TY - JOUR T1 - Meta-analyses of genome-wide association studies identify multiple loci associated with pulmonary function. JF - Nat Genet Y1 - 2010 A1 - Hancock, Dana B A1 - Eijgelsheim, Mark A1 - Wilk, Jemma B A1 - Gharib, Sina A A1 - Loehr, Laura R A1 - Marciante, Kristin D A1 - Franceschini, Nora A1 - van Durme, Yannick M T A A1 - Chen, Ting-Hsu A1 - Barr, R Graham A1 - Schabath, Matthew B A1 - Couper, David J A1 - Brusselle, Guy G A1 - Psaty, Bruce M A1 - van Duijn, Cornelia M A1 - Rotter, Jerome I A1 - Uitterlinden, André G A1 - Hofman, Albert A1 - Punjabi, Naresh M A1 - Rivadeneira, Fernando A1 - Morrison, Alanna C A1 - Enright, Paul L A1 - North, Kari E A1 - Heckbert, Susan R A1 - Lumley, Thomas A1 - Stricker, Bruno H C A1 - O'Connor, George T A1 - London, Stephanie J KW - Databases, Genetic KW - Female KW - Forced Expiratory Volume KW - Genetic Predisposition to Disease KW - Genome, Human KW - Genome-Wide Association Study KW - Humans KW - Lung KW - Lung Diseases KW - Male KW - Meta-Analysis as Topic KW - Polymorphism, Single Nucleotide KW - Spirometry KW - Vital Capacity AB -

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

VL - 42 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20010835?dopt=Abstract ER - TY - JOUR T1 - A meta-analysis of four genome-wide association studies of survival to age 90 years or older: the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium. JF - J Gerontol A Biol Sci Med Sci Y1 - 2010 A1 - Newman, Anne B A1 - Walter, Stefan A1 - Lunetta, Kathryn L A1 - Garcia, Melissa E A1 - Slagboom, P Eline A1 - Christensen, Kaare A1 - Arnold, Alice M A1 - Aspelund, Thor A1 - Aulchenko, Yurii S A1 - Benjamin, Emelia J A1 - Christiansen, Lene A1 - D'Agostino, Ralph B A1 - Fitzpatrick, Annette L A1 - Franceschini, Nora A1 - Glazer, Nicole L A1 - Gudnason, Vilmundur A1 - Hofman, Albert A1 - Kaplan, Robert A1 - Karasik, David A1 - Kelly-Hayes, Margaret A1 - Kiel, Douglas P A1 - Launer, Lenore J A1 - Marciante, Kristin D A1 - Massaro, Joseph M A1 - Miljkovic, Iva A1 - Nalls, Michael A A1 - Hernandez, Dena A1 - Psaty, Bruce M A1 - Rivadeneira, Fernando A1 - Rotter, Jerome A1 - Seshadri, Sudha A1 - Smith, Albert V A1 - Taylor, Kent D A1 - Tiemeier, Henning A1 - Uh, Hae-Won A1 - Uitterlinden, André G A1 - Vaupel, James W A1 - Walston, Jeremy A1 - Westendorp, Rudi G J A1 - Harris, Tamara B A1 - Lumley, Thomas A1 - van Duijn, Cornelia M A1 - Murabito, Joanne M KW - Adult KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Alleles KW - Cohort Studies KW - Confidence Intervals KW - Female KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Longevity KW - Male KW - Middle Aged KW - Odds Ratio KW - Polymorphism, Single Nucleotide AB -

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

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

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

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

VL - 65 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20304771?dopt=Abstract ER - TY - JOUR T1 - Association of genetic variants and incident coronary heart disease in multiethnic cohorts: the PAGE study. JF - Circ Cardiovasc Genet Y1 - 2011 A1 - Franceschini, Nora A1 - Carty, Cara A1 - Bůzková, Petra A1 - Reiner, Alex P A1 - Garrett, Tiana A1 - Lin, Yi A1 - Vöckler, Jens-S A1 - Hindorff, Lucia A A1 - Cole, Shelley A A1 - Boerwinkle, Eric A1 - Lin, Dan-Yu A1 - Bookman, Ebony A1 - Best, Lyle G A1 - Bella, Jonathan N A1 - Eaton, Charles A1 - Greenland, Philip A1 - Jenny, Nancy A1 - North, Kari E A1 - Taverna, Darin A1 - Young, Alicia M A1 - Deelman, Ewa A1 - Kooperberg, Charles A1 - Psaty, Bruce A1 - Heiss, Gerardo KW - Aged KW - Aged, 80 and over KW - Continental Population Groups KW - Coronary Disease KW - Female KW - Genome-Wide Association Study KW - Humans KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Prospective Studies AB -

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

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

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

VL - 4 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22042884?dopt=Abstract ER - TY - JOUR T1 - Association of genetic variation with systolic and diastolic blood pressure among African Americans: the Candidate Gene Association Resource study. JF - Hum Mol Genet Y1 - 2011 A1 - Fox, Ervin R A1 - Young, J Hunter A1 - Li, Yali A1 - Dreisbach, Albert W A1 - Keating, Brendan J A1 - Musani, Solomon K A1 - Liu, Kiang A1 - Morrison, Alanna C A1 - Ganesh, Santhi A1 - Kutlar, Abdullah A1 - Ramachandran, Vasan S A1 - Polak, Josef F A1 - Fabsitz, Richard R A1 - Dries, Daniel L A1 - Farlow, Deborah N A1 - Redline, Susan A1 - Adeyemo, Adebowale A1 - Hirschorn, Joel N A1 - Sun, Yan V A1 - Wyatt, Sharon B A1 - Penman, Alan D A1 - Palmas, Walter A1 - Rotter, Jerome I A1 - Townsend, Raymond R A1 - Doumatey, Ayo P A1 - Tayo, Bamidele O A1 - Mosley, Thomas H A1 - Lyon, Helen N A1 - Kang, Sun J A1 - Rotimi, Charles N A1 - Cooper, Richard S A1 - Franceschini, Nora A1 - Curb, J David A1 - Martin, Lisa W A1 - Eaton, Charles B A1 - Kardia, Sharon L R A1 - Taylor, Herman A A1 - Caulfield, Mark J A1 - Ehret, Georg B A1 - Johnson, Toby A1 - Chakravarti, Aravinda A1 - Zhu, Xiaofeng A1 - Levy, Daniel KW - Adult KW - African Americans KW - Aged KW - Blood Pressure KW - Cohort Studies KW - Diastole KW - European Continental Ancestry Group KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Hypertension KW - Male KW - Middle Aged KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Systole AB -

