - Hofman, Albert A1 - Uitterlinden, André G A1 - Rivadeneira, Fernando A1 - Aulchenko, Yurii S A1 - Polasek, Ozren A1 - Hastie, Nick A1 - Vitart, Veronique A1 - Helmer, Catherine A1 - Wang, Jie Jin A1 - Stengel, Bénédicte A1 - Ruggiero, Daniela A1 - Bergmann, Sven A1 - Kähönen, Mika A1 - Viikari, Jorma A1 - Nikopensius, Tiit A1 - Province, Michael A1 - Colhoun, Helen A1 - Doney, Alex A1 - Robino, Antonietta A1 - Krämer, Bernhard K A1 - Portas, Laura A1 - Ford, Ian A1 - Buckley, Brendan M A1 - Adam, Martin A1 - Thun, Gian-Andri A1 - Paulweber, Bernhard A1 - Haun, Margot A1 - Sala, Cinzia A1 - Mitchell, Paul A1 - Ciullo, Marina A1 - Vollenweider, Peter A1 - Raitakari, Olli A1 - Metspalu, Andres A1 - Palmer, Colin A1 - Gasparini, Paolo A1 - Pirastu, Mario A1 - Jukema, J Wouter A1 - Probst-Hensch, Nicole M A1 - Kronenberg, Florian A1 - Toniolo, Daniela A1 - Gudnason, Vilmundur A1 - Shuldiner, Alan R A1 - Coresh, Josef A1 - Schmidt, Reinhold A1 - Ferrucci, Luigi A1 - van Duijn, Cornelia M A1 - Borecki, Ingrid A1 - Kardia, Sharon L R A1 - Liu, Yongmei A1 - Curhan, Gary C A1 - Rudan, Igor A1 - Gyllensten, Ulf A1 - Wilson, James F A1 - Franke, Andre A1 - Pramstaller, Peter P A1 - Rettig, Rainer A1 - Prokopenko, Inga A1 - Witteman, Jacqueline A1 - Hayward, Caroline A1 - Ridker, Paul M A1 - Bochud, Murielle A1 - Heid, Iris M A1 - Siscovick, David S A1 - Fox, Caroline S A1 - Kao, W Linda A1 - Böger, Carsten A KW - Databases, Genetic KW - European Continental Ancestry Group KW - Gene Frequency KW - Genetic Variation KW - Genome-Wide Association Study KW - Humans KW - Kidney KW - Mendelian Randomization Analysis KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Renal Insufficiency, Chronic AB -

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.

VL - 24 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24029420?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association analyses identify 18 new loci associated with serum urate concentrations. JF - Nat Genet Y1 - 2013 A1 - Köttgen, Anna A1 - Albrecht, Eva A1 - Teumer, Alexander A1 - Vitart, Veronique A1 - Krumsiek, Jan A1 - Hundertmark, Claudia A1 - Pistis, Giorgio A1 - Ruggiero, Daniela A1 - O'Seaghdha, Conall M A1 - Haller, Toomas A1 - Yang, Qiong A1 - Tanaka, Toshiko A1 - Johnson, Andrew D A1 - Kutalik, Zoltán A1 - Smith, Albert V A1 - Shi, Julia A1 - Struchalin, Maksim A1 - Middelberg, Rita P S A1 - Brown, Morris J A1 - Gaffo, Angelo L A1 - Pirastu, Nicola A1 - Li, Guo A1 - Hayward, Caroline A1 - Zemunik, Tatijana A1 - Huffman, Jennifer A1 - Yengo, Loic A1 - Zhao, Jing Hua A1 - Demirkan, Ayse A1 - Feitosa, Mary F A1 - Liu, Xuan A1 - Malerba, Giovanni A1 - Lopez, Lorna M A1 - van der Harst, Pim A1 - Li, Xinzhong A1 - Kleber, Marcus E A1 - Hicks, Andrew A A1 - Nolte, Ilja M A1 - Johansson, Asa A1 - Murgia, Federico A1 - Wild, Sarah H A1 - Bakker, Stephan J L A1 - Peden, John F A1 - Dehghan, Abbas A1 - Steri, Maristella A1 - Tenesa, Albert A1 - Lagou, Vasiliki A1 - Salo, Perttu A1 - Mangino, Massimo A1 - Rose, Lynda M A1 - Lehtimäki, Terho A1 - Woodward, Owen M A1 - Okada, Yukinori A1 - Tin, Adrienne A1 - Müller, Christian A1 - Oldmeadow, Christopher A1 - Putku, Margus A1 - Czamara, Darina A1 - Kraft, Peter A1 - Frogheri, Laura A1 - Thun, Gian Andri A1 - Grotevendt, Anne A1 - Gislason, Gauti Kjartan A1 - Harris, Tamara B A1 - Launer, Lenore J A1 - McArdle, Patrick A1 - Shuldiner, Alan R A1 - Boerwinkle, Eric A1 - Coresh, Josef A1 - Schmidt, Helena A1 - Schallert, Michael A1 - Martin, Nicholas G A1 - Montgomery, Grant W A1 - Kubo, Michiaki A1 - Nakamura, Yusuke A1 - Tanaka, Toshihiro A1 - Munroe, Patricia B A1 - Samani, Nilesh J A1 - Jacobs, David R A1 - Liu, Kiang A1 - D'Adamo, Pio A1 - Ulivi, Sheila A1 - Rotter, Jerome I A1 - Psaty, Bruce M A1 - Vollenweider, Peter A1 - Waeber, Gérard A1 - Campbell, Susan A1 - Devuyst, Olivier A1 - Navarro, Pau A1 - Kolcic, Ivana A1 - Hastie, Nicholas A1 - Balkau, Beverley A1 - Froguel, Philippe A1 - Esko, Tõnu A1 - Salumets, Andres A1 - Khaw, Kay Tee A1 - Langenberg, Claudia A1 - Wareham, Nicholas J A1 - Isaacs, Aaron A1 - Kraja, Aldi A1 - Zhang, Qunyuan A1 - Wild, Philipp S A1 - Scott, Rodney J A1 - Holliday, Elizabeth G A1 - Org, Elin A1 - Viigimaa, Margus A1 - Bandinelli, Stefania A1 - Metter, Jeffrey E A1 - Lupo, Antonio A1 - Trabetti, Elisabetta A1 - Sorice, Rossella A1 - Döring, Angela A1 - Lattka, Eva A1 - Strauch, Konstantin A1 - Theis, Fabian A1 - Waldenberger, Melanie A1 - Wichmann, H-Erich A1 - Davies, Gail A1 - Gow, Alan J A1 - Bruinenberg, Marcel A1 - Stolk, Ronald P A1 - Kooner, Jaspal S A1 - Zhang, Weihua A1 - Winkelmann, Bernhard R A1 - Boehm, Bernhard O A1 - Lucae, Susanne A1 - Penninx, Brenda W A1 - Smit, Johannes H A1 - Curhan, Gary A1 - Mudgal, Poorva A1 - Plenge, Robert M A1 - Portas, Laura A1 - Persico, Ivana A1 - Kirin, Mirna A1 - Wilson, James F A1 - Mateo Leach, Irene A1 - van Gilst, Wiek H A1 - Goel, Anuj A1 - Ongen, Halit A1 - Hofman, Albert A1 - Rivadeneira, Fernando A1 - Uitterlinden, André G A1 - Imboden, Medea A1 - von Eckardstein, Arnold A1 - Cucca, Francesco A1 - Nagaraja, Ramaiah A1 - Piras, Maria Grazia A1 - Nauck, Matthias A1 - Schurmann, Claudia A1 - Budde, Kathrin A1 - Ernst, Florian A1 - Farrington, Susan M A1 - Theodoratou, Evropi A1 - Prokopenko, Inga A1 - Stumvoll, Michael A1 - Jula, Antti A1 - Perola, Markus A1 - Salomaa, Veikko A1 - Shin, So-Youn A1 - Spector, Tim D A1 - Sala, Cinzia A1 - Ridker, Paul M A1 - Kähönen, Mika A1 - Viikari, Jorma A1 - Hengstenberg, Christian A1 - Nelson, Christopher P A1 - Meschia, James F A1 - Nalls, Michael A A1 - Sharma, Pankaj A1 - Singleton, Andrew B A1 - Kamatani, Naoyuki A1 - Zeller, Tanja A1 - Burnier, Michel A1 - Attia, John A1 - Laan, Maris A1 - Klopp, Norman A1 - Hillege, Hans L A1 - Kloiber, Stefan A1 - Choi, Hyon A1 - Pirastu, Mario A1 - Tore, Silvia A1 - Probst-Hensch, Nicole M A1 - Völzke, Henry A1 - Gudnason, Vilmundur A1 - Parsa, Afshin A1 - Schmidt, Reinhold A1 - Whitfield, John B A1 - Fornage, Myriam A1 - Gasparini, Paolo A1 - Siscovick, David S A1 - Polasek, Ozren A1 - Campbell, Harry A1 - Rudan, Igor A1 - Bouatia-Naji, Nabila A1 - Metspalu, Andres A1 - Loos, Ruth J F A1 - van Duijn, Cornelia M A1 - Borecki, Ingrid B A1 - Ferrucci, Luigi A1 - Gambaro, Giovanni A1 - Deary, Ian J A1 - Wolffenbuttel, Bruce H R A1 - Chambers, John C A1 - März, Winfried A1 - Pramstaller, Peter P A1 - Snieder, Harold A1 - Gyllensten, Ulf A1 - Wright, Alan F A1 - Navis, Gerjan A1 - Watkins, Hugh A1 - Witteman, Jacqueline C M A1 - Sanna, Serena A1 - Schipf, Sabine A1 - Dunlop, Malcolm G A1 - Tönjes, Anke A1 - Ripatti, Samuli A1 - Soranzo, Nicole A1 - Toniolo, Daniela A1 - Chasman, Daniel I A1 - Raitakari, Olli A1 - Kao, W H Linda A1 - Ciullo, Marina A1 - Fox, Caroline S A1 - Caulfield, Mark A1 - Bochud, Murielle A1 - Gieger, Christian KW - Analysis of Variance KW - European Continental Ancestry Group KW - Gene Frequency KW - Genetic Loci KW - Genome-Wide Association Study KW - Glucose KW - Gout KW - Humans KW - Inhibins KW - Polymorphism, Single Nucleotide KW - Signal Transduction KW - Uric Acid AB -

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.

VL - 45 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23263486?dopt=Abstract ER - TY - JOUR T1 - Meta-analysis of genome-wide association studies identifies six new Loci for serum calcium concentrations. JF - PLoS Genet Y1 - 2013 A1 - O'Seaghdha, Conall M A1 - Wu, Hongsheng A1 - Yang, Qiong A1 - Kapur, Karen A1 - Guessous, Idris A1 - Zuber, Annie Mercier A1 - Köttgen, Anna A1 - Stoudmann, Candice A1 - Teumer, Alexander A1 - Kutalik, Zoltán A1 - Mangino, Massimo A1 - Dehghan, Abbas A1 - Zhang, Weihua A1 - Eiriksdottir, Gudny A1 - Li, Guo A1 - Tanaka, Toshiko A1 - Portas, Laura A1 - Lopez, Lorna M A1 - Hayward, Caroline A1 - Lohman, Kurt A1 - Matsuda, Koichi A1 - Padmanabhan, Sandosh A1 - Firsov, Dmitri A1 - Sorice, Rossella A1 - Ulivi, Sheila A1 - Brockhaus, A Catharina A1 - Kleber, Marcus E A1 - Mahajan, Anubha A1 - Ernst, Florian D A1 - Gudnason, Vilmundur A1 - Launer, Lenore J A1 - Mace, Aurelien A1 - Boerwinckle, Eric A1 - Arking, Dan E A1 - Tanikawa, Chizu A1 - Nakamura, Yusuke A1 - Brown, Morris J A1 - Gaspoz, Jean-Michel A1 - Theler, Jean-Marc A1 - Siscovick, David S A1 - Psaty, Bruce M A1 - Bergmann, Sven A1 - Vollenweider, Peter A1 - Vitart, Veronique A1 - Wright, Alan F A1 - Zemunik, Tatijana A1 - Boban, Mladen A1 - Kolcic, Ivana A1 - Navarro, Pau A1 - Brown, Edward M A1 - Estrada, Karol A1 - Ding, Jingzhong A1 - Harris, Tamara B A1 - Bandinelli, Stefania A1 - Hernandez, Dena A1 - Singleton, Andrew B A1 - Girotto, Giorgia A1 - Ruggiero, Daniela A1 - d'Adamo, Adamo Pio A1 - Robino, Antonietta A1 - Meitinger, Thomas A1 - Meisinger, Christa A1 - Davies, Gail A1 - Starr, John M A1 - Chambers, John C A1 - Boehm, Bernhard O A1 - Winkelmann, Bernhard R A1 - Huang, Jie A1 - Murgia, Federico A1 - Wild, Sarah H A1 - Campbell, Harry A1 - Morris, Andrew P A1 - Franco, Oscar H A1 - Hofman, Albert A1 - Uitterlinden, André G A1 - Rivadeneira, Fernando A1 - Völker, Uwe A1 - Hannemann, Anke A1 - Biffar, Reiner A1 - Hoffmann, Wolfgang A1 - Shin, So-Youn A1 - Lescuyer, Pierre A1 - Henry, Hughes A1 - Schurmann, Claudia A1 - Munroe, Patricia B A1 - Gasparini, Paolo A1 - Pirastu, Nicola A1 - Ciullo, Marina A1 - Gieger, Christian A1 - März, Winfried A1 - Lind, Lars A1 - Spector, Tim D A1 - Smith, Albert V A1 - Rudan, Igor A1 - Wilson, James F A1 - Polasek, Ozren A1 - Deary, Ian J A1 - Pirastu, Mario A1 - Ferrucci, Luigi A1 - Liu, Yongmei A1 - Kestenbaum, Bryan A1 - Kooner, Jaspal S A1 - Witteman, Jacqueline C M A1 - Nauck, Matthias A1 - Kao, W H Linda A1 - Wallaschofski, Henri A1 - Bonny, Olivier A1 - Fox, Caroline S A1 - Bochud, Murielle KW - Animals KW - Bone and Bones KW - Bone Density KW - Calcium KW - European Continental Ancestry Group KW - Gene Expression Regulation KW - Genome-Wide Association Study KW - Homeostasis KW - Humans KW - Kidney KW - Mice KW - Polymorphism, Single Nucleotide AB -

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.

VL - 9 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24068962?dopt=Abstract ER - TY - JOUR T1 - Association of a cystatin C gene variant with cystatin C levels, CKD, and risk of incident cardiovascular disease and mortality. JF - Am J Kidney Dis Y1 - 2014 A1 - O'Seaghdha, Conall M A1 - Tin, Adrienne A1 - Yang, Qiong A1 - Katz, Ronit A1 - Liu, Yongmei A1 - Harris, Tamara A1 - Astor, Brad A1 - Coresh, Josef A1 - Fox, Caroline S A1 - Kao, W H Linda A1 - Shlipak, Michael G KW - Aged KW - Bias KW - Biomarkers KW - Cardiovascular Diseases KW - Creatinine KW - Cystatin C KW - Female KW - Genetic Variation KW - Glomerular Filtration Rate KW - Humans KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Renal Insufficiency, Chronic KW - Risk Assessment KW - Risk Factors KW - Severity of Illness Index KW - Statistics as Topic KW - Survival Rate AB -

BACKGROUND: Carriers of the T allele of the single-nucleotide polymorphism rs13038305 tend to have lower cystatin C levels and higher cystatin C-based estimated glomerular filtration rate (eGFRcys). Adjusting for this genetic effect on cystatin C concentrations may improve GFR estimation, reclassify cases of chronic kidney disease (CKD), and strengthen risk estimates for cardiovascular disease (CVD) and mortality.

STUDY DESIGN: Observational.

SETTING & POPULATION: 4 population-based cohorts: Atherosclerosis Risk in Communities (ARIC), Cardiovascular Health (CHS), Framingham Heart (FHS), and Health, Aging, and Body Composition (Health ABC) studies.

PREDICTORS: We estimated the association of rs13038305 with eGFRcys and serum creatinine-based eGFR (eGFRcr) and performed longitudinal analyses of the associations of eGFRcys with mortality and cardiovascular events following adjustment for rs13038305.

OUTCOMES: We assessed reclassification by genotype-adjusted eGFRcys across CKD categories: <45, 45-59, 60-89, and ≥ 90 mL/min/1.73 m(2). We compared mortality and CVD outcomes in those reclassified to a worse eGFRcys category with those unaffected. Results were combined using fixed-effect inverse-variance meta-analysis.

RESULTS: In 14,645 participants, each copy of the T allele of rs13038305 (frequency, 21%) was associated with a 6.4% lower cystatin C concentration, 5.5-mL/min/1.73 m(2) higher eGFRcys, and 36% [95% CI, 29%-41%] lower odds of CKD. Associations with CVD (HR, 1.17; 95% CI, 1.14-1.20) and mortality (HR, 1.22; 95% CI, 1.19-1.24) per 10-mL/min/1.73 m(2) lower eGFRcys were similar with or without rs13038305 adjustment. 1,134 (7.7%) participants were reclassified to a worse CKD category following rs13038305 adjustment, and rates of CVD and mortality were higher in individuals who were reclassified. However, the overall net reclassification index was not significant for either outcome, at 0.009 (95% CI, -0.003 to 0.022) for mortality and 0.014 (95% CI, 0.0 to 0.028) for CVD.

LIMITATIONS: rs13038305 explains only a small proportion of cystatin C variation.

CONCLUSIONS: Statistical adjustment can correct a genetic bias in GFR estimates based on cystatin C in carriers of the T allele of rs13038305 and result in changes in disease classification. However, on a population level, the effects on overall reclassification of CKD status are modest.

VL - 63 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23932088?dopt=Abstract ER - TY - JOUR T1 - A genetic association study of D-dimer levels with 50K SNPs from a candidate gene chip in four ethnic groups. JF - Thromb Res Y1 - 2014 A1 - Weng, Lu-Chen A1 - Tang, Weihong A1 - Rich, Stephen S A1 - Smith, Nicholas L A1 - Redline, Susan A1 - O'Donnell, Christopher J A1 - Basu, Saonli A1 - Reiner, Alexander P A1 - Delaney, Joseph A A1 - Tracy, Russell P A1 - Palmer, Cameron D A1 - Young, Taylor A1 - Yang, Qiong A1 - Folsom, Aaron R A1 - Cushman, Mary KW - Adult KW - Aged KW - Cardiovascular Diseases KW - Ethnic Groups KW - Factor V KW - Female KW - Fibrin Fibrinogen Degradation Products KW - Fibrinogen KW - Genetic Association Studies KW - Genotype KW - Humans KW - Male KW - Middle Aged KW - Oligonucleotide Array Sequence Analysis KW - Polymorphism, Single Nucleotide KW - Young Adult AB -

INTRODUCTION: D-dimer, a fibrin degradation product, is related to risk of cardiovascular disease and venous thromboembolism. Genetic determinants of D-dimer are not well characterized; notably, few data have been reported for African American (AA), Asian, and Hispanic populations.

MATERIALS AND METHODS: We conducted a large-scale candidate gene association study to identify variants in genes associated with D-dimer levels in multi-ethnic populations. Four cohorts, comprising 6,848 European Americans (EAs), 2,192 AAs, 670 Asians, and 1,286 Hispanics in the National Heart, Lung, and Blood Institute Candidate Gene Association Resource consortium, were assembled. Approximately 50,000 genotyped single nucleotide polymorphisms (SNPs) in 2,000 cardiovascular disease gene loci were analyzed by linear regression, adjusting for age, sex, study site, and principal components in each cohort and ethnic group. Results across studies were combined within each ethnic group by meta-analysis.

RESULTS: Twelve SNPs in coagulation factor V (F5) and 3 SNPs in the fibrinogen alpha chain (FGA) were significantly associated with D-dimer level in EAs with p<2.0×10(-6). The signal for the most associated SNP in F5 (rs6025, factor V Leiden) was replicated in Hispanics (p=0.023), while that for the top functional SNP in FGA (rs6050) was replicated in AAs (p=0.006). No additional SNPs were significantly associated with D-dimer.

CONCLUSIONS: Our study replicated previously reported associations of D-dimer with SNPs in F5 and FGA in EAs; we demonstrated replication of the association of D-dimer with FGA rs6050 in AAs and the factor V Leiden variant in Hispanics.

VL - 134 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24908450?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association study for circulating tissue plasminogen activator levels and functional follow-up implicates endothelial STXBP5 and STX2. JF - Arterioscler Thromb Vasc Biol Y1 - 2014 A1 - Huang, Jie A1 - Huffman, Jennifer E A1 - Yamakuchi, Munekazu A1 - Yamkauchi, Munekazu A1 - Trompet, Stella A1 - Asselbergs, Folkert W A1 - Sabater-Lleal, Maria A1 - Trégouët, David-Alexandre A1 - Chen, Wei-Min A1 - Smith, Nicholas L A1 - Kleber, Marcus E A1 - Shin, So-Youn A1 - Becker, Diane M A1 - Tang, Weihong A1 - Dehghan, Abbas A1 - Johnson, Andrew D A1 - Truong, Vinh A1 - Folkersen, Lasse A1 - Yang, Qiong A1 - Oudot-Mellkah, Tiphaine A1 - Buckley, Brendan M A1 - Moore, Jason H A1 - Williams, Frances M K A1 - Campbell, Harry A1 - Silbernagel, Günther A1 - Vitart, Veronique A1 - Rudan, Igor A1 - Tofler, Geoffrey H A1 - Navis, Gerjan J A1 - DeStefano, Anita A1 - Wright, Alan F A1 - Chen, Ming-Huei A1 - de Craen, Anton J M A1 - Worrall, Bradford B A1 - Rudnicka, Alicja R A1 - Rumley, Ann A1 - Bookman, Ebony B A1 - Psaty, Bruce M A1 - Chen, Fang A1 - Keene, Keith L A1 - Franco, Oscar H A1 - Böhm, Bernhard O A1 - Uitterlinden, André G A1 - Carter, Angela M A1 - Jukema, J Wouter A1 - Sattar, Naveed A1 - Bis, Joshua C A1 - Ikram, Mohammad A A1 - Sale, Michèle M A1 - McKnight, Barbara A1 - Fornage, Myriam A1 - Ford, Ian A1 - Taylor, Kent A1 - Slagboom, P Eline A1 - McArdle, Wendy L A1 - Hsu, Fang-Chi A1 - Franco-Cereceda, Anders A1 - Goodall, Alison H A1 - Yanek, Lisa R A1 - Furie, Karen L A1 - Cushman, Mary A1 - Hofman, Albert A1 - Witteman, Jacqueline C M A1 - Folsom, Aaron R A1 - Basu, Saonli A1 - Matijevic, Nena A1 - van Gilst, Wiek H A1 - Wilson, James F A1 - Westendorp, Rudi G J A1 - Kathiresan, Sekar A1 - Reilly, Muredach P A1 - Tracy, Russell P A1 - Polasek, Ozren A1 - Winkelmann, Bernhard R A1 - Grant, Peter J A1 - Hillege, Hans L A1 - Cambien, Francois A1 - Stott, David J A1 - Lowe, Gordon D A1 - Spector, Timothy D A1 - Meigs, James B A1 - März, Winfried A1 - Eriksson, Per A1 - Becker, Lewis C A1 - Morange, Pierre-Emmanuel A1 - Soranzo, Nicole A1 - Williams, Scott M A1 - Hayward, Caroline A1 - van der Harst, Pim A1 - Hamsten, Anders A1 - Lowenstein, Charles J A1 - Strachan, David P A1 - O'Donnell, Christopher J KW - Aged KW - Cells, Cultured KW - Coronary Artery Disease KW - Endothelial Cells KW - Europe KW - Female KW - Gene Expression Regulation KW - Gene Silencing KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Male KW - Middle Aged KW - Nerve Tissue Proteins KW - Phenotype KW - Polymorphism, Single Nucleotide KW - R-SNARE Proteins KW - Risk Factors KW - Stroke KW - Syntaxin 1 KW - Tissue Plasminogen Activator KW - Transfection KW - United States KW - Up-Regulation AB -

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.

VL - 34 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24578379?dopt=Abstract ER - TY - JOUR T1 - Association of Alzheimer's disease GWAS loci with MRI markers of brain aging. JF - Neurobiol Aging Y1 - 2015 A1 - Chauhan, Ganesh A1 - Adams, Hieab H H A1 - Bis, Joshua C A1 - Weinstein, Galit A1 - Yu, Lei A1 - Töglhofer, Anna Maria A1 - Smith, Albert Vernon A1 - van der Lee, Sven J A1 - Gottesman, Rebecca F A1 - Thomson, Russell A1 - Wang, Jing A1 - Yang, Qiong A1 - Niessen, Wiro J A1 - Lopez, Oscar L A1 - Becker, James T A1 - Phan, Thanh G A1 - Beare, Richard J A1 - Arfanakis, Konstantinos A1 - Fleischman, Debra A1 - Vernooij, Meike W A1 - Mazoyer, Bernard A1 - Schmidt, Helena A1 - Srikanth, Velandai A1 - Knopman, David S A1 - Jack, Clifford R A1 - Amouyel, Philippe A1 - Hofman, Albert A1 - DeCarli, Charles A1 - Tzourio, Christophe A1 - van Duijn, Cornelia M A1 - Bennett, David A A1 - Schmidt, Reinhold A1 - Longstreth, William T A1 - Mosley, Thomas H A1 - Fornage, Myriam A1 - Launer, Lenore J A1 - Seshadri, Sudha A1 - Ikram, M Arfan A1 - Debette, Stephanie KW - Aging KW - Alleles KW - Alzheimer Disease KW - Apolipoproteins E KW - Brain KW - Female KW - Genome-Wide Association Study KW - Hippocampus KW - Humans KW - Magnetic Resonance Imaging KW - Male KW - Organ Size KW - Polymorphism, Single Nucleotide KW - Risk KW - Sialic Acid Binding Ig-like Lectin 3 AB -

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.

VL - 36 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25670335?dopt=Abstract ER - TY - JOUR T1 - Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease. JF - Neurology Y1 - 2015 A1 - Rannikmae, Kristiina A1 - Davies, Gail A1 - Thomson, Pippa A A1 - Bevan, Steve A1 - Devan, William J A1 - Falcone, Guido J A1 - Traylor, Matthew A1 - Anderson, Christopher D A1 - Battey, Thomas W K A1 - Radmanesh, Farid A1 - Deka, Ranjan A1 - Woo, Jessica G A1 - Martin, Lisa J A1 - Jimenez-Conde, Jordi A1 - Selim, Magdy A1 - Brown, Devin L A1 - Silliman, Scott L A1 - Kidwell, Chelsea S A1 - Montaner, Joan A1 - Langefeld, Carl D A1 - Slowik, Agnieszka A1 - Hansen, Bjorn M A1 - Lindgren, Arne G A1 - Meschia, James F A1 - Fornage, Myriam A1 - Bis, Joshua C A1 - Debette, Stephanie A1 - Ikram, Mohammad A A1 - Longstreth, Will T A1 - Schmidt, Reinhold A1 - Zhang, Cathy R A1 - Yang, Qiong A1 - Sharma, Pankaj A1 - Kittner, Steven J A1 - Mitchell, Braxton D A1 - Holliday, Elizabeth G A1 - Levi, Christopher R A1 - Attia, John A1 - Rothwell, Peter M A1 - Poole, Deborah L A1 - Boncoraglio, Giorgio B A1 - Psaty, Bruce M A1 - Malik, Rainer A1 - Rost, Natalia A1 - Worrall, Bradford B A1 - Dichgans, Martin A1 - Van Agtmael, Tom A1 - Woo, Daniel A1 - Markus, Hugh S A1 - Seshadri, Sudha A1 - Rosand, Jonathan A1 - Sudlow, Cathie L M KW - Cerebral Small Vessel Diseases KW - Collagen Type IV KW - Genetic Association Studies KW - Genetic Variation KW - Humans KW - Polymorphism, Single Nucleotide AB -

OBJECTIVES: We hypothesized that common variants in the collagen genes COL4A1/COL4A2 are associated with sporadic forms of cerebral small vessel disease.

METHODS: We conducted meta-analyses of existing genotype data among individuals of European ancestry to determine associations of 1,070 common single nucleotide polymorphisms (SNPs) in the COL4A1/COL4A2 genomic region with the following: intracerebral hemorrhage and its subtypes (deep, lobar) (1,545 cases, 1,485 controls); ischemic stroke and its subtypes (cardioembolic, large vessel disease, lacunar) (12,389 cases, 62,004 controls); and white matter hyperintensities (2,733 individuals with ischemic stroke and 9,361 from population-based cohorts with brain MRI data). We calculated a statistical significance threshold that accounted for multiple testing and linkage disequilibrium between SNPs (p < 0.000084).

RESULTS: Three intronic SNPs in COL4A2 were significantly associated with deep intracerebral hemorrhage (lead SNP odds ratio [OR] 1.29, 95% confidence interval [CI] 1.14-1.46, p = 0.00003; r(2) > 0.9 between SNPs). Although SNPs associated with deep intracerebral hemorrhage did not reach our significance threshold for association with lacunar ischemic stroke (lead SNP OR 1.10, 95% CI 1.03-1.18, p = 0.0073), and with white matter hyperintensity volume in symptomatic ischemic stroke patients (lead SNP OR 1.07, 95% CI 1.01-1.13, p = 0.016), the direction of association was the same. There was no convincing evidence of association with white matter hyperintensities in population-based studies or with non-small vessel disease cerebrovascular phenotypes.

CONCLUSIONS: Our results indicate an association between common variation in the COL4A2 gene and symptomatic small vessel disease, particularly deep intracerebral hemorrhage. These findings merit replication studies, including in ethnic groups of non-European ancestry.

VL - 84 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25653287?dopt=Abstract ER - TY - JOUR T1 - Gene-centric approach identifies new and known loci for FVIII activity and VWF antigen levels in European Americans and African Americans. JF - Am J Hematol Y1 - 2015 A1 - Tang, Weihong A1 - Cushman, Mary A1 - Green, David A1 - Rich, Stephen S A1 - Lange, Leslie A A1 - Yang, Qiong A1 - Tracy, Russell P A1 - Tofler, Geoffrey H A1 - Basu, Saonli A1 - Wilson, James G A1 - Keating, Brendan J A1 - Weng, Lu-Chen A1 - Taylor, Herman A A1 - Jacobs, David R A1 - Delaney, Joseph A A1 - Palmer, Cameron D A1 - Young, Taylor A1 - Pankow, James S A1 - O'Donnell, Christopher J A1 - Smith, Nicholas L A1 - Reiner, Alexander P A1 - Folsom, Aaron R KW - Adult KW - African Americans KW - Aged KW - European Continental Ancestry Group KW - Factor VIII KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Humans KW - Male KW - Methionine Adenosyltransferase KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Venous Thromboembolism KW - von Willebrand Factor AB -

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.

VL - 90 IS - 6 ER - TY - JOUR T1 - Genes from a translational analysis support a multifactorial nature of white matter hyperintensities. JF - Stroke Y1 - 2015 A1 - Lopez, Lorna M A1 - Hill, W David A1 - Harris, Sarah E A1 - Valdes Hernandez, Maria A1 - Munoz Maniega, Susana A1 - Bastin, Mark E A1 - Bailey, Emma A1 - Smith, Colin A1 - McBride, Martin A1 - McClure, John A1 - Graham, Delyth A1 - Dominiczak, Anna A1 - Yang, Qiong A1 - Fornage, Myriam A1 - Ikram, M Arfan A1 - Debette, Stephanie A1 - Launer, Lenore A1 - Bis, Joshua C A1 - Schmidt, Reinhold A1 - Seshadri, Sudha A1 - Porteous, David J A1 - Starr, John A1 - Deary, Ian J A1 - Wardlaw, Joanna M KW - Aged KW - Alzheimer Disease KW - Animals KW - Brain KW - Causality KW - Dementia KW - Female KW - Genome-Wide Association Study KW - Humans KW - Leukoencephalopathies KW - Male KW - Polymorphism, Single Nucleotide KW - Rats KW - Rats, Inbred SHR KW - Rats, Wistar KW - Risk Factors KW - Translational Medical Research KW - White Matter AB -

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.