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

VL - 20 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21378095?dopt=Abstract ER - TY - JOUR T1 - A bivariate genome-wide approach to metabolic syndrome: STAMPEED consortium. JF - Diabetes Y1 - 2011 A1 - Kraja, Aldi T A1 - Vaidya, Dhananjay A1 - Pankow, James S A1 - Goodarzi, Mark O A1 - Assimes, Themistocles L A1 - Kullo, Iftikhar J A1 - Sovio, Ulla A1 - Mathias, Rasika A A1 - Sun, Yan V A1 - Franceschini, Nora A1 - Absher, Devin A1 - Li, Guo A1 - Zhang, Qunyuan A1 - Feitosa, Mary F A1 - Glazer, Nicole L A1 - Haritunians, Talin A1 - Hartikainen, Anna-Liisa A1 - Knowles, Joshua W A1 - North, Kari E A1 - Iribarren, Carlos A1 - Kral, Brian A1 - Yanek, Lisa A1 - O'Reilly, Paul F A1 - McCarthy, Mark I A1 - Jaquish, Cashell A1 - Couper, David J A1 - Chakravarti, Aravinda A1 - Psaty, Bruce M A1 - Becker, Lewis C A1 - Province, Michael A A1 - Boerwinkle, Eric A1 - Quertermous, Thomas A1 - Palotie, Leena A1 - Jarvelin, Marjo-Riitta A1 - Becker, Diane M A1 - Kardia, Sharon L R A1 - Rotter, Jerome I A1 - Chen, Yii-Der Ida A1 - Borecki, Ingrid B KW - Adult KW - Aged KW - Female KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Male KW - Meta-Analysis as Topic KW - Metabolic Syndrome KW - Middle Aged KW - Phenotype KW - Polymorphism, Single Nucleotide AB -

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

VL - 60 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21386085?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 - Genetic association for renal traits among participants of African ancestry reveals new loci for renal function. JF - PLoS Genet Y1 - 2011 A1 - Liu, Ching-Ti A1 - Garnaas, Maija K A1 - Tin, Adrienne A1 - Köttgen, Anna A1 - Franceschini, Nora A1 - Peralta, Carmen A A1 - de Boer, Ian H A1 - Lu, Xiaoning A1 - Atkinson, Elizabeth A1 - Ding, Jingzhong A1 - Nalls, Michael A1 - Shriner, Daniel A1 - Coresh, Josef A1 - Kutlar, Abdullah A1 - Bibbins-Domingo, Kirsten A1 - Siscovick, David A1 - Akylbekova, Ermeg A1 - Wyatt, Sharon A1 - Astor, Brad A1 - Mychaleckjy, Josef A1 - Li, Man A1 - Reilly, Muredach P A1 - Townsend, Raymond R A1 - Adeyemo, Adebowale A1 - Zonderman, Alan B A1 - de Andrade, Mariza A1 - Turner, Stephen T A1 - Mosley, Thomas H A1 - Harris, Tamara B A1 - Rotimi, Charles N A1 - Liu, Yongmei A1 - Kardia, Sharon L R A1 - Evans, Michele K A1 - Shlipak, Michael G A1 - Kramer, Holly A1 - Flessner, Michael F A1 - Dreisbach, Albert W A1 - Goessling, Wolfram A1 - Cupples, L Adrienne A1 - Kao, W Linda A1 - Fox, Caroline S KW - Adaptor Proteins, Vesicular Transport KW - Adult KW - African Continental Ancestry Group KW - Aged KW - Animals KW - Female KW - Gene Knockdown Techniques KW - Genetic Association Studies KW - Genetic Loci KW - Genome-Wide Association Study KW - Glomerular Filtration Rate KW - Humans KW - KCNQ1 Potassium Channel KW - Kidney KW - Kidney Failure, Chronic KW - Male KW - Middle Aged KW - Neoplasm Proteins KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Zebrafish AB -

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

VL - 7 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21931561?dopt=Abstract ER - TY - JOUR T1 - Genetic determinants of lipid traits in diverse populations from the population architecture using genomics and epidemiology (PAGE) study. JF - PLoS Genet Y1 - 2011 A1 - Dumitrescu, Logan A1 - Carty, Cara L A1 - Taylor, Kira A1 - Schumacher, Fredrick R A1 - Hindorff, Lucia A A1 - Ambite, José L A1 - Anderson, Garnet A1 - Best, Lyle G A1 - Brown-Gentry, Kristin A1 - Bůzková, Petra A1 - Carlson, Christopher S A1 - Cochran, Barbara A1 - Cole, Shelley A A1 - Devereux, Richard B A1 - Duggan, Dave A1 - Eaton, Charles B A1 - Fornage, Myriam A1 - Franceschini, Nora A1 - Haessler, Jeff A1 - Howard, Barbara V A1 - Johnson, Karen C A1 - Laston, Sandra A1 - Kolonel, Laurence N A1 - Lee, Elisa T A1 - MacCluer, Jean W A1 - Manolio, Teri A A1 - Pendergrass, Sarah A A1 - Quibrera, Miguel A1 - Shohet, Ralph V A1 - Wilkens, Lynne R A1 - Haiman, Christopher A A1 - Le Marchand, Loïc A1 - Buyske, Steven A1 - Kooperberg, Charles A1 - North, Kari E A1 - Crawford, Dana C KW - Adolescent KW - Adult KW - Aged KW - Aged, 80 and over KW - Continental Population Groups KW - Female KW - Gene Frequency KW - Genetics, Population KW - Genome-Wide Association Study KW - Humans KW - Linkage Disequilibrium KW - Lipid Metabolism KW - Lipoproteins, HDL KW - Lipoproteins, LDL KW - Male KW - Middle Aged KW - Molecular Epidemiology KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci KW - Risk Factors KW - Triglycerides KW - Young Adult AB -

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

VL - 7 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21738485?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association and large-scale follow up identifies 16 new loci influencing lung function. JF - Nat Genet Y1 - 2011 A1 - Soler Artigas, Maria A1 - Loth, Daan W A1 - Wain, Louise V A1 - Gharib, Sina A A1 - Obeidat, Ma'en A1 - Tang, Wenbo A1 - Zhai, Guangju A1 - Zhao, Jing Hua A1 - Smith, Albert Vernon A1 - Huffman, Jennifer E A1 - Albrecht, Eva A1 - Jackson, Catherine M A1 - Evans, David M A1 - Cadby, Gemma A1 - Fornage, Myriam A1 - Manichaikul, Ani A1 - Lopez, Lorna M A1 - Johnson, Toby A1 - Aldrich, Melinda C A1 - Aspelund, Thor A1 - Barroso, Inês A1 - Campbell, Harry A1 - Cassano, Patricia A A1 - Couper, David J A1 - Eiriksdottir, Gudny A1 - Franceschini, Nora A1 - Garcia, Melissa A1 - Gieger, Christian A1 - Gislason, Gauti Kjartan A1 - Grkovic, Ivica A1 - Hammond, Christopher J A1 - Hancock, Dana B A1 - Harris, Tamara B A1 - Ramasamy, Adaikalavan A1 - Heckbert, Susan R A1 - Heliövaara, Markku A1 - Homuth, Georg A1 - Hysi, Pirro G A1 - James, Alan L A1 - Jankovic, Stipan A1 - Joubert, Bonnie R A1 - Karrasch, Stefan A1 - Klopp, Norman A1 - Koch, Beate A1 - Kritchevsky, Stephen B A1 - Launer, Lenore J A1 - Liu, Yongmei A1 - Loehr, Laura R A1 - Lohman, Kurt A1 - Loos, Ruth J F A1 - Lumley, Thomas A1 - Al Balushi, Khalid A A1 - Ang, Wei Q A1 - Barr, R Graham A1 - Beilby, John A1 - Blakey, John D A1 - Boban, Mladen A1 - Boraska, Vesna A1 - Brisman, Jonas A1 - Britton, John R A1 - Brusselle, Guy G A1 - Cooper, Cyrus A1 - Curjuric, Ivan A1 - Dahgam, Santosh A1 - Deary, Ian J A1 - Ebrahim, Shah A1 - Eijgelsheim, Mark A1 - Francks, Clyde A1 - Gaysina, Darya A1 - Granell, Raquel A1 - Gu, Xiangjun A1 - Hankinson, John L A1 - Hardy, Rebecca A1 - Harris, Sarah E A1 - Henderson, John A1 - Henry, Amanda A1 - Hingorani, Aroon D A1 - Hofman, Albert A1 - Holt, Patrick G A1 - Hui, Jennie A1 - Hunter, Michael L A1 - Imboden, Medea A1 - Jameson, Karen A A1 - Kerr, Shona M A1 - Kolcic, Ivana A1 - Kronenberg, Florian A1 - Liu, Jason Z A1 - Marchini, Jonathan A1 - McKeever, Tricia A1 - Morris, Andrew D A1 - Olin, Anna-Carin A1 - Porteous, David J A1 - Postma, Dirkje S A1 - Rich, Stephen S A1 - Ring, Susan M A1 - Rivadeneira, Fernando A1 - Rochat, Thierry A1 - Sayer, Avan Aihie A1 - Sayers, Ian A1 - Sly, Peter D A1 - Smith, George Davey A1 - Sood, Akshay A1 - Starr, John M A1 - Uitterlinden, André G A1 - Vonk, Judith M A1 - Wannamethee, S Goya A1 - Whincup, Peter H A1 - Wijmenga, Cisca A1 - Williams, O Dale A1 - Wong, Andrew A1 - Mangino, Massimo A1 - Marciante, Kristin D A1 - McArdle, Wendy L A1 - Meibohm, Bernd A1 - Morrison, Alanna C A1 - North, Kari E A1 - Omenaas, Ernst A1 - Palmer, Lyle J A1 - Pietiläinen, Kirsi H A1 - Pin, Isabelle A1 - Pola Sbreve Ek, Ozren A1 - Pouta, Anneli A1 - Psaty, Bruce M A1 - Hartikainen, Anna-Liisa A1 - Rantanen, Taina A1 - Ripatti, Samuli A1 - Rotter, Jerome I A1 - Rudan, Igor A1 - Rudnicka, Alicja R A1 - Schulz, Holger A1 - Shin, So-Youn A1 - Spector, Tim D A1 - Surakka, Ida A1 - Vitart, Veronique A1 - Völzke, Henry A1 - Wareham, Nicholas J A1 - Warrington, Nicole M A1 - Wichmann, H-Erich A1 - Wild, Sarah H A1 - Wilk, Jemma B A1 - Wjst, Matthias A1 - Wright, Alan F A1 - Zgaga, Lina A1 - Zemunik, Tatijana A1 - Pennell, Craig E A1 - Nyberg, Fredrik A1 - Kuh, Diana A1 - Holloway, John W A1 - Boezen, H Marike A1 - Lawlor, Debbie A A1 - Morris, Richard W A1 - Probst-Hensch, Nicole A1 - Kaprio, Jaakko A1 - Wilson, James F A1 - Hayward, Caroline A1 - Kähönen, Mika A1 - Heinrich, Joachim A1 - Musk, Arthur W A1 - Jarvis, Deborah L A1 - Gläser, Sven A1 - Jarvelin, Marjo-Riitta A1 - Ch Stricker, Bruno H A1 - Elliott, Paul A1 - O'Connor, George T A1 - Strachan, David P A1 - London, Stephanie J A1 - Hall, Ian P A1 - Gudnason, Vilmundur A1 - Tobin, Martin D KW - Child KW - European Continental Ancestry Group KW - Genome-Wide Association Study KW - Humans KW - Pulmonary Disease, Chronic Obstructive KW - Respiratory Function Tests AB -

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

VL - 43 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21946350?dopt=Abstract ER - TY - JOUR T1 - A genome-wide association study of aging. JF - Neurobiol Aging Y1 - 2011 A1 - Walter, Stefan A1 - Atzmon, Gil A1 - Demerath, Ellen W A1 - Garcia, Melissa E A1 - Kaplan, Robert C A1 - Kumari, Meena A1 - Lunetta, Kathryn L A1 - Milaneschi, Yuri A1 - Tanaka, Toshiko A1 - Tranah, Gregory J A1 - Völker, Uwe A1 - Yu, Lei A1 - Arnold, Alice A1 - Benjamin, Emelia J A1 - Biffar, Reiner A1 - Buchman, Aron S A1 - Boerwinkle, Eric A1 - Couper, David A1 - De Jager, Philip L A1 - Evans, Denis A A1 - Harris, Tamara B A1 - Hoffmann, Wolfgang A1 - Hofman, Albert A1 - Karasik, David A1 - Kiel, Douglas P A1 - Kocher, Thomas A1 - Kuningas, Maris A1 - Launer, Lenore J A1 - Lohman, Kurt K A1 - Lutsey, Pamela L A1 - Mackenbach, Johan A1 - Marciante, Kristin A1 - Psaty, Bruce M A1 - Reiman, Eric M A1 - Rotter, Jerome I A1 - Seshadri, Sudha A1 - Shardell, Michelle D A1 - Smith, Albert V A1 - van Duijn, Cornelia A1 - Walston, Jeremy A1 - Zillikens, M Carola A1 - Bandinelli, Stefania A1 - Baumeister, Sebastian E A1 - Bennett, David A A1 - Ferrucci, Luigi A1 - Gudnason, Vilmundur A1 - Kivimaki, Mika A1 - Liu, Yongmei A1 - Murabito, Joanne M A1 - Newman, Anne B A1 - Tiemeier, Henning A1 - Franceschini, Nora KW - Aging KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Longevity AB -

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

VL - 32 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21782286?dopt=Abstract ER - TY - JOUR T1 - Meta-analysis of genome-wide association studies from the CHARGE consortium identifies common variants associated with carotid intima media thickness and plaque. JF - Nat Genet Y1 - 2011 A1 - Bis, Joshua C A1 - Kavousi, Maryam A1 - Franceschini, Nora A1 - Isaacs, Aaron A1 - Abecasis, Goncalo R A1 - Schminke, Ulf A1 - Post, Wendy S A1 - Smith, Albert V A1 - Cupples, L Adrienne A1 - Markus, Hugh S A1 - Schmidt, Reinhold A1 - Huffman, Jennifer E A1 - Lehtimäki, Terho A1 - Baumert, Jens A1 - Münzel, Thomas A1 - Heckbert, Susan R A1 - Dehghan, Abbas A1 - North, Kari A1 - Oostra, Ben A1 - Bevan, Steve A1 - Stoegerer, Eva-Maria A1 - Hayward, Caroline A1 - Raitakari, Olli A1 - Meisinger, Christa A1 - Schillert, Arne A1 - Sanna, Serena A1 - Völzke, Henry A1 - Cheng, Yu-Ching A1 - Thorsson, Bolli A1 - Fox, Caroline S A1 - Rice, Kenneth A1 - Rivadeneira, Fernando A1 - Nambi, Vijay A1 - Halperin, Eran A1 - Petrovic, Katja E A1 - Peltonen, Leena A1 - Wichmann, H Erich A1 - Schnabel, Renate B A1 - Dörr, Marcus A1 - Parsa, Afshin A1 - Aspelund, Thor A1 - Demissie, Serkalem A1 - Kathiresan, Sekar A1 - Reilly, Muredach P A1 - Taylor, Kent A1 - Uitterlinden, Andre A1 - Couper, David J A1 - Sitzer, Matthias A1 - Kähönen, Mika A1 - Illig, Thomas A1 - Wild, Philipp S A1 - Orrù, Marco A1 - Lüdemann, Jan A1 - Shuldiner, Alan R A1 - Eiriksdottir, Gudny A1 - White, Charles C A1 - Rotter, Jerome I A1 - Hofman, Albert A1 - Seissler, Jochen A1 - Zeller, Tanja A1 - Usala, Gianluca A1 - Ernst, Florian A1 - Launer, Lenore J A1 - D'Agostino, Ralph B A1 - O'Leary, Daniel H A1 - Ballantyne, Christie A1 - Thiery, Joachim A1 - Ziegler, Andreas A1 - Lakatta, Edward G A1 - Chilukoti, Ravi Kumar A1 - Harris, Tamara B A1 - Wolf, Philip A A1 - Psaty, Bruce M A1 - Polak, Joseph F A1 - Li, Xia A1 - Rathmann, Wolfgang A1 - Uda, Manuela A1 - Boerwinkle, Eric A1 - Klopp, Norman A1 - Schmidt, Helena A1 - Wilson, James F A1 - Viikari, Jorma A1 - Koenig, Wolfgang A1 - Blankenberg, Stefan A1 - Newman, Anne B A1 - Witteman, Jacqueline A1 - Heiss, Gerardo A1 - Duijn, Cornelia van A1 - Scuteri, Angelo A1 - Homuth, Georg A1 - Mitchell, Braxton D A1 - Gudnason, Vilmundur A1 - O'Donnell, Christopher J KW - Adult KW - Aged KW - Aging KW - Atherosclerosis KW - Carotid Intima-Media Thickness KW - Cohort Studies KW - Coronary Artery Disease KW - European Continental Ancestry Group KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genome, Human KW - Genome-Wide Association Study KW - Genotype KW - Heart KW - Humans KW - Middle Aged KW - Phenotype KW - Plaque, Atherosclerotic KW - Polymorphism, Single Nucleotide KW - Risk Factors AB -