VL - 46 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25586835?dopt=Abstract ER - TY - JOUR T1 - Genome-wide studies of verbal declarative memory in nondemented older people: the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium. JF - Biol Psychiatry Y1 - 2015 A1 - Debette, Stephanie A1 - Ibrahim Verbaas, Carla A A1 - Bressler, Jan A1 - Schuur, Maaike A1 - Smith, Albert A1 - Bis, Joshua C A1 - Davies, Gail A1 - Wolf, Christiane A1 - Gudnason, Vilmundur A1 - Chibnik, Lori B A1 - Yang, Qiong A1 - DeStefano, Anita L A1 - de Quervain, Dominique J F A1 - Srikanth, Velandai A1 - Lahti, Jari A1 - Grabe, Hans J A1 - Smith, Jennifer A A1 - Priebe, Lutz A1 - Yu, Lei A1 - Karbalai, Nazanin A1 - Hayward, Caroline A1 - Wilson, James F A1 - Campbell, Harry A1 - Petrovic, Katja A1 - Fornage, Myriam A1 - Chauhan, Ganesh A1 - Yeo, Robin A1 - Boxall, Ruth A1 - Becker, James A1 - Stegle, Oliver A1 - Mather, Karen A A1 - Chouraki, Vincent A1 - Sun, Qi A1 - Rose, Lynda M A1 - Resnick, Susan A1 - Oldmeadow, Christopher A1 - Kirin, Mirna A1 - Wright, Alan F A1 - Jonsdottir, Maria K A1 - Au, Rhoda A1 - Becker, Albert A1 - Amin, Najaf A1 - Nalls, Mike A A1 - Turner, Stephen T A1 - Kardia, Sharon L R A1 - Oostra, Ben A1 - Windham, Gwen A1 - Coker, Laura H A1 - Zhao, Wei A1 - Knopman, David S A1 - Heiss, Gerardo A1 - Griswold, Michael E A1 - Gottesman, Rebecca F A1 - Vitart, Veronique A1 - Hastie, Nicholas D A1 - Zgaga, Lina A1 - Rudan, Igor A1 - Polasek, Ozren A1 - Holliday, Elizabeth G A1 - Schofield, Peter A1 - Choi, Seung Hoan A1 - Tanaka, Toshiko A1 - An, Yang A1 - Perry, Rodney T A1 - Kennedy, Richard E A1 - Sale, Michèle M A1 - Wang, Jing A1 - Wadley, Virginia G A1 - Liewald, David C A1 - Ridker, Paul M A1 - Gow, Alan J A1 - Pattie, Alison A1 - Starr, John M A1 - Porteous, David A1 - Liu, Xuan A1 - Thomson, Russell A1 - Armstrong, Nicola J A1 - Eiriksdottir, Gudny A1 - Assareh, Arezoo A A1 - Kochan, Nicole A A1 - Widen, Elisabeth A1 - Palotie, Aarno A1 - Hsieh, Yi-Chen A1 - Eriksson, Johan G A1 - Vogler, Christian A1 - van Swieten, John C A1 - Shulman, Joshua M A1 - Beiser, Alexa A1 - Rotter, Jerome A1 - Schmidt, Carsten O A1 - Hoffmann, Wolfgang A1 - Nöthen, Markus M A1 - Ferrucci, Luigi A1 - Attia, John A1 - Uitterlinden, André G A1 - Amouyel, Philippe A1 - Dartigues, Jean-François A1 - Amieva, Hélène A1 - Räikkönen, Katri A1 - Garcia, Melissa A1 - Wolf, Philip A A1 - Hofman, Albert A1 - Longstreth, W T A1 - Psaty, Bruce M A1 - Boerwinkle, Eric A1 - DeJager, Philip L A1 - Sachdev, Perminder S A1 - Schmidt, Reinhold A1 - Breteler, Monique M B A1 - Teumer, Alexander A1 - Lopez, Oscar L A1 - Cichon, Sven A1 - Chasman, Daniel I A1 - Grodstein, Francine A1 - Müller-Myhsok, Bertram A1 - Tzourio, Christophe A1 - Papassotiropoulos, Andreas A1 - Bennett, David A A1 - Ikram, M Arfan A1 - Deary, Ian J A1 - van Duijn, Cornelia M A1 - Launer, Lenore A1 - Fitzpatrick, Annette L A1 - Seshadri, Sudha A1 - Mosley, Thomas H KW - Aged KW - Aged, 80 and over KW - Aging KW - Apolipoproteins E KW - Claudin-5 KW - Cohort Studies KW - Female KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Male KW - Memory Disorders KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Proteins KW - Proteoglycans KW - Regression Analysis KW - Sulfotransferases KW - Verbal Learning AB -

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.

VL - 77 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25648963?dopt=Abstract ER - TY - JOUR T1 - Multiethnic genome-wide association study of cerebral white matter hyperintensities on MRI. JF - Circ Cardiovasc Genet Y1 - 2015 A1 - Verhaaren, Benjamin F J A1 - Debette, Stephanie A1 - Bis, Joshua C A1 - Smith, Jennifer A A1 - Ikram, M Kamran A1 - Adams, Hieab H A1 - Beecham, Ashley H A1 - Rajan, Kumar B A1 - Lopez, Lorna M A1 - Barral, Sandra A1 - van Buchem, Mark A A1 - van der Grond, Jeroen A1 - Smith, Albert V A1 - Hegenscheid, Katrin A1 - Aggarwal, Neelum T A1 - de Andrade, Mariza A1 - Atkinson, Elizabeth J A1 - Beekman, Marian A1 - Beiser, Alexa S A1 - Blanton, Susan H A1 - Boerwinkle, Eric A1 - Brickman, Adam M A1 - Bryan, R Nick A1 - Chauhan, Ganesh A1 - Chen, Christopher P L H A1 - Chouraki, Vincent A1 - de Craen, Anton J M A1 - Crivello, Fabrice A1 - Deary, Ian J A1 - Deelen, Joris A1 - De Jager, Philip L A1 - Dufouil, Carole A1 - Elkind, Mitchell S V A1 - Evans, Denis A A1 - Freudenberger, Paul A1 - Gottesman, Rebecca F A1 - Guðnason, Vilmundur A1 - Habes, Mohamad A1 - Heckbert, Susan R A1 - Heiss, Gerardo A1 - Hilal, Saima A1 - Hofer, Edith A1 - Hofman, Albert A1 - Ibrahim-Verbaas, Carla A A1 - Knopman, David S A1 - Lewis, Cora E A1 - Liao, Jiemin A1 - Liewald, David C M A1 - Luciano, Michelle A1 - van der Lugt, Aad A1 - Martinez, Oliver O A1 - Mayeux, Richard A1 - Mazoyer, Bernard A1 - Nalls, Mike A1 - Nauck, Matthias A1 - Niessen, Wiro J A1 - Oostra, Ben A A1 - Psaty, Bruce M A1 - Rice, Kenneth M A1 - Rotter, Jerome I A1 - von Sarnowski, Bettina A1 - Schmidt, Helena A1 - Schreiner, Pamela J A1 - Schuur, Maaike A1 - Sidney, Stephen S A1 - Sigurdsson, Sigurdur A1 - Slagboom, P Eline A1 - Stott, David J M A1 - van Swieten, John C A1 - Teumer, Alexander A1 - Töglhofer, Anna Maria A1 - Traylor, Matthew A1 - Trompet, Stella A1 - Turner, Stephen T A1 - Tzourio, Christophe A1 - Uh, Hae-Won A1 - Uitterlinden, André G A1 - Vernooij, Meike W A1 - Wang, Jing J A1 - Wong, Tien Y A1 - Wardlaw, Joanna M A1 - Windham, B Gwen A1 - Wittfeld, Katharina A1 - Wolf, Christiane A1 - Wright, Clinton B A1 - Yang, Qiong A1 - Zhao, Wei A1 - Zijdenbos, Alex A1 - Jukema, J Wouter A1 - Sacco, Ralph L A1 - Kardia, Sharon L R A1 - Amouyel, Philippe A1 - Mosley, Thomas H A1 - Longstreth, W T A1 - DeCarli, Charles C A1 - van Duijn, Cornelia M A1 - Schmidt, Reinhold A1 - Launer, Lenore J A1 - Grabe, Hans J A1 - Seshadri, Sudha S A1 - Ikram, M Arfan A1 - Fornage, Myriam KW - Aged KW - Aged, 80 and over KW - Chromosomes, Human KW - Continental Population Groups KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Humans KW - Male KW - Meta-Analysis as Topic KW - Middle Aged KW - Models, Genetic KW - Stroke KW - White Matter AB -

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.

VL - 8 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25663218?dopt=Abstract ER - TY - JOUR T1 - White Matter Lesion Progression: Genome-Wide Search for Genetic Influences. JF - Stroke Y1 - 2015 A1 - Hofer, Edith A1 - Cavalieri, Margherita A1 - Bis, Joshua C A1 - DeCarli, Charles A1 - Fornage, Myriam A1 - Sigurdsson, Sigurdur A1 - Srikanth, Velandai A1 - Trompet, Stella A1 - Verhaaren, Benjamin F J A1 - Wolf, Christiane A1 - Yang, Qiong A1 - Adams, Hieab H H A1 - Amouyel, Philippe A1 - Beiser, Alexa A1 - Buckley, Brendan M A1 - Callisaya, Michele A1 - Chauhan, Ganesh A1 - de Craen, Anton J M A1 - Dufouil, Carole A1 - van Duijn, Cornelia M A1 - Ford, Ian A1 - Freudenberger, Paul A1 - Gottesman, Rebecca F A1 - Gudnason, Vilmundur A1 - Heiss, Gerardo A1 - Hofman, Albert A1 - Lumley, Thomas A1 - Martinez, Oliver A1 - Mazoyer, Bernard A1 - Moran, Chris A1 - Niessen, Wiro J A1 - Phan, Thanh A1 - Psaty, Bruce M A1 - Satizabal, Claudia L A1 - Sattar, Naveed A1 - Schilling, Sabrina A1 - Shibata, Dean K A1 - Slagboom, P Eline A1 - Smith, Albert A1 - Stott, David J A1 - Taylor, Kent D A1 - Thomson, Russell A1 - Töglhofer, Anna M A1 - Tzourio, Christophe A1 - van Buchem, Mark A1 - Wang, Jing A1 - Westendorp, Rudi G J A1 - Windham, B Gwen A1 - Vernooij, Meike W A1 - Zijdenbos, Alex A1 - Beare, Richard A1 - Debette, Stephanie A1 - Ikram, M Arfan A1 - Jukema, J Wouter A1 - Launer, Lenore J A1 - Longstreth, W T A1 - Mosley, Thomas H A1 - Seshadri, Sudha A1 - Schmidt, Helena A1 - Schmidt, Reinhold KW - Adult KW - Aged KW - Cohort Studies KW - Disease Progression KW - Female KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Leukoencephalopathies KW - Male KW - Middle Aged KW - Prospective Studies KW - White Matter AB -

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.

VL - 46 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26451028?dopt=Abstract ER - TY - JOUR T1 - A meta-analysis of 120 246 individuals identifies 18 new loci for fibrinogen concentration. JF - Hum Mol Genet Y1 - 2016 A1 - de Vries, Paul S A1 - Chasman, Daniel I A1 - Sabater-Lleal, Maria A1 - Chen, Ming-Huei A1 - Huffman, Jennifer E A1 - Steri, Maristella A1 - Tang, Weihong A1 - Teumer, Alexander A1 - Marioni, Riccardo E A1 - Grossmann, Vera A1 - Hottenga, Jouke J A1 - Trompet, Stella A1 - Müller-Nurasyid, Martina A1 - Zhao, Jing Hua A1 - Brody, Jennifer A A1 - Kleber, Marcus E A1 - Guo, Xiuqing A1 - Wang, Jie Jin A1 - Auer, Paul L A1 - Attia, John R A1 - Yanek, Lisa R A1 - Ahluwalia, Tarunveer S A1 - Lahti, Jari A1 - Venturini, Cristina A1 - Tanaka, Toshiko A1 - Bielak, Lawrence F A1 - Joshi, Peter K A1 - Rocanin-Arjo, Ares A1 - Kolcic, Ivana A1 - Navarro, Pau A1 - Rose, Lynda M A1 - Oldmeadow, Christopher A1 - Riess, Helene A1 - Mazur, Johanna A1 - Basu, Saonli A1 - Goel, Anuj A1 - Yang, Qiong A1 - Ghanbari, Mohsen A1 - Willemsen, Gonneke A1 - Rumley, Ann A1 - Fiorillo, Edoardo A1 - de Craen, Anton J M A1 - Grotevendt, Anne A1 - Scott, Robert A1 - Taylor, Kent D A1 - Delgado, Graciela E A1 - Yao, Jie A1 - Kifley, Annette A1 - Kooperberg, Charles A1 - Qayyum, Rehan A1 - Lopez, Lorna M A1 - Berentzen, Tina L A1 - Räikkönen, Katri A1 - Mangino, Massimo A1 - Bandinelli, Stefania A1 - Peyser, Patricia A A1 - Wild, Sarah A1 - Trégouët, David-Alexandre A1 - Wright, Alan F A1 - Marten, Jonathan A1 - Zemunik, Tatijana A1 - Morrison, Alanna C A1 - Sennblad, Bengt A1 - Tofler, Geoffrey A1 - de Maat, Moniek P M A1 - de Geus, Eco J C A1 - Lowe, Gordon D A1 - Zoledziewska, Magdalena A1 - Sattar, Naveed A1 - Binder, Harald A1 - Völker, Uwe A1 - Waldenberger, Melanie A1 - Khaw, Kay-Tee A1 - McKnight, Barbara A1 - Huang, Jie A1 - Jenny, Nancy S A1 - Holliday, Elizabeth G A1 - Qi, Lihong A1 - Mcevoy, Mark G A1 - Becker, Diane M A1 - Starr, John M A1 - Sarin, Antti-Pekka A1 - Hysi, Pirro G A1 - Hernandez, Dena G A1 - Jhun, Min A A1 - Campbell, Harry A1 - Hamsten, Anders A1 - Rivadeneira, Fernando A1 - McArdle, Wendy L A1 - Slagboom, P Eline A1 - Zeller, Tanja A1 - Koenig, Wolfgang A1 - Psaty, Bruce M A1 - Haritunians, Talin A1 - Liu, Jingmin A1 - Palotie, Aarno A1 - Uitterlinden, André G A1 - Stott, David J A1 - Hofman, Albert A1 - Franco, Oscar H A1 - Polasek, Ozren A1 - Rudan, Igor A1 - Morange, Pierre-Emmanuel A1 - Wilson, James F A1 - Kardia, Sharon L R A1 - Ferrucci, Luigi A1 - Spector, Tim D A1 - Eriksson, Johan G A1 - Hansen, Torben A1 - Deary, Ian J A1 - Becker, Lewis C A1 - Scott, Rodney J A1 - Mitchell, Paul A1 - März, Winfried A1 - Wareham, Nick J A1 - Peters, Annette A1 - Greinacher, Andreas A1 - Wild, Philipp S A1 - Jukema, J Wouter A1 - Boomsma, Dorret I A1 - Hayward, Caroline A1 - Cucca, Francesco A1 - Tracy, Russell A1 - Watkins, Hugh A1 - Reiner, Alex P A1 - Folsom, Aaron R A1 - Ridker, Paul M A1 - O'Donnell, Christopher J A1 - Smith, Nicholas L A1 - Strachan, David P A1 - Dehghan, Abbas AB -

Genome-wide association studies have previously identified 23 genetic loci associated with circulating fibrinogen concentration. These studies used HapMap imputation and did not examine the X-chromosome. 1000 Genomes imputation provides better coverage of uncommon variants, and includes indels. We conducted a genome-wide association analysis of 34 studies imputed to the 1000 Genomes Project reference panel and including ∼120 000 participants of European ancestry (95 806 participants with data on the X-chromosome). Approximately 10.7 million single-nucleotide polymorphisms and 1.2 million indels were examined. We identified 41 genome-wide significant fibrinogen loci; of which, 18 were newly identified. There were no genome-wide significant signals on the X-chromosome. The lead variants of five significant loci were indels. We further identified six additional independent signals, including three rare variants, at two previously characterized loci: FGB and IRF1. Together the 41 loci explain 3% of the variance in plasma fibrinogen concentration.

VL - 25 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26561523?dopt=Abstract ER - TY - JOUR T1 - SOS2 and ACP1 Loci Identified through Large-Scale Exome Chip Analysis Regulate Kidney Development and Function. JF - J Am Soc Nephrol Y1 - 2016 A1 - Li, Man A1 - Li, Yong A1 - Weeks, Olivia A1 - Mijatovic, Vladan A1 - Teumer, Alexander A1 - Huffman, Jennifer E A1 - Tromp, Gerard A1 - Fuchsberger, Christian A1 - Gorski, Mathias A1 - Lyytikäinen, Leo-Pekka A1 - Nutile, Teresa A1 - Sedaghat, Sanaz A1 - Sorice, Rossella A1 - Tin, Adrienne A1 - Yang, Qiong A1 - Ahluwalia, Tarunveer S A1 - Arking, Dan E A1 - Bihlmeyer, Nathan A A1 - Böger, Carsten A A1 - Carroll, Robert J A1 - Chasman, Daniel I A1 - Cornelis, Marilyn C A1 - Dehghan, Abbas A1 - Faul, Jessica D A1 - Feitosa, Mary F A1 - Gambaro, Giovanni A1 - Gasparini, Paolo A1 - Giulianini, Franco A1 - Heid, Iris A1 - Huang, Jinyan A1 - Imboden, Medea A1 - Jackson, Anne U A1 - Jeff, Janina A1 - Jhun, Min A A1 - Katz, Ronit A1 - Kifley, Annette A1 - Kilpeläinen, Tuomas O A1 - Kumar, Ashish A1 - Laakso, Markku A1 - Li-Gao, Ruifang A1 - Lohman, Kurt A1 - Lu, Yingchang A1 - Mägi, Reedik A1 - Malerba, Giovanni A1 - Mihailov, Evelin A1 - Mohlke, Karen L A1 - Mook-Kanamori, Dennis O A1 - Robino, Antonietta A1 - Ruderfer, Douglas A1 - Salvi, Erika A1 - Schick, Ursula M A1 - Schulz, Christina-Alexandra A1 - Smith, Albert V A1 - Smith, Jennifer A A1 - Traglia, Michela A1 - Yerges-Armstrong, Laura M A1 - Zhao, Wei A1 - Goodarzi, Mark O A1 - Kraja, Aldi T A1 - Liu, Chunyu A1 - Wessel, Jennifer A1 - Boerwinkle, Eric A1 - Borecki, Ingrid B A1 - Bork-Jensen, Jette A1 - Bottinger, Erwin P A1 - Braga, Daniele A1 - Brandslund, Ivan A1 - Brody, Jennifer A A1 - Campbell, Archie A1 - Carey, David J A1 - Christensen, Cramer A1 - Coresh, Josef A1 - Crook, Errol A1 - Curhan, Gary C A1 - Cusi, Daniele A1 - de Boer, Ian H A1 - de Vries, Aiko P J A1 - Denny, Joshua C A1 - Devuyst, Olivier A1 - Dreisbach, Albert W A1 - Endlich, Karlhans A1 - Esko, Tõnu A1 - Franco, Oscar H A1 - Fulop, Tibor A1 - Gerhard, Glenn S A1 - Glümer, Charlotte A1 - Gottesman, Omri A1 - Grarup, Niels A1 - Gudnason, Vilmundur A1 - Harris, Tamara B A1 - Hayward, Caroline A1 - Hocking, Lynne A1 - Hofman, Albert A1 - Hu, Frank B A1 - Husemoen, Lise Lotte N A1 - Jackson, Rebecca D A1 - Jørgensen, Torben A1 - Jørgensen, Marit E A1 - Kähönen, Mika A1 - Kardia, Sharon L R A1 - König, Wolfgang A1 - Kooperberg, Charles A1 - Kriebel, Jennifer A1 - Launer, Lenore J A1 - Lauritzen, Torsten A1 - Lehtimäki, Terho A1 - Levy, Daniel A1 - Linksted, Pamela A1 - Linneberg, Allan A1 - Liu, Yongmei A1 - Loos, Ruth J F A1 - Lupo, Antonio A1 - Meisinger, Christine A1 - Melander, Olle A1 - Metspalu, Andres A1 - Mitchell, Paul A1 - Nauck, Matthias A1 - Nürnberg, Peter A1 - Orho-Melander, Marju A1 - Parsa, Afshin A1 - Pedersen, Oluf A1 - Peters, Annette A1 - Peters, Ulrike A1 - Polasek, Ozren A1 - Porteous, David A1 - Probst-Hensch, Nicole M A1 - Psaty, Bruce M A1 - Qi, Lu A1 - Raitakari, Olli T A1 - Reiner, Alex P A1 - Rettig, Rainer A1 - Ridker, Paul M A1 - Rivadeneira, Fernando A1 - Rossouw, Jacques E A1 - Schmidt, Frank A1 - Siscovick, David A1 - Soranzo, Nicole A1 - Strauch, Konstantin A1 - Toniolo, Daniela A1 - Turner, Stephen T A1 - Uitterlinden, André G A1 - Ulivi, Sheila A1 - Velayutham, Dinesh A1 - Völker, Uwe A1 - Völzke, Henry A1 - Waldenberger, Melanie A1 - Wang, Jie Jin A1 - Weir, David R A1 - Witte, Daniel A1 - Kuivaniemi, Helena A1 - Fox, Caroline S A1 - Franceschini, Nora A1 - Goessling, Wolfram A1 - Köttgen, Anna A1 - Chu, Audrey Y AB -

Genome-wide association studies have identified >50 common variants associated with kidney function, but these variants do not fully explain the variation in eGFR. We performed a two-stage meta-analysis of associations between genotypes from the Illumina exome array and eGFR on the basis of serum creatinine (eGFRcrea) among participants of European ancestry from the CKDGen Consortium (nStage1: 111,666; nStage2: 48,343). In single-variant analyses, we identified single nucleotide polymorphisms at seven new loci associated with eGFRcrea (PPM1J, EDEM3, ACP1, SPEG, EYA4, CYP1A1, and ATXN2L; PStage1<3.7×10(-7)), of which most were common and annotated as nonsynonymous variants. Gene-based analysis identified associations of functional rare variants in three genes with eGFRcrea, including a novel association with the SOS Ras/Rho guanine nucleotide exchange factor 2 gene, SOS2 (P=5.4×10(-8) by sequence kernel association test). Experimental follow-up in zebrafish embryos revealed changes in glomerular gene expression and renal tubule morphology in the embryonic kidney of acp1- and sos2-knockdowns. These developmental abnormalities associated with altered blood clearance rate and heightened prevalence of edema. This study expands the number of loci associated with kidney function and identifies novel genes with potential roles in kidney formation.

ER - TY - JOUR T1 - Association Between Telomere Length and Risk of Cancer and Non-Neoplastic Diseases: A Mendelian Randomization Study. JF - JAMA Oncol Y1 - 2017 A1 - Haycock, Philip C A1 - Burgess, Stephen A1 - Nounu, Aayah A1 - Zheng, Jie A1 - Okoli, George N A1 - Bowden, Jack A1 - Wade, Kaitlin Hazel A1 - Timpson, Nicholas J A1 - Evans, David M A1 - Willeit, Peter A1 - Aviv, Abraham A1 - Gaunt, Tom R A1 - Hemani, Gibran A1 - Mangino, Massimo A1 - Ellis, Hayley Patricia A1 - Kurian, Kathreena M A1 - Pooley, Karen A A1 - Eeles, Rosalind A A1 - Lee, Jeffrey E A1 - Fang, Shenying A1 - Chen, Wei V A1 - Law, Matthew H A1 - Bowdler, Lisa M A1 - Iles, Mark M A1 - Yang, Qiong A1 - Worrall, Bradford B A1 - Markus, Hugh Stephen A1 - Hung, Rayjean J A1 - Amos, Chris I A1 - Spurdle, Amanda B A1 - Thompson, Deborah J A1 - O'Mara, Tracy A A1 - Wolpin, Brian A1 - Amundadottir, Laufey A1 - Stolzenberg-Solomon, Rachael A1 - Trichopoulou, Antonia A1 - Onland-Moret, N Charlotte A1 - Lund, Eiliv A1 - Duell, Eric J A1 - Canzian, Federico A1 - Severi, Gianluca A1 - Overvad, Kim A1 - Gunter, Marc J A1 - Tumino, Rosario A1 - Svenson, Ulrika A1 - van Rij, Andre A1 - Baas, Annette F A1 - Bown, Matthew J A1 - Samani, Nilesh J A1 - van t'Hof, Femke N G A1 - Tromp, Gerard A1 - Jones, Gregory T A1 - Kuivaniemi, Helena A1 - Elmore, James R A1 - Johansson, Mattias A1 - Mckay, James A1 - Scelo, Ghislaine A1 - Carreras-Torres, Robert A1 - Gaborieau, Valerie A1 - Brennan, Paul A1 - Bracci, Paige M A1 - Neale, Rachel E A1 - Olson, Sara H A1 - Gallinger, Steven A1 - Li, Donghui A1 - Petersen, Gloria M A1 - Risch, Harvey A A1 - Klein, Alison P A1 - Han, Jiali A1 - Abnet, Christian C A1 - Freedman, Neal D A1 - Taylor, Philip R A1 - Maris, John M A1 - Aben, Katja K A1 - Kiemeney, Lambertus A A1 - Vermeulen, Sita H A1 - Wiencke, John K A1 - Walsh, Kyle M A1 - Wrensch, Margaret A1 - Rice, Terri A1 - Turnbull, Clare A1 - Litchfield, Kevin A1 - Paternoster, Lavinia A1 - Standl, Marie A1 - Abecasis, Goncalo R A1 - SanGiovanni, John Paul A1 - Li, Yong A1 - Mijatovic, Vladan A1 - Sapkota, Yadav A1 - Low, Siew-Kee A1 - Zondervan, Krina T A1 - Montgomery, Grant W A1 - Nyholt, Dale R A1 - van Heel, David A A1 - Hunt, Karen A1 - Arking, Dan E A1 - Ashar, Foram N A1 - Sotoodehnia, Nona A1 - Woo, Daniel A1 - Rosand, Jonathan A1 - Comeau, Mary E A1 - Brown, W Mark A1 - Silverman, Edwin K A1 - Hokanson, John E A1 - Cho, Michael H A1 - Hui, Jennie A1 - Ferreira, Manuel A A1 - Thompson, Philip J A1 - Morrison, Alanna C A1 - Felix, Janine F A1 - Smith, Nicholas L A1 - Christiano, Angela M A1 - Petukhova, Lynn A1 - Betz, Regina C A1 - Fan, Xing A1 - Zhang, Xuejun A1 - Zhu, Caihong A1 - Langefeld, Carl D A1 - Thompson, Susan D A1 - Wang, Feijie A1 - Lin, Xu A1 - Schwartz, David A A1 - Fingerlin, Tasha A1 - Rotter, Jerome I A1 - Cotch, Mary Frances A1 - Jensen, Richard A A1 - Munz, Matthias A1 - Dommisch, Henrik A1 - Schaefer, Arne S A1 - Han, Fang A1 - Ollila, Hanna M A1 - Hillary, Ryan P A1 - Albagha, Omar A1 - Ralston, Stuart H A1 - Zeng, Chenjie A1 - Zheng, Wei A1 - Shu, Xiao-Ou A1 - Reis, Andre A1 - Uebe, Steffen A1 - Hüffmeier, Ulrike A1 - Kawamura, Yoshiya A1 - Otowa, Takeshi A1 - Sasaki, Tsukasa A1 - Hibberd, Martin Lloyd A1 - Davila, Sonia A1 - Xie, Gang A1 - Siminovitch, Katherine A1 - Bei, Jin-Xin A1 - Zeng, Yi-Xin A1 - Försti, Asta A1 - Chen, Bowang A1 - Landi, Stefano A1 - Franke, Andre A1 - Fischer, Annegret A1 - Ellinghaus, David A1 - Flores, Carlos A1 - Noth, Imre A1 - Ma, Shwu-Fan A1 - Foo, Jia Nee A1 - Liu, Jianjun A1 - Kim, Jong-Won A1 - Cox, David G A1 - Delattre, Olivier A1 - Mirabeau, Olivier A1 - Skibola, Christine F A1 - Tang, Clara S A1 - Garcia-Barcelo, Merce A1 - Chang, Kai-Ping A1 - Su, Wen-Hui A1 - Chang, Yu-Sun A1 - Martin, Nicholas G A1 - Gordon, Scott A1 - Wade, Tracey D A1 - Lee, Chaeyoung A1 - Kubo, Michiaki A1 - Cha, Pei-Chieng A1 - Nakamura, Yusuke A1 - Levy, Daniel A1 - Kimura, Masayuki A1 - Hwang, Shih-Jen A1 - Hunt, Steven A1 - Spector, Tim A1 - Soranzo, Nicole A1 - Manichaikul, Ani W A1 - Barr, R Graham A1 - Kahali, Bratati A1 - Speliotes, Elizabeth A1 - Yerges-Armstrong, Laura M A1 - Cheng, Ching-Yu A1 - Jonas, Jost B A1 - Wong, Tien Yin A1 - Fogh, Isabella A1 - Lin, Kuang A1 - Powell, John F A1 - Rice, Kenneth A1 - Relton, Caroline L A1 - Martin, Richard M A1 - Davey Smith, George KW - Adult KW - Aged KW - Aged, 80 and over KW - Cardiovascular Diseases KW - Female KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Germ-Line Mutation KW - Humans KW - Male KW - Mendelian Randomization Analysis KW - Middle Aged KW - Neoplasms KW - Polymorphism, Single Nucleotide KW - Risk Assessment KW - Telomere KW - Telomere Homeostasis AB -

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.

VL - 3 IS - 5 ER - TY - JOUR T1 - Comparison of HapMap and 1000 Genomes Reference Panels in a Large-Scale Genome-Wide Association Study. JF - PLoS One Y1 - 2017 A1 - de Vries, Paul S A1 - Sabater-Lleal, Maria A1 - Chasman, Daniel I A1 - Trompet, Stella A1 - Ahluwalia, Tarunveer S A1 - Teumer, Alexander A1 - Kleber, Marcus E A1 - Chen, Ming-Huei A1 - Wang, Jie Jin A1 - Attia, John R A1 - Marioni, Riccardo E A1 - Steri, Maristella A1 - Weng, Lu-Chen A1 - Pool, Rene A1 - Grossmann, Vera A1 - Brody, Jennifer A A1 - Venturini, Cristina A1 - Tanaka, Toshiko A1 - Rose, Lynda M A1 - Oldmeadow, Christopher A1 - Mazur, Johanna A1 - Basu, Saonli A1 - Frånberg, Mattias A1 - Yang, Qiong A1 - Ligthart, Symen A1 - Hottenga, Jouke J A1 - Rumley, Ann A1 - Mulas, Antonella A1 - de Craen, Anton J M A1 - Grotevendt, Anne A1 - Taylor, Kent D A1 - Delgado, Graciela E A1 - Kifley, Annette A1 - Lopez, Lorna M A1 - Berentzen, Tina L A1 - Mangino, Massimo A1 - Bandinelli, Stefania A1 - Morrison, Alanna C A1 - Hamsten, Anders A1 - Tofler, Geoffrey A1 - de Maat, Moniek P M A1 - Draisma, Harmen H M A1 - Lowe, Gordon D A1 - Zoledziewska, Magdalena A1 - Sattar, Naveed A1 - Lackner, Karl J A1 - Völker, Uwe A1 - McKnight, Barbara A1 - Huang, Jie A1 - Holliday, Elizabeth G A1 - McEvoy, Mark A A1 - Starr, John M A1 - Hysi, Pirro G A1 - Hernandez, Dena G A1 - Guan, Weihua A1 - Rivadeneira, Fernando A1 - McArdle, Wendy L A1 - Slagboom, P Eline A1 - Zeller, Tanja A1 - Psaty, Bruce M A1 - Uitterlinden, André G A1 - de Geus, Eco J C A1 - Stott, David J A1 - Binder, Harald A1 - Hofman, Albert A1 - Franco, Oscar H A1 - Rotter, Jerome I A1 - Ferrucci, Luigi A1 - Spector, Tim D A1 - Deary, Ian J A1 - März, Winfried A1 - Greinacher, Andreas A1 - Wild, Philipp S A1 - Cucca, Francesco A1 - Boomsma, Dorret I A1 - Watkins, Hugh A1 - Tang, Weihong A1 - Ridker, Paul M A1 - Jukema, Jan W A1 - Scott, Rodney J A1 - Mitchell, Paul A1 - Hansen, Torben A1 - O'Donnell, Christopher J A1 - Smith, Nicholas L A1 - Strachan, David P A1 - Dehghan, Abbas AB -

An increasing number of genome-wide association (GWA) studies are now using the higher resolution 1000 Genomes Project reference panel (1000G) for imputation, with the expectation that 1000G imputation will lead to the discovery of additional associated loci when compared to HapMap imputation. In order to assess the improvement of 1000G over HapMap imputation in identifying associated loci, we compared the results of GWA studies of circulating fibrinogen based on the two reference panels. Using both HapMap and 1000G imputation we performed a meta-analysis of 22 studies comprising the same 91,953 individuals. We identified six additional signals using 1000G imputation, while 29 loci were associated using both HapMap and 1000G imputation. One locus identified using HapMap imputation was not significant using 1000G imputation. The genome-wide significance threshold of 5×10-8 is based on the number of independent statistical tests using HapMap imputation, and 1000G imputation may lead to further independent tests that should be corrected for. When using a stricter Bonferroni correction for the 1000G GWA study (P-value < 2.5×10-8), the number of loci significant only using HapMap imputation increased to 4 while the number of loci significant only using 1000G decreased to 5. In conclusion, 1000G imputation enabled the identification of 20% more loci than HapMap imputation, although the advantage of 1000G imputation became less clear when a stricter Bonferroni correction was used. More generally, our results provide insights that are applicable to the implementation of other dense reference panels that are under development.