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

VL - 43 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21909108?dopt=Abstract ER - TY - JOUR T1 - Association between chromosome 9p21 variants and the ankle-brachial index identified by a meta-analysis of 21 genome-wide association studies. JF - Circ Cardiovasc Genet Y1 - 2012 A1 - Murabito, Joanne M A1 - White, Charles C A1 - Kavousi, Maryam A1 - Sun, Yan V A1 - Feitosa, Mary F A1 - Nambi, Vijay A1 - Lamina, Claudia A1 - Schillert, Arne A1 - Coassin, Stefan A1 - Bis, Joshua C A1 - Broer, Linda A1 - Crawford, Dana C A1 - Franceschini, Nora A1 - Frikke-Schmidt, Ruth A1 - Haun, Margot A1 - Holewijn, Suzanne A1 - Huffman, Jennifer E A1 - Hwang, Shih-Jen A1 - Kiechl, Stefan A1 - Kollerits, Barbara A1 - Montasser, May E A1 - Nolte, Ilja M A1 - Rudock, Megan E A1 - Senft, Andrea A1 - Teumer, Alexander A1 - van der Harst, Pim A1 - Vitart, Veronique A1 - Waite, Lindsay L A1 - Wood, Andrew R A1 - Wassel, Christina L A1 - Absher, Devin M A1 - Allison, Matthew A A1 - Amin, Najaf A1 - Arnold, Alice A1 - Asselbergs, Folkert W A1 - Aulchenko, Yurii A1 - Bandinelli, Stefania A1 - Barbalic, Maja A1 - Boban, Mladen A1 - Brown-Gentry, Kristin A1 - Couper, David J A1 - Criqui, Michael H A1 - Dehghan, Abbas A1 - den Heijer, Martin A1 - Dieplinger, Benjamin A1 - Ding, Jingzhong A1 - Dörr, Marcus A1 - Espinola-Klein, Christine A1 - Felix, Stephan B A1 - Ferrucci, Luigi A1 - Folsom, Aaron R A1 - Fraedrich, Gustav A1 - Gibson, Quince A1 - Goodloe, Robert A1 - Gunjaca, Grgo A1 - Haltmayer, Meinhard A1 - Heiss, Gerardo A1 - Hofman, Albert A1 - Kieback, Arne A1 - Kiemeney, Lambertus A A1 - Kolcic, Ivana A1 - Kullo, Iftikhar J A1 - Kritchevsky, Stephen B A1 - Lackner, Karl J A1 - Li, Xiaohui A1 - Lieb, Wolfgang A1 - Lohman, Kurt A1 - Meisinger, Christa A1 - Melzer, David A1 - Mohler, Emile R A1 - Mudnic, Ivana A1 - Mueller, Thomas A1 - Navis, Gerjan A1 - Oberhollenzer, Friedrich A1 - Olin, Jeffrey W A1 - O'Connell, Jeff A1 - O'Donnell, Christopher J A1 - Palmas, Walter A1 - Penninx, Brenda W A1 - Petersmann, Astrid A1 - Polasek, Ozren A1 - Psaty, Bruce M A1 - Rantner, Barbara A1 - Rice, Ken A1 - Rivadeneira, Fernando A1 - Rotter, Jerome I A1 - Seldenrijk, Adrie A1 - Stadler, Marietta A1 - Summerer, Monika A1 - Tanaka, Toshiko A1 - Tybjaerg-Hansen, Anne A1 - Uitterlinden, André G A1 - van Gilst, Wiek H A1 - Vermeulen, Sita H A1 - Wild, Sarah H A1 - Wild, Philipp S A1 - Willeit, Johann A1 - Zeller, Tanja A1 - Zemunik, Tatijana A1 - Zgaga, Lina A1 - Assimes, Themistocles L A1 - Blankenberg, Stefan A1 - Boerwinkle, Eric A1 - Campbell, Harry A1 - Cooke, John P A1 - de Graaf, Jacqueline A1 - Herrington, David A1 - Kardia, Sharon L R A1 - Mitchell, Braxton D A1 - Murray, Anna A1 - Münzel, Thomas A1 - Newman, Anne B A1 - Oostra, Ben A A1 - Rudan, Igor A1 - Shuldiner, Alan R A1 - Snieder, Harold A1 - van Duijn, Cornelia M A1 - Völker, Uwe A1 - Wright, Alan F A1 - Wichmann, H-Erich A1 - Wilson, James F A1 - Witteman, Jacqueline C M A1 - Liu, Yongmei A1 - Hayward, Caroline A1 - Borecki, Ingrid B A1 - Ziegler, Andreas A1 - North, Kari E A1 - Cupples, L Adrienne A1 - Kronenberg, Florian KW - Adult KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Alleles KW - Ankle Brachial Index KW - Chromosomes, Human, Pair 9 KW - Cohort Studies KW - Cyclin-Dependent Kinase Inhibitor p15 KW - Female KW - Genome-Wide Association Study KW - Genotype KW - HapMap Project KW - Humans KW - Logistic Models KW - Male KW - Middle Aged KW - Peripheral Vascular Diseases KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Risk Factors KW - Sex Factors AB -