VL - 12 IS - 1 ER - TY - JOUR T1 - Genome-wide Trans-ethnic Meta-analysis Identifies Seven Genetic Loci Influencing Erythrocyte Traits and a Role for RBPMS in Erythropoiesis. JF - Am J Hum Genet Y1 - 2017 A1 - van Rooij, Frank J A A1 - Qayyum, Rehan A1 - Smith, Albert V A1 - Zhou, Yi A1 - Trompet, Stella A1 - Tanaka, Toshiko A1 - Keller, Margaux F A1 - Chang, Li-Ching A1 - Schmidt, Helena A1 - Yang, Min-Lee A1 - Chen, Ming-Huei A1 - Hayes, James A1 - Johnson, Andrew D A1 - Yanek, Lisa R A1 - Mueller, Christian A1 - Lange, Leslie A1 - Floyd, James S A1 - Ghanbari, Mohsen A1 - Zonderman, Alan B A1 - Jukema, J Wouter A1 - Hofman, Albert A1 - van Duijn, Cornelia M A1 - Desch, Karl C A1 - Saba, Yasaman A1 - Ozel, Ayse B A1 - Snively, Beverly M A1 - Wu, Jer-Yuarn A1 - Schmidt, Reinhold A1 - Fornage, Myriam A1 - Klein, Robert J A1 - Fox, Caroline S A1 - Matsuda, Koichi A1 - Kamatani, Naoyuki A1 - Wild, Philipp S A1 - Stott, David J A1 - Ford, Ian A1 - Slagboom, P Eline A1 - Yang, Jaden A1 - Chu, Audrey Y A1 - Lambert, Amy J A1 - Uitterlinden, André G A1 - Franco, Oscar H A1 - Hofer, Edith A1 - Ginsburg, David A1 - Hu, Bella A1 - Keating, Brendan A1 - Schick, Ursula M A1 - Brody, Jennifer A A1 - Li, Jun Z A1 - Chen, Zhao A1 - Zeller, Tanja A1 - Guralnik, Jack M A1 - Chasman, Daniel I A1 - Peters, Luanne L A1 - Kubo, Michiaki A1 - Becker, Diane M A1 - Li, Jin A1 - Eiriksdottir, Gudny A1 - Rotter, Jerome I A1 - Levy, Daniel A1 - Grossmann, Vera A1 - Patel, Kushang V A1 - Chen, Chien-Hsiun A1 - Ridker, Paul M A1 - Tang, Hua A1 - Launer, Lenore J A1 - Rice, Kenneth M A1 - Li-Gao, Ruifang A1 - Ferrucci, Luigi A1 - Evans, Michelle K A1 - Choudhuri, Avik A1 - Trompouki, Eirini A1 - Abraham, Brian J A1 - Yang, Song A1 - Takahashi, Atsushi A1 - Kamatani, Yoichiro A1 - Kooperberg, Charles A1 - Harris, Tamara B A1 - Jee, Sun Ha A1 - Coresh, Josef A1 - Tsai, Fuu-Jen A1 - Longo, Dan L A1 - Chen, Yuan-Tsong A1 - Felix, Janine F A1 - Yang, Qiong A1 - Psaty, Bruce M A1 - Boerwinkle, Eric A1 - Becker, Lewis C A1 - Mook-Kanamori, Dennis O A1 - Wilson, James G A1 - Gudnason, Vilmundur A1 - O'Donnell, Christopher J A1 - Dehghan, Abbas A1 - Cupples, L Adrienne A1 - Nalls, Michael A A1 - Morris, Andrew P A1 - Okada, Yukinori A1 - Reiner, Alexander P A1 - Zon, Leonard I A1 - Ganesh, Santhi K AB -

Genome-wide association studies (GWASs) have identified loci for erythrocyte traits in primarily European ancestry populations. We conducted GWAS meta-analyses of six erythrocyte traits in 71,638 individuals from European, East Asian, and African ancestries using a Bayesian approach to account for heterogeneity in allelic effects and variation in the structure of linkage disequilibrium between ethnicities. We identified seven loci for erythrocyte traits including a locus (RBPMS/GTF2E2) associated with mean corpuscular hemoglobin and mean corpuscular volume. Statistical fine-mapping at this locus pointed to RBPMS at this locus and excluded nearby GTF2E2. Using zebrafish morpholino to evaluate loss of function, we observed a strong in vivo erythropoietic effect for RBPMS but not for GTF2E2, supporting the statistical fine-mapping at this locus and demonstrating that RBPMS is a regulator of erythropoiesis. Our findings show the utility of trans-ethnic GWASs for discovery and characterization of genetic loci influencing hematologic traits.

VL - 100 IS - 1 ER - TY - JOUR T1 - Large-scale analyses of common and rare variants identify 12 new loci associated with atrial fibrillation. JF - Nat Genet Y1 - 2017 A1 - Christophersen, Ingrid E A1 - Rienstra, Michiel A1 - Roselli, Carolina A1 - Yin, Xiaoyan A1 - Geelhoed, Bastiaan A1 - Barnard, John A1 - Lin, Honghuang A1 - Arking, Dan E A1 - Smith, Albert V A1 - Albert, Christine M A1 - Chaffin, Mark A1 - Tucker, Nathan R A1 - Li, Molong A1 - Klarin, Derek A1 - Bihlmeyer, Nathan A A1 - Low, Siew-Kee A1 - Weeke, Peter E A1 - Müller-Nurasyid, Martina A1 - Smith, J Gustav A1 - Brody, Jennifer A A1 - Niemeijer, Maartje N A1 - Dörr, Marcus A1 - Trompet, Stella A1 - Huffman, Jennifer A1 - Gustafsson, Stefan A1 - Schurmann, Claudia A1 - Kleber, Marcus E A1 - Lyytikäinen, Leo-Pekka A1 - Seppälä, Ilkka A1 - Malik, Rainer A1 - Horimoto, Andrea R V R A1 - Perez, Marco A1 - Sinisalo, Juha A1 - Aeschbacher, Stefanie A1 - Thériault, Sébastien A1 - Yao, Jie A1 - Radmanesh, Farid A1 - Weiss, Stefan A1 - Teumer, Alexander A1 - Choi, Seung Hoan A1 - Weng, Lu-Chen A1 - Clauss, Sebastian A1 - Deo, Rajat A1 - Rader, Daniel J A1 - Shah, Svati H A1 - Sun, Albert A1 - Hopewell, Jemma C A1 - Debette, Stephanie A1 - Chauhan, Ganesh A1 - Yang, Qiong A1 - Worrall, Bradford B A1 - Paré, Guillaume A1 - Kamatani, Yoichiro A1 - Hagemeijer, Yanick P A1 - Verweij, Niek A1 - Siland, Joylene E A1 - Kubo, Michiaki A1 - Smith, Jonathan D A1 - Van Wagoner, David R A1 - Bis, Joshua C A1 - Perz, Siegfried A1 - Psaty, Bruce M A1 - Ridker, Paul M A1 - Magnani, Jared W A1 - Harris, Tamara B A1 - Launer, Lenore J A1 - Shoemaker, M Benjamin A1 - Padmanabhan, Sandosh A1 - Haessler, Jeffrey A1 - Bartz, Traci M A1 - Waldenberger, Melanie A1 - Lichtner, Peter A1 - Arendt, Marina A1 - Krieger, Jose E A1 - Kähönen, Mika A1 - Risch, Lorenz A1 - Mansur, Alfredo J A1 - Peters, Annette A1 - Smith, Blair H A1 - Lind, Lars A1 - Scott, Stuart A A1 - Lu, Yingchang A1 - Bottinger, Erwin B A1 - Hernesniemi, Jussi A1 - Lindgren, Cecilia M A1 - Wong, Jorge A A1 - Huang, Jie A1 - Eskola, Markku A1 - Morris, Andrew P A1 - Ford, Ian A1 - Reiner, Alex P A1 - Delgado, Graciela A1 - Chen, Lin Y A1 - Chen, Yii-Der Ida A1 - Sandhu, Roopinder K A1 - Li, Man A1 - Boerwinkle, Eric A1 - Eisele, Lewin A1 - Lannfelt, Lars A1 - Rost, Natalia A1 - Anderson, Christopher D A1 - Taylor, Kent D A1 - Campbell, Archie A1 - Magnusson, Patrik K A1 - Porteous, David A1 - Hocking, Lynne J A1 - Vlachopoulou, Efthymia A1 - Pedersen, Nancy L A1 - Nikus, Kjell A1 - Orho-Melander, Marju A1 - Hamsten, Anders A1 - Heeringa, Jan A1 - Denny, Joshua C A1 - Kriebel, Jennifer A1 - Darbar, Dawood A1 - Newton-Cheh, Christopher A1 - Shaffer, Christian A1 - Macfarlane, Peter W A1 - Heilmann-Heimbach, Stefanie A1 - Almgren, Peter A1 - Huang, Paul L A1 - Sotoodehnia, Nona A1 - Soliman, Elsayed Z A1 - Uitterlinden, André G A1 - Hofman, Albert A1 - Franco, Oscar H A1 - Völker, Uwe A1 - Jöckel, Karl-Heinz A1 - Sinner, Moritz F A1 - Lin, Henry J A1 - Guo, Xiuqing A1 - Dichgans, Martin A1 - Ingelsson, Erik A1 - Kooperberg, Charles A1 - Melander, Olle A1 - Loos, Ruth J F A1 - Laurikka, Jari A1 - Conen, David A1 - Rosand, Jonathan A1 - van der Harst, Pim A1 - Lokki, Marja-Liisa A1 - Kathiresan, Sekar A1 - Pereira, Alexandre A1 - Jukema, J Wouter A1 - Hayward, Caroline A1 - Rotter, Jerome I A1 - März, Winfried A1 - Lehtimäki, Terho A1 - Stricker, Bruno H A1 - Chung, Mina K A1 - Felix, Stephan B A1 - Gudnason, Vilmundur A1 - Alonso, Alvaro A1 - Roden, Dan M A1 - Kääb, Stefan A1 - Chasman, Daniel I A1 - Heckbert, Susan R A1 - Benjamin, Emelia J A1 - Tanaka, Toshihiro A1 - Lunetta, Kathryn L A1 - Lubitz, Steven A A1 - Ellinor, Patrick T AB -

Atrial fibrillation affects more than 33 million people worldwide and increases the risk of stroke, heart failure, and death. Fourteen genetic loci have been associated with atrial fibrillation in European and Asian ancestry groups. To further define the genetic basis of atrial fibrillation, we performed large-scale, trans-ancestry meta-analyses of common and rare variant association studies. The genome-wide association studies (GWAS) included 17,931 individuals with atrial fibrillation and 115,142 referents; the exome-wide association studies (ExWAS) and rare variant association studies (RVAS) involved 22,346 cases and 132,086 referents. We identified 12 new genetic loci that exceeded genome-wide significance, implicating genes involved in cardiac electrical and structural remodeling. Our results nearly double the number of known genetic loci for atrial fibrillation, provide insights into the molecular basis of atrial fibrillation, and may facilitate the identification of new potential targets for drug discovery.

VL - 49 IS - 6 ER - TY - JOUR T1 - Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease. JF - Nat Genet Y1 - 2017 A1 - Sims, Rebecca A1 - van der Lee, Sven J A1 - Naj, Adam C A1 - Bellenguez, Céline A1 - Badarinarayan, Nandini A1 - Jakobsdottir, Johanna A1 - Kunkle, Brian W A1 - Boland, Anne A1 - Raybould, Rachel A1 - Bis, Joshua C A1 - Martin, Eden R A1 - Grenier-Boley, Benjamin A1 - Heilmann-Heimbach, Stefanie A1 - Chouraki, Vincent A1 - Kuzma, Amanda B A1 - Sleegers, Kristel A1 - Vronskaya, Maria A1 - Ruiz, Agustin A1 - Graham, Robert R A1 - Olaso, Robert A1 - Hoffmann, Per A1 - Grove, Megan L A1 - Vardarajan, Badri N A1 - Hiltunen, Mikko A1 - Nöthen, Markus M A1 - White, Charles C A1 - Hamilton-Nelson, Kara L A1 - Epelbaum, Jacques A1 - Maier, Wolfgang A1 - Choi, Seung-Hoan A1 - Beecham, Gary W A1 - Dulary, Cécile A1 - Herms, Stefan A1 - Smith, Albert V A1 - Funk, Cory C A1 - Derbois, Céline A1 - Forstner, Andreas J A1 - Ahmad, Shahzad A1 - Li, Hongdong A1 - Bacq, Delphine A1 - Harold, Denise A1 - Satizabal, Claudia L A1 - Valladares, Otto A1 - Squassina, Alessio A1 - Thomas, Rhodri A1 - Brody, Jennifer A A1 - Qu, Liming A1 - Sánchez-Juan, Pascual A1 - Morgan, Taniesha A1 - Wolters, Frank J A1 - Zhao, Yi A1 - Garcia, Florentino Sanchez A1 - Denning, Nicola A1 - Fornage, Myriam A1 - Malamon, John A1 - Naranjo, Maria Candida Deniz A1 - Majounie, Elisa A1 - Mosley, Thomas H A1 - Dombroski, Beth A1 - Wallon, David A1 - Lupton, Michelle K A1 - Dupuis, Josée A1 - Whitehead, Patrice A1 - Fratiglioni, Laura A1 - Medway, Christopher A1 - Jian, Xueqiu A1 - Mukherjee, Shubhabrata A1 - Keller, Lina A1 - Brown, Kristelle A1 - Lin, Honghuang A1 - Cantwell, Laura B A1 - Panza, Francesco A1 - McGuinness, Bernadette A1 - Moreno-Grau, Sonia A1 - Burgess, Jeremy D A1 - Solfrizzi, Vincenzo A1 - Proitsi, Petra A1 - Adams, Hieab H A1 - Allen, Mariet A1 - Seripa, Davide A1 - Pastor, Pau A1 - Cupples, L Adrienne A1 - Price, Nathan D A1 - Hannequin, Didier A1 - Frank-García, Ana A1 - Levy, Daniel A1 - Chakrabarty, Paramita A1 - Caffarra, Paolo A1 - Giegling, Ina A1 - Beiser, Alexa S A1 - Giedraitis, Vilmantas A1 - Hampel, Harald A1 - Garcia, Melissa E A1 - Wang, Xue A1 - Lannfelt, Lars A1 - Mecocci, Patrizia A1 - Eiriksdottir, Gudny A1 - Crane, Paul K A1 - Pasquier, Florence A1 - Boccardi, Virginia A1 - Henández, Isabel A1 - Barber, Robert C A1 - Scherer, Martin A1 - Tarraga, Lluis A1 - Adams, Perrie M A1 - Leber, Markus A1 - Chen, Yuning A1 - Albert, Marilyn S A1 - Riedel-Heller, Steffi A1 - Emilsson, Valur A1 - Beekly, Duane A1 - Braae, Anne A1 - Schmidt, Reinhold A1 - Blacker, Deborah A1 - Masullo, Carlo A1 - Schmidt, Helena A1 - Doody, Rachelle S A1 - Spalletta, Gianfranco A1 - Jr, W T Longstreth A1 - Fairchild, Thomas J A1 - Bossù, Paola A1 - Lopez, Oscar L A1 - Frosch, Matthew P A1 - Sacchinelli, Eleonora A1 - Ghetti, Bernardino A1 - Yang, Qiong A1 - Huebinger, Ryan M A1 - Jessen, Frank A1 - Li, Shuo A1 - Kamboh, M Ilyas A1 - Morris, John A1 - Sotolongo-Grau, Oscar A1 - Katz, Mindy J A1 - Corcoran, Chris A1 - Dunstan, Melanie A1 - Braddel, Amy A1 - Thomas, Charlene A1 - Meggy, Alun A1 - Marshall, Rachel A1 - Gerrish, Amy A1 - Chapman, Jade A1 - Aguilar, Miquel A1 - Taylor, Sarah A1 - Hill, Matt A1 - Fairén, Mònica Díez A1 - Hodges, Angela A1 - Vellas, Bruno A1 - Soininen, Hilkka A1 - Kloszewska, Iwona A1 - Daniilidou, Makrina A1 - Uphill, James A1 - Patel, Yogen A1 - Hughes, Joseph T A1 - Lord, Jenny A1 - Turton, James A1 - Hartmann, Annette M A1 - Cecchetti, Roberta A1 - Fenoglio, Chiara A1 - Serpente, Maria A1 - Arcaro, Marina A1 - Caltagirone, Carlo A1 - Orfei, Maria Donata A1 - Ciaramella, Antonio A1 - Pichler, Sabrina A1 - Mayhaus, Manuel A1 - Gu, Wei A1 - Lleo, Alberto A1 - Fortea, Juan A1 - Blesa, Rafael A1 - Barber, Imelda S A1 - Brookes, Keeley A1 - Cupidi, Chiara A1 - Maletta, Raffaele Giovanni A1 - Carrell, David A1 - Sorbi, Sandro A1 - Moebus, Susanne A1 - Urbano, Maria A1 - Pilotto, Alberto A1 - Kornhuber, Johannes A1 - Bosco, Paolo A1 - Todd, Stephen A1 - Craig, David A1 - Johnston, Janet A1 - Gill, Michael A1 - Lawlor, Brian A1 - Lynch, Aoibhinn A1 - Fox, Nick C A1 - Hardy, John A1 - Albin, Roger L A1 - Apostolova, Liana G A1 - Arnold, Steven E A1 - Asthana, Sanjay A1 - Atwood, Craig S A1 - Baldwin, Clinton T A1 - Barnes, Lisa L A1 - Barral, Sandra A1 - Beach, Thomas G A1 - Becker, James T A1 - Bigio, Eileen H A1 - Bird, Thomas D A1 - Boeve, Bradley F A1 - Bowen, James D A1 - Boxer, Adam A1 - Burke, James R A1 - Burns, Jeffrey M A1 - Buxbaum, Joseph D A1 - Cairns, Nigel J A1 - Cao, Chuanhai A1 - Carlson, Chris S A1 - Carlsson, Cynthia M A1 - Carney, Regina M A1 - Carrasquillo, Minerva M A1 - Carroll, Steven L A1 - Diaz, Carolina Ceballos A1 - Chui, Helena C A1 - Clark, David G A1 - Cribbs, David H A1 - Crocco, Elizabeth A A1 - DeCarli, Charles A1 - Dick, Malcolm A1 - Duara, Ranjan A1 - Evans, Denis A A1 - Faber, Kelley M A1 - Fallon, Kenneth B A1 - Fardo, David W A1 - Farlow, Martin R A1 - Ferris, Steven A1 - Foroud, Tatiana M A1 - Galasko, Douglas R A1 - Gearing, Marla A1 - Geschwind, Daniel H A1 - Gilbert, John R A1 - Graff-Radford, Neill R A1 - Green, Robert C A1 - Growdon, John H A1 - Hamilton, Ronald L A1 - Harrell, Lindy E A1 - Honig, Lawrence S A1 - Huentelman, Matthew J A1 - Hulette, Christine M A1 - Hyman, Bradley T A1 - Jarvik, Gail P A1 - Abner, Erin A1 - Jin, Lee-Way A1 - Jun, Gyungah A1 - Karydas, Anna A1 - Kaye, Jeffrey A A1 - Kim, Ronald A1 - Kowall, Neil W A1 - Kramer, Joel H A1 - LaFerla, Frank M A1 - Lah, James J A1 - Leverenz, James B A1 - Levey, Allan I A1 - Li, Ge A1 - Lieberman, Andrew P A1 - Lunetta, Kathryn L A1 - Lyketsos, Constantine G A1 - Marson, Daniel C A1 - Martiniuk, Frank A1 - Mash, Deborah C A1 - Masliah, Eliezer A1 - McCormick, Wayne C A1 - McCurry, Susan M A1 - McDavid, Andrew N A1 - McKee, Ann C A1 - Mesulam, Marsel A1 - Miller, Bruce L A1 - Miller, Carol A A1 - Miller, Joshua W A1 - Morris, John C A1 - Murrell, Jill R A1 - Myers, Amanda J A1 - O'Bryant, Sid A1 - Olichney, John M A1 - Pankratz, Vernon S A1 - Parisi, Joseph E A1 - Paulson, Henry L A1 - Perry, William A1 - Peskind, Elaine A1 - Pierce, Aimee A1 - Poon, Wayne W A1 - Potter, Huntington A1 - Quinn, Joseph F A1 - Raj, Ashok A1 - Raskind, Murray A1 - Reisberg, Barry A1 - Reitz, Christiane A1 - Ringman, John M A1 - Roberson, Erik D A1 - Rogaeva, Ekaterina A1 - Rosen, Howard J A1 - Rosenberg, Roger N A1 - Sager, Mark A A1 - Saykin, Andrew J A1 - Schneider, Julie A A1 - Schneider, Lon S A1 - Seeley, William W A1 - Smith, Amanda G A1 - Sonnen, Joshua A A1 - Spina, Salvatore A1 - Stern, Robert A A1 - Swerdlow, Russell H A1 - Tanzi, Rudolph E A1 - Thornton-Wells, Tricia A A1 - Trojanowski, John Q A1 - Troncoso, Juan C A1 - Van Deerlin, Vivianna M A1 - Van Eldik, Linda J A1 - Vinters, Harry V A1 - Vonsattel, Jean Paul A1 - Weintraub, Sandra A1 - Welsh-Bohmer, Kathleen A A1 - Wilhelmsen, Kirk C A1 - Williamson, Jennifer A1 - Wingo, Thomas S A1 - Woltjer, Randall L A1 - Wright, Clinton B A1 - Yu, Chang-En A1 - Yu, Lei A1 - Garzia, Fabienne A1 - Golamaully, Feroze A1 - Septier, Gislain A1 - Engelborghs, Sebastien A1 - Vandenberghe, Rik A1 - De Deyn, Peter P A1 - Fernadez, Carmen Muñoz A1 - Benito, Yoland Aladro A1 - Thonberg, Håkan A1 - Forsell, Charlotte A1 - Lilius, Lena A1 - Kinhult-Ståhlbom, Anne A1 - Kilander, Lena A1 - Brundin, RoseMarie A1 - Concari, Letizia A1 - Helisalmi, Seppo A1 - Koivisto, Anne Maria A1 - Haapasalo, Annakaisa A1 - Dermecourt, Vincent A1 - Fiévet, Nathalie A1 - Hanon, Olivier A1 - Dufouil, Carole A1 - Brice, Alexis A1 - Ritchie, Karen A1 - Dubois, Bruno A1 - Himali, Jayanadra J A1 - Keene, C Dirk A1 - Tschanz, JoAnn A1 - Fitzpatrick, Annette L A1 - Kukull, Walter A A1 - Norton, Maria A1 - Aspelund, Thor A1 - Larson, Eric B A1 - Munger, Ron A1 - Rotter, Jerome I A1 - Lipton, Richard B A1 - Bullido, María J A1 - Hofman, Albert A1 - Montine, Thomas J A1 - Coto, Eliecer A1 - Boerwinkle, Eric A1 - Petersen, Ronald C A1 - Alvarez, Victoria A1 - Rivadeneira, Fernando A1 - Reiman, Eric M A1 - Gallo, Maura A1 - O'Donnell, Christopher J A1 - Reisch, Joan S A1 - Bruni, Amalia Cecilia A1 - Royall, Donald R A1 - Dichgans, Martin A1 - Sano, Mary A1 - Galimberti, Daniela A1 - St George-Hyslop, Peter A1 - Scarpini, Elio A1 - Tsuang, Debby W A1 - Mancuso, Michelangelo A1 - Bonuccelli, Ubaldo A1 - Winslow, Ashley R A1 - Daniele, Antonio A1 - Wu, Chuang-Kuo A1 - Peters, Oliver A1 - Nacmias, Benedetta A1 - Riemenschneider, Matthias A1 - Heun, Reinhard A1 - Brayne, Carol A1 - Rubinsztein, David C A1 - Bras, Jose A1 - Guerreiro, Rita A1 - Al-Chalabi, Ammar A1 - Shaw, Christopher E A1 - Collinge, John A1 - Mann, David A1 - Tsolaki, Magda A1 - Clarimon, Jordi A1 - Sussams, Rebecca A1 - Lovestone, Simon A1 - O'Donovan, Michael C A1 - Owen, Michael J A1 - Behrens, Timothy W A1 - Mead, Simon A1 - Goate, Alison M A1 - Uitterlinden, André G A1 - Holmes, Clive A1 - Cruchaga, Carlos A1 - Ingelsson, Martin A1 - Bennett, David A A1 - Powell, John A1 - Golde, Todd E A1 - Graff, Caroline A1 - De Jager, Philip L A1 - Morgan, Kevin A1 - Ertekin-Taner, Nilufer A1 - Combarros, Onofre A1 - Psaty, Bruce M A1 - Passmore, Peter A1 - Younkin, Steven G A1 - Berr, Claudine A1 - Gudnason, Vilmundur A1 - Rujescu, Dan A1 - Dickson, Dennis W A1 - Dartigues, Jean-François A1 - DeStefano, Anita L A1 - Ortega-Cubero, Sara A1 - Hakonarson, Hakon A1 - Campion, Dominique A1 - Boada, Merce A1 - Kauwe, John Keoni A1 - Farrer, Lindsay A A1 - Van Broeckhoven, Christine A1 - Ikram, M Arfan A1 - Jones, Lesley A1 - Haines, Jonathan L A1 - Tzourio, Christophe A1 - Launer, Lenore J A1 - Escott-Price, Valentina A1 - Mayeux, Richard A1 - Deleuze, Jean-Francois A1 - Amin, Najaf A1 - Holmans, Peter A A1 - Pericak-Vance, Margaret A A1 - Amouyel, Philippe A1 - van Duijn, Cornelia M A1 - Ramirez, Alfredo A1 - Wang, Li-San A1 - Lambert, Jean-Charles A1 - Seshadri, Sudha A1 - Williams, Julie A1 - Schellenberg, Gerard D KW - Adaptor Proteins, Signal Transducing KW - Alzheimer Disease KW - Amino Acid Sequence KW - Case-Control Studies KW - Exome KW - Gene Expression Profiling KW - Gene Frequency KW - Genetic Predisposition to Disease KW - Genotype KW - Humans KW - Immunity, Innate KW - Linkage Disequilibrium KW - Membrane Glycoproteins KW - Microglia KW - Odds Ratio KW - Phospholipase C gamma KW - Polymorphism, Single Nucleotide KW - Protein Interaction Maps KW - Receptors, Immunologic KW - Sequence Homology, Amino Acid AB -

We identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10-8) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 × 10-10, odds ratio (OR) = 0.68, minor allele frequency (MAF)cases = 0.0059, MAFcontrols = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10-10, OR = 1.43, MAFcases = 0.011, MAFcontrols = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10-14, OR = 1.67, MAFcases = 0.0143, MAFcontrols = 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.

VL - 49 IS - 9 ER - TY - JOUR T1 - Exome Chip Analysis Identifies Low-Frequency and Rare Variants in for White Matter Hyperintensities on Brain Magnetic Resonance Imaging. JF - Stroke Y1 - 2018 A1 - Jian, Xueqiu A1 - Satizabal, Claudia L A1 - Smith, Albert V A1 - Wittfeld, Katharina A1 - Bis, Joshua C A1 - Smith, Jennifer A A1 - Hsu, Fang-Chi A1 - Nho, Kwangsik A1 - Hofer, Edith A1 - Hagenaars, Saskia P A1 - Nyquist, Paul A A1 - Mishra, Aniket A1 - Adams, Hieab H H A1 - Li, Shuo A1 - Teumer, Alexander A1 - Zhao, Wei A1 - Freedman, Barry I A1 - Saba, Yasaman A1 - Yanek, Lisa R A1 - Chauhan, Ganesh A1 - van Buchem, Mark A A1 - Cushman, Mary A1 - Royle, Natalie A A1 - Bryan, R Nick A1 - Niessen, Wiro J A1 - Windham, Beverly G A1 - DeStefano, Anita L A1 - Habes, Mohamad A1 - Heckbert, Susan R A1 - Palmer, Nicholette D A1 - Lewis, Cora E A1 - Eiriksdottir, Gudny A1 - Maillard, Pauline A1 - Mathias, Rasika A A1 - Homuth, Georg A1 - Valdés-Hernández, Maria Del C A1 - Divers, Jasmin A1 - Beiser, Alexa S A1 - Langner, Sönke A1 - Rice, Kenneth M A1 - Bastin, Mark E A1 - Yang, Qiong A1 - Maldjian, Joseph A A1 - Starr, John M A1 - Sidney, Stephen A1 - Risacher, Shannon L A1 - Uitterlinden, André G A1 - Gudnason, Vilmundur G A1 - Nauck, Matthias A1 - Rotter, Jerome I A1 - Schreiner, Pamela J A1 - Boerwinkle, Eric A1 - van Duijn, Cornelia M A1 - Mazoyer, Bernard A1 - von Sarnowski, Bettina A1 - Gottesman, Rebecca F A1 - Levy, Daniel A1 - Sigurdsson, Sigurdur A1 - Vernooij, Meike W A1 - Turner, Stephen T A1 - Schmidt, Reinhold A1 - Wardlaw, Joanna M A1 - Psaty, Bruce M A1 - Mosley, Thomas H A1 - DeCarli, Charles S A1 - Saykin, Andrew J A1 - Bowden, Donald W A1 - Becker, Diane M A1 - Deary, Ian J A1 - Schmidt, Helena A1 - Kardia, Sharon L R A1 - Ikram, M Arfan A1 - Debette, Stephanie A1 - Grabe, Hans J A1 - Longstreth, W T A1 - Seshadri, Sudha A1 - Launer, Lenore J A1 - Fornage, Myriam AB -

BACKGROUND AND PURPOSE: White matter hyperintensities (WMH) on brain magnetic resonance imaging are typical signs of cerebral small vessel disease and may indicate various preclinical, age-related neurological disorders, such as stroke. Though WMH are highly heritable, known common variants explain a small proportion of the WMH variance. The contribution of low-frequency/rare coding variants to WMH burden has not been explored.

METHODS: In the discovery sample we recruited 20 719 stroke/dementia-free adults from 13 population-based cohort studies within the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, among which 17 790 were of European ancestry and 2929 of African ancestry. We genotyped these participants at ≈250 000 mostly exonic variants with Illumina HumanExome BeadChip arrays. We performed ethnicity-specific linear regression on rank-normalized WMH in each study separately, which were then combined in meta-analyses to test for association with single variants and genes aggregating the effects of putatively functional low-frequency/rare variants. We then sought replication of the top findings in 1192 adults (European ancestry) with whole exome/genome sequencing data from 2 independent studies.

RESULTS: At 17q25, we confirmed the association of multiple common variants in , , and (<6×10). We also identified a novel association with 2 low-frequency nonsynonymous variants in (lead, rs34136221; =4.5×10) partially independent of known common signal (=1.4×10). We further identified a locus at 2q33 containing common variants in , , and (lead, rs2351524; =1.9×10). Although our novel findings were not replicated because of limited power and possible differences in study design, meta-analysis of the discovery and replication samples yielded stronger association for the 2 low-frequency variants (=2.8×10).

CONCLUSIONS: Both common and low-frequency/rare functional variants influence WMH. Larger replication and experimental follow-up are essential to confirm our findings and uncover the biological causal mechanisms of age-related WMH.

ER - TY - JOUR T1 - Genome-wide analyses identify a role for SLC17A4 and AADAT in thyroid hormone regulation. JF - Nat Commun Y1 - 2018 A1 - Teumer, Alexander A1 - Chaker, Layal A1 - Groeneweg, Stefan A1 - Li, Yong A1 - Di Munno, Celia A1 - Barbieri, Caterina A1 - Schultheiss, Ulla T A1 - Traglia, Michela A1 - Ahluwalia, Tarunveer S A1 - Akiyama, Masato A1 - Appel, Emil Vincent R A1 - Arking, Dan E A1 - Arnold, Alice A1 - Astrup, Arne A1 - Beekman, Marian A1 - Beilby, John P A1 - Bekaert, Sofie A1 - Boerwinkle, Eric A1 - Brown, Suzanne J A1 - De Buyzere, Marc A1 - Campbell, Purdey J A1 - Ceresini, Graziano A1 - Cerqueira, Charlotte A1 - Cucca, Francesco A1 - Deary, Ian J A1 - Deelen, Joris A1 - Eckardt, Kai-Uwe A1 - Ekici, Arif B A1 - Eriksson, Johan G A1 - Ferrrucci, Luigi A1 - Fiers, Tom A1 - Fiorillo, Edoardo A1 - Ford, Ian A1 - Fox, Caroline S A1 - Fuchsberger, Christian A1 - Galesloot, Tessel E A1 - Gieger, Christian A1 - Gögele, Martin A1 - De Grandi, Alessandro A1 - Grarup, Niels A1 - Greiser, Karin Halina A1 - Haljas, Kadri A1 - Hansen, Torben A1 - Harris, Sarah E A1 - van Heemst, Diana A1 - den Heijer, Martin A1 - Hicks, Andrew A A1 - den Hollander, Wouter A1 - Homuth, Georg A1 - Hui, Jennie A1 - Ikram, M Arfan A1 - Ittermann, Till A1 - Jensen, Richard A A1 - Jing, Jiaojiao A1 - Jukema, J Wouter A1 - Kajantie, Eero A1 - Kamatani, Yoichiro A1 - Kasbohm, Elisa A1 - Kaufman, Jean-Marc A1 - Kiemeney, Lambertus A A1 - Kloppenburg, Margreet A1 - Kronenberg, Florian A1 - Kubo, Michiaki A1 - Lahti, Jari A1 - Lapauw, Bruno A1 - Li, Shuo A1 - Liewald, David C M A1 - Lim, Ee Mun A1 - Linneberg, Allan A1 - Marina, Michela A1 - Mascalzoni, Deborah A1 - Matsuda, Koichi A1 - Medenwald, Daniel A1 - Meisinger, Christa A1 - Meulenbelt, Ingrid A1 - De Meyer, Tim A1 - Meyer zu Schwabedissen, Henriette E A1 - Mikolajczyk, Rafael A1 - Moed, Matthijs A1 - Netea-Maier, Romana T A1 - Nolte, Ilja M A1 - Okada, Yukinori A1 - Pala, Mauro A1 - Pattaro, Cristian A1 - Pedersen, Oluf A1 - Petersmann, Astrid A1 - Porcu, Eleonora A1 - Postmus, Iris A1 - Pramstaller, Peter P A1 - Psaty, Bruce M A1 - Ramos, Yolande F M A1 - Rawal, Rajesh A1 - Redmond, Paul A1 - Richards, J Brent A1 - Rietzschel, Ernst R A1 - Rivadeneira, Fernando A1 - Roef, Greet A1 - Rotter, Jerome I A1 - Sala, Cinzia F A1 - Schlessinger, David A1 - Selvin, Elizabeth A1 - Slagboom, P Eline A1 - Soranzo, Nicole A1 - Sørensen, Thorkild I A A1 - Spector, Timothy D A1 - Starr, John M A1 - Stott, David J A1 - Taes, Youri A1 - Taliun, Daniel A1 - Tanaka, Toshiko A1 - Thuesen, Betina A1 - Tiller, Daniel A1 - Toniolo, Daniela A1 - Uitterlinden, André G A1 - Visser, W Edward A1 - Walsh, John P A1 - Wilson, Scott G A1 - Wolffenbuttel, Bruce H R A1 - Yang, Qiong A1 - Zheng, Hou-Feng A1 - Cappola, Anne A1 - Peeters, Robin P A1 - Naitza, Silvia A1 - Völzke, Henry A1 - Sanna, Serena A1 - Köttgen, Anna A1 - Visser, Theo J A1 - Medici, Marco AB -

Thyroid dysfunction is an important public health problem, which affects 10% of the general population and increases the risk of cardiovascular morbidity and mortality. Many aspects of thyroid hormone regulation have only partly been elucidated, including its transport, metabolism, and genetic determinants. Here we report a large meta-analysis of genome-wide association studies for thyroid function and dysfunction, testing 8 million genetic variants in up to 72,167 individuals. One-hundred-and-nine independent genetic variants are associated with these traits. A genetic risk score, calculated to assess their combined effects on clinical end points, shows significant associations with increased risk of both overt (Graves' disease) and subclinical thyroid disease, as well as clinical complications. By functional follow-up on selected signals, we identify a novel thyroid hormone transporter (SLC17A4) and a metabolizing enzyme (AADAT). Together, these results provide new knowledge about thyroid hormone physiology and disease, opening new possibilities for therapeutic targets.

VL - 9 IS - 1 ER - TY - JOUR T1 - Genome-wide association study of 23,500 individuals identifies 7 loci associated with brain ventricular volume. JF - Nat Commun Y1 - 2018 A1 - Vojinovic, Dina A1 - Adams, Hieab H A1 - Jian, Xueqiu A1 - Yang, Qiong A1 - Smith, Albert Vernon A1 - Bis, Joshua C A1 - Teumer, Alexander A1 - Scholz, Markus A1 - Armstrong, Nicola J A1 - Hofer, Edith A1 - Saba, Yasaman A1 - Luciano, Michelle A1 - Bernard, Manon A1 - Trompet, Stella A1 - Yang, Jingyun A1 - Gillespie, Nathan A A1 - van der Lee, Sven J A1 - Neumann, Alexander A1 - Ahmad, Shahzad A1 - Andreassen, Ole A A1 - Ames, David A1 - Amin, Najaf A1 - Arfanakis, Konstantinos A1 - Bastin, Mark E A1 - Becker, Diane M A1 - Beiser, Alexa S A1 - Beyer, Frauke A1 - Brodaty, Henry A1 - Bryan, R Nick A1 - Bülow, Robin A1 - Dale, Anders M A1 - De Jager, Philip L A1 - Deary, Ian J A1 - DeCarli, Charles A1 - Fleischman, Debra A A1 - Gottesman, Rebecca F A1 - van der Grond, Jeroen A1 - Gudnason, Vilmundur A1 - Harris, Tamara B A1 - Homuth, Georg A1 - Knopman, David S A1 - Kwok, John B A1 - Lewis, Cora E A1 - Li, Shuo A1 - Loeffler, Markus A1 - Lopez, Oscar L A1 - Maillard, Pauline A1 - El Marroun, Hanan A1 - Mather, Karen A A1 - Mosley, Thomas H A1 - Muetzel, Ryan L A1 - Nauck, Matthias A1 - Nyquist, Paul A A1 - Panizzon, Matthew S A1 - Pausova, Zdenka A1 - Psaty, Bruce M A1 - Rice, Ken A1 - Rotter, Jerome I A1 - Royle, Natalie A1 - Satizabal, Claudia L A1 - Schmidt, Reinhold A1 - Schofield, Peter R A1 - Schreiner, Pamela J A1 - Sidney, Stephen A1 - Stott, David J A1 - Thalamuthu, Anbupalam A1 - Uitterlinden, André G A1 - Valdés Hernández, Maria C A1 - Vernooij, Meike W A1 - Wen, Wei A1 - White, Tonya A1 - Witte, A Veronica A1 - Wittfeld, Katharina A1 - Wright, Margaret J A1 - Yanek, Lisa R A1 - Tiemeier, Henning A1 - Kremen, William S A1 - Bennett, David A A1 - Jukema, J Wouter A1 - Paus, Tomáš A1 - Wardlaw, Joanna M A1 - Schmidt, Helena A1 - Sachdev, Perminder S A1 - Villringer, Arno A1 - Grabe, Hans Jörgen A1 - Longstreth, W T A1 - van Duijn, Cornelia M A1 - Launer, Lenore J A1 - Seshadri, Sudha A1 - Ikram, M Arfan A1 - Fornage, Myriam AB -

The volume of the lateral ventricles (LV) increases with age and their abnormal enlargement is a key feature of several neurological and psychiatric diseases. Although lateral ventricular volume is heritable, a comprehensive investigation of its genetic determinants is lacking. In this meta-analysis of genome-wide association studies of 23,533 healthy middle-aged to elderly individuals from 26 population-based cohorts, we identify 7 genetic loci associated with LV volume. These loci map to chromosomes 3q28, 7p22.3, 10p12.31, 11q23.1, 12q23.3, 16q24.2, and 22q13.1 and implicate pathways related to tau pathology, S1P signaling, and cytoskeleton organization. We also report a significant genetic overlap between the thalamus and LV volumes (ρ = -0.59, p-value = 3.14 × 10), suggesting that these brain structures may share a common biology. These genetic associations of LV volume provide insights into brain morphology.

VL - 9 IS - 1 ER - TY - JOUR T1 - Large-scale whole-exome sequencing association studies identify rare functional variants influencing serum urate levels. JF - Nat Commun Y1 - 2018 A1 - Tin, Adrienne A1 - Li, Yong A1 - Brody, Jennifer A A1 - Nutile, Teresa A1 - Chu, Audrey Y A1 - Huffman, Jennifer E A1 - Yang, Qiong A1 - Chen, Ming-Huei A1 - Robinson-Cohen, Cassianne A1 - Mace, Aurelien A1 - Liu, Jun A1 - Demirkan, Ayse A1 - Sorice, Rossella A1 - Sedaghat, Sanaz A1 - Swen, Melody A1 - Yu, Bing A1 - Ghasemi, Sahar A1 - Teumer, Alexanda A1 - Vollenweider, Peter A1 - Ciullo, Marina A1 - Li, Meng A1 - Uitterlinden, André G A1 - Kraaij, Robert A1 - Amin, Najaf A1 - van Rooij, Jeroen A1 - Kutalik, Zoltán A1 - Dehghan, Abbas A1 - McKnight, Barbara A1 - van Duijn, Cornelia M A1 - Morrison, Alanna A1 - Psaty, Bruce M A1 - Boerwinkle, Eric A1 - Fox, Caroline S A1 - Woodward, Owen M A1 - Köttgen, Anna KW - Exome KW - Genetic Predisposition to Disease KW - Glucose Transport Proteins, Facilitative KW - Humans KW - Kidney Function Tests KW - Meta-Analysis as Topic KW - Organic Anion Transporters KW - Organic Cation Transport Proteins KW - Protein Structure, Secondary KW - Uric Acid AB -

Elevated serum urate levels can cause gout, an excruciating disease with suboptimal treatment. Previous GWAS identified common variants with modest effects on serum urate. Here we report large-scale whole-exome sequencing association studies of serum urate and kidney function among ≤19,517 European ancestry and African-American individuals. We identify aggregate associations of low-frequency damaging variants in the urate transporters SLC22A12 (URAT1; p = 1.3 × 10) and SLC2A9 (p = 4.5 × 10). Gout risk in rare SLC22A12 variant carriers is halved (OR = 0.5, p = 4.9 × 10). Selected rare variants in SLC22A12 are validated in transport studies, confirming three as loss-of-function (R325W, R405C, and T467M) and illustrating the therapeutic potential of the new URAT1-blocker lesinurad. In SLC2A9, mapping of rare variants of large effects onto the predicted protein structure reveals new residues that may affect urate binding. These findings provide new insights into the genetic architecture of serum urate, and highlight molecular targets in SLC22A12 and SLC2A9 for lowering serum urate and preventing gout.

VL - 9 IS - 1 ER - TY - JOUR T1 - Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes. JF - Nat Genet Y1 - 2018 A1 - Malik, Rainer A1 - Chauhan, Ganesh A1 - Traylor, Matthew A1 - Sargurupremraj, Muralidharan A1 - Okada, Yukinori A1 - Mishra, Aniket A1 - Rutten-Jacobs, Loes A1 - Giese, Anne-Katrin A1 - van der Laan, Sander W A1 - Gretarsdottir, Solveig A1 - Anderson, Christopher D A1 - Chong, Michael A1 - Adams, Hieab H H A1 - Ago, Tetsuro A1 - Almgren, Peter A1 - Amouyel, Philippe A1 - Ay, Hakan A1 - Bartz, Traci M A1 - Benavente, Oscar R A1 - Bevan, Steve A1 - Boncoraglio, Giorgio B A1 - Brown, Robert D A1 - Butterworth, Adam S A1 - Carrera, Caty A1 - Carty, Cara L A1 - Chasman, Daniel I A1 - Chen, Wei-Min A1 - Cole, John W A1 - Correa, Adolfo A1 - Cotlarciuc, Ioana A1 - Cruchaga, Carlos A1 - Danesh, John A1 - de Bakker, Paul I W A1 - DeStefano, Anita L A1 - den Hoed, Marcel A1 - Duan, Qing A1 - Engelter, Stefan T A1 - Falcone, Guido J A1 - Gottesman, Rebecca F A1 - Grewal, Raji P A1 - Gudnason, Vilmundur A1 - Gustafsson, Stefan A1 - Haessler, Jeffrey A1 - Harris, Tamara B A1 - Hassan, Ahamad A1 - Havulinna, Aki S A1 - Heckbert, Susan R A1 - Holliday, Elizabeth G A1 - Howard, George A1 - Hsu, Fang-Chi A1 - Hyacinth, Hyacinth I A1 - Ikram, M Arfan A1 - Ingelsson, Erik A1 - Irvin, Marguerite R A1 - Jian, Xueqiu A1 - Jimenez-Conde, Jordi A1 - Johnson, Julie A A1 - Jukema, J Wouter A1 - Kanai, Masahiro A1 - Keene, Keith L A1 - Kissela, Brett M A1 - Kleindorfer, Dawn O A1 - Kooperberg, Charles A1 - Kubo, Michiaki A1 - Lange, Leslie A A1 - Langefeld, Carl D A1 - Langenberg, Claudia A1 - Launer, Lenore J A1 - Lee, Jin-Moo A1 - Lemmens, Robin A1 - Leys, Didier A1 - Lewis, Cathryn M A1 - Lin, Wei-Yu A1 - Lindgren, Arne G A1 - Lorentzen, Erik A1 - Magnusson, Patrik K A1 - Maguire, Jane A1 - Manichaikul, Ani A1 - McArdle, Patrick F A1 - Meschia, James F A1 - Mitchell, Braxton D A1 - Mosley, Thomas H A1 - Nalls, Michael A A1 - Ninomiya, Toshiharu A1 - O'Donnell, Martin J A1 - Psaty, Bruce M A1 - Pulit, Sara L A1 - Rannikmae, Kristiina A1 - Reiner, Alexander P A1 - Rexrode, Kathryn M A1 - Rice, Kenneth A1 - Rich, Stephen S A1 - Ridker, Paul M A1 - Rost, Natalia S A1 - Rothwell, Peter M A1 - Rotter, Jerome I A1 - Rundek, Tatjana A1 - Sacco, Ralph L A1 - Sakaue, Saori A1 - Sale, Michèle M A1 - Salomaa, Veikko A1 - Sapkota, Bishwa R A1 - Schmidt, Reinhold A1 - Schmidt, Carsten O A1 - Schminke, Ulf A1 - Sharma, Pankaj A1 - Slowik, Agnieszka A1 - Sudlow, Cathie L M A1 - Tanislav, Christian A1 - Tatlisumak, Turgut A1 - Taylor, Kent D A1 - Thijs, Vincent N S A1 - Thorleifsson, Gudmar A1 - Thorsteinsdottir, Unnur A1 - Tiedt, Steffen A1 - Trompet, Stella A1 - Tzourio, Christophe A1 - van Duijn, Cornelia M A1 - Walters, Matthew A1 - Wareham, Nicholas J A1 - Wassertheil-Smoller, Sylvia A1 - Wilson, James G A1 - Wiggins, Kerri L A1 - Yang, Qiong A1 - Yusuf, Salim A1 - Bis, Joshua C A1 - Pastinen, Tomi A1 - Ruusalepp, Arno A1 - Schadt, Eric E A1 - Koplev, Simon A1 - Björkegren, Johan L M A1 - Codoni, Veronica A1 - Civelek, Mete A1 - Smith, Nicholas L A1 - Trégouët, David A A1 - Christophersen, Ingrid E A1 - Roselli, Carolina A1 - Lubitz, Steven A A1 - Ellinor, Patrick T A1 - Tai, E Shyong A1 - Kooner, Jaspal S A1 - Kato, Norihiro A1 - He, Jiang A1 - van der Harst, Pim A1 - Elliott, Paul A1 - Chambers, John C A1 - Takeuchi, Fumihiko A1 - Johnson, Andrew D A1 - Sanghera, Dharambir K A1 - Melander, Olle A1 - Jern, Christina A1 - Strbian, Daniel A1 - Fernandez-Cadenas, Israel A1 - Longstreth, W T A1 - Rolfs, Arndt A1 - Hata, Jun A1 - Woo, Daniel A1 - Rosand, Jonathan A1 - Paré, Guillaume A1 - Hopewell, Jemma C A1 - Saleheen, Danish A1 - Stefansson, Kari A1 - Worrall, Bradford B A1 - Kittner, Steven J A1 - Seshadri, Sudha A1 - Fornage, Myriam A1 - Markus, Hugh S A1 - Howson, Joanna M M A1 - Kamatani, Yoichiro A1 - Debette, Stephanie A1 - Dichgans, Martin A1 - Malik, Rainer A1 - Chauhan, Ganesh A1 - Traylor, Matthew A1 - Sargurupremraj, Muralidharan A1 - Okada, Yukinori A1 - Mishra, Aniket A1 - Rutten-Jacobs, Loes A1 - Giese, Anne-Katrin A1 - van der Laan, Sander W A1 - Gretarsdottir, Solveig A1 - Anderson, Christopher D A1 - Chong, Michael A1 - Adams, Hieab H H A1 - Ago, Tetsuro A1 - Almgren, Peter A1 - Amouyel, Philippe A1 - Ay, Hakan A1 - Bartz, Traci M A1 - Benavente, Oscar R A1 - Bevan, Steve A1 - Boncoraglio, Giorgio B A1 - Brown, Robert D A1 - Butterworth, Adam S A1 - Carrera, Caty A1 - Carty, Cara L A1 - Chasman, Daniel I A1 - Chen, Wei-Min A1 - Cole, John W A1 - Correa, Adolfo A1 - Cotlarciuc, Ioana A1 - Cruchaga, Carlos A1 - Danesh, John A1 - de Bakker, Paul I W A1 - DeStefano, Anita L A1 - Hoed, Marcel den A1 - Duan, Qing A1 - Engelter, Stefan T A1 - Falcone, Guido J A1 - Gottesman, Rebecca F A1 - Grewal, Raji P A1 - Gudnason, Vilmundur A1 - Gustafsson, Stefan A1 - Haessler, Jeffrey A1 - Harris, Tamara B A1 - Hassan, Ahamad A1 - Havulinna, Aki S A1 - Heckbert, Susan R A1 - Holliday, Elizabeth G A1 - Howard, George A1 - Hsu, Fang-Chi A1 - Hyacinth, Hyacinth I A1 - Ikram, M Arfan A1 - Ingelsson, Erik A1 - Irvin, Marguerite R A1 - Jian, Xueqiu A1 - Jimenez-Conde, Jordi A1 - Johnson, Julie A A1 - Jukema, J Wouter A1 - Kanai, Masahiro A1 - Keene, Keith L A1 - Kissela, Brett M A1 - Kleindorfer, Dawn O A1 - Kooperberg, Charles A1 - Kubo, Michiaki A1 - Lange, Leslie A A1 - Langefeld, Carl D A1 - Langenberg, Claudia A1 - Launer, Lenore J A1 - Lee, Jin-Moo A1 - Lemmens, Robin A1 - Leys, Didier A1 - Lewis, Cathryn M A1 - Lin, Wei-Yu A1 - Lindgren, Arne G A1 - Lorentzen, Erik A1 - Magnusson, Patrik K A1 - Maguire, Jane A1 - Manichaikul, Ani A1 - McArdle, Patrick F A1 - Meschia, James F A1 - Mitchell, Braxton D A1 - Mosley, Thomas H A1 - Nalls, Michael A A1 - Ninomiya, Toshiharu A1 - O'Donnell, Martin J A1 - Psaty, Bruce M A1 - Pulit, Sara L A1 - Rannikmae, Kristiina A1 - Reiner, Alexander P A1 - Rexrode, Kathryn M A1 - Rice, Kenneth A1 - Rich, Stephen S A1 - Ridker, Paul M A1 - Rost, Natalia S A1 - Rothwell, Peter M A1 - Rotter, Jerome I A1 - Rundek, Tatjana A1 - Sacco, Ralph L A1 - Sakaue, Saori A1 - Sale, Michèle M A1 - Salomaa, Veikko A1 - Sapkota, Bishwa R A1 - Schmidt, Reinhold A1 - Schmidt, Carsten O A1 - Schminke, Ulf A1 - Sharma, Pankaj A1 - Slowik, Agnieszka A1 - Sudlow, Cathie L M A1 - Tanislav, Christian A1 - Tatlisumak, Turgut A1 - Taylor, Kent D A1 - Thijs, Vincent N S A1 - Thorleifsson, Gudmar A1 - Thorsteinsdottir, Unnur A1 - Tiedt, Steffen A1 - Trompet, Stella A1 - Tzourio, Christophe A1 - van Duijn, Cornelia M A1 - Walters, Matthew A1 - Wareham, Nicholas J A1 - Wassertheil-Smoller, Sylvia A1 - Wilson, James G A1 - Wiggins, Kerri L A1 - Yang, Qiong A1 - Yusuf, Salim A1 - Amin, Najaf A1 - Aparicio, Hugo S A1 - Arnett, Donna K A1 - Attia, John A1 - Beiser, Alexa S A1 - Berr, Claudine A1 - Buring, Julie E A1 - Bustamante, Mariana A1 - Caso, Valeria A1 - Cheng, Yu-Ching A1 - Choi, Seung Hoan A1 - Chowhan, Ayesha A1 - Cullell, Natalia A1 - Dartigues, Jean-François A1 - Delavaran, Hossein A1 - Delgado, Pilar A1 - Dörr, Marcus A1 - Engström, Gunnar A1 - Ford, Ian A1 - Gurpreet, Wander S A1 - Hamsten, Anders A1 - Heitsch, Laura A1 - Hozawa, Atsushi A1 - Ibanez, Laura A1 - Ilinca, Andreea A1 - Ingelsson, Martin A1 - Iwasaki, Motoki A1 - Jackson, Rebecca D A1 - Jood, Katarina A1 - Jousilahti, Pekka A1 - Kaffashian, Sara A1 - Kalra, Lalit A1 - Kamouchi, Masahiro A1 - Kitazono, Takanari A1 - Kjartansson, Olafur A1 - Kloss, Manja A1 - Koudstaal, Peter J A1 - Krupinski, Jerzy A1 - Labovitz, Daniel L A1 - Laurie, Cathy C A1 - Levi, Christopher R A1 - Li, Linxin A1 - Lind, Lars A1 - Lindgren, Cecilia M A1 - Lioutas, Vasileios A1 - Liu, Yong Mei A1 - Lopez, Oscar L A1 - Makoto, Hirata A1 - Martinez-Majander, Nicolas A1 - Matsuda, Koichi A1 - Minegishi, Naoko A1 - Montaner, Joan A1 - Morris, Andrew P A1 - Muiño, Elena A1 - Müller-Nurasyid, Martina A1 - Norrving, Bo A1 - Ogishima, Soichi A1 - Parati, Eugenio A A1 - Peddareddygari, Leema Reddy A1 - Pedersen, Nancy L A1 - Pera, Joanna A1 - Perola, Markus A1 - Pezzini, Alessandro A1 - Pileggi, Silvana A1 - Rabionet, Raquel A1 - Riba-Llena, Iolanda A1 - Ribasés, Marta A1 - Romero, Jose R A1 - Roquer, Jaume A1 - Rudd, Anthony G A1 - Sarin, Antti-Pekka A1 - Sarju, Ralhan A1 - Sarnowski, Chloe A1 - Sasaki, Makoto A1 - Satizabal, Claudia L A1 - Satoh, Mamoru A1 - Sattar, Naveed A1 - Sawada, Norie A1 - Sibolt, Gerli A1 - Sigurdsson, Ásgeir A1 - Smith, Albert A1 - Sobue, Kenji A1 - Soriano-Tárraga, Carolina A1 - Stanne, Tara A1 - Stine, O Colin A1 - Stott, David J A1 - Strauch, Konstantin A1 - Takai, Takako A1 - Tanaka, Hideo A1 - Tanno, Kozo A1 - Teumer, Alexander A1 - Tomppo, Liisa A1 - Torres-Aguila, Nuria P A1 - Touze, Emmanuel A1 - Tsugane, Shoichiro A1 - Uitterlinden, André G A1 - Valdimarsson, Einar M A1 - van der Lee, Sven J A1 - Völzke, Henry A1 - Wakai, Kenji A1 - Weir, David A1 - Williams, Stephen R A1 - Wolfe, Charles D A A1 - Wong, Quenna A1 - Xu, Huichun A1 - Yamaji, Taiki A1 - Sanghera, Dharambir K A1 - Melander, Olle A1 - Jern, Christina A1 - Strbian, Daniel A1 - Fernandez-Cadenas, Israel A1 - Longstreth, W T A1 - Rolfs, Arndt A1 - Hata, Jun A1 - Woo, Daniel A1 - Rosand, Jonathan A1 - Paré, Guillaume A1 - Hopewell, Jemma C A1 - Saleheen, Danish A1 - Stefansson, Kari A1 - Worrall, Bradford B A1 - Kittner, Steven J A1 - Seshadri, Sudha A1 - Fornage, Myriam A1 - Markus, Hugh S A1 - Howson, Joanna M M A1 - Kamatani, Yoichiro A1 - Debette, Stephanie A1 - Dichgans, Martin AB -

Stroke has multiple etiologies, but the underlying genes and pathways are largely unknown. We conducted a multiancestry genome-wide-association meta-analysis in 521,612 individuals (67,162 cases and 454,450 controls) and discovered 22 new stroke risk loci, bringing the total to 32. We further found shared genetic variation with related vascular traits, including blood pressure, cardiac traits, and venous thromboembolism, at individual loci (n = 18), and using genetic risk scores and linkage-disequilibrium-score regression. Several loci exhibited distinct association and pleiotropy patterns for etiological stroke subtypes. Eleven new susceptibility loci indicate mechanisms not previously implicated in stroke pathophysiology, with prioritization of risk variants and genes accomplished through bioinformatics analyses using extensive functional datasets. Stroke risk loci were significantly enriched in drug targets for antithrombotic therapy.

VL - 50 IS - 4 ER - TY - JOUR T1 - Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function. JF - Nat Commun Y1 - 2018 A1 - Davies, Gail A1 - Lam, Max A1 - Harris, Sarah E A1 - Trampush, Joey W A1 - Luciano, Michelle A1 - Hill, W David A1 - Hagenaars, Saskia P A1 - Ritchie, Stuart J A1 - Marioni, Riccardo E A1 - Fawns-Ritchie, Chloe A1 - Liewald, David C M A1 - Okely, Judith A A1 - Ahola-Olli, Ari V A1 - Barnes, Catriona L K A1 - Bertram, Lars A1 - Bis, Joshua C A1 - Burdick, Katherine E A1 - Christoforou, Andrea A1 - DeRosse, Pamela A1 - Djurovic, Srdjan A1 - Espeseth, Thomas A1 - Giakoumaki, Stella A1 - Giddaluru, Sudheer A1 - Gustavson, Daniel E A1 - Hayward, Caroline A1 - Hofer, Edith A1 - Ikram, M Arfan A1 - Karlsson, Robert A1 - Knowles, Emma A1 - Lahti, Jari A1 - Leber, Markus A1 - Li, Shuo A1 - Mather, Karen A A1 - Melle, Ingrid A1 - Morris, Derek A1 - Oldmeadow, Christopher A1 - Palviainen, Teemu A1 - Payton, Antony A1 - Pazoki, Raha A1 - Petrovic, Katja A1 - Reynolds, Chandra A A1 - Sargurupremraj, Muralidharan A1 - Scholz, Markus A1 - Smith, Jennifer A A1 - Smith, Albert V A1 - Terzikhan, Natalie A1 - Thalamuthu, Anbupalam A1 - Trompet, Stella A1 - van der Lee, Sven J A1 - Ware, Erin B A1 - Windham, B Gwen A1 - Wright, Margaret J A1 - Yang, Jingyun A1 - Yu, Jin A1 - Ames, David A1 - Amin, Najaf A1 - Amouyel, Philippe A1 - Andreassen, Ole A A1 - Armstrong, Nicola J A1 - Assareh, Amelia A A1 - Attia, John R A1 - Attix, Deborah A1 - Avramopoulos, Dimitrios A1 - Bennett, David A A1 - Böhmer, Anne C A1 - Boyle, Patricia A A1 - Brodaty, Henry A1 - Campbell, Harry A1 - Cannon, Tyrone D A1 - Cirulli, Elizabeth T A1 - Congdon, Eliza A1 - Conley, Emily Drabant A1 - Corley, Janie A1 - Cox, Simon R A1 - Dale, Anders M A1 - Dehghan, Abbas A1 - Dick, Danielle A1 - Dickinson, Dwight A1 - Eriksson, Johan G A1 - Evangelou, Evangelos A1 - Faul, Jessica D A1 - Ford, Ian A1 - Freimer, Nelson A A1 - Gao, He A1 - Giegling, Ina A1 - Gillespie, Nathan A A1 - Gordon, Scott D A1 - Gottesman, Rebecca F A1 - Griswold, Michael E A1 - Gudnason, Vilmundur A1 - Harris, Tamara B A1 - Hartmann, Annette M A1 - Hatzimanolis, Alex A1 - Heiss, Gerardo A1 - Holliday, Elizabeth G A1 - Joshi, Peter K A1 - Kähönen, Mika A1 - Kardia, Sharon L R A1 - Karlsson, Ida A1 - Kleineidam, Luca A1 - Knopman, David S A1 - Kochan, Nicole A A1 - Konte, Bettina A1 - Kwok, John B A1 - Le Hellard, Stephanie A1 - Lee, Teresa A1 - Lehtimäki, Terho A1 - Li, Shu-Chen A1 - Liu, Tian A1 - Koini, Marisa A1 - London, Edythe A1 - Longstreth, Will T A1 - Lopez, Oscar L A1 - Loukola, Anu A1 - Luck, Tobias A1 - Lundervold, Astri J A1 - Lundquist, Anders A1 - Lyytikäinen, Leo-Pekka A1 - Martin, Nicholas G A1 - Montgomery, Grant W A1 - Murray, Alison D A1 - Need, Anna C A1 - Noordam, Raymond A1 - Nyberg, Lars A1 - Ollier, William A1 - Papenberg, Goran A1 - Pattie, Alison A1 - Polasek, Ozren A1 - Poldrack, Russell A A1 - Psaty, Bruce M A1 - Reppermund, Simone A1 - Riedel-Heller, Steffi G A1 - Rose, Richard J A1 - Rotter, Jerome I A1 - Roussos, Panos A1 - Rovio, Suvi P A1 - Saba, Yasaman A1 - Sabb, Fred W A1 - Sachdev, Perminder S A1 - Satizabal, Claudia L A1 - Schmid, Matthias A1 - Scott, Rodney J A1 - Scult, Matthew A A1 - Simino, Jeannette A1 - Slagboom, P Eline A1 - Smyrnis, Nikolaos A1 - Soumaré, Aïcha A1 - Stefanis, Nikos C A1 - Stott, David J A1 - Straub, Richard E A1 - Sundet, Kjetil A1 - Taylor, Adele M A1 - Taylor, Kent D A1 - Tzoulaki, Ioanna A1 - Tzourio, Christophe A1 - Uitterlinden, Andre A1 - Vitart, Veronique A1 - Voineskos, Aristotle N A1 - Kaprio, Jaakko A1 - Wagner, Michael A1 - Wagner, Holger A1 - Weinhold, Leonie A1 - Wen, K Hoyan A1 - Widen, Elisabeth A1 - Yang, Qiong A1 - Zhao, Wei A1 - Adams, Hieab H H A1 - Arking, Dan E A1 - Bilder, Robert M A1 - Bitsios, Panos A1 - Boerwinkle, Eric A1 - Chiba-Falek, Ornit A1 - Corvin, Aiden A1 - De Jager, Philip L A1 - Debette, Stephanie A1 - Donohoe, Gary A1 - Elliott, Paul A1 - Fitzpatrick, Annette L A1 - Gill, Michael A1 - Glahn, David C A1 - Hägg, Sara A1 - Hansell, Narelle K A1 - Hariri, Ahmad R A1 - Ikram, M Kamran A1 - Jukema, J Wouter A1 - Vuoksimaa, Eero A1 - Keller, Matthew C A1 - Kremen, William S A1 - Launer, Lenore A1 - Lindenberger, Ulman A1 - Palotie, Aarno A1 - Pedersen, Nancy L A1 - Pendleton, Neil A1 - Porteous, David J A1 - Räikkönen, Katri A1 - Raitakari, Olli T A1 - Ramirez, Alfredo A1 - Reinvang, Ivar A1 - Rudan, Igor A1 - Schmidt, Reinhold A1 - Schmidt, Helena A1 - Schofield, Peter W A1 - Schofield, Peter R A1 - Starr, John M A1 - Steen, Vidar M A1 - Trollor, Julian N A1 - Turner, Steven T A1 - van Duijn, Cornelia M A1 - Villringer, Arno A1 - Weinberger, Daniel R A1 - Weir, David R A1 - Wilson, James F A1 - Malhotra, Anil A1 - McIntosh, Andrew M A1 - Gale, Catharine R A1 - Seshadri, Sudha A1 - Mosley, Thomas H A1 - Bressler, Jan A1 - Lencz, Todd A1 - Deary, Ian J AB -

General cognitive function is a prominent and relatively stable human trait that is associated with many important life outcomes. We combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300,486; age 16-102) and find 148 genome-wide significant independent loci (P < 5 × 10) associated with general cognitive function. Within the novel genetic loci are variants associated with neurodegenerative and neurodevelopmental disorders, physical and psychiatric illnesses, and brain structure. Gene-based analyses find 709 genes associated with general cognitive function. Expression levels across the cortex are associated with general cognitive function. Using polygenic scores, up to 4.3% of variance in general cognitive function is predicted in independent samples. We detect significant genetic overlap between general cognitive function, reaction time, and many health variables including eyesight, hypertension, and longevity. In conclusion we identify novel genetic loci and pathways contributing to the heritability of general cognitive function.