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

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

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

VL - 5 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22199011?dopt=Abstract ER - TY - JOUR T1 - Associations between incident ischemic stroke events and stroke and cardiovascular disease-related genome-wide association studies single nucleotide polymorphisms in the Population Architecture Using Genomics and Epidemiology study. JF - Circ Cardiovasc Genet Y1 - 2012 A1 - Carty, Cara L A1 - Bůzková, Petra A1 - Fornage, Myriam A1 - Franceschini, Nora A1 - Cole, Shelley A1 - Heiss, Gerardo A1 - Hindorff, Lucia A A1 - Howard, Barbara V A1 - Mann, Sue A1 - Martin, Lisa W A1 - Zhang, Ying A1 - Matise, Tara C A1 - Prentice, Ross A1 - Reiner, Alexander P A1 - Kooperberg, Charles KW - Aged KW - Aged, 80 and over KW - Cardiovascular Diseases KW - Cholesterol, HDL KW - Cholesterol, LDL KW - European Continental Ancestry Group KW - Female KW - Genetics, Population KW - Genome-Wide Association Study KW - Genomics KW - Humans KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Risk Factors KW - Stroke KW - Triglycerides AB -

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

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

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

VL - 5 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22403240?dopt=Abstract ER - TY - JOUR T1 - Consistent directions of effect for established type 2 diabetes risk variants across populations: the population architecture using Genomics and Epidemiology (PAGE) Consortium. JF - Diabetes Y1 - 2012 A1 - Haiman, Christopher A A1 - Fesinmeyer, Megan D A1 - Spencer, Kylee L A1 - Bůzková, Petra A1 - Voruganti, V Saroja A1 - Wan, Peggy A1 - Haessler, Jeff A1 - Franceschini, Nora A1 - Monroe, Kristine R A1 - Howard, Barbara V A1 - Jackson, Rebecca D A1 - Florez, Jose C A1 - Kolonel, Laurence N A1 - Buyske, Steven A1 - Goodloe, Robert J A1 - Liu, Simin A1 - Manson, JoAnn E A1 - Meigs, James B A1 - Waters, Kevin A1 - Mukamal, Kenneth J A1 - Pendergrass, Sarah A A1 - Shrader, Peter A1 - Wilkens, Lynne R A1 - Hindorff, Lucia A A1 - Ambite, Jose Luis A1 - North, Kari E A1 - Peters, Ulrike A1 - Crawford, Dana C A1 - Le Marchand, Loïc A1 - Pankow, James S KW - Adult KW - Aged KW - Aged, 80 and over KW - Alleles KW - Diabetes Mellitus, Type 2 KW - Female KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Male KW - Metagenomics KW - Middle Aged KW - Population Groups KW - Risk KW - Risk Factors AB -

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

VL - 61 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22474029?dopt=Abstract ER - TY - JOUR T1 - Evaluation of the metabochip genotyping array in African Americans and implications for fine mapping of GWAS-identified loci: the PAGE study. JF - PLoS One Y1 - 2012 A1 - Buyske, Steven A1 - Wu, Ying A1 - Carty, Cara L A1 - Cheng, Iona A1 - Assimes, Themistocles L A1 - Dumitrescu, Logan A1 - Hindorff, Lucia A A1 - Mitchell, Sabrina A1 - Ambite, Jose Luis A1 - Boerwinkle, Eric A1 - Bůzková, Petra A1 - Carlson, Chris S A1 - Cochran, Barbara A1 - Duggan, David A1 - Eaton, Charles B A1 - Fesinmeyer, Megan D A1 - Franceschini, Nora A1 - Haessler, Jeffrey A1 - Jenny, Nancy A1 - Kang, Hyun Min A1 - Kooperberg, Charles A1 - Lin, Yi A1 - Le Marchand, Loïc A1 - Matise, Tara C A1 - Robinson, Jennifer G A1 - Rodriguez, Carlos A1 - Schumacher, Fredrick R A1 - Voight, Benjamin F A1 - Young, Alicia A1 - Manolio, Teri A A1 - Mohlke, Karen L A1 - Haiman, Christopher A A1 - Peters, Ulrike A1 - Crawford, Dana C A1 - North, Kari E KW - African Americans KW - Cardiovascular Diseases KW - Cholesterol Ester Transfer Proteins KW - Cholesterol, HDL KW - Cholesterol, LDL KW - Chromosomes, Human KW - Cohort Studies KW - Gene Frequency KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Metabolic Diseases KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci AB -

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

VL - 7 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22539988?dopt=Abstract ER - TY - JOUR T1 - Genetic determinants of the ankle-brachial index: a meta-analysis of a cardiovascular candidate gene 50K SNP panel in the candidate gene association resource (CARe) consortium. JF - Atherosclerosis Y1 - 2012 A1 - Wassel, Christina L A1 - Lamina, Claudia A1 - Nambi, Vijay A1 - Coassin, Stefan A1 - Mukamal, Kenneth J A1 - Ganesh, Santhi K A1 - Jacobs, David R A1 - Franceschini, Nora A1 - Papanicolaou, George J A1 - Gibson, Quince A1 - Yanek, Lisa R A1 - van der Harst, Pim A1 - Ferguson, Jane F A1 - Crawford, Dana C A1 - Waite, Lindsay L A1 - Allison, Matthew A A1 - Criqui, Michael H A1 - McDermott, Mary M A1 - Mehra, Reena A1 - Cupples, L Adrienne A1 - Hwang, Shih-Jen A1 - Redline, Susan A1 - Kaplan, Robert C A1 - Heiss, Gerardo A1 - Rotter, Jerome I A1 - Boerwinkle, Eric A1 - Taylor, Herman A A1 - Eraso, Luis H A1 - Haun, Margot A1 - Li, Mingyao A1 - Meisinger, Christa A1 - O'Connell, Jeffrey R A1 - Shuldiner, Alan R A1 - Tybjærg-Hansen, Anne A1 - Frikke-Schmidt, Ruth A1 - Kollerits, Barbara A1 - Rantner, Barbara A1 - Dieplinger, Benjamin A1 - Stadler, Marietta A1 - Mueller, Thomas A1 - Haltmayer, Meinhard A1 - Klein-Weigel, Peter A1 - Summerer, Monika A1 - Wichmann, H-Erich A1 - Asselbergs, Folkert W A1 - Navis, Gerjan A1 - Mateo Leach, Irene A1 - Brown-Gentry, Kristin A1 - Goodloe, Robert A1 - Assimes, Themistocles L A1 - Becker, Diane M A1 - Cooke, John P A1 - Absher, Devin M A1 - Olin, Jeffrey W A1 - Mitchell, Braxton D A1 - Reilly, Muredach P A1 - Mohler, Emile R A1 - North, Kari E A1 - Reiner, Alexander P A1 - Kronenberg, Florian A1 - Murabito, Joanne M KW - Adult KW - African Americans KW - Aged KW - Ankle Brachial Index KW - Aryl Hydrocarbon Hydroxylases KW - Cytochrome P-450 CYP2B6 KW - European Continental Ancestry Group KW - Female KW - Humans KW - Male KW - Middle Aged KW - Oxidoreductases, N-Demethylating KW - Peripheral Arterial Disease KW - Polymorphism, Single Nucleotide KW - Risk Factors KW - Transcription Factor 7-Like 2 Protein AB -

BACKGROUND: Candidate gene association studies for peripheral artery disease (PAD), including subclinical disease assessed with the ankle-brachial index (ABI), have been limited by the modest number of genes examined. We conducted a two stage meta-analysis of ∼50,000 SNPs across ∼2100 candidate genes to identify genetic variants for ABI.