VL - 9 IS - 1 ER - TY - JOUR T1 - Association of variants in HTRA1 and NOTCH3 with MRI-defined extremes of cerebral small vessel disease in older subjects. JF - Brain Y1 - 2019 A1 - Mishra, Aniket A1 - Chauhan, Ganesh A1 - Violleau, Marie-Helene A1 - Vojinovic, Dina A1 - Jian, Xueqiu A1 - Bis, Joshua C A1 - Li, Shuo A1 - Saba, Yasaman A1 - Grenier-Boley, Benjamin A1 - Yang, Qiong A1 - Bartz, Traci M A1 - Hofer, Edith A1 - Soumaré, Aïcha A1 - Peng, Fen A1 - Duperron, Marie-Gabrielle A1 - Foglio, Mario A1 - Mosley, Thomas H A1 - Schmidt, Reinhold A1 - Psaty, Bruce M A1 - Launer, Lenore J A1 - Boerwinkle, Eric A1 - Zhu, Yicheng A1 - Mazoyer, Bernard A1 - Lathrop, Mark A1 - Bellenguez, Céline A1 - van Duijn, Cornelia M A1 - Ikram, M Arfan A1 - Schmidt, Helena A1 - Longstreth, W T A1 - Fornage, Myriam A1 - Seshadri, Sudha A1 - Joutel, Anne A1 - Tzourio, Christophe A1 - Debette, Stephanie AB -

We report a composite extreme phenotype design using distribution of white matter hyperintensities and brain infarcts in a population-based cohort of older persons for gene-mapping of cerebral small vessel disease. We demonstrate its application in the 3C-Dijon whole exome sequencing (WES) study (n = 1924, nWESextremes = 512), with both single variant and gene-based association tests. We used other population-based cohort studies participating in the CHARGE consortium for replication, using whole exome sequencing (nWES = 2,868, nWESextremes = 956) and genome-wide genotypes (nGW = 9924, nGWextremes = 3308). We restricted our study to candidate genes known to harbour mutations for Mendelian small vessel disease: NOTCH3, HTRA1, COL4A1, COL4A2 and TREX1. We identified significant associations of a common intronic variant in HTRA1, rs2293871 using single variant association testing (Pdiscovery = 8.21 × 10-5, Preplication = 5.25 × 10-3, Pcombined = 4.72 × 10-5) and of NOTCH3 using gene-based tests (Pdiscovery = 1.61 × 10-2, Preplication = 3.99 × 10-2, Pcombined = 5.31 × 10-3). Follow-up analysis identified significant association of rs2293871 with small vessel ischaemic stroke, and two blood expression quantitative trait loci of HTRA1 in linkage disequilibrium. Additionally, we identified two participants in the 3C-Dijon cohort (0.4%) carrying heterozygote genotypes at known pathogenic variants for familial small vessel disease within NOTCH3 and HTRA1. In conclusion, our proof-of-concept study provides strong evidence that using a novel composite MRI-derived phenotype for extremes of small vessel disease can facilitate the identification of genetic variants underlying small vessel disease, both common variants and those with rare and low frequency. The findings demonstrate shared mechanisms and a continuum between genes underlying Mendelian small vessel disease and those contributing to the common, multifactorial form of the disease.

ER - TY - JOUR T1 - A catalog of genetic loci associated with kidney function from analyses of a million individuals. JF - Nat Genet Y1 - 2019 A1 - Wuttke, Matthias A1 - Li, Yong A1 - Li, Man A1 - Sieber, Karsten B A1 - Feitosa, Mary F A1 - Gorski, Mathias A1 - Tin, Adrienne A1 - Wang, Lihua A1 - Chu, Audrey Y A1 - Hoppmann, Anselm A1 - Kirsten, Holger A1 - Giri, Ayush A1 - Chai, Jin-Fang A1 - Sveinbjornsson, Gardar A1 - Tayo, Bamidele O A1 - Nutile, Teresa A1 - Fuchsberger, Christian A1 - Marten, Jonathan A1 - Cocca, Massimiliano A1 - Ghasemi, Sahar A1 - Xu, Yizhe A1 - Horn, Katrin A1 - Noce, Damia A1 - van der Most, Peter J A1 - Sedaghat, Sanaz A1 - Yu, Zhi A1 - Akiyama, Masato A1 - Afaq, Saima A1 - Ahluwalia, Tarunveer S A1 - Almgren, Peter A1 - Amin, Najaf A1 - Arnlöv, Johan A1 - Bakker, Stephan J L A1 - Bansal, Nisha A1 - Baptista, Daniela A1 - Bergmann, Sven A1 - Biggs, Mary L A1 - Biino, Ginevra A1 - Boehnke, Michael A1 - Boerwinkle, Eric A1 - Boissel, Mathilde A1 - Bottinger, Erwin P A1 - Boutin, Thibaud S A1 - Brenner, Hermann A1 - Brumat, Marco A1 - Burkhardt, Ralph A1 - Butterworth, Adam S A1 - Campana, Eric A1 - Campbell, Archie A1 - Campbell, Harry A1 - Canouil, Mickaël A1 - Carroll, Robert J A1 - Catamo, Eulalia A1 - Chambers, John C A1 - Chee, Miao-Ling A1 - Chee, Miao-Li A1 - Chen, Xu A1 - Cheng, Ching-Yu A1 - Cheng, Yurong A1 - Christensen, Kaare A1 - Cifkova, Renata A1 - Ciullo, Marina A1 - Concas, Maria Pina A1 - Cook, James P A1 - Coresh, Josef A1 - Corre, Tanguy A1 - Sala, Cinzia Felicita A1 - Cusi, Daniele A1 - Danesh, John A1 - Daw, E Warwick A1 - de Borst, Martin H A1 - De Grandi, Alessandro A1 - de Mutsert, Renée A1 - de Vries, Aiko P J A1 - Degenhardt, Frauke A1 - Delgado, Graciela A1 - Demirkan, Ayse A1 - Di Angelantonio, Emanuele A1 - Dittrich, Katalin A1 - Divers, Jasmin A1 - Dorajoo, Rajkumar A1 - Eckardt, Kai-Uwe A1 - Ehret, Georg A1 - Elliott, Paul A1 - Endlich, Karlhans A1 - Evans, Michele K A1 - Felix, Janine F A1 - Foo, Valencia Hui Xian A1 - Franco, Oscar H A1 - Franke, Andre A1 - Freedman, Barry I A1 - Freitag-Wolf, Sandra A1 - Friedlander, Yechiel A1 - Froguel, Philippe A1 - Gansevoort, Ron T A1 - Gao, He A1 - Gasparini, Paolo A1 - Gaziano, J Michael A1 - Giedraitis, Vilmantas A1 - Gieger, Christian A1 - Girotto, Giorgia A1 - Giulianini, Franco A1 - Gögele, Martin A1 - Gordon, Scott D A1 - Gudbjartsson, Daniel F A1 - Gudnason, Vilmundur A1 - Haller, Toomas A1 - Hamet, Pavel A1 - Harris, Tamara B A1 - Hartman, Catharina A A1 - Hayward, Caroline A1 - Hellwege, Jacklyn N A1 - Heng, Chew-Kiat A1 - Hicks, Andrew A A1 - Hofer, Edith A1 - Huang, Wei A1 - Hutri-Kähönen, Nina A1 - Hwang, Shih-Jen A1 - Ikram, M Arfan A1 - Indridason, Olafur S A1 - Ingelsson, Erik A1 - Ising, Marcus A1 - Jaddoe, Vincent W V A1 - Jakobsdottir, Johanna A1 - Jonas, Jost B A1 - Joshi, Peter K A1 - Josyula, Navya Shilpa A1 - Jung, Bettina A1 - Kähönen, Mika A1 - Kamatani, Yoichiro A1 - Kammerer, Candace M A1 - Kanai, Masahiro A1 - Kastarinen, Mika A1 - Kerr, Shona M A1 - Khor, Chiea-Chuen A1 - Kiess, Wieland A1 - Kleber, Marcus E A1 - Koenig, Wolfgang A1 - Kooner, Jaspal S A1 - Körner, Antje A1 - Kovacs, Peter A1 - Kraja, Aldi T A1 - Krajcoviechova, Alena A1 - Kramer, Holly A1 - Krämer, Bernhard K A1 - Kronenberg, Florian A1 - Kubo, Michiaki A1 - Kuhnel, Brigitte A1 - Kuokkanen, Mikko A1 - Kuusisto, Johanna A1 - La Bianca, Martina A1 - Laakso, Markku A1 - Lange, Leslie A A1 - Langefeld, Carl D A1 - Lee, Jeannette Jen-Mai A1 - Lehne, Benjamin A1 - Lehtimäki, Terho A1 - Lieb, Wolfgang A1 - Lim, Su-Chi A1 - Lind, Lars A1 - Lindgren, Cecilia M A1 - Liu, Jun A1 - Liu, Jianjun A1 - Loeffler, Markus A1 - Loos, Ruth J F A1 - Lucae, Susanne A1 - Lukas, Mary Ann A1 - Lyytikäinen, Leo-Pekka A1 - Mägi, Reedik A1 - Magnusson, Patrik K E A1 - Mahajan, Anubha A1 - Martin, Nicholas G A1 - Martins, Jade A1 - März, Winfried A1 - Mascalzoni, Deborah A1 - Matsuda, Koichi A1 - Meisinger, Christa A1 - Meitinger, Thomas A1 - Melander, Olle A1 - Metspalu, Andres A1 - Mikaelsdottir, Evgenia K A1 - Milaneschi, Yuri A1 - Miliku, Kozeta A1 - Mishra, Pashupati P A1 - Mohlke, Karen L A1 - Mononen, Nina A1 - Montgomery, Grant W A1 - Mook-Kanamori, Dennis O A1 - Mychaleckyj, Josyf C A1 - Nadkarni, Girish N A1 - Nalls, Mike A A1 - Nauck, Matthias A1 - Nikus, Kjell A1 - Ning, Boting A1 - Nolte, Ilja M A1 - Noordam, Raymond A1 - O'Connell, Jeffrey A1 - O'Donoghue, Michelle L A1 - Olafsson, Isleifur A1 - Oldehinkel, Albertine J A1 - Orho-Melander, Marju A1 - Ouwehand, Willem H A1 - Padmanabhan, Sandosh A1 - Palmer, Nicholette D A1 - Palsson, Runolfur A1 - Penninx, Brenda W J H A1 - Perls, Thomas A1 - Perola, Markus A1 - Pirastu, Mario A1 - Pirastu, Nicola A1 - Pistis, Giorgio A1 - Podgornaia, Anna I A1 - Polasek, Ozren A1 - Ponte, Belen A1 - Porteous, David J A1 - Poulain, Tanja A1 - Pramstaller, Peter P A1 - Preuss, Michael H A1 - Prins, Bram P A1 - Province, Michael A A1 - Rabelink, Ton J A1 - Raffield, Laura M A1 - Raitakari, Olli T A1 - Reilly, Dermot F A1 - Rettig, Rainer A1 - Rheinberger, Myriam A1 - Rice, Kenneth M A1 - Ridker, Paul M A1 - Rivadeneira, Fernando A1 - Rizzi, Federica A1 - Roberts, David J A1 - Robino, Antonietta A1 - Rossing, Peter A1 - Rudan, Igor A1 - Rueedi, Rico A1 - Ruggiero, Daniela A1 - Ryan, Kathleen A A1 - Saba, Yasaman A1 - Sabanayagam, Charumathi A1 - Salomaa, Veikko A1 - Salvi, Erika A1 - Saum, Kai-Uwe A1 - Schmidt, Helena A1 - Schmidt, Reinhold A1 - Schöttker, Ben A1 - Schulz, Christina-Alexandra A1 - Schupf, Nicole A1 - Shaffer, Christian M A1 - Shi, Yuan A1 - Smith, Albert V A1 - Smith, Blair H A1 - Soranzo, Nicole A1 - Spracklen, Cassandra N A1 - Strauch, Konstantin A1 - Stringham, Heather M A1 - Stumvoll, Michael A1 - Svensson, Per O A1 - Szymczak, Silke A1 - Tai, E-Shyong A1 - Tajuddin, Salman M A1 - Tan, Nicholas Y Q A1 - Taylor, Kent D A1 - Teren, Andrej A1 - Tham, Yih-Chung A1 - Thiery, Joachim A1 - Thio, Chris H L A1 - Thomsen, Hauke A1 - Thorleifsson, Gudmar A1 - Toniolo, Daniela A1 - Tönjes, Anke A1 - Tremblay, Johanne A1 - Tzoulaki, Ioanna A1 - Uitterlinden, André G A1 - Vaccargiu, Simona A1 - van Dam, Rob M A1 - van der Harst, Pim A1 - van Duijn, Cornelia M A1 - Velez Edward, Digna R A1 - Verweij, Niek A1 - Vogelezang, Suzanne A1 - Völker, Uwe A1 - Vollenweider, Peter A1 - Waeber, Gérard A1 - Waldenberger, Melanie A1 - Wallentin, Lars A1 - Wang, Ya Xing A1 - Wang, Chaolong A1 - Waterworth, Dawn M A1 - Bin Wei, Wen A1 - White, Harvey A1 - Whitfield, John B A1 - Wild, Sarah H A1 - Wilson, James F A1 - Wojczynski, Mary K A1 - Wong, Charlene A1 - Wong, Tien-Yin A1 - Xu, Liang A1 - Yang, Qiong A1 - Yasuda, Masayuki A1 - Yerges-Armstrong, Laura M A1 - Zhang, Weihua A1 - Zonderman, Alan B A1 - Rotter, Jerome I A1 - Bochud, Murielle A1 - Psaty, Bruce M A1 - Vitart, Veronique A1 - Wilson, James G A1 - Dehghan, Abbas A1 - Parsa, Afshin A1 - Chasman, Daniel I A1 - Ho, Kevin A1 - Morris, Andrew P A1 - Devuyst, Olivier A1 - Akilesh, Shreeram A1 - Pendergrass, Sarah A A1 - Sim, Xueling A1 - Böger, Carsten A A1 - Okada, Yukinori A1 - Edwards, Todd L A1 - Snieder, Harold A1 - Stefansson, Kari A1 - Hung, Adriana M A1 - Heid, Iris M A1 - Scholz, Markus A1 - Teumer, Alexander A1 - Köttgen, Anna A1 - Pattaro, Cristian KW - Chromosome Mapping KW - European Continental Ancestry Group KW - Genetic Association Studies KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Glomerular Filtration Rate KW - Humans KW - Inheritance Patterns KW - Kidney Function Tests KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci KW - Quantitative Trait, Heritable KW - Renal Insufficiency, Chronic KW - Uromodulin AB -

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.

VL - 51 IS - 6 ER - TY - JOUR T1 - Genetic architecture of subcortical brain structures in 38,851 individuals. JF - Nat Genet Y1 - 2019 A1 - Satizabal, Claudia L A1 - Adams, Hieab H H A1 - Hibar, Derrek P A1 - White, Charles C A1 - Knol, Maria J A1 - Stein, Jason L A1 - Scholz, Markus A1 - Sargurupremraj, Muralidharan A1 - Jahanshad, Neda A1 - Roshchupkin, Gennady V A1 - Smith, Albert V A1 - Bis, Joshua C A1 - Jian, Xueqiu A1 - Luciano, Michelle A1 - Hofer, Edith A1 - Teumer, Alexander A1 - van der Lee, Sven J A1 - Yang, Jingyun A1 - Yanek, Lisa R A1 - Lee, Tom V A1 - Li, Shuo A1 - Hu, Yanhui A1 - Koh, Jia Yu A1 - Eicher, John D A1 - Desrivières, Sylvane A1 - Arias-Vasquez, Alejandro A1 - Chauhan, Ganesh A1 - Athanasiu, Lavinia A1 - Rentería, Miguel E A1 - Kim, Sungeun A1 - Hoehn, David A1 - Armstrong, Nicola J A1 - Chen, Qiang A1 - Holmes, Avram J A1 - den Braber, Anouk A1 - Kloszewska, Iwona A1 - Andersson, Micael A1 - Espeseth, Thomas A1 - Grimm, Oliver A1 - Abramovic, Lucija A1 - Alhusaini, Saud A1 - Milaneschi, Yuri A1 - Papmeyer, Martina A1 - Axelsson, Tomas A1 - Ehrlich, Stefan A1 - Roiz-Santiañez, Roberto A1 - Kraemer, Bernd A1 - Håberg, Asta K A1 - Jones, Hannah J A1 - Pike, G Bruce A1 - Stein, Dan J A1 - Stevens, Allison A1 - Bralten, Janita A1 - Vernooij, Meike W A1 - Harris, Tamara B A1 - Filippi, Irina A1 - Witte, A Veronica A1 - Guadalupe, Tulio A1 - Wittfeld, Katharina A1 - Mosley, Thomas H A1 - Becker, James T A1 - Doan, Nhat Trung A1 - Hagenaars, Saskia P A1 - Saba, Yasaman A1 - Cuellar-Partida, Gabriel A1 - Amin, Najaf A1 - Hilal, Saima A1 - Nho, Kwangsik A1 - Mirza-Schreiber, Nazanin A1 - Arfanakis, Konstantinos A1 - Becker, Diane M A1 - Ames, David A1 - Goldman, Aaron L A1 - Lee, Phil H A1 - Boomsma, Dorret I A1 - Lovestone, Simon A1 - Giddaluru, Sudheer A1 - Le Hellard, Stephanie A1 - Mattheisen, Manuel A1 - Bohlken, Marc M A1 - Kasperaviciute, Dalia A1 - Schmaal, Lianne A1 - Lawrie, Stephen M A1 - Agartz, Ingrid A1 - Walton, Esther A1 - Tordesillas-Gutierrez, Diana A1 - Davies, Gareth E A1 - Shin, Jean A1 - Ipser, Jonathan C A1 - Vinke, Louis N A1 - Hoogman, Martine A1 - Jia, Tianye A1 - Burkhardt, Ralph A1 - Klein, Marieke A1 - Crivello, Fabrice A1 - Janowitz, Deborah A1 - Carmichael, Owen A1 - Haukvik, Unn K A1 - Aribisala, Benjamin S A1 - Schmidt, Helena A1 - Strike, Lachlan T A1 - Cheng, Ching-Yu A1 - Risacher, Shannon L A1 - Pütz, Benno A1 - Fleischman, Debra A A1 - Assareh, Amelia A A1 - Mattay, Venkata S A1 - Buckner, Randy L A1 - Mecocci, Patrizia A1 - Dale, Anders M A1 - Cichon, Sven A1 - Boks, Marco P A1 - Matarin, Mar A1 - Penninx, Brenda W J H A1 - Calhoun, Vince D A1 - Chakravarty, M Mallar A1 - Marquand, Andre F A1 - Macare, Christine A1 - Kharabian Masouleh, Shahrzad A1 - Oosterlaan, Jaap A1 - Amouyel, Philippe A1 - Hegenscheid, Katrin A1 - Rotter, Jerome I A1 - Schork, Andrew J A1 - Liewald, David C M A1 - de Zubicaray, Greig I A1 - Wong, Tien Yin A1 - Shen, Li A1 - Sämann, Philipp G A1 - Brodaty, Henry A1 - Roffman, Joshua L A1 - de Geus, Eco J C A1 - Tsolaki, Magda A1 - Erk, Susanne A1 - van Eijk, Kristel R A1 - Cavalleri, Gianpiero L A1 - van der Wee, Nic J A A1 - McIntosh, Andrew M A1 - Gollub, Randy L A1 - Bulayeva, Kazima B A1 - Bernard, Manon A1 - Richards, Jennifer S A1 - Himali, Jayandra J A1 - Loeffler, Markus A1 - Rommelse, Nanda A1 - Hoffmann, Wolfgang A1 - Westlye, Lars T A1 - Valdés Hernández, Maria C A1 - Hansell, Narelle K A1 - van Erp, Theo G M A1 - Wolf, Christiane A1 - Kwok, John B J A1 - Vellas, Bruno A1 - Heinz, Andreas A1 - Olde Loohuis, Loes M A1 - Delanty, Norman A1 - Ho, Beng-Choon A1 - Ching, Christopher R K A1 - Shumskaya, Elena A1 - Singh, Baljeet A1 - Hofman, Albert A1 - van der Meer, Dennis A1 - Homuth, Georg A1 - Psaty, Bruce M A1 - Bastin, Mark E A1 - Montgomery, Grant W A1 - Foroud, Tatiana M A1 - Reppermund, Simone A1 - Hottenga, Jouke-Jan A1 - Simmons, Andrew A1 - Meyer-Lindenberg, Andreas A1 - Cahn, Wiepke A1 - Whelan, Christopher D A1 - van Donkelaar, Marjolein M J A1 - Yang, Qiong A1 - Hosten, Norbert A1 - Green, Robert C A1 - Thalamuthu, Anbupalam A1 - Mohnke, Sebastian A1 - Hulshoff Pol, Hilleke E A1 - Lin, Honghuang A1 - Jack, Clifford R A1 - Schofield, Peter R A1 - Mühleisen, Thomas W A1 - Maillard, Pauline A1 - Potkin, Steven G A1 - Wen, Wei A1 - Fletcher, Evan A1 - Toga, Arthur W A1 - Gruber, Oliver A1 - Huentelman, Matthew A1 - Davey Smith, George A1 - Launer, Lenore J A1 - Nyberg, Lars A1 - Jönsson, Erik G A1 - Crespo-Facorro, Benedicto A1 - Koen, Nastassja A1 - Greve, Douglas N A1 - Uitterlinden, André G A1 - Weinberger, Daniel R A1 - Steen, Vidar M A1 - Fedko, Iryna O A1 - Groenewold, Nynke A A1 - Niessen, Wiro J A1 - Toro, Roberto A1 - Tzourio, Christophe A1 - Longstreth, William T A1 - Ikram, M Kamran A1 - Smoller, Jordan W A1 - van Tol, Marie-Jose A1 - Sussmann, Jessika E A1 - Paus, Tomáš A1 - Lemaître, Hervé A1 - Schroeter, Matthias L A1 - Mazoyer, Bernard A1 - Andreassen, Ole A A1 - Holsboer, Florian A1 - Depondt, Chantal A1 - Veltman, Dick J A1 - Turner, Jessica A A1 - Pausova, Zdenka A1 - Schumann, Gunter A1 - van Rooij, Daan A1 - Djurovic, Srdjan A1 - Deary, Ian J A1 - McMahon, Katie L A1 - Müller-Myhsok, Bertram A1 - Brouwer, Rachel M A1 - Soininen, Hilkka A1 - Pandolfo, Massimo A1 - Wassink, Thomas H A1 - Cheung, Joshua W A1 - Wolfers, Thomas A1 - Martinot, Jean-Luc A1 - Zwiers, Marcel P A1 - Nauck, Matthias A1 - Melle, Ingrid A1 - Martin, Nicholas G A1 - Kanai, Ryota A1 - Westman, Eric A1 - Kahn, René S A1 - Sisodiya, Sanjay M A1 - White, Tonya A1 - Saremi, Arvin A1 - van Bokhoven, Hans A1 - Brunner, Han G A1 - Völzke, Henry A1 - Wright, Margaret J A1 - van 't Ent, Dennis A1 - Nöthen, Markus M A1 - Ophoff, Roel A A1 - Buitelaar, Jan K A1 - Fernández, Guillén A1 - Sachdev, Perminder S A1 - Rietschel, Marcella A1 - van Haren, Neeltje E M A1 - Fisher, Simon E A1 - Beiser, Alexa S A1 - Francks, Clyde A1 - Saykin, Andrew J A1 - Mather, Karen A A1 - Romanczuk-Seiferth, Nina A1 - Hartman, Catharina A A1 - DeStefano, Anita L A1 - Heslenfeld, Dirk J A1 - Weiner, Michael W A1 - Walter, Henrik A1 - Hoekstra, Pieter J A1 - Nyquist, Paul A A1 - Franke, Barbara A1 - Bennett, David A A1 - Grabe, Hans J A1 - Johnson, Andrew D A1 - Chen, Christopher A1 - van Duijn, Cornelia M A1 - Lopez, Oscar L A1 - Fornage, Myriam A1 - Wardlaw, Joanna M A1 - Schmidt, Reinhold A1 - DeCarli, Charles A1 - De Jager, Philip L A1 - Villringer, Arno A1 - Debette, Stephanie A1 - Gudnason, Vilmundur A1 - Medland, Sarah E A1 - Shulman, Joshua M A1 - Thompson, Paul M A1 - Seshadri, Sudha A1 - Ikram, M Arfan AB -

Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.