METHODS AND RESULTS: We studied subjects of European ancestry from 8 studies (n=21,547, 55% women, mean age 44-73 years) and African American ancestry from 5 studies (n=7267, 60% women, mean age 41-73 years) involved in the candidate gene association resource (CARe) consortium. In each ethnic group, additive genetic models were used (with each additional copy of the minor allele corresponding to the given beta) to test each SNP for association with continuous ABI (excluding ABI>1.40) and PAD (defined as ABI<0.90) using linear or logistic regression with adjustment for known PAD risk factors and population stratification. We then conducted a fixed-effects inverse-variance weighted meta-analyses considering a p<2×10(-6) to denote statistical significance.

RESULTS: In the European ancestry discovery meta-analyses, rs2171209 in SYTL3 (β=-0.007, p=6.02×10(-7)) and rs290481 in TCF7L2 (β=-0.008, p=7.01×10(-7)) were significantly associated with ABI. None of the SNP associations for PAD were significant, though a SNP in CYP2B6 (p=4.99×10(-5)) was among the strongest associations. These 3 genes are linked to key PAD risk factors (lipoprotein(a), type 2 diabetes, and smoking behavior, respectively). We sought replication in 6 population-based and 3 clinical samples (n=15,440) for rs290481 and rs2171209. However, in the replication stage (rs2171209, p=0.75; rs290481, p=0.19) and in the combined discovery and replication analysis the SNP-ABI associations were no longer significant (rs2171209, p=1.14×10(-3); rs290481, p=8.88×10(-5)). In African Americans, none of the SNP associations for ABI or PAD achieved an experiment-wide level of significance.

CONCLUSIONS: Genetic determinants of ABI and PAD remain elusive. Follow-up of these preliminary findings may uncover important biology given the known gene-risk factor associations. New and more powerful approaches to PAD gene discovery are warranted.

VL - 222 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22361517?dopt=Abstract ER - TY - JOUR T1 - Genetic variants in Arhgef11 are associated with kidney injury in the Dahl salt-sensitive rat. JF - Hypertension Y1 - 2012 A1 - Williams, Jan M A1 - Johnson, Ashley C A1 - Stelloh, Cary A1 - Dreisbach, Albert W A1 - Franceschini, Nora A1 - Regner, Kevin R A1 - Townsend, Raymond R A1 - Roman, Richard J A1 - Garrett, Michael R KW - 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine KW - Animals KW - Animals, Congenic KW - Blood Pressure KW - Blotting, Western KW - Chromosome Mapping KW - Gene Expression Profiling KW - Genetic Predisposition to Disease KW - Guanine Nucleotide Exchange Factors KW - Humans KW - Kidney KW - Kidney Diseases KW - Male KW - Polymorphism, Single Nucleotide KW - Protein Kinase Inhibitors KW - Proteinuria KW - Quantitative Trait Loci KW - Rats KW - Rats, Inbred Dahl KW - Rats, Inbred SHR KW - Renal Circulation KW - Reverse Transcriptase Polymerase Chain Reaction KW - rho-Associated Kinases KW - rhoA GTP-Binding Protein KW - Signal Transduction AB -

A previous genetic analysis comparing the Dahl salt-sensitive (S) rat with the spontaneously hypertensive rat identified a major locus on chromosome 2 that influences proteinuria in the S rat. In the present study, blood pressure, proteinuria, and renal hemodynamics were evaluated in congenic strains with small segments of the protective spontaneously hypertensive rat genome on the S background. Proteinuria and renal function were significantly improved in the congenic strains compared with the S. The causative locus interval was narrowed to <375 kb on the basis of congenic strains, haplotype data, comparative mapping, and concordance with human genetic studies. Sequencing of the coding region of genes in this region identified 36 single nucleotide polymorphisms (13 nonsynonymous and 23 synonymous). Gene expression profiling indicated that only a few genes exhibited differential expression. Arhgef11, Pear1, and Sh2d2 were identified as important candidate genes that may be linked to kidney injury in the S rat. In particular, Arhgef11 plays an important role in the activation of the Rho-ROCK signaling pathway. Inhibition of this pathway using fasudil resulted in a significant reduction of proteinuria in treated S rats (compared with untreated S). However, no difference was observed between treated or untreated spontaneously hypertensive rat or congenic strains. The homologous region in humans was found to be associated with estimated glomerular filtration rate in the Candidate Gene Association Resource population. In summary, these findings demonstrate that allelic variants in Arhgef11, acting through the Rho-ROCK pathway, could influence kidney injury in the S as well as provide insight into human kidney disease.

VL - 60 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22987919?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association studies identify CHRNA5/3 and HTR4 in the development of airflow obstruction. JF - Am J Respir Crit Care Med Y1 - 2012 A1 - Wilk, Jemma B A1 - Shrine, Nick R G A1 - Loehr, Laura R A1 - Zhao, Jing Hua A1 - Manichaikul, Ani A1 - Lopez, Lorna M A1 - Smith, Albert Vernon A1 - Heckbert, Susan R A1 - Smolonska, Joanna A1 - Tang, Wenbo A1 - Loth, Daan W A1 - Curjuric, Ivan A1 - Hui, Jennie A1 - Cho, Michael H A1 - Latourelle, Jeanne C A1 - Henry, Amanda P A1 - Aldrich, Melinda A1 - Bakke, Per A1 - Beaty, Terri H A1 - Bentley, Amy R A1 - Borecki, Ingrid B A1 - Brusselle, Guy G A1 - Burkart, Kristin M A1 - Chen, Ting-Hsu A1 - Couper, David A1 - Crapo, James D A1 - Davies, Gail A1 - Dupuis, Josée A1 - Franceschini, Nora A1 - Gulsvik, Amund A1 - Hancock, Dana B A1 - Harris, Tamara B A1 - Hofman, Albert A1 - Imboden, Medea A1 - James, Alan L A1 - Khaw, Kay-Tee A1 - Lahousse, Lies A1 - Launer, Lenore J A1 - Litonjua, Augusto A1 - Liu, Yongmei A1 - Lohman, Kurt K A1 - Lomas, David A A1 - Lumley, Thomas A1 - Marciante, Kristin D A1 - McArdle, Wendy L A1 - Meibohm, Bernd A1 - Morrison, Alanna C A1 - Musk, Arthur W A1 - Myers, Richard H A1 - North, Kari E A1 - Postma, Dirkje S A1 - Psaty, Bruce M A1 - Rich, Stephen S A1 - Rivadeneira, Fernando A1 - Rochat, Thierry A1 - Rotter, Jerome I A1 - Soler Artigas, Maria A1 - Starr, John M A1 - Uitterlinden, André G A1 - Wareham, Nicholas J A1 - Wijmenga, Cisca A1 - Zanen, Pieter A1 - Province, Michael A A1 - Silverman, Edwin K A1 - Deary, Ian J A1 - Palmer, Lyle J A1 - Cassano, Patricia A A1 - Gudnason, Vilmundur A1 - Barr, R Graham A1 - Loos, Ruth J F A1 - Strachan, David P A1 - London, Stephanie J A1 - Boezen, H Marike A1 - Probst-Hensch, Nicole A1 - Gharib, Sina A A1 - Hall, Ian P A1 - O'Connor, George T A1 - Tobin, Martin D A1 - Stricker, Bruno H KW - Aged KW - Female KW - Forced Expiratory Volume KW - Genome-Wide Association Study KW - Humans KW - Male KW - Middle Aged KW - Nerve Tissue Proteins KW - Polymorphism, Single Nucleotide KW - Pulmonary Disease, Chronic Obstructive KW - Receptors, Nicotinic KW - Receptors, Serotonin, 5-HT4 KW - Smoking KW - Vital Capacity AB -

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

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

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

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

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

VL - 186 IS - 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22837378?dopt=Abstract ER - TY - JOUR T1 - Genome-wide joint meta-analysis of SNP and SNP-by-smoking interaction identifies novel loci for pulmonary function. JF - PLoS Genet Y1 - 2012 A1 - Hancock, Dana B A1 - Soler Artigas, Maria A1 - Gharib, Sina A A1 - Henry, Amanda A1 - Manichaikul, Ani A1 - Ramasamy, Adaikalavan A1 - Loth, Daan W A1 - Imboden, Medea A1 - Koch, Beate A1 - McArdle, Wendy L A1 - Smith, Albert V A1 - Smolonska, Joanna A1 - Sood, Akshay A1 - Tang, Wenbo A1 - Wilk, Jemma B A1 - Zhai, Guangju A1 - Zhao, Jing Hua A1 - Aschard, Hugues A1 - Burkart, Kristin M A1 - Curjuric, Ivan A1 - Eijgelsheim, Mark A1 - Elliott, Paul A1 - Gu, Xiangjun A1 - Harris, Tamara B A1 - Janson, Christer A1 - Homuth, Georg A1 - Hysi, Pirro G A1 - Liu, Jason Z A1 - Loehr, Laura R A1 - Lohman, Kurt A1 - Loos, Ruth J F A1 - Manning, Alisa K A1 - Marciante, Kristin D A1 - Obeidat, Ma'en A1 - Postma, Dirkje S A1 - Aldrich, Melinda C A1 - Brusselle, Guy G A1 - Chen, Ting-Hsu A1 - Eiriksdottir, Gudny A1 - Franceschini, Nora A1 - Heinrich, Joachim A1 - Rotter, Jerome I A1 - Wijmenga, Cisca A1 - Williams, O Dale A1 - Bentley, Amy R A1 - Hofman, Albert A1 - Laurie, Cathy C A1 - Lumley, Thomas A1 - Morrison, Alanna C A1 - Joubert, Bonnie R A1 - Rivadeneira, Fernando A1 - Couper, David J A1 - Kritchevsky, Stephen B A1 - Liu, Yongmei A1 - Wjst, Matthias A1 - Wain, Louise V A1 - Vonk, Judith M A1 - Uitterlinden, André G A1 - Rochat, Thierry A1 - Rich, Stephen S A1 - Psaty, Bruce M A1 - O'Connor, George T A1 - North, Kari E A1 - Mirel, Daniel B A1 - Meibohm, Bernd A1 - Launer, Lenore J A1 - Khaw, Kay-Tee A1 - Hartikainen, Anna-Liisa A1 - Hammond, Christopher J A1 - Gläser, Sven A1 - Marchini, Jonathan A1 - Kraft, Peter A1 - Wareham, Nicholas J A1 - Völzke, Henry A1 - Stricker, Bruno H C A1 - Spector, Timothy D A1 - Probst-Hensch, Nicole M A1 - Jarvis, Deborah A1 - Jarvelin, Marjo-Riitta A1 - Heckbert, Susan R A1 - Gudnason, Vilmundur A1 - Boezen, H Marike A1 - Barr, R Graham A1 - Cassano, Patricia A A1 - Strachan, David P A1 - Fornage, Myriam A1 - Hall, Ian P A1 - Dupuis, Josée A1 - Tobin, Martin D A1 - London, Stephanie J KW - Forced Expiratory Volume KW - Gene Expression KW - Genome, Human KW - Genome-Wide Association Study KW - HLA-DQ Antigens KW - HLA-DQ beta-Chains KW - Humans KW - Lung KW - Nerve Tissue Proteins KW - Polymorphism, Single Nucleotide KW - Potassium Channels, Inwardly Rectifying KW - Pulmonary Disease, Chronic Obstructive KW - Receptors, Cell Surface KW - Smoking KW - SOX9 Transcription Factor KW - Vital Capacity AB -

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

VL - 8 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23284291?dopt=Abstract ER - TY - JOUR T1 - Meta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways. JF - Nat Genet Y1 - 2012 A1 - Stolk, Lisette A1 - Perry, John R B A1 - Chasman, Daniel I A1 - He, Chunyan A1 - Mangino, Massimo A1 - Sulem, Patrick A1 - Barbalic, Maja A1 - Broer, Linda A1 - Byrne, Enda M A1 - Ernst, Florian A1 - Esko, Tõnu A1 - Franceschini, Nora A1 - Gudbjartsson, Daniel F A1 - Hottenga, Jouke-Jan A1 - Kraft, Peter A1 - McArdle, Patrick F A1 - Porcu, Eleonora A1 - Shin, So-Youn A1 - Smith, Albert V A1 - van Wingerden, Sophie A1 - Zhai, Guangju A1 - Zhuang, Wei V A1 - Albrecht, Eva A1 - Alizadeh, Behrooz Z A1 - Aspelund, Thor A1 - Bandinelli, Stefania A1 - Lauc, Lovorka Barac A1 - Beckmann, Jacques S A1 - Boban, Mladen A1 - Boerwinkle, Eric A1 - Broekmans, Frank J A1 - Burri, Andrea A1 - Campbell, Harry A1 - Chanock, Stephen J A1 - Chen, Constance A1 - Cornelis, Marilyn C A1 - Corre, Tanguy A1 - Coviello, Andrea D A1 - D'Adamo, Pio A1 - Davies, Gail A1 - de Faire, Ulf A1 - de Geus, Eco J C A1 - Deary, Ian J A1 - Dedoussis, George V Z A1 - Deloukas, Panagiotis A1 - Ebrahim, Shah A1 - Eiriksdottir, Gudny A1 - Emilsson, Valur A1 - Eriksson, Johan G A1 - Fauser, Bart C J M A1 - Ferreli, Liana A1 - Ferrucci, Luigi A1 - Fischer, Krista A1 - Folsom, Aaron R A1 - Garcia, Melissa E A1 - Gasparini, Paolo A1 - Gieger, Christian A1 - Glazer, Nicole A1 - Grobbee, Diederick E A1 - Hall, Per A1 - Haller, Toomas A1 - Hankinson, Susan E A1 - Hass, Merli A1 - Hayward, Caroline A1 - Heath, Andrew C A1 - Hofman, Albert A1 - Ingelsson, Erik A1 - Janssens, A Cecile J W A1 - Johnson, Andrew D A1 - Karasik, David A1 - Kardia, Sharon L R A1 - Keyzer, Jules A1 - Kiel, Douglas P A1 - Kolcic, Ivana A1 - Kutalik, Zoltán A1 - Lahti, Jari A1 - Lai, Sandra A1 - Laisk, Triin A1 - Laven, Joop S E A1 - Lawlor, Debbie A A1 - Liu, Jianjun A1 - Lopez, Lorna M A1 - Louwers, Yvonne V A1 - Magnusson, Patrik K E A1 - Marongiu, Mara A1 - Martin, Nicholas G A1 - Klaric, Irena Martinovic A1 - Masciullo, Corrado A1 - McKnight, Barbara A1 - Medland, Sarah E A1 - Melzer, David A1 - Mooser, Vincent A1 - Navarro, Pau A1 - Newman, Anne B A1 - Nyholt, Dale R A1 - Onland-Moret, N Charlotte A1 - Palotie, Aarno A1 - Paré, Guillaume A1 - Parker, Alex N A1 - Pedersen, Nancy L A1 - Peeters, Petra H M A1 - Pistis, Giorgio A1 - Plump, Andrew S A1 - Polasek, Ozren A1 - Pop, Victor J M A1 - Psaty, Bruce M A1 - Räikkönen, Katri A1 - Rehnberg, Emil A1 - Rotter, Jerome I A1 - Rudan, Igor A1 - Sala, Cinzia A1 - Salumets, Andres A1 - Scuteri, Angelo A1 - Singleton, Andrew A1 - Smith, Jennifer A A1 - Snieder, Harold A1 - Soranzo, Nicole A1 - Stacey, Simon N A1 - Starr, John M A1 - Stathopoulou, Maria G A1 - Stirrups, Kathleen A1 - Stolk, Ronald P A1 - Styrkarsdottir, Unnur A1 - Sun, Yan V A1 - Tenesa, Albert A1 - Thorand, Barbara A1 - Toniolo, Daniela A1 - Tryggvadottir, Laufey A1 - Tsui, Kim A1 - Ulivi, Sheila A1 - van Dam, Rob M A1 - van der Schouw, Yvonne T A1 - van Gils, Carla H A1 - van Nierop, Peter A1 - Vink, Jacqueline M A1 - Visscher, Peter M A1 - Voorhuis, Marlies A1 - Waeber, Gérard A1 - Wallaschofski, Henri A1 - Wichmann, H Erich A1 - Widen, Elisabeth A1 - Wijnands-van Gent, Colette J M A1 - Willemsen, Gonneke A1 - Wilson, James F A1 - Wolffenbuttel, Bruce H R A1 - Wright, Alan F A1 - Yerges-Armstrong, Laura M A1 - Zemunik, Tatijana A1 - Zgaga, Lina A1 - Zillikens, M Carola A1 - Zygmunt, Marek A1 - Arnold, Alice M A1 - Boomsma, Dorret I A1 - Buring, Julie E A1 - Crisponi, Laura A1 - Demerath, Ellen W A1 - Gudnason, Vilmundur A1 - Harris, Tamara B A1 - Hu, Frank B A1 - Hunter, David J A1 - Launer, Lenore J A1 - Metspalu, Andres A1 - Montgomery, Grant W A1 - Oostra, Ben A A1 - Ridker, Paul M A1 - Sanna, Serena A1 - Schlessinger, David A1 - Spector, Tim D A1 - Stefansson, Kari A1 - Streeten, Elizabeth A A1 - Thorsteinsdottir, Unnur A1 - Uda, Manuela A1 - Uitterlinden, André G A1 - van Duijn, Cornelia M A1 - Völzke, Henry A1 - Murray, Anna A1 - Murabito, Joanne M A1 - Visser, Jenny A A1 - Lunetta, Kathryn L KW - Age Factors KW - DNA Helicases KW - DNA Polymerase gamma KW - DNA Primase KW - DNA Repair KW - DNA Repair Enzymes KW - DNA-Directed DNA Polymerase KW - European Continental Ancestry Group KW - Exodeoxyribonucleases KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Humans KW - Immunity KW - Menopause KW - Polymorphism, Single Nucleotide KW - Proteins AB -