VL - 51 IS - 11 ER - TY - JOUR T1 - Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing. JF - Nat Genet Y1 - 2019 A1 - Kunkle, Brian W A1 - Grenier-Boley, Benjamin A1 - Sims, Rebecca A1 - Bis, Joshua C A1 - Damotte, Vincent A1 - Naj, Adam C A1 - Boland, Anne A1 - Vronskaya, Maria A1 - van der Lee, Sven J A1 - Amlie-Wolf, Alexandre A1 - Bellenguez, Céline A1 - Frizatti, Aura A1 - Chouraki, Vincent A1 - Martin, Eden R A1 - Sleegers, Kristel A1 - Badarinarayan, Nandini A1 - Jakobsdottir, Johanna A1 - Hamilton-Nelson, Kara L A1 - Moreno-Grau, Sonia A1 - Olaso, Robert A1 - Raybould, Rachel A1 - Chen, Yuning A1 - Kuzma, Amanda B A1 - Hiltunen, Mikko A1 - Morgan, Taniesha A1 - Ahmad, Shahzad A1 - Vardarajan, Badri N A1 - Epelbaum, Jacques A1 - Hoffmann, Per A1 - Boada, Merce A1 - Beecham, Gary W A1 - Garnier, Jean-Guillaume A1 - Harold, Denise A1 - Fitzpatrick, Annette L A1 - Valladares, Otto A1 - Moutet, Marie-Laure A1 - Gerrish, Amy A1 - Smith, Albert V A1 - Qu, Liming A1 - Bacq, Delphine A1 - Denning, Nicola A1 - Jian, Xueqiu A1 - Zhao, Yi A1 - Del Zompo, Maria A1 - Fox, Nick C A1 - Choi, Seung-Hoan A1 - Mateo, Ignacio A1 - Hughes, Joseph T A1 - Adams, Hieab H A1 - Malamon, John A1 - Sanchez-Garcia, Florentino A1 - Patel, Yogen A1 - Brody, Jennifer A A1 - Dombroski, Beth A A1 - Naranjo, Maria Candida Deniz A1 - Daniilidou, Makrina A1 - Eiriksdottir, Gudny A1 - Mukherjee, Shubhabrata A1 - Wallon, David A1 - Uphill, James A1 - Aspelund, Thor A1 - Cantwell, Laura B A1 - Garzia, Fabienne A1 - Galimberti, Daniela A1 - Hofer, Edith A1 - Butkiewicz, Mariusz A1 - Fin, Bertrand A1 - Scarpini, Elio A1 - Sarnowski, Chloe A1 - Bush, Will S A1 - Meslage, Stéphane A1 - Kornhuber, Johannes A1 - White, Charles C A1 - Song, Yuenjoo A1 - Barber, Robert C A1 - Engelborghs, Sebastiaan A1 - Sordon, Sabrina A1 - Voijnovic, Dina A1 - Adams, Perrie M A1 - Vandenberghe, Rik A1 - Mayhaus, Manuel A1 - Cupples, L Adrienne A1 - Albert, Marilyn S A1 - De Deyn, Peter P A1 - Gu, Wei A1 - Himali, Jayanadra J A1 - Beekly, Duane A1 - Squassina, Alessio A1 - Hartmann, Annette M A1 - Orellana, Adelina A1 - Blacker, Deborah A1 - Rodriguez-Rodriguez, Eloy A1 - Lovestone, Simon A1 - Garcia, Melissa E A1 - Doody, Rachelle S A1 - Munoz-Fernadez, Carmen A1 - Sussams, Rebecca A1 - Lin, Honghuang A1 - Fairchild, Thomas J A1 - Benito, Yolanda A A1 - Holmes, Clive A1 - Karamujić-Čomić, Hata A1 - Frosch, Matthew P A1 - Thonberg, Håkan A1 - Maier, Wolfgang A1 - Roschupkin, Gena A1 - Ghetti, Bernardino A1 - Giedraitis, Vilmantas A1 - Kawalia, Amit A1 - Li, Shuo A1 - Huebinger, Ryan M A1 - Kilander, Lena A1 - Moebus, Susanne A1 - Hernandez, Isabel A1 - Kamboh, M Ilyas A1 - Brundin, RoseMarie A1 - Turton, James A1 - Yang, Qiong A1 - Katz, Mindy J A1 - Concari, Letizia A1 - Lord, Jenny A1 - Beiser, Alexa S A1 - Keene, C Dirk A1 - Helisalmi, Seppo A1 - Kloszewska, Iwona A1 - Kukull, Walter A A1 - Koivisto, Anne Maria A1 - Lynch, Aoibhinn A1 - Tarraga, Lluis A1 - Larson, Eric B A1 - Haapasalo, Annakaisa A1 - Lawlor, Brian A1 - Mosley, Thomas H A1 - Lipton, Richard B A1 - Solfrizzi, Vincenzo A1 - Gill, Michael A1 - Longstreth, W T A1 - Montine, Thomas J A1 - Frisardi, Vincenza A1 - Diez-Fairen, Monica A1 - Rivadeneira, Fernando A1 - Petersen, Ronald C A1 - Deramecourt, Vincent A1 - Alvarez, Ignacio A1 - Salani, Francesca A1 - Ciaramella, Antonio A1 - Boerwinkle, Eric A1 - Reiman, Eric M A1 - Fiévet, Nathalie A1 - Rotter, Jerome I A1 - Reisch, Joan S A1 - Hanon, Olivier A1 - Cupidi, Chiara A1 - Andre Uitterlinden, A G A1 - Royall, Donald R A1 - Dufouil, Carole A1 - Maletta, Raffaele Giovanni A1 - de Rojas, Itziar A1 - Sano, Mary A1 - Brice, Alexis A1 - Cecchetti, Roberta A1 - George-Hyslop, Peter St A1 - Ritchie, Karen A1 - Tsolaki, Magda A1 - Tsuang, Debby W A1 - Dubois, Bruno A1 - Craig, David A1 - Wu, Chuang-Kuo A1 - Soininen, Hilkka A1 - Avramidou, Despoina A1 - Albin, Roger L A1 - Fratiglioni, Laura A1 - Germanou, Antonia A1 - Apostolova, Liana G A1 - Keller, Lina A1 - Koutroumani, Maria A1 - Arnold, Steven E A1 - Panza, Francesco A1 - Gkatzima, Olymbia A1 - Asthana, Sanjay A1 - Hannequin, Didier A1 - Whitehead, Patrice A1 - Atwood, Craig S A1 - Caffarra, Paolo A1 - Hampel, Harald A1 - Quintela, Inés A1 - Carracedo, Angel A1 - Lannfelt, Lars A1 - Rubinsztein, David C A1 - Barnes, Lisa L A1 - Pasquier, Florence A1 - Frölich, Lutz A1 - Barral, Sandra A1 - McGuinness, Bernadette A1 - Beach, Thomas G A1 - Johnston, Janet A A1 - Becker, James T A1 - Passmore, Peter A1 - Bigio, Eileen H A1 - Schott, Jonathan M A1 - Bird, Thomas D A1 - Warren, Jason D A1 - Boeve, Bradley F A1 - Lupton, Michelle K A1 - Bowen, James D A1 - Proitsi, Petra A1 - Boxer, Adam A1 - Powell, John F A1 - Burke, James R A1 - Kauwe, John S K A1 - Burns, Jeffrey M A1 - Mancuso, Michelangelo A1 - Buxbaum, Joseph D A1 - Bonuccelli, Ubaldo A1 - Cairns, Nigel J A1 - McQuillin, Andrew A1 - Cao, Chuanhai A1 - Livingston, Gill A1 - Carlson, Chris S A1 - Bass, Nicholas J A1 - Carlsson, Cynthia M A1 - Hardy, John A1 - Carney, Regina M A1 - Bras, Jose A1 - Carrasquillo, Minerva M A1 - Guerreiro, Rita A1 - Allen, Mariet A1 - Chui, Helena C A1 - Fisher, Elizabeth A1 - Masullo, Carlo A1 - Crocco, Elizabeth A A1 - DeCarli, Charles A1 - Bisceglio, Gina A1 - Dick, Malcolm A1 - Ma, Li A1 - Duara, Ranjan A1 - Graff-Radford, Neill R A1 - Evans, Denis A A1 - Hodges, Angela A1 - Faber, Kelley M A1 - Scherer, Martin A1 - Fallon, Kenneth B A1 - Riemenschneider, Matthias A1 - Fardo, David W A1 - Heun, Reinhard A1 - Farlow, Martin R A1 - Kölsch, Heike A1 - Ferris, Steven A1 - Leber, Markus A1 - Foroud, Tatiana M A1 - Heuser, Isabella A1 - Galasko, Douglas R A1 - Giegling, Ina A1 - Gearing, Marla A1 - Hüll, Michael A1 - Geschwind, Daniel H A1 - Gilbert, John R A1 - Morris, John A1 - Green, Robert C A1 - Mayo, Kevin A1 - Growdon, John H A1 - Feulner, Thomas A1 - Hamilton, Ronald L A1 - Harrell, Lindy E A1 - Drichel, Dmitriy A1 - Honig, Lawrence S A1 - Cushion, Thomas D A1 - Huentelman, Matthew J A1 - Hollingworth, Paul A1 - Hulette, Christine M A1 - Hyman, Bradley T A1 - Marshall, Rachel A1 - Jarvik, Gail P A1 - Meggy, Alun A1 - Abner, Erin A1 - Menzies, Georgina E A1 - Jin, Lee-Way A1 - Leonenko, Ganna A1 - Real, Luis M A1 - Jun, Gyungah R A1 - Baldwin, Clinton T A1 - Grozeva, Detelina A1 - Karydas, Anna A1 - Russo, Giancarlo A1 - Kaye, Jeffrey A A1 - Kim, Ronald A1 - Jessen, Frank A1 - Kowall, Neil W A1 - Vellas, Bruno A1 - Kramer, Joel H A1 - Vardy, Emma A1 - LaFerla, Frank M A1 - Jöckel, Karl-Heinz A1 - Lah, James J A1 - Dichgans, Martin A1 - Leverenz, James B A1 - Mann, David A1 - Levey, Allan I A1 - Pickering-Brown, Stuart A1 - Lieberman, Andrew P A1 - Klopp, Norman A1 - Lunetta, Kathryn L A1 - Wichmann, H-Erich A1 - Lyketsos, Constantine G A1 - Morgan, Kevin A1 - Marson, Daniel C A1 - Brown, Kristelle A1 - Martiniuk, Frank A1 - Medway, Christopher A1 - Mash, Deborah C A1 - Nöthen, Markus M A1 - Masliah, Eliezer A1 - Hooper, Nigel M A1 - McCormick, Wayne C A1 - Daniele, Antonio A1 - McCurry, Susan M A1 - Bayer, Anthony A1 - McDavid, Andrew N A1 - Gallacher, John A1 - McKee, Ann C A1 - van den Bussche, Hendrik A1 - Mesulam, Marsel A1 - Brayne, Carol A1 - Miller, Bruce L A1 - Riedel-Heller, Steffi A1 - Miller, Carol A A1 - Miller, Joshua W A1 - Al-Chalabi, Ammar A1 - Morris, John C A1 - Shaw, Christopher E A1 - Myers, Amanda J A1 - Wiltfang, Jens A1 - O'Bryant, Sid A1 - Olichney, John M A1 - Alvarez, Victoria A1 - Parisi, Joseph E A1 - Singleton, Andrew B A1 - Paulson, Henry L A1 - Collinge, John A1 - Perry, William R A1 - Mead, Simon A1 - Peskind, Elaine A1 - Cribbs, David H A1 - Rossor, Martin A1 - Pierce, Aimee A1 - Ryan, Natalie S A1 - Poon, Wayne W A1 - Nacmias, Benedetta A1 - Potter, Huntington A1 - Sorbi, Sandro A1 - Quinn, Joseph F A1 - Sacchinelli, Eleonora A1 - Raj, Ashok A1 - Spalletta, Gianfranco A1 - Raskind, Murray A1 - Caltagirone, Carlo A1 - Bossù, Paola A1 - Orfei, Maria Donata A1 - Reisberg, Barry A1 - Clarke, Robert A1 - Reitz, Christiane A1 - Smith, A David A1 - Ringman, John M A1 - Warden, Donald A1 - Roberson, Erik D A1 - Wilcock, Gordon A1 - Rogaeva, Ekaterina A1 - Bruni, Amalia Cecilia A1 - Rosen, Howard J A1 - Gallo, Maura A1 - Rosenberg, Roger N A1 - Ben-Shlomo, Yoav A1 - Sager, Mark A A1 - Mecocci, Patrizia A1 - Saykin, Andrew J A1 - Pastor, Pau A1 - Cuccaro, Michael L A1 - Vance, Jeffery M A1 - Schneider, Julie A A1 - Schneider, Lori S A1 - Slifer, Susan A1 - Seeley, William W A1 - Smith, Amanda G A1 - Sonnen, Joshua A A1 - Spina, Salvatore A1 - Stern, Robert A A1 - Swerdlow, Russell H A1 - Tang, Mitchell A1 - Tanzi, Rudolph E A1 - Trojanowski, John Q A1 - Troncoso, Juan C A1 - Van Deerlin, Vivianna M A1 - Van Eldik, Linda J A1 - Vinters, Harry V A1 - Vonsattel, Jean Paul A1 - Weintraub, Sandra A1 - Welsh-Bohmer, Kathleen A A1 - Wilhelmsen, Kirk C A1 - Williamson, Jennifer A1 - Wingo, Thomas S A1 - Woltjer, Randall L A1 - Wright, Clinton B A1 - Yu, Chang-En A1 - Yu, Lei A1 - Saba, Yasaman A1 - Pilotto, Alberto A1 - Bullido, María J A1 - Peters, Oliver A1 - Crane, Paul K A1 - Bennett, David A1 - Bosco, Paola A1 - Coto, Eliecer A1 - Boccardi, Virginia A1 - De Jager, Phil L A1 - Lleo, Alberto A1 - Warner, Nick A1 - Lopez, Oscar L A1 - Ingelsson, Martin A1 - Deloukas, Panagiotis A1 - Cruchaga, Carlos A1 - Graff, Caroline A1 - Gwilliam, Rhian A1 - Fornage, Myriam A1 - Goate, Alison M A1 - Sánchez-Juan, Pascual A1 - Kehoe, Patrick G A1 - Amin, Najaf A1 - Ertekin-Taner, Nilifur A1 - Berr, Claudine A1 - Debette, Stephanie A1 - Love, Seth A1 - Launer, Lenore J A1 - Younkin, Steven G A1 - Dartigues, Jean-François A1 - Corcoran, Chris A1 - Ikram, M Arfan A1 - Dickson, Dennis W A1 - Nicolas, Gaël A1 - Campion, Dominique A1 - Tschanz, JoAnn A1 - Schmidt, Helena A1 - Hakonarson, Hakon A1 - Clarimon, Jordi A1 - Munger, Ron A1 - Schmidt, Reinhold A1 - Farrer, Lindsay A A1 - Van Broeckhoven, Christine A1 - C O'Donovan, Michael A1 - DeStefano, Anita L A1 - Jones, Lesley A1 - Haines, Jonathan L A1 - Deleuze, Jean-Francois A1 - Owen, Michael J A1 - Gudnason, Vilmundur A1 - Mayeux, Richard A1 - Escott-Price, Valentina A1 - Psaty, Bruce M A1 - Ramirez, Alfredo A1 - Wang, Li-San A1 - Ruiz, Agustin A1 - van Duijn, Cornelia M A1 - Holmans, Peter A A1 - Seshadri, Sudha A1 - Williams, Julie A1 - Amouyel, Phillippe A1 - Schellenberg, Gerard D A1 - Lambert, Jean-Charles A1 - Pericak-Vance, Margaret A AB -

Risk for late-onset Alzheimer's disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer's or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aβ processing are associated not only with early-onset autosomal dominant Alzheimer's disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 × 10), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.

VL - 51 IS - 3 ER - TY - JOUR T1 - Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels. JF - Nat Genet Y1 - 2019 A1 - Tin, Adrienne A1 - Marten, Jonathan A1 - Halperin Kuhns, Victoria L A1 - Li, Yong A1 - Wuttke, Matthias A1 - Kirsten, Holger A1 - Sieber, Karsten B A1 - Qiu, Chengxiang A1 - Gorski, Mathias A1 - Yu, Zhi A1 - Giri, Ayush A1 - Sveinbjornsson, Gardar A1 - Li, Man A1 - Chu, Audrey Y A1 - Hoppmann, Anselm A1 - O'Connor, Luke J A1 - Prins, Bram A1 - Nutile, Teresa A1 - Noce, Damia A1 - Akiyama, Masato A1 - Cocca, Massimiliano A1 - Ghasemi, Sahar A1 - van der Most, Peter J A1 - Horn, Katrin A1 - Xu, Yizhe A1 - Fuchsberger, Christian A1 - Sedaghat, Sanaz A1 - Afaq, Saima A1 - Amin, Najaf A1 - Arnlöv, Johan A1 - Bakker, Stephan J L A1 - Bansal, Nisha A1 - Baptista, Daniela A1 - Bergmann, Sven A1 - Biggs, Mary L A1 - Biino, Ginevra A1 - Boerwinkle, Eric A1 - Bottinger, Erwin P A1 - Boutin, Thibaud S A1 - Brumat, Marco A1 - Burkhardt, Ralph A1 - Campana, Eric A1 - Campbell, Archie A1 - Campbell, Harry A1 - Carroll, Robert J A1 - Catamo, Eulalia A1 - Chambers, John C A1 - Ciullo, Marina A1 - Concas, Maria Pina A1 - Coresh, Josef A1 - Corre, Tanguy A1 - Cusi, Daniele A1 - Felicita, Sala Cinzia A1 - de Borst, Martin H A1 - De Grandi, Alessandro A1 - de Mutsert, Renée A1 - de Vries, Aiko P J A1 - Delgado, Graciela A1 - Demirkan, Ayse A1 - Devuyst, Olivier A1 - Dittrich, Katalin A1 - Eckardt, Kai-Uwe A1 - Ehret, Georg A1 - Endlich, Karlhans A1 - Evans, Michele K A1 - Gansevoort, Ron T A1 - Gasparini, Paolo A1 - Giedraitis, Vilmantas A1 - Gieger, Christian A1 - Girotto, Giorgia A1 - Gögele, Martin A1 - Gordon, Scott D A1 - Gudbjartsson, Daniel F A1 - Gudnason, Vilmundur A1 - Haller, Toomas A1 - Hamet, Pavel A1 - Harris, Tamara B A1 - Hayward, Caroline A1 - Hicks, Andrew A A1 - Hofer, Edith A1 - Holm, Hilma A1 - Huang, Wei A1 - Hutri-Kähönen, Nina A1 - Hwang, Shih-Jen A1 - Ikram, M Arfan A1 - Lewis, Raychel M A1 - Ingelsson, Erik A1 - Jakobsdottir, Johanna A1 - Jonsdottir, Ingileif A1 - Jonsson, Helgi A1 - Joshi, Peter K A1 - Josyula, Navya Shilpa A1 - Jung, Bettina A1 - Kähönen, Mika A1 - Kamatani, Yoichiro A1 - Kanai, Masahiro A1 - Kerr, Shona M A1 - Kiess, Wieland A1 - Kleber, Marcus E A1 - Koenig, Wolfgang A1 - Kooner, Jaspal S A1 - Körner, Antje A1 - Kovacs, Peter A1 - Krämer, Bernhard K A1 - Kronenberg, Florian A1 - Kubo, Michiaki A1 - Kuhnel, Brigitte A1 - La Bianca, Martina A1 - Lange, Leslie A A1 - Lehne, Benjamin A1 - Lehtimäki, Terho A1 - Liu, Jun A1 - Loeffler, Markus A1 - Loos, Ruth J F A1 - Lyytikäinen, Leo-Pekka A1 - Mägi, Reedik A1 - Mahajan, Anubha A1 - Martin, Nicholas G A1 - März, Winfried A1 - Mascalzoni, Deborah A1 - Matsuda, Koichi A1 - Meisinger, Christa A1 - Meitinger, Thomas A1 - Metspalu, Andres A1 - Milaneschi, Yuri A1 - O'Donnell, Christopher J A1 - Wilson, Otis D A1 - Gaziano, J Michael A1 - Mishra, Pashupati P A1 - Mohlke, Karen L A1 - Mononen, Nina A1 - Montgomery, Grant W A1 - Mook-Kanamori, Dennis O A1 - Müller-Nurasyid, Martina A1 - Nadkarni, Girish N A1 - Nalls, Mike A A1 - Nauck, Matthias A1 - Nikus, Kjell A1 - Ning, Boting A1 - Nolte, Ilja M A1 - Noordam, Raymond A1 - O'Connell, Jeffrey R A1 - Olafsson, Isleifur A1 - Padmanabhan, Sandosh A1 - Penninx, Brenda W J H A1 - Perls, Thomas A1 - Peters, Annette A1 - Pirastu, Mario A1 - Pirastu, Nicola A1 - Pistis, Giorgio A1 - Polasek, Ozren A1 - Ponte, Belen A1 - Porteous, David J A1 - Poulain, Tanja A1 - Preuss, Michael H A1 - Rabelink, Ton J A1 - Raffield, Laura M A1 - Raitakari, Olli T A1 - Rettig, Rainer A1 - Rheinberger, Myriam A1 - Rice, Kenneth M A1 - Rizzi, Federica A1 - Robino, Antonietta A1 - Rudan, Igor A1 - Krajcoviechova, Alena A1 - Cifkova, Renata A1 - Rueedi, Rico A1 - Ruggiero, Daniela A1 - Ryan, Kathleen A A1 - Saba, Yasaman A1 - Salvi, Erika A1 - Schmidt, Helena A1 - Schmidt, Reinhold A1 - Shaffer, Christian M A1 - Smith, Albert V A1 - Smith, Blair H A1 - Spracklen, Cassandra N A1 - Strauch, Konstantin A1 - Stumvoll, Michael A1 - Sulem, Patrick A1 - Tajuddin, Salman M A1 - Teren, Andrej A1 - Thiery, Joachim A1 - Thio, Chris H L A1 - Thorsteinsdottir, Unnur A1 - Toniolo, Daniela A1 - Tönjes, Anke A1 - Tremblay, Johanne A1 - Uitterlinden, André G A1 - Vaccargiu, Simona A1 - van der Harst, Pim A1 - van Duijn, Cornelia M A1 - Verweij, Niek A1 - Völker, Uwe A1 - Vollenweider, Peter A1 - Waeber, Gérard A1 - Waldenberger, Melanie A1 - Whitfield, John B A1 - Wild, Sarah H A1 - Wilson, James F A1 - Yang, Qiong A1 - Zhang, Weihua A1 - Zonderman, Alan B A1 - Bochud, Murielle A1 - Wilson, James G A1 - Pendergrass, Sarah A A1 - Ho, Kevin A1 - Parsa, Afshin A1 - Pramstaller, Peter P A1 - Psaty, Bruce M A1 - Böger, Carsten A A1 - Snieder, Harold A1 - Butterworth, Adam S A1 - Okada, Yukinori A1 - Edwards, Todd L A1 - Stefansson, Kari A1 - Susztak, Katalin A1 - Scholz, Markus A1 - Heid, Iris M A1 - Hung, Adriana M A1 - Teumer, Alexander A1 - Pattaro, Cristian A1 - Woodward, Owen M A1 - Vitart, Veronique A1 - Köttgen, Anna AB -

Elevated serum urate levels cause gout and correlate with cardiometabolic diseases via poorly understood mechanisms. We performed a trans-ancestry genome-wide association study of serum urate in 457,690 individuals, identifying 183 loci (147 previously unknown) that improve the prediction of gout in an independent cohort of 334,880 individuals. Serum urate showed significant genetic correlations with many cardiometabolic traits, with genetic causality analyses supporting a substantial role for pleiotropy. Enrichment analysis, fine-mapping of urate-associated loci and colocalization with gene expression in 47 tissues implicated the kidney and liver as the main target organs and prioritized potentially causal genes and variants, including the transcriptional master regulators in the liver and kidney, HNF1A and HNF4A. Experimental validation showed that HNF4A transactivated the promoter of ABCG2, encoding a major urate transporter, in kidney cells, and that HNF4A p.Thr139Ile is a functional variant. Transcriptional coregulation within and across organs may be a general mechanism underlying the observed pleiotropy between urate and cardiometabolic traits.

VL - 51 IS - 10 ER - TY - JOUR T1 - The genetic architecture of the human cerebral cortex JF - Science Y1 - 2020 A1 - Grasby, Katrina L. A1 - Jahanshad, Neda A1 - Painter, Jodie N. A1 - Colodro-Conde, Lucía A1 - Bralten, Janita A1 - Hibar, Derrek P. A1 - Lind, Penelope A. A1 - Pizzagalli, Fabrizio A1 - Ching, Christopher R. K. A1 - McMahon, Mary Agnes B. A1 - Shatokhina, Natalia A1 - Zsembik, Leo C. P. A1 - Thomopoulos, Sophia I. A1 - Zhu, Alyssa H. A1 - Strike, Lachlan T. A1 - Agartz, Ingrid A1 - Alhusaini, Saud A1 - Almeida, Marcio A. A. A1 - Alnæs, Dag A1 - Amlien, Inge K. A1 - Andersson, Micael A1 - Ard, Tyler A1 - Armstrong, Nicola J. A1 - Ashley-Koch, Allison A1 - Atkins, Joshua R. A1 - Bernard, Manon A1 - Brouwer, Rachel M. A1 - Buimer, Elizabeth E. L. A1 - Bülow, Robin A1 - Bürger, Christian A1 - Cannon, Dara M. A1 - Chakravarty, Mallar A1 - Chen, Qiang A1 - Cheung, Joshua W. A1 - Couvy-Duchesne, Baptiste A1 - Dale, Anders M. A1 - Dalvie, Shareefa A1 - de Araujo, Tânia K. A1 - de Zubicaray, Greig I. A1 - de Zwarte, Sonja M. C. A1 - den Braber, Anouk A1 - Doan, Nhat Trung A1 - Dohm, Katharina A1 - Ehrlich, Stefan A1 - Engelbrecht, Hannah-Ruth A1 - Erk, Susanne A1 - Fan, Chun Chieh A1 - Fedko, Iryna O. A1 - Foley, Sonya F. A1 - Ford, Judith M. A1 - Fukunaga, Masaki A1 - Garrett, Melanie E. A1 - Ge, Tian A1 - Giddaluru, Sudheer A1 - Goldman, Aaron L. A1 - Green, Melissa J. A1 - Groenewold, Nynke A. A1 - Grotegerd, Dominik A1 - Gurholt, Tiril P. A1 - Gutman, Boris A. A1 - Hansell, Narelle K. A1 - Harris, Mathew A. A1 - Harrison, Marc B. A1 - Haswell, Courtney C. A1 - Hauser, Michael A1 - Herms, Stefan A1 - Heslenfeld, Dirk J. A1 - Ho, New Fei A1 - Hoehn, David A1 - Hoffmann, Per A1 - Holleran, Laurena A1 - Hoogman, Martine A1 - Hottenga, Jouke-Jan A1 - Ikeda, Masashi A1 - Janowitz, Deborah A1 - Jansen, Iris E. A1 - Jia, Tianye A1 - Jockwitz, Christiane A1 - Kanai, Ryota A1 - Karama, Sherif A1 - Kasperaviciute, Dalia A1 - Kaufmann, Tobias A1 - Kelly, Sinead A1 - Kikuchi, Masataka A1 - Klein, Marieke A1 - Knapp, Michael A1 - Knodt, Annchen R. A1 - Krämer, Bernd A1 - Lam, Max A1 - Lancaster, Thomas M. A1 - Lee, Phil H. A1 - Lett, Tristram A. A1 - Lewis, Lindsay B. A1 - Lopes-Cendes, Iscia A1 - Luciano, Michelle A1 - Macciardi, Fabio A1 - Marquand, Andre F. A1 - Mathias, Samuel R. A1 - Melzer, Tracy R. A1 - Milaneschi, Yuri A1 - Mirza-Schreiber, Nazanin A1 - Moreira, Jose C. V. A1 - Mühleisen, Thomas W. A1 - Müller-Myhsok, Bertram A1 - Najt, Pablo A1 - Nakahara, Soichiro A1 - Nho, Kwangsik A1 - Olde Loohuis, Loes M. A1 - Orfanos, Dimitri Papadopoulos A1 - Pearson, John F. A1 - Pitcher, Toni L. A1 - Pütz, Benno A1 - Quidé, Yann A1 - Ragothaman, Anjanibhargavi A1 - Rashid, Faisal M. A1 - Reay, William R. A1 - Redlich, Ronny A1 - Reinbold, Céline S. A1 - Repple, Jonathan A1 - Richard, Geneviève A1 - Riedel, Brandalyn C. A1 - Risacher, Shannon L. A1 - Rocha, Cristiane S. A1 - Mota, Nina Roth A1 - Salminen, Lauren A1 - Saremi, Arvin A1 - Saykin, Andrew J. A1 - Schlag, Fenja A1 - Schmaal, Lianne A1 - Schofield, Peter R. A1 - Secolin, Rodrigo A1 - Shapland, Chin Yang A1 - Shen, Li A1 - Shin, Jean A1 - Shumskaya, Elena A1 - Sønderby, Ida E. A1 - Sprooten, Emma A1 - Tansey, Katherine E. A1 - Teumer, Alexander A1 - Thalamuthu, Anbupalam A1 - Tordesillas-Gutierrez, Diana A1 - Turner, Jessica A. A1 - Uhlmann, Anne A1 - Vallerga, Costanza Ludovica A1 - van der Meer, Dennis A1 - van Donkelaar, Marjolein M. J. A1 - van Eijk, Liza A1 - van Erp, Theo G. M. A1 - van Haren, Neeltje E. M. A1 - van Rooij, Daan A1 - van Tol, Marie-Jose A1 - Veldink, Jan H. A1 - Verhoef, Ellen A1 - Walton, Esther A1 - Wang, Mingyuan A1 - Wang, Yunpeng A1 - Wardlaw, Joanna M. A1 - Wen, Wei A1 - Westlye, Lars T. A1 - Whelan, Christopher D. A1 - Witt, Stephanie H. A1 - Wittfeld, Katharina A1 - Wolf, Christiane A1 - Wolfers, Thomas A1 - Wu, Jing Qin A1 - Yasuda, Clarissa L. A1 - Zaremba, Dario A1 - Zhang, Zuo A1 - Zwiers, Marcel P. A1 - Artiges, Eric A1 - Assareh, Amelia A. A1 - Ayesa-Arriola, Rosa A1 - Belger, Aysenil A1 - Brandt, Christine L. A1 - Brown, Gregory G. A1 - Cichon, Sven A1 - Curran, Joanne E. A1 - Davies, Gareth E. A1 - Degenhardt, Franziska A1 - Dennis, Michelle F. A1 - Dietsche, Bruno A1 - Djurovic, Srdjan A1 - Doherty, Colin P. A1 - Espiritu, Ryan A1 - Garijo, Daniel A1 - Gil, Yolanda A1 - Gowland, Penny A. A1 - Green, Robert C. A1 - Häusler, Alexander N. A1 - Heindel, Walter A1 - Ho, Beng-Choon A1 - Hoffmann, Wolfgang U. A1 - Holsboer, Florian A1 - Homuth, Georg A1 - Hosten, Norbert A1 - Jack, Clifford R. A1 - Jang, MiHyun A1 - Jansen, Andreas A1 - Kimbrel, Nathan A. A1 - Kolskår, Knut A1 - Koops, Sanne A1 - Krug, Axel A1 - Lim, Kelvin O. A1 - Luykx, Jurjen J. A1 - Mathalon, Daniel H. A1 - Mather, Karen A. A1 - Mattay, Venkata S. A1 - Matthews, Sarah A1 - Mayoral Van Son, Jaqueline A1 - McEwen, Sarah C. A1 - Melle, Ingrid A1 - Morris, Derek W. A1 - Mueller, Bryon A. A1 - Nauck, Matthias A1 - Nordvik, Jan E. A1 - Nöthen, Markus M. A1 - O’Leary, Daniel S. A1 - Opel, Nils A1 - Martinot, Marie-Laure Paillère A1 - Pike, G. Bruce A1 - Preda, Adrian A1 - Quinlan, Erin B. A1 - Rasser, Paul E. A1 - Ratnakar, Varun A1 - Reppermund, Simone A1 - Steen, Vidar M. A1 - Tooney, Paul A. A1 - Torres, Fábio R. A1 - Veltman, Dick J. A1 - Voyvodic, James T. A1 - Whelan, Robert A1 - White, Tonya A1 - Yamamori, Hidenaga A1 - Adams, Hieab H. H. A1 - Bis, Joshua C. A1 - Debette, Stephanie A1 - DeCarli, Charles A1 - Fornage, Myriam A1 - Gudnason, Vilmundur A1 - Hofer, Edith A1 - Ikram, M. Arfan A1 - Launer, Lenore A1 - Longstreth, W. T. A1 - Lopez, Oscar L. A1 - Mazoyer, Bernard A1 - Mosley, Thomas H. A1 - Roshchupkin, Gennady V. A1 - Satizabal, Claudia L. A1 - Schmidt, Reinhold A1 - Seshadri, Sudha A1 - Yang, Qiong A1 - Alvim, Marina K. M. A1 - Ames, David A1 - Anderson, Tim J. A1 - Andreassen, Ole A. A1 - Arias-Vasquez, Alejandro A1 - Bastin, Mark E. A1 - Baune, Bernhard T. A1 - Beckham, Jean C. A1 - Blangero, John A1 - Boomsma, Dorret I. A1 - Brodaty, Henry A1 - Brunner, Han G. A1 - Buckner, Randy L. A1 - Buitelaar, Jan K. A1 - Bustillo, Juan R. A1 - Cahn, Wiepke A1 - Cairns, Murray J. A1 - Calhoun, Vince A1 - Carr, Vaughan J. A1 - Caseras, Xavier A1 - Caspers, Svenja A1 - Cavalleri, Gianpiero L. A1 - Cendes, Fernando A1 - Corvin, Aiden A1 - Crespo-Facorro, Benedicto A1 - Dalrymple-Alford, John C. A1 - Dannlowski, Udo A1 - de Geus, Eco J. C. A1 - Deary, Ian J. A1 - Delanty, Norman A1 - Depondt, Chantal A1 - Desrivières, Sylvane A1 - Donohoe, Gary A1 - Espeseth, Thomas A1 - Fernández, Guillén A1 - Fisher, Simon E. A1 - Flor, Herta A1 - Forstner, Andreas J. A1 - Francks, Clyde A1 - Franke, Barbara A1 - Glahn, David C. 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A1 - Posthuma, Danielle A1 - Rietschel, Marcella A1 - Roffman, Joshua L. A1 - Rowland, Laura M. A1 - Sachdev, Perminder S. A1 - Sämann, Philipp G. A1 - Schall, Ulrich A1 - Schumann, Gunter A1 - Scott, Rodney J. A1 - Sim, Kang A1 - Sisodiya, Sanjay M. A1 - Smoller, Jordan W. A1 - Sommer, Iris E. A1 - St Pourcain, Beate A1 - Stein, Dan J. A1 - Toga, Arthur W. A1 - Trollor, Julian N. A1 - Van der Wee, Nic J. A. A1 - van ’t Ent, Dennis A1 - Völzke, Henry A1 - Walter, Henrik A1 - Weber, Bernd A1 - Weinberger, Daniel R. A1 - Wright, Margaret J. A1 - Zhou, Juan A1 - Stein, Jason L. A1 - Thompson, Paul M. A1 - Medland, Sarah E. VL - 367 UR - https://www.sciencemag.org/lookup/doi/10.1126/science.aay6690https://syndication.highwire.org/content/doi/10.1126/science.aay6690https://syndication.highwire.org/content/doi/10.1126/science.aay6690 IS - 6484 JO - Science ER - TY - JOUR T1 - Meta-analysis uncovers genome-wide significant variants for rapid kidney function decline. JF - Kidney Int Y1 - 2020 A1 - Gorski, Mathias A1 - Jung, Bettina A1 - Li, Yong A1 - Matias-Garcia, Pamela R A1 - Wuttke, Matthias A1 - Coassin, Stefan A1 - Thio, Chris H L A1 - Kleber, Marcus E A1 - Winkler, Thomas W A1 - Wanner, Veronika A1 - Chai, Jin-Fang A1 - Chu, Audrey Y A1 - Cocca, Massimiliano A1 - Feitosa, Mary F A1 - Ghasemi, Sahar A1 - Hoppmann, Anselm A1 - Horn, Katrin A1 - Li, Man A1 - Nutile, Teresa A1 - Scholz, Markus A1 - Sieber, Karsten B A1 - Teumer, Alexander A1 - Tin, Adrienne A1 - Wang, Judy A1 - Tayo, Bamidele O A1 - Ahluwalia, Tarunveer S A1 - Almgren, Peter A1 - Bakker, Stephan J L A1 - Banas, Bernhard A1 - Bansal, Nisha A1 - Biggs, Mary L A1 - Boerwinkle, Eric A1 - Bottinger, Erwin P A1 - Brenner, Hermann A1 - Carroll, Robert J A1 - Chalmers, John A1 - Chee, Miao-Li A1 - Chee, Miao-Ling A1 - Cheng, Ching-Yu A1 - Coresh, Josef A1 - de Borst, Martin H A1 - Degenhardt, Frauke A1 - Eckardt, Kai-Uwe A1 - Endlich, Karlhans A1 - Franke, Andre A1 - Freitag-Wolf, Sandra A1 - Gampawar, Piyush A1 - Gansevoort, Ron T A1 - Ghanbari, Mohsen A1 - Gieger, Christian A1 - Hamet, Pavel A1 - Ho, Kevin A1 - Hofer, Edith A1 - Holleczek, Bernd A1 - Xian Foo, Valencia Hui A1 - Hutri-Kähönen, Nina A1 - Hwang, Shih-Jen A1 - Ikram, M Arfan A1 - Josyula, Navya Shilpa A1 - Kähönen, Mika A1 - Khor, Chiea-Chuen A1 - Koenig, Wolfgang A1 - Kramer, Holly A1 - Krämer, Bernhard K A1 - Kuhnel, Brigitte A1 - Lange, Leslie A A1 - Lehtimäki, Terho A1 - Lieb, Wolfgang A1 - Loos, Ruth J F A1 - Lukas, Mary Ann A1 - Lyytikäinen, Leo-Pekka A1 - Meisinger, Christa A1 - Meitinger, Thomas A1 - Melander, Olle A1 - Milaneschi, Yuri A1 - Mishra, Pashupati P A1 - Mononen, Nina A1 - Mychaleckyj, Josyf C A1 - Nadkarni, Girish N A1 - Nauck, Matthias A1 - Nikus, Kjell A1 - Ning, Boting A1 - Nolte, Ilja M A1 - O'Donoghue, Michelle L A1 - Orho-Melander, Marju A1 - Pendergrass, Sarah A A1 - Penninx, Brenda W J H A1 - Preuss, Michael H A1 - Psaty, Bruce M A1 - Raffield, Laura M A1 - Raitakari, Olli T A1 - Rettig, Rainer A1 - Rheinberger, Myriam A1 - Rice, Kenneth M A1 - Rosenkranz, Alexander R A1 - Rossing, Peter A1 - Rotter, Jerome I A1 - Sabanayagam, Charumathi A1 - Schmidt, Helena A1 - Schmidt, Reinhold A1 - Schöttker, Ben A1 - Schulz, Christina-Alexandra A1 - Sedaghat, Sanaz A1 - Shaffer, Christian M A1 - Strauch, Konstantin A1 - Szymczak, Silke A1 - Taylor, Kent D A1 - Tremblay, Johanne A1 - Chaker, Layal A1 - van der Harst, Pim A1 - van der Most, Peter J A1 - Verweij, Niek A1 - Völker, Uwe A1 - Waldenberger, Melanie A1 - Wallentin, Lars A1 - Waterworth, Dawn M A1 - White, Harvey D A1 - Wilson, James G A1 - Wong, Tien-Yin A1 - Woodward, Mark A1 - Yang, Qiong A1 - Yasuda, Masayuki A1 - Yerges-Armstrong, Laura M A1 - Zhang, Yan A1 - Snieder, Harold A1 - Wanner, Christoph A1 - Böger, Carsten A A1 - Köttgen, Anna A1 - Kronenberg, Florian A1 - Pattaro, Cristian A1 - Heid, Iris M AB -

Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m/year or more ("Rapid3"; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m at follow-up among those with eGFRcrea 60 mL/min/1.73m or more at baseline ("CKDi25"; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT (2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized variants and genes underneath these loci. The OR2S2 locus is novel for any eGFRcrea trait including interesting candidates. For the five genome-wide significant lead variants, we found supporting effects for annual change in blood urea nitrogen or cystatin-based eGFR, but not for GATM or LARP4B. Individuals at high compared to those at low genetic risk (8-14 vs 0-5 adverse alleles) had a 1.20-fold increased risk of acute kidney injury (95% confidence interval 1.08-1.33). Thus, our identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function.