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

VL - 44 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22267201?dopt=Abstract ER - TY - JOUR T1 - Ultraconserved elements in the human genome: association and transmission analyses of highly constrained single-nucleotide polymorphisms. JF - Genetics Y1 - 2012 A1 - Chiang, Charleston W K A1 - Liu, Ching-Ti A1 - Lettre, Guillaume A1 - Lange, Leslie A A1 - Jorgensen, Neal W A1 - Keating, Brendan J A1 - Vedantam, Sailaja A1 - Nock, Nora L A1 - Franceschini, Nora A1 - Reiner, Alex P A1 - Demerath, Ellen W A1 - Boerwinkle, Eric A1 - Rotter, Jerome I A1 - Wilson, James G A1 - North, Kari E A1 - Papanicolaou, George J A1 - Cupples, L Adrienne A1 - Murabito, Joanne M A1 - Hirschhorn, Joel N KW - Alleles KW - Animals KW - Body Height KW - Body Mass Index KW - Child KW - Conserved Sequence KW - Dogs KW - Evolution, Molecular KW - Female KW - Genetic Fitness KW - Genetic Variation KW - Genome, Human KW - Genotype KW - Humans KW - Inheritance Patterns KW - Male KW - Mice KW - Pedigree KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Rats KW - Reproduction KW - Young Adult AB -

Ultraconserved elements in the human genome likely harbor important biological functions as they are dosage sensitive and are able to direct tissue-specific expression. Because they are under purifying selection, variants in these elements may have a lower frequency in the population but a higher likelihood of association with complex traits. We tested a set of highly constrained SNPs (hcSNPs) distributed genome-wide among ultraconserved and nearly ultraconserved elements for association with seven traits related to reproductive (age at natural menopause, number of children, age at first child, and age at last child) and overall [longevity, body mass index (BMI), and height] fitness. Using up to 24,047 European-American samples from the National Heart, Lung, and Blood Institute Candidate Gene Association Resource (CARe), we observed an excess of associations with BMI and height. In an independent replication panel the most strongly associated SNPs showed an 8.4-fold enrichment of associations at the nominal level, including three variants in previously identified loci and one in a locus (DENND1A) previously shown to be associated with polycystic ovary syndrome. Finally, using 1430 family trios, we showed that the transmissions from heterozygous parents to offspring of the derived alleles of rare (frequency ≤ 0.5%) hcSNPs are not biased, particularly after adjusting for the rates of genotype missingness and error in the data. The lack of transmission bias ruled out an immediately and strongly deleterious effect due to the rare derived alleles, consistent with the observation that mice homozygous for the deletion of ultraconserved elements showed no overt phenotype. Our study also illustrated the importance of carefully modeling potential technical confounders when analyzing genotype data of rare variants.

VL - 192 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22714408?dopt=Abstract ER - TY - JOUR T1 - Association of functional polymorphism rs2231142 (Q141K) in the ABCG2 gene with serum uric acid and gout in 4 US populations: the PAGE Study. JF - Am J Epidemiol Y1 - 2013 A1 - Zhang, Lili A1 - Spencer, Kylee L A1 - Voruganti, V Saroja A1 - Jorgensen, Neal W A1 - Fornage, Myriam A1 - Best, Lyle G A1 - Brown-Gentry, Kristin D A1 - Cole, Shelley A A1 - Crawford, Dana C A1 - Deelman, Ewa A1 - Franceschini, Nora A1 - Gaffo, Angelo L A1 - Glenn, Kimberly R A1 - Heiss, Gerardo A1 - Jenny, Nancy S A1 - Köttgen, Anna A1 - Li, Qiong A1 - Liu, Kiang A1 - Matise, Tara C A1 - North, Kari E A1 - Umans, Jason G A1 - Kao, W H Linda KW - Adult KW - African Americans KW - Age Distribution KW - ATP-Binding Cassette Transporters KW - Comorbidity KW - European Continental Ancestry Group KW - Female KW - Genetic Predisposition to Disease KW - Genetics, Population KW - Genome-Wide Association Study KW - Gout KW - Hormone Replacement Therapy KW - Humans KW - Indians, North American KW - Male KW - Mexican Americans KW - Middle Aged KW - Neoplasm Proteins KW - Polymorphism, Genetic KW