ER - TY - JOUR T1 - Association of low-frequency and rare coding variants with information processing speed. JF - Transl Psychiatry Y1 - 2021 A1 - Bressler, Jan A1 - Davies, Gail A1 - Smith, Albert V A1 - Saba, Yasaman A1 - Bis, Joshua C A1 - Jian, Xueqiu A1 - Hayward, Caroline A1 - Yanek, Lisa A1 - Smith, Jennifer A A1 - Mirza, Saira S A1 - Wang, Ruiqi A1 - Adams, Hieab H H A1 - Becker, Diane A1 - Boerwinkle, Eric A1 - Campbell, Archie A1 - Cox, Simon R A1 - Eiriksdottir, Gudny A1 - Fawns-Ritchie, Chloe A1 - Gottesman, Rebecca F A1 - Grove, Megan L A1 - Guo, Xiuqing A1 - Hofer, Edith A1 - Kardia, Sharon L R A1 - Knol, Maria J A1 - Koini, Marisa A1 - Lopez, Oscar L A1 - Marioni, Riccardo E A1 - Nyquist, Paul A1 - Pattie, Alison A1 - Polasek, Ozren A1 - Porteous, David J A1 - Rudan, Igor A1 - Satizabal, Claudia L A1 - Schmidt, Helena A1 - Schmidt, Reinhold A1 - Sidney, Stephen A1 - Simino, Jeannette A1 - Smith, Blair H A1 - Turner, Stephen T A1 - van der Lee, Sven J A1 - Ware, Erin B A1 - Whitmer, Rachel A A1 - Yaffe, Kristine A1 - Yang, Qiong A1 - Zhao, Wei A1 - Gudnason, Vilmundur A1 - Launer, Lenore J A1 - Fitzpatrick, Annette L A1 - Psaty, Bruce M A1 - Fornage, Myriam A1 - Arfan Ikram, M A1 - van Duijn, Cornelia M A1 - Seshadri, Sudha A1 - Mosley, Thomas H A1 - Deary, Ian J KW - Adult KW - Aging KW - Cognition KW - Genome-Wide Association Study KW - Geroscience KW - Humans KW - Polymorphism, Single Nucleotide KW - Ubiquitin-Protein Ligases AB -

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.

VL - 11 IS - 1 ER - TY - JOUR T1 - Differential and shared genetic effects on kidney function between diabetic and non-diabetic individuals. JF - Commun Biol Y1 - 2022 A1 - Winkler, Thomas W A1 - Rasheed, Humaira A1 - Teumer, Alexander A1 - Gorski, Mathias A1 - Rowan, Bryce X A1 - Stanzick, Kira J A1 - Thomas, Laurent F A1 - Tin, Adrienne A1 - Hoppmann, Anselm A1 - Chu, Audrey Y A1 - Tayo, Bamidele A1 - Thio, Chris H L A1 - Cusi, Daniele A1 - Chai, Jin-Fang A1 - Sieber, Karsten B A1 - Horn, Katrin A1 - Li, Man A1 - Scholz, Markus A1 - Cocca, Massimiliano A1 - Wuttke, Matthias A1 - van der Most, Peter J A1 - Yang, Qiong A1 - Ghasemi, Sahar A1 - Nutile, Teresa A1 - Li, Yong A1 - Pontali, Giulia A1 - Günther, Felix A1 - Dehghan, Abbas A1 - Correa, Adolfo A1 - Parsa, Afshin A1 - Feresin, Agnese A1 - de Vries, Aiko P J A1 - Zonderman, Alan B A1 - Smith, Albert V A1 - Oldehinkel, Albertine J A1 - De Grandi, Alessandro A1 - Rosenkranz, Alexander R A1 - Franke, Andre A1 - Teren, Andrej A1 - Metspalu, Andres A1 - Hicks, Andrew A A1 - Morris, Andrew P A1 - Tönjes, Anke A1 - Morgan, Anna A1 - Podgornaia, Anna I A1 - Peters, Annette A1 - Körner, Antje A1 - Mahajan, Anubha A1 - Campbell, Archie A1 - Freedman, Barry I A1 - Spedicati, Beatrice A1 - Ponte, Belen A1 - Schöttker, Ben A1 - Brumpton, Ben A1 - Banas, Bernhard A1 - Krämer, Bernhard K A1 - Jung, Bettina A1 - Åsvold, Bjørn Olav A1 - Smith, Blair H A1 - Ning, Boting A1 - Penninx, Brenda W J H A1 - Vanderwerff, Brett R A1 - Psaty, Bruce M A1 - Kammerer, Candace M A1 - Langefeld, Carl D A1 - Hayward, Caroline A1 - Spracklen, Cassandra N A1 - Robinson-Cohen, Cassianne A1 - Hartman, Catharina A A1 - Lindgren, Cecilia M A1 - Wang, Chaolong A1 - Sabanayagam, Charumathi A1 - Heng, Chew-Kiat A1 - Lanzani, Chiara A1 - Khor, Chiea-Chuen A1 - Cheng, Ching-Yu A1 - Fuchsberger, Christian A1 - Gieger, Christian A1 - Shaffer, Christian M A1 - Schulz, Christina-Alexandra A1 - Willer, Cristen J A1 - Chasman, Daniel I A1 - Gudbjartsson, Daniel F A1 - Ruggiero, Daniela A1 - Toniolo, Daniela A1 - Czamara, Darina A1 - Porteous, David J A1 - Waterworth, Dawn M A1 - Mascalzoni, Deborah A1 - Mook-Kanamori, Dennis O A1 - Reilly, Dermot F A1 - Daw, E Warwick A1 - Hofer, Edith A1 - Boerwinkle, Eric A1 - Salvi, Erika A1 - Bottinger, Erwin P A1 - Tai, E-Shyong A1 - Catamo, Eulalia A1 - Rizzi, Federica A1 - Guo, Feng A1 - Rivadeneira, Fernando A1 - Guilianini, Franco A1 - Sveinbjornsson, Gardar A1 - Ehret, Georg A1 - Waeber, Gérard A1 - Biino, Ginevra A1 - Girotto, Giorgia A1 - Pistis, Giorgio A1 - Nadkarni, Girish N A1 - Delgado, Graciela E A1 - Montgomery, Grant W A1 - Snieder, Harold A1 - Campbell, Harry A1 - White, Harvey D A1 - Gao, He A1 - Stringham, Heather M A1 - Schmidt, Helena A1 - Li, Hengtong A1 - Brenner, Hermann A1 - Holm, Hilma A1 - Kirsten, Holgen A1 - Kramer, Holly A1 - Rudan, Igor A1 - Nolte, Ilja M A1 - Tzoulaki, Ioanna A1 - Olafsson, Isleifur A1 - Martins, Jade A1 - Cook, James P A1 - Wilson, James F A1 - Halbritter, Jan A1 - Felix, Janine F A1 - Divers, Jasmin A1 - Kooner, Jaspal S A1 - Lee, Jeannette Jen-Mai A1 - O'Connell, Jeffrey A1 - Rotter, Jerome I A1 - Liu, Jianjun A1 - Xu, Jie A1 - Thiery, Joachim A1 - Arnlöv, Johan A1 - Kuusisto, Johanna A1 - Jakobsdottir, Johanna A1 - Tremblay, Johanne A1 - Chambers, John C A1 - Whitfield, John B A1 - Gaziano, John M A1 - Marten, Jonathan A1 - Coresh, Josef A1 - Jonas, Jost B A1 - Mychaleckyj, Josyf C A1 - Christensen, Kaare A1 - Eckardt, Kai-Uwe A1 - Mohlke, Karen L A1 - Endlich, Karlhans A1 - Dittrich, Katalin A1 - Ryan, Kathleen A A1 - Rice, Kenneth M A1 - Taylor, Kent D A1 - Ho, Kevin A1 - Nikus, Kjell A1 - Matsuda, Koichi A1 - Strauch, Konstantin A1 - Miliku, Kozeta A1 - Hveem, Kristian A1 - Lind, Lars A1 - Wallentin, Lars A1 - Yerges-Armstrong, Laura M A1 - Raffield, Laura M A1 - Phillips, Lawrence S A1 - Launer, Lenore J A1 - Lyytikäinen, Leo-Pekka A1 - Lange, Leslie A A1 - Citterio, Lorena A1 - Klaric, Lucija A1 - Ikram, M Arfan A1 - Ising, Marcus A1 - Kleber, Marcus E A1 - Francescatto, Margherita A1 - Concas, Maria Pina A1 - Ciullo, Marina A1 - Piratsu, Mario A1 - Orho-Melander, Marju A1 - Laakso, Markku A1 - Loeffler, Markus A1 - Perola, Markus A1 - de Borst, Martin H A1 - Gögele, Martin A1 - Bianca, Martina La A1 - Lukas, Mary Ann A1 - Feitosa, Mary F A1 - Biggs, Mary L A1 - Wojczynski, Mary K A1 - Kavousi, Maryam A1 - Kanai, Masahiro A1 - Akiyama, Masato A1 - Yasuda, Masayuki A1 - Nauck, Matthias A1 - Waldenberger, Melanie A1 - Chee, Miao-Li A1 - Chee, Miao-Ling A1 - Boehnke, Michael A1 - Preuss, Michael H A1 - Stumvoll, Michael A1 - Province, Michael A A1 - Evans, Michele K A1 - O'Donoghue, Michelle L A1 - Kubo, Michiaki A1 - Kähönen, Mika A1 - Kastarinen, Mika A1 - Nalls, Mike A A1 - Kuokkanen, Mikko A1 - Ghanbari, Mohsen A1 - Bochud, Murielle A1 - Josyula, Navya Shilpa A1 - Martin, Nicholas G A1 - Tan, Nicholas Y Q A1 - Palmer, Nicholette D A1 - Pirastu, Nicola A1 - Schupf, Nicole A1 - Verweij, Niek A1 - Hutri-Kähönen, Nina A1 - Mononen, Nina A1 - Bansal, Nisha A1 - Devuyst, Olivier A1 - Melander, Olle A1 - Raitakari, Olli T A1 - Polasek, Ozren A1 - Manunta, Paolo A1 - Gasparini, Paolo A1 - Mishra, Pashupati P A1 - Sulem, Patrick A1 - Magnusson, Patrik K E A1 - Elliott, Paul A1 - Ridker, Paul M A1 - Hamet, Pavel A1 - Svensson, Per O A1 - Joshi, Peter K A1 - Kovacs, Peter A1 - Pramstaller, Peter P A1 - Rossing, Peter A1 - Vollenweider, Peter A1 - van der Harst, Pim A1 - Dorajoo, Rajkumar A1 - Sim, Ralene Z H A1 - Burkhardt, Ralph A1 - Tao, Ran A1 - Noordam, Raymond A1 - Mägi, Reedik A1 - Schmidt, Reinhold A1 - de Mutsert, Renée A1 - Rueedi, Rico A1 - van Dam, Rob M A1 - Carroll, Robert J A1 - Gansevoort, Ron T A1 - Loos, Ruth J F A1 - Felicita, Sala Cinzia A1 - Sedaghat, Sanaz A1 - Padmanabhan, Sandosh A1 - Freitag-Wolf, Sandra A1 - Pendergrass, Sarah A A1 - Graham, Sarah E A1 - Gordon, Scott D A1 - Hwang, Shih-Jen A1 - Kerr, Shona M A1 - Vaccargiu, Simona A1 - Patil, Snehal B A1 - Hallan, Stein A1 - Bakker, Stephan J L A1 - Lim, Su-Chi A1 - Lucae, Susanne A1 - Vogelezang, Suzanne A1 - Bergmann, Sven A1 - Corre, Tanguy A1 - Ahluwalia, Tarunveer S A1 - Lehtimäki, Terho A1 - Boutin, Thibaud S A1 - Meitinger, Thomas A1 - Wong, Tien-Yin A1 - Bergler, Tobias A1 - Rabelink, Ton J A1 - Esko, Tõnu A1 - Haller, Toomas A1 - Thorsteinsdottir, Unnur A1 - Völker, Uwe A1 - Foo, Valencia Hui Xian A1 - Salomaa, Veikko A1 - Vitart, Veronique A1 - Giedraitis, Vilmantas A1 - Gudnason, Vilmundur A1 - Jaddoe, Vincent W V A1 - Huang, Wei A1 - Zhang, Weihua A1 - Wei, Wen Bin A1 - Kiess, Wieland A1 - März, Winfried A1 - Koenig, Wolfgang A1 - Lieb, Wolfgang A1 - Gào, Xīn A1 - Sim, Xueling A1 - Wang, Ya Xing A1 - Friedlander, Yechiel A1 - Tham, Yih-Chung A1 - Kamatani, Yoichiro A1 - Okada, Yukinori A1 - Milaneschi, Yuri A1 - Yu, Zhi A1 - Stark, Klaus J A1 - Stefansson, Kari A1 - Böger, Carsten A A1 - Hung, Adriana M A1 - Kronenberg, Florian A1 - Köttgen, Anna A1 - Pattaro, Cristian A1 - Heid, Iris M KW - Creatinine KW - Diabetes Mellitus KW - Diabetic Nephropathies KW - Genome-Wide Association Study KW - Glomerular Filtration Rate KW - Humans KW - Kidney AB -

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.

VL - 5 IS - 1 ER - TY - JOUR T1 - Epigenetic and integrative cross-omics analyses of cerebral white matter hyperintensities on MRI. JF - Brain Y1 - 2022 A1 - Yang, Yunju A1 - Knol, Maria J A1 - Wang, Ruiqi A1 - Mishra, Aniket A1 - Liu, Dan A1 - Luciano, Michelle A1 - Teumer, Alexander A1 - Armstrong, Nicola A1 - Bis, Joshua C A1 - Jhun, Min A A1 - Li, Shuo A1 - Adams, Hieab H H A1 - Aziz, Nasir Ahmad A1 - Bastin, Mark E A1 - Bourgey, Mathieu A1 - Brody, Jennifer A A1 - Frenzel, Stefan A1 - Gottesman, Rebecca F A1 - Hosten, Norbert A1 - Hou, Lifang A1 - Kardia, Sharon L R A1 - Lohner, Valerie A1 - Marquis, Pascale A1 - Maniega, Susana Muñoz A1 - Satizabal, Claudia L A1 - Sorond, Farzaneh A A1 - Valdés Hernández, Maria C A1 - van Duijn, Cornelia M A1 - Vernooij, Meike W A1 - Wittfeld, Katharina A1 - Yang, Qiong A1 - Zhao, Wei A1 - Boerwinkle, Eric A1 - Levy, Daniel A1 - Deary, Ian J A1 - Jiang, Jiyang A1 - Mather, Karen A A1 - Mosley, Thomas H A1 - Psaty, Bruce M A1 - Sachdev, Perminder S A1 - Smith, Jennifer A A1 - Sotoodehnia, Nona A1 - DeCarli, Charles S A1 - Breteler, Monique M B A1 - Arfan Ikram, M A1 - Grabe, Hans J A1 - Wardlaw, Joanna A1 - Longstreth, W T A1 - Launer, Lenore J A1 - Seshadri, Sudha A1 - Debette, Stephanie A1 - Fornage, Myriam AB -

Cerebral white matter hyperintensities on MRI are markers of cerebral small vessel disease, a major risk factor for dementia and stroke. Despite the successful identification of multiple genetic variants associated with this highly heritable condition, its genetic architecture remains incompletely understood. More specifically, the role of DNA methylation has received little attention. We investigated the association between white matter hyperintensity burden and DNA methylation in blood at approximately 450,000 CpG sites in 9,732 middle-aged to older adults from 14 community-based studies. Single-CpG and region-based association analyses were carried out. Functional annotation and integrative cross-omics analyses were performed to identify novel genes underlying the relationship between DNA methylation and white matter hyperintensities. We identified 12 single-CpG and 46 region-based DNA methylation associations with white matter hyperintensity burden. Our top discovery single CpG, cg24202936 (P = 7.6 × 10-8), was associated with F2 expression in blood (P = 6.4 × 10-5), and colocalized with FOLH1 expression in brain (posterior probability =0.75). Our top differentially methylated regions were in PRMT1 and in CCDC144NL-AS1, which were also represented in single-CpG associations (cg17417856 and cg06809326, respectively). Through Mendelian randomization analyses cg06809326 was putatively associated with white matter hyperintensity burden (P = 0.03) and expression of CCDC144NL-AS1 possibly mediated this association. Differentially methylated region analysis, joint epigenetic association analysis, and multi-omics colocalization analysis consistently identified a role of DNA methylation near SH3PXD2A, a locus previously identified in genome-wide association studies of white matter hyperintensities. Gene set enrichment analyses revealed functions of the identified DNA methylation loci in the blood-brain barrier and in the immune response. Integrative cross-omics analysis identified 19 key regulatory genes in two networks related to extracellular matrix organization, and lipid and lipoprotein metabolism. A drug repositioning analysis indicated antihyperlipidemic agents, more specifically peroxisome proliferator-activated receptor alpha, as possible target drugs for white matter hyperintensities. Our epigenome-wide association study and integrative cross-omics analyses implicate novel genes influencing white matter hyperintensity burden, which converged on pathways related to the immune response and to a compromised blood brain barrier possibly due to disrupted cell-cell and cell-extracellular matrix interactions. The results also suggest that antihyperlipidemic therapy may contribute to lowering risk for white matter hyperintensities possibly through protection against blood brain barrier disruption.

ER - TY - JOUR T1 - Genetic loci and prioritization of genes for kidney function decline derived from a meta-analysis of 62 longitudinal genome-wide association studies. JF - Kidney Int Y1 - 2022 A1 - Gorski, Mathias A1 - Rasheed, Humaira A1 - Teumer, Alexander A1 - Thomas, Laurent F A1 - Graham, Sarah E A1 - Sveinbjornsson, Gardar A1 - Winkler, Thomas W A1 - Günther, Felix A1 - Stark, Klaus J A1 - Chai, Jin-Fang A1 - Tayo, Bamidele O A1 - Wuttke, Matthias A1 - Li, Yong A1 - Tin, Adrienne A1 - Ahluwalia, Tarunveer S A1 - Arnlöv, Johan A1 - Åsvold, Bjørn Olav A1 - Bakker, Stephan J L A1 - Banas, Bernhard A1 - Bansal, Nisha A1 - Biggs, Mary L A1 - Biino, Ginevra A1 - Böhnke, Michael A1 - Boerwinkle, Eric A1 - Bottinger, Erwin P A1 - Brenner, Hermann A1 - Brumpton, Ben A1 - Carroll, Robert J A1 - Chaker, Layal A1 - Chalmers, John A1 - Chee, Miao-Li A1 - Chee, Miao-Ling A1 - Cheng, Ching-Yu A1 - Chu, Audrey Y A1 - Ciullo, Marina A1 - Cocca, Massimiliano A1 - Cook, James P A1 - Coresh, Josef A1 - Cusi, Daniele A1 - de Borst, Martin H A1 - Degenhardt, Frauke A1 - Eckardt, Kai-Uwe A1 - Endlich, Karlhans A1 - Evans, Michele K A1 - Feitosa, Mary F A1 - Franke, Andre A1 - Freitag-Wolf, Sandra A1 - Fuchsberger, Christian A1 - Gampawar, Piyush A1 - Gansevoort, Ron T A1 - Ghanbari, Mohsen A1 - Ghasemi, Sahar A1 - Giedraitis, Vilmantas A1 - Gieger, Christian A1 - Gudbjartsson, Daniel F A1 - Hallan, Stein A1 - Hamet, Pavel A1 - Hishida, Asahi A1 - Ho, Kevin A1 - Hofer, Edith A1 - Holleczek, Bernd A1 - Holm, Hilma A1 - Hoppmann, Anselm A1 - Horn, Katrin A1 - Hutri-Kähönen, Nina A1 - Hveem, Kristian A1 - Hwang, Shih-Jen A1 - Ikram, M Arfan A1 - Josyula, Navya Shilpa A1 - Jung, Bettina A1 - Kähönen, Mika A1 - Karabegović, Irma A1 - Khor, Chiea-Chuen A1 - Koenig, Wolfgang A1 - Kramer, Holly A1 - Krämer, Bernhard K A1 - Kuhnel, Brigitte A1 - Kuusisto, Johanna A1 - Laakso, Markku A1 - Lange, Leslie A A1 - Lehtimäki, Terho A1 - Li, Man A1 - Lieb, Wolfgang A1 - Lind, Lars A1 - Lindgren, Cecilia M A1 - Loos, Ruth J F A1 - Lukas, Mary Ann A1 - Lyytikäinen, Leo-Pekka A1 - Mahajan, Anubha A1 - Matias-Garcia, Pamela R A1 - Meisinger, Christa A1 - Meitinger, Thomas A1 - Melander, Olle A1 - Milaneschi, Yuri A1 - Mishra, Pashupati P A1 - Mononen, Nina A1 - Morris, Andrew P A1 - Mychaleckyj, Josyf C A1 - Nadkarni, Girish N A1 - Naito, Mariko A1 - Nakatochi, Masahiro A1 - Nalls, Mike A A1 - Nauck, Matthias A1 - Nikus, Kjell A1 - Ning, Boting A1 - Nolte, Ilja M A1 - Nutile, Teresa A1 - O'Donoghue, Michelle L A1 - O'Connell, Jeffrey A1 - Olafsson, Isleifur A1 - Orho-Melander, Marju A1 - Parsa, Afshin A1 - Pendergrass, Sarah A A1 - Penninx, Brenda W J H A1 - Pirastu, Mario A1 - Preuss, Michael H A1 - Psaty, Bruce M A1 - Raffield, Laura M A1 - Raitakari, Olli T A1 - Rheinberger, Myriam A1 - Rice, Kenneth M A1 - Rizzi, Federica A1 - Rosenkranz, Alexander R A1 - Rossing, Peter A1 - Rotter, Jerome I A1 - Ruggiero, Daniela A1 - Ryan, Kathleen A A1 - Sabanayagam, Charumathi A1 - Salvi, Erika A1 - Schmidt, Helena A1 - Schmidt, Reinhold A1 - Scholz, Markus A1 - Schöttker, Ben A1 - Schulz, Christina-Alexandra A1 - Sedaghat, Sanaz A1 - Shaffer, Christian M A1 - Sieber, Karsten B A1 - Sim, Xueling A1 - Sims, Mario A1 - Snieder, Harold A1 - Stanzick, Kira J A1 - Thorsteinsdottir, Unnur A1 - Stocker, Hannah A1 - Strauch, Konstantin A1 - Stringham, Heather M A1 - Sulem, Patrick A1 - Szymczak, Silke A1 - Taylor, Kent D A1 - Thio, Chris H L A1 - Tremblay, Johanne A1 - Vaccargiu, Simona A1 - van der Harst, Pim A1 - van der Most, Peter J A1 - Verweij, Niek A1 - Völker, Uwe A1 - Wakai, Kenji A1 - Waldenberger, Melanie A1 - Wallentin, Lars A1 - Wallner, Stefan A1 - Wang, Judy A1 - Waterworth, Dawn M A1 - White, Harvey D A1 - Willer, Cristen J A1 - Wong, Tien-Yin A1 - Woodward, Mark A1 - Yang, Qiong A1 - Yerges-Armstrong, Laura M A1 - Zimmermann, Martina A1 - Zonderman, Alan B A1 - Bergler, Tobias A1 - Stefansson, Kari A1 - Böger, Carsten A A1 - Pattaro, Cristian A1 - Köttgen, Anna A1 - Kronenberg, Florian A1 - Heid, Iris M AB -

Estimated glomerular filtration rate (eGFR) reflects kidney function. Progressive eGFR-decline can lead to kidney failure, necessitating dialysis or transplantation. Hundreds of loci from genome-wide association studies (GWAS) for eGFR help explain population cross section variability. Since the contribution of these or other loci to eGFR-decline remains largely unknown, we derived GWAS for annual eGFR-decline and meta-analyzed 62 longitudinal studies with eGFR assessed twice over time in all 343,339 individuals and in high-risk groups. We also explored different covariate adjustment. Twelve genome-wide significant independent variants for eGFR-decline unadjusted or adjusted for eGFR-baseline (11 novel, one known for this phenotype), including nine variants robustly associated across models were identified. All loci for eGFR-decline were known for cross-sectional eGFR and thus distinguished a subgroup of eGFR loci. Seven of the nine variants showed variant-by-age interaction on eGFR cross section (further about 350,000 individuals), which linked genetic associations for eGFR-decline with age-dependency of genetic cross-section associations. Clinically important were two to four-fold greater genetic effects on eGFR-decline in high-risk subgroups. Five variants associated also with chronic kidney disease progression mapped to genes with functional in-silico evidence (UMOD, SPATA7, GALNTL5, TPPP). An unfavorable versus favorable nine-variant genetic profile showed increased risk odds ratios of 1.35 for kidney failure (95% confidence intervals 1.03-1.77) and 1.27 for acute kidney injury (95% confidence intervals 1.08-1.50) in over 2000 cases each, with matched controls). Thus, we provide a large data resource, genetic loci, and prioritized genes for kidney function decline, which help inform drug development pipelines revealing important insights into the age-dependency of kidney function genetics.

ER - TY - JOUR T1 - Genome-wide meta-analyses reveal novel loci for verbal short-term memory and learning. JF - Mol Psychiatry Y1 - 2022 A1 - Lahti, Jari A1 - Tuominen, Samuli A1 - Yang, Qiong A1 - Pergola, Giulio A1 - Ahmad, Shahzad A1 - Amin, Najaf A1 - Armstrong, Nicola J A1 - Beiser, Alexa A1 - Bey, Katharina A1 - Bis, Joshua C A1 - Boerwinkle, Eric A1 - Bressler, Jan A1 - Campbell, Archie A1 - Campbell, Harry A1 - Chen, Qiang A1 - Corley, Janie A1 - Cox, Simon R A1 - Davies, Gail A1 - De Jager, Philip L A1 - Derks, Eske M A1 - Faul, Jessica D A1 - Fitzpatrick, Annette L A1 - Fohner, Alison E A1 - Ford, Ian A1 - Fornage, Myriam A1 - Gerring, Zachary A1 - Grabe, Hans J A1 - Grodstein, Francine A1 - Gudnason, Vilmundur A1 - Simonsick, Eleanor A1 - Holliday, Elizabeth G A1 - Joshi, Peter K A1 - Kajantie, Eero A1 - Kaprio, Jaakko A1 - Karell, Pauliina A1 - Kleineidam, Luca A1 - Knol, Maria J A1 - Kochan, Nicole A A1 - Kwok, John B A1 - Leber, Markus A1 - Lam, Max A1 - Lee, Teresa A1 - Li, Shuo A1 - Loukola, Anu A1 - Luck, Tobias A1 - Marioni, Riccardo E A1 - Mather, Karen A A1 - Medland, Sarah A1 - Mirza, Saira S A1 - Nalls, Mike A A1 - Nho, Kwangsik A1 - O'Donnell, Adrienne A1 - Oldmeadow, Christopher A1 - Painter, Jodie A1 - Pattie, Alison A1 - Reppermund, Simone A1 - Risacher, Shannon L A1 - Rose, Richard J A1 - Sadashivaiah, Vijay A1 - Scholz, Markus A1 - Satizabal, Claudia L A1 - Schofield, Peter W A1 - Schraut, Katharina E A1 - Scott, Rodney J A1 - Simino, Jeannette A1 - Smith, Albert V A1 - Smith, Jennifer A A1 - Stott, David J A1 - Surakka, Ida A1 - Teumer, Alexander A1 - Thalamuthu, Anbupalam A1 - Trompet, Stella A1 - Turner, Stephen T A1 - van der Lee, Sven J A1 - Villringer, Arno A1 - Völker, Uwe A1 - Wilson, Robert S A1 - Wittfeld, Katharina A1 - Vuoksimaa, Eero A1 - Xia, Rui A1 - Yaffe, Kristine A1 - Yu, Lei A1 - Zare, Habil A1 - Zhao, Wei A1 - Ames, David A1 - Attia, John A1 - Bennett, David A A1 - Brodaty, Henry A1 - Chasman, Daniel I A1 - Goldman, Aaron L A1 - Hayward, Caroline A1 - Ikram, M Arfan A1 - Jukema, J Wouter A1 - Kardia, Sharon L R A1 - Lencz, Todd A1 - Loeffler, Markus A1 - Mattay, Venkata S A1 - Palotie, Aarno A1 - Psaty, Bruce M A1 - Ramirez, Alfredo A1 - Ridker, Paul M A1 - Riedel-Heller, Steffi G A1 - Sachdev, Perminder S A1 - Saykin, Andrew J A1 - Scherer, Martin A1 - Schofield, Peter R A1 - Sidney, Stephen A1 - Starr, John M A1 - Trollor, Julian A1 - Ulrich, William A1 - Wagner, Michael A1 - Weir, David R A1 - Wilson, James F A1 - Wright, Margaret J A1 - Weinberger, Daniel R A1 - Debette, Stephanie A1 - Eriksson, Johan G A1 - Mosley, Thomas H A1 - Launer, Lenore J A1 - van Duijn, Cornelia M A1 - Deary, Ian J A1 - Seshadri, Sudha A1 - Räikkönen, Katri AB -

Understanding the genomic basis of memory processes may help in combating neurodegenerative disorders. Hence, we examined the associations of common genetic variants with verbal short-term memory and verbal learning in adults without dementia or stroke (N = 53,637). We identified novel loci in the intronic region of CDH18, and at 13q21 and 3p21.1, as well as an expected signal in the APOE/APOC1/TOMM40 region. These results replicated in an independent sample. Functional and bioinformatic analyses supported many of these loci and further implicated POC1. We showed that polygenic score for verbal learning associated with brain activation in right parieto-occipital region during working memory task. Finally, we showed genetic correlations of these memory traits with several neurocognitive and health outcomes. Our findings suggest a role of several genomic loci in verbal memory processes.

ER - TY - JOUR T1 - New insights into the genetic etiology of Alzheimer's disease and related dementias. JF - Nat Genet Y1 - 2022 A1 - Bellenguez, Céline A1 - Küçükali, Fahri A1 - Jansen, Iris E A1 - Kleineidam, Luca A1 - Moreno-Grau, Sonia A1 - Amin, Najaf A1 - Naj, Adam C A1 - Campos-Martin, Rafael A1 - Grenier-Boley, Benjamin A1 - Andrade, Victor A1 - Holmans, Peter A A1 - Boland, Anne A1 - Damotte, Vincent A1 - van der Lee, Sven J A1 - Costa, Marcos R A1 - Kuulasmaa, Teemu A1 - Yang, Qiong A1 - de Rojas, Itziar A1 - Bis, Joshua C A1 - Yaqub, Amber A1 - Prokic, Ivana A1 - Chapuis, Julien A1 - Ahmad, Shahzad A1 - Giedraitis, Vilmantas A1 - Aarsland, Dag A1 - Garcia-Gonzalez, Pablo A1 - Abdelnour, Carla A1 - Alarcón-Martín, Emilio A1 - Alcolea, Daniel A1 - Alegret, Montserrat A1 - Alvarez, Ignacio A1 - Alvarez, Victoria A1 - Armstrong, Nicola J A1 - Tsolaki, Anthoula A1 - Antunez, Carmen A1 - Appollonio, Ildebrando A1 - Arcaro, Marina A1 - Archetti, Silvana A1 - Pastor, Alfonso Arias A1 - Arosio, Beatrice A1 - Athanasiu, Lavinia A1 - Bailly, Henri A1 - Banaj, Nerisa A1 - Baquero, Miquel A1 - Barral, Sandra A1 - Beiser, Alexa A1 - Pastor, Ana Belén A1 - Below, Jennifer E A1 - Benchek, Penelope A1 - Benussi, Luisa A1 - Berr, Claudine A1 - Besse, Céline A1 - Bessi, Valentina A1 - Binetti, Giuliano A1 - Bizarro, Alessandra A1 - Blesa, Rafael A1 - Boada, Merce A1 - Boerwinkle, Eric A1 - Borroni, Barbara A1 - Boschi, Silvia A1 - Bossù, Paola A1 - Bråthen, Geir A1 - Bressler, Jan A1 - Bresner, Catherine A1 - Brodaty, Henry A1 - Brookes, Keeley J A1 - Brusco, Luis Ignacio A1 - Buiza-Rueda, Dolores A1 - Bûrger, Katharina A1 - Burholt, Vanessa A1 - Bush, William S A1 - Calero, Miguel A1 - Cantwell, Laura B A1 - Chene, Geneviève A1 - Chung, Jaeyoon A1 - Cuccaro, Michael L A1 - Carracedo, Angel A1 - Cecchetti, Roberta A1 - Cervera-Carles, Laura A1 - Charbonnier, Camille A1 - Chen, Hung-Hsin A1 - Chillotti, Caterina A1 - Ciccone, Simona A1 - Claassen, Jurgen A H R A1 - Clark, Christopher A1 - Conti, Elisa A1 - Corma-Gómez, Anaïs A1 - Costantini, Emanuele A1 - Custodero, Carlo A1 - Daian, Delphine A1 - Dalmasso, Maria Carolina A1 - Daniele, Antonio A1 - Dardiotis, Efthimios A1 - Dartigues, Jean-François A1 - de Deyn, Peter Paul A1 - de Paiva Lopes, Katia A1 - de Witte, Lot D A1 - Debette, Stephanie A1 - Deckert, Jürgen A1 - Del Ser, Teodoro A1 - Denning, Nicola A1 - DeStefano, Anita A1 - Dichgans, Martin A1 - Diehl-Schmid, Janine A1 - Diez-Fairen, Monica A1 - Rossi, Paolo Dionigi A1 - Djurovic, Srdjan A1 - Duron, Emmanuelle A1 - Düzel, Emrah A1 - Dufouil, Carole A1 - Eiriksdottir, Gudny A1 - Engelborghs, Sebastiaan A1 - Escott-Price, Valentina A1 - Espinosa, Ana A1 - Ewers, Michael A1 - Faber, Kelley M A1 - Fabrizio, Tagliavini A1 - Nielsen, Sune Fallgaard A1 - Fardo, David W A1 - Farotti, Lucia A1 - Fenoglio, Chiara A1 - Fernández-Fuertes, Marta A1 - Ferrari, Raffaele A1 - Ferreira, Catarina B A1 - Ferri, Evelyn A1 - Fin, Bertrand A1 - Fischer, Peter A1 - Fladby, Tormod A1 - Fließbach, Klaus A1 - Fongang, Bernard A1 - Fornage, Myriam A1 - Fortea, Juan A1 - Foroud, Tatiana M A1 - Fostinelli, Silvia A1 - Fox, Nick C A1 - Franco-Macías, Emlio A1 - Bullido, María J A1 - Frank-García, Ana A1 - Froelich, Lutz A1 - Fulton-Howard, Brian A1 - Galimberti, Daniela A1 - García-Alberca, Jose Maria A1 - Garcia-Gonzalez, Pablo A1 - Garcia-Madrona, Sebastian A1 - Garcia-Ribas, Guillermo A1 - Ghidoni, Roberta A1 - Giegling, Ina A1 - Giorgio, Giaccone A1 - Goate, Alison M A1 - Goldhardt, Oliver A1 - Gomez-Fonseca, Duber A1 - González-Perez, Antonio A1 - Graff, Caroline A1 - Grande, Giulia A1 - Green, Emma A1 - Grimmer, Timo A1 - Grünblatt, Edna A1 - Grunin, Michelle A1 - Gudnason, Vilmundur A1 - Guetta-Baranes, Tamar A1 - Haapasalo, Annakaisa A1 - Hadjigeorgiou, Georgios A1 - Haines, Jonathan L A1 - Hamilton-Nelson, Kara L A1 - Hampel, Harald A1 - Hanon, Olivier A1 - Hardy, John A1 - Hartmann, Annette M A1 - Hausner, Lucrezia A1 - Harwood, Janet A1 - Heilmann-Heimbach, Stefanie A1 - Helisalmi, Seppo A1 - Heneka, Michael T A1 - Hernandez, Isabel A1 - Herrmann, Martin J A1 - Hoffmann, Per A1 - Holmes, Clive A1 - Holstege, Henne A1 - Vilas, Raquel Huerto A1 - Hulsman, Marc A1 - Humphrey, Jack A1 - Biessels, Geert Jan A1 - Jian, Xueqiu A1 - Johansson, Charlotte A1 - Jun, Gyungah R A1 - Kastumata, Yuriko A1 - Kauwe, John A1 - Kehoe, Patrick G A1 - Kilander, Lena A1 - Ståhlbom, Anne Kinhult A1 - Kivipelto, Miia A1 - Koivisto, Anne A1 - Kornhuber, Johannes A1 - Kosmidis, Mary H A1 - Kukull, Walter A A1 - Kuksa, Pavel P A1 - Kunkle, Brian W A1 - Kuzma, Amanda B A1 - Lage, Carmen A1 - Laukka, Erika J A1 - Launer, Lenore A1 - Lauria, Alessandra A1 - Lee, Chien-Yueh A1 - Lehtisalo, Jenni A1 - Lerch, Ondrej A1 - Lleo, Alberto A1 - Longstreth, William A1 - Lopez, Oscar A1 - de Munain, Adolfo Lopez A1 - Love, Seth A1 - Löwemark, Malin A1 - Luckcuck, Lauren A1 - Lunetta, Kathryn L A1 - Ma, Yiyi A1 - Macías, Juan A1 - MacLeod, Catherine A A1 - Maier, Wolfgang A1 - Mangialasche, Francesca A1 - Spallazzi, Marco A1 - Marquié, Marta A1 - Marshall, Rachel A1 - Martin, Eden R A1 - Montes, Angel Martín A1 - Rodríguez, Carmen Martínez A1 - Masullo, Carlo A1 - Mayeux, Richard A1 - Mead, Simon A1 - Mecocci, Patrizia A1 - Medina, Miguel A1 - Meggy, Alun A1 - Mehrabian, Shima A1 - Mendoza, Silvia A1 - Menéndez-González, Manuel A1 - Mir, Pablo A1 - Moebus, Susanne A1 - Mol, Merel A1 - Molina-Porcel, Laura A1 - Montrreal, Laura A1 - Morelli, Laura A1 - Moreno, Fermin A1 - Morgan, Kevin A1 - Mosley, Thomas A1 - Nöthen, Markus M A1 - Muchnik, Carolina A1 - Mukherjee, Shubhabrata A1 - Nacmias, Benedetta A1 - Ngandu, Tiia A1 - Nicolas, Gaël A1 - Nordestgaard, Børge G A1 - Olaso, Robert A1 - Orellana, Adelina A1 - Orsini, Michela A1 - Ortega, Gemma A1 - Padovani, Alessandro A1 - Paolo, Caffarra A1 - Papenberg, Goran A1 - Parnetti, Lucilla A1 - Pasquier, Florence A1 - Pastor, Pau A1 - Peloso, Gina A1 - Pérez-Cordón, Alba A1 - Pérez-Tur, Jordi A1 - Pericard, Pierre A1 - Peters, Oliver A1 - Pijnenburg, Yolande A L A1 - Pineda, Juan A A1 - Piñol-Ripoll, Gerard A1 - Pisanu, Claudia A1 - Polak, Thomas A1 - Popp, Julius A1 - Posthuma, Danielle A1 - Priller, Josef A1 - Puerta, Raquel A1 - Quenez, Olivier A1 - Quintela, Inés A1 - Thomassen, Jesper Qvist A1 - Rábano, Alberto A1 - Rainero, Innocenzo A1 - Rajabli, Farid A1 - Ramakers, Inez A1 - Real, Luis M A1 - Reinders, Marcel J T A1 - Reitz, Christiane A1 - Reyes-Dumeyer, Dolly A1 - Ridge, Perry A1 - Riedel-Heller, Steffi A1 - Riederer, Peter A1 - Roberto, Natalia A1 - Rodriguez-Rodriguez, Eloy A1 - Rongve, Arvid A1 - Allende, Irene Rosas A1 - Rosende-Roca, Maitée A1 - Royo, Jose Luis A1 - Rubino, Elisa A1 - Rujescu, Dan A1 - Sáez, María Eugenia A1 - Sakka, Paraskevi A1 - Saltvedt, Ingvild A1 - Sanabria, Ángela A1 - Sánchez-Arjona, María Bernal A1 - Sanchez-Garcia, Florentino A1 - Juan, Pascual Sánchez A1 - Sánchez-Valle, Raquel A1 - Sando, Sigrid B A1 - Sarnowski, Chloe A1 - Satizabal, Claudia L A1 - Scamosci, Michela A1 - Scarmeas, Nikolaos A1 - Scarpini, Elio A1 - Scheltens, Philip A1 - Scherbaum, Norbert A1 - Scherer, Martin A1 - Schmid, Matthias A1 - Schneider, Anja A1 - Schott, Jonathan M A1 - Selbæk, Geir A1 - Seripa, Davide A1 - Serrano, Manuel A1 - Sha, Jin A1 - Shadrin, Alexey A A1 - Skrobot, Olivia A1 - Slifer, Susan A1 - Snijders, Gijsje J L A1 - Soininen, Hilkka A1 - Solfrizzi, Vincenzo A1 - Solomon, Alina A1 - Song, Yeunjoo A1 - Sorbi, Sandro A1 - Sotolongo-Grau, Oscar A1 - Spalletta, Gianfranco A1 - Spottke, Annika A1 - Squassina, Alessio A1 - Stordal, Eystein A1 - Tartan, Juan Pablo A1 - Tarraga, Lluis A1 - Tesí, Niccolo A1 - Thalamuthu, Anbupalam A1 - Thomas, Tegos A1 - Tosto, Giuseppe A1 - Traykov, Latchezar A1 - Tremolizzo, Lucio A1 - Tybjærg-Hansen, Anne A1 - Uitterlinden, Andre A1 - Ullgren, Abbe A1 - Ulstein, Ingun A1 - Valero, Sergi A1 - Valladares, Otto A1 - Broeckhoven, Christine Van A1 - Vance, Jeffery A1 - Vardarajan, Badri N A1 - van der Lugt, Aad A1 - Dongen, Jasper Van A1 - van Rooij, Jeroen A1 - van Swieten, John A1 - Vandenberghe, Rik A1 - Verhey, Frans A1 - Vidal, Jean-Sébastien A1 - Vogelgsang, Jonathan A1 - Vyhnalek, Martin A1 - Wagner, Michael A1 - Wallon, David A1 - Wang, Li-San A1 - Wang, Ruiqi A1 - Weinhold, Leonie A1 - Wiltfang, Jens A1 - Windle, Gill A1 - Woods, Bob A1 - Yannakoulia, Mary A1 - Zare, Habil A1 - Zhao, Yi A1 - Zhang, Xiaoling A1 - Zhu, Congcong A1 - Zulaica, Miren A1 - Farrer, Lindsay A A1 - Psaty, Bruce M A1 - Ghanbari, Mohsen A1 - Raj, Towfique A1 - Sachdev, Perminder A1 - Mather, Karen A1 - Jessen, Frank A1 - Ikram, M Arfan A1 - de Mendonça, Alexandre A1 - Hort, Jakub A1 - Tsolaki, Magda A1 - Pericak-Vance, Margaret A A1 - Amouyel, Philippe A1 - Williams, Julie A1 - Frikke-Schmidt, Ruth A1 - Clarimon, Jordi A1 - Deleuze, Jean-Francois A1 - Rossi, Giacomina A1 - Seshadri, Sudha A1 - Andreassen, Ole A A1 - Ingelsson, Martin A1 - Hiltunen, Mikko A1 - Sleegers, Kristel A1 - Schellenberg, Gerard D A1 - van Duijn, Cornelia M A1 - Sims, Rebecca A1 - van der Flier, Wiesje M A1 - Ruiz, Agustin A1 - Ramirez, Alfredo A1 - Lambert, Jean-Charles KW - Alzheimer Disease KW - Cognitive Dysfunction KW - Genome-Wide Association Study KW - Humans KW - tau Proteins AB -

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.

VL - 54 IS - 4 ER - TY - JOUR T1 - Stroke genetics informs drug discovery and risk prediction across ancestries. JF - Nature Y1 - 2022 A1 - Mishra, Aniket A1 - Malik, Rainer A1 - Hachiya, Tsuyoshi A1 - Jürgenson, Tuuli A1 - Namba, Shinichi A1 - Posner, Daniel C A1 - Kamanu, Frederick K A1 - Koido, Masaru A1 - Le Grand, Quentin A1 - Shi, Mingyang A1 - He, Yunye A1 - Georgakis, Marios K A1 - Caro, Ilana A1 - Krebs, Kristi A1 - Liaw, Yi-Ching A1 - Vaura, Felix C A1 - Lin, Kuang A1 - Winsvold, Bendik Slagsvold A1 - Srinivasasainagendra, Vinodh A1 - Parodi, Livia A1 - Bae, Hee-Joon A1 - Chauhan, Ganesh A1 - Chong, Michael R A1 - Tomppo, Liisa A1 - Akinyemi, Rufus A1 - Roshchupkin, Gennady V A1 - Habib, Naomi A1 - Jee, Yon Ho A1 - Thomassen, Jesper Qvist A1 - Abedi, Vida A1 - Cárcel-Márquez, Jara A1 - Nygaard, Marianne A1 - Leonard, Hampton L A1 - Yang, Chaojie A1 - Yonova-Doing, Ekaterina A1 - Knol, Maria J A1 - Lewis, Adam J A1 - Judy, Renae L A1 - Ago, Tetsuro A1 - Amouyel, Philippe A1 - Armstrong, Nicole D A1 - Bakker, Mark K A1 - Bartz, Traci M A1 - Bennett, David A A1 - Bis, Joshua C A1 - Bordes, Constance A1 - Børte, Sigrid A1 - Cain, Anael A1 - Ridker, Paul M A1 - Cho, Kelly A1 - Chen, Zhengming A1 - Cruchaga, Carlos A1 - Cole, John W A1 - De Jager, Phil L A1 - de Cid, Rafael A1 - Endres, Matthias A1 - Ferreira, Leslie E A1 - Geerlings, Mirjam I A1 - Gasca, Natalie C A1 - Gudnason, Vilmundur A1 - Hata, Jun A1 - He, Jing A1 - Heath, Alicia K A1 - Ho, Yuk-Lam A1 - Havulinna, Aki S A1 - Hopewell, Jemma C A1 - Hyacinth, Hyacinth I A1 - Inouye, Michael A1 - Jacob, Mina A A1 - Jeon, Christina E A1 - Jern, Christina A1 - Kamouchi, Masahiro A1 - Keene, Keith L A1 - Kitazono, Takanari A1 - Kittner, Steven J A1 - Konuma, Takahiro A1 - Kumar, Amit A1 - Lacaze, Paul A1 - Launer, Lenore J A1 - Lee, Keon-Joo A1 - Lepik, Kaido A1 - Li, Jiang A1 - Li, Liming A1 - Manichaikul, Ani A1 - Markus, Hugh S A1 - Marston, Nicholas A A1 - Meitinger, Thomas A1 - Mitchell, Braxton D A1 - Montellano, Felipe A A1 - Morisaki, Takayuki A1 - Mosley, Thomas H A1 - Nalls, Mike A A1 - Nordestgaard, Børge G A1 - O'Donnell, Martin J A1 - Okada, Yukinori A1 - Onland-Moret, N Charlotte A1 - Ovbiagele, Bruce A1 - Peters, Annette A1 - Psaty, Bruce M A1 - Rich, Stephen S A1 - Rosand, Jonathan A1 - Sabatine, Marc S A1 - Sacco, Ralph L A1 - Saleheen, Danish A1 - Sandset, Else Charlotte A1 - Salomaa, Veikko A1 - Sargurupremraj, Muralidharan A1 - Sasaki, Makoto A1 - Satizabal, Claudia L A1 - Schmidt, Carsten O A1 - Shimizu, Atsushi A1 - Smith, Nicholas L A1 - Sloane, Kelly L A1 - Sutoh, Yoichi A1 - Sun, Yan V A1 - Tanno, Kozo A1 - Tiedt, Steffen A1 - Tatlisumak, Turgut A1 - Torres-Aguila, Nuria P A1 - Tiwari, Hemant K A1 - Trégouët, David-Alexandre A1 - Trompet, Stella A1 - Tuladhar, Anil Man A1 - Tybjærg-Hansen, Anne A1 - van Vugt, Marion A1 - Vibo, Riina A1 - Verma, Shefali S A1 - Wiggins, Kerri L A1 - Wennberg, Patrik A1 - Woo, Daniel A1 - Wilson, Peter W F A1 - Xu, Huichun A1 - Yang, Qiong A1 - Yoon, Kyungheon A1 - Millwood, Iona Y A1 - Gieger, Christian A1 - Ninomiya, Toshiharu A1 - Grabe, Hans J A1 - Jukema, J Wouter A1 - Rissanen, Ina L A1 - Strbian, Daniel A1 - Kim, Young Jin A1 - Chen, Pei-Hsin A1 - Mayerhofer, Ernst A1 - Howson, Joanna M M A1 - Irvin, Marguerite R A1 - Adams, Hieab A1 - Wassertheil-Smoller, Sylvia A1 - Christensen, Kaare A1 - Ikram, Mohammad A A1 - Rundek, Tatjana A1 - Worrall, Bradford B A1 - Lathrop, G Mark A1 - Riaz, Moeen A1 - Simonsick, Eleanor M A1 - Kõrv, Janika A1 - França, Paulo H C A1 - Zand, Ramin A1 - Prasad, Kameshwar A1 - Frikke-Schmidt, Ruth A1 - de Leeuw, Frank-Erik A1 - Liman, Thomas A1 - Haeusler, Karl Georg A1 - Ruigrok, Ynte M A1 - Heuschmann, Peter Ulrich A1 - Longstreth, W T A1 - Jung, Keum Ji A1 - Bastarache, Lisa A1 - Paré, Guillaume A1 - Damrauer, Scott M A1 - Chasman, Daniel I A1 - Rotter, Jerome I A1 - Anderson, Christopher D A1 - Zwart, John-Anker A1 - Niiranen, Teemu J A1 - Fornage, Myriam A1 - Liaw, Yung-Po A1 - Seshadri, Sudha A1 - Fernandez-Cadenas, Israel A1 - Walters, Robin G A1 - Ruff, Christian T A1 - Owolabi, Mayowa O A1 - Huffman, Jennifer E A1 - Milani, Lili A1 - Kamatani, Yoichiro A1 - Dichgans, Martin A1 - Debette, Stephanie AB -

Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.

ER - TY - JOUR T1 - Complexities of cerebral small vessel disease, blood pressure, and dementia relationship: new insights from genetics. JF - medRxiv Y1 - 2023 A1 - Sargurupremraj, Muralidharan A1 - Soumaré, Aïcha A1 - Bis, Joshua C A1 - Surakka, Ida A1 - Jürgenson, Tuuli A1 - Joly, Pierre A1 - Knol, Maria J A1 - Wang, Ruiqi A1 - Yang, Qiong A1 - Satizabal, Claudia L A1 - Gudjonsson, Alexander A1 - Mishra, Aniket A1 - Bouteloup, Vincent A1 - Phuah, Chia-Ling A1 - van Duijn, Cornelia M A1 - Cruchaga, Carlos A1 - Dufouil, Carole A1 - Chene, Geneviève A1 - Lopez, Oscar A1 - Psaty, Bruce M A1 - Tzourio, Christophe A1 - Amouyel, Philippe A1 - Adams, Hieab H A1 - Jacqmin-Gadda, Hélène A1 - Ikram, Mohammad Arfan A1 - Gudnason, Vilmundur A1 - Milani, Lili A1 - Winsvold, Bendik S A1 - Hveem, Kristian A1 - Matthews, Paul M A1 - Longstreth, W T A1 - Seshadri, Sudha A1 - Launer, Lenore J A1 - Debette, Stephanie AB -

IMPORTANCE: There is increasing recognition that vascular disease, which can be treated, is a key contributor to dementia risk. However, the contribution of specific markers of vascular disease is unclear and, as a consequence, optimal prevention strategies remain unclear.

OBJECTIVE: To disentangle the causal relation of several key vascular traits to dementia risk: (i) white matter hyperintensity (WMH) burden, a highly prevalent imaging marker of covert cerebral small vessel disease (cSVD); (ii) clinical stroke; and (iii) blood pressure (BP), the leading risk factor for cSVD and stroke, for which efficient therapies exist. To account for potential epidemiological biases inherent to late-onset conditions like dementia.

DESIGN SETTING AND PARTICIPANTS: This study first explored the association of genetically determined WMH, BP levels and stroke risk with AD using summary-level data from large genome-wide association studies (GWASs) in a two-sample Mendelian randomization (MR) framework. Second, leveraging individual-level data from large longitudinal population-based cohorts and biobanks with prospective dementia surveillance, the association of weighted genetic risk scores (wGRSs) for WMH, BP, and stroke with incident all-cause-dementia was explored using Cox-proportional hazard and multi-state models. The data analysis was performed from July 26, 2020, through July 24, 2022.

EXPOSURES: Genetically determined levels of WMH volume and BP (systolic, diastolic and pulse blood pressures) and genetic liability to stroke.

MAIN OUTCOMES AND MEASURES: The summary-level MR analyses focused on the outcomes from GWAS of clinically diagnosed AD (n-cases=21,982) and GWAS additionally including self-reported parental history of dementia as a proxy for AD diagnosis (AD , n-cases=53,042). For the longitudinal analyses, individual-level data of 157,698 participants with 10,699 incident all-cause-dementia were studied, exploring AD, vascular or mixed dementia in secondary analyses.

RESULTS: In the two-sample MR analyses, WMH showed strong evidence for a causal association with increased risk of AD (OR, 1.16; 95%CI:1.05-1.28; P=.003) and AD (OR, 1.28; 95%CI:1.07-1.53; P=.008), after accounting for genetically determined pulse pressure for the latter. Genetically predicted BP traits showed evidence for a protective association with both clinically defined AD and AD , with evidence for confounding by shared genetic instruments. In longitudinal analyses the wGRSs for WMH, but not BP or stroke, showed suggestive association with incident all-cause-dementia (HR, 1.02; 95%CI:1.00-1.04; P=.06). BP and stroke wGRSs were strongly associated with mortality but there was no evidence for selective survival bias during follow-up. In secondary analyses, polygenic scores with more liberal instrument definition showed association of both WMH and stroke with all-cause-dementia, AD, and vascular or mixed dementia; associations of stroke, but not WMH, with dementia outcomes were markedly attenuated after adjusting for interim stroke.

CONCLUSION: These findings provide converging evidence that WMH is a leading vascular contributor to dementia risk, which may better capture the brain damage caused by BP (and other etiologies) than BP itself and should be targeted in priority for dementia prevention in the population.

KEY POINTS: Do instrumental variable analyses leveraging genetic information provide evidence for a causal association of various vascular traits with Alzheimer's disease (AD) and all-cause-dementia? How do these associations compare for white matter hyperintensity (WMH) burden, a highly prevalent marker of covert cerebral small vessel disease (cSVD), stroke, and blood pressure traits, the strongest known risk factor for cSVD and stroke? Using Mendelian randomization (MR) leveraging large, published genome-wide association studies, this study showed a putative causal association of larger WMH burden with increased AD risk after accounting for pulse pressure effects, and some evidence for association of lower BP with AD risk with possible confounding by shared genetic instruments. Longitudinal analyses on individual-level data also supported association of genetically determined WMH with incident all-cause-dementia and AD, independently of interim stroke. This study using complementary genetic epidemiology approaches, identified increasing WMH burden to be associated with dementia and AD risk, suggesting the association as specific for cSVD and independent of BP and stroke.

ER - TY - JOUR T1 - Sleep Architecture, Obstructive Sleep Apnea, and Cognitive Function in Adults. JF - JAMA Netw Open Y1 - 2023 A1 - Pase, Matthew P A1 - Harrison, Stephanie A1 - Misialek, Jeffrey R A1 - Kline, Christopher E A1 - Cavuoto, Marina A1 - Baril, Andree-Ann A1 - Yiallourou, Stephanie A1 - Bisson, Alycia A1 - Himali, Dibya A1 - Leng, Yue A1 - Yang, Qiong A1 - Seshadri, Sudha A1 - Beiser, Alexa A1 - Gottesman, Rebecca F A1 - Redline, Susan A1 - Lopez, Oscar A1 - Lutsey, Pamela L A1 - Yaffe, Kristine A1 - Stone, Katie L A1 - Purcell, Shaun M A1 - Himali, Jayandra J AB -

IMPORTANCE: Good sleep is essential for health, yet associations between sleep and dementia risk remain incompletely understood. The Sleep and Dementia Consortium was established to study associations between polysomnography (PSG)-derived sleep and the risk of dementia and related cognitive and brain magnetic resonance imaging endophenotypes.

OBJECTIVE: To investigate association of sleep architecture and obstructive sleep apnea (OSA) with cognitive function in the Sleep and Dementia Consortium.

DESIGN, SETTING, AND PARTICIPANTS: The Sleep and Dementia Consortium curated data from 5 population-based cohorts across the US with methodologically consistent, overnight, home-based type II PSG and neuropsychological assessments over 5 years of follow-up: the Atherosclerosis Risk in Communities study, Cardiovascular Health Study, Framingham Heart Study (FHS), Osteoporotic Fractures in Men Study, and Study of Osteoporotic Fractures. Sleep metrics were harmonized centrally and then distributed to participating cohorts for cohort-specific analysis using linear regression; study-level estimates were pooled in random effects meta-analyses. Results were adjusted for demographic variables, the time between PSG and neuropsychological assessment (0-5 years), body mass index, antidepressant use, and sedative use. There were 5946 participants included in the pooled analyses without stroke or dementia. Data were analyzed from March 2020 to June 2023.

EXPOSURES: Measures of sleep architecture and OSA derived from in-home PSG.

MAIN OUTCOMES AND MEASURES: The main outcomes were global cognitive composite z scores derived from principal component analysis, with cognitive domains investigated as secondary outcomes. Higher scores indicated better performance.

RESULTS: Across cohorts, 5946 adults (1875 females [31.5%]; mean age range, 58-89 years) were included. The median (IQR) wake after sleep onset time ranged from 44 (27-73) to 101 (66-147) minutes, and the prevalence of moderate to severe OSA ranged from 16.9% to 28.9%. Across cohorts, higher sleep maintenance efficiency (pooled β per 1% increase, 0.08; 95% CI, 0.03 to 0.14; P < .01) and lower wake after sleep onset (pooled β per 1-min increase, -0.07; 95% CI, -0.13 to -0.01 per 1-min increase; P = .02) were associated with better global cognition. Mild to severe OSA (apnea-hypopnea index [AHI] ≥5) was associated with poorer global cognition (pooled β, -0.06; 95% CI, -0.11 to -0.01; P = .01) vs AHI less than 5; comparable results were found for moderate to severe OSA (pooled β, -0.06; 95% CI, -0.11 to -0.01; P = .02) vs AHI less than 5. Differences in sleep stages were not associated with cognition.

CONCLUSIONS AND RELEVANCE: This study found that better sleep consolidation and the absence of OSA were associated with better global cognition over 5 years of follow-up. These findings suggest that the role of interventions to improve sleep for maintaining cognitive function requires investigation.

VL - 6 IS - 7 ER - TY - JOUR T1 - Multi-omics and pathway analyses of genome-wide associations implicate regulation and immunity in verbal declarative memory performance. JF - Alzheimers Res Ther Y1 - 2024 A1 - Mei, Hao A1 - Simino, Jeannette A1 - Li, Lianna A1 - Jiang, Fan A1 - Bis, Joshua C A1 - Davies, Gail A1 - Hill, W David A1 - Xia, Charley A1 - Gudnason, Vilmundur A1 - Yang, Qiong A1 - Lahti, Jari A1 - Smith, Jennifer A A1 - Kirin, Mirna A1 - De Jager, Philip A1 - Armstrong, Nicola J A1 - Ghanbari, Mohsen A1 - Kolcic, Ivana A1 - Moran, Christopher A1 - Teumer, Alexander A1 - Sargurupremraj, Murali A1 - Mahmud, Shamsed A1 - Fornage, Myriam A1 - Zhao, Wei A1 - Satizabal, Claudia L A1 - Polasek, Ozren A1 - Räikkönen, Katri A1 - Liewald, David C A1 - Homuth, Georg A1 - Callisaya, Michele A1 - Mather, Karen A A1 - Windham, B Gwen A1 - Zemunik, Tatijana A1 - Palotie, Aarno A1 - Pattie, Alison A1 - van der Auwera, Sandra A1 - Thalamuthu, Anbupalam A1 - Knopman, David S A1 - Rudan, Igor A1 - Starr, John M A1 - Wittfeld, Katharina A1 - Kochan, Nicole A A1 - Griswold, Michael E A1 - Vitart, Veronique A1 - Brodaty, Henry A1 - Gottesman, Rebecca A1 - Cox, Simon R A1 - Psaty, Bruce M A1 - Boerwinkle, Eric A1 - Chasman, Daniel I A1 - Grodstein, Francine A1 - Sachdev, Perminder S A1 - Srikanth, Velandai A1 - Hayward, Caroline A1 - Wilson, James F A1 - Eriksson, Johan G A1 - Kardia, Sharon L R A1 - Grabe, Hans J A1 - Bennett, David A A1 - Ikram, M Arfan A1 - Deary, Ian J A1 - van Duijn, Cornelia M A1 - Launer, Lenore A1 - Fitzpatrick, Annette L A1 - Seshadri, Sudha A1 - Bressler, Jan A1 - Debette, Stephanie A1 - Mosley, Thomas H KW - Aged KW - Cognition KW - Genome-Wide Association Study KW - Humans KW - Memory KW - MicroRNAs KW - Multiomics KW - Polymorphism, Single Nucleotide AB -

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.

VL - 16 IS - 1 ER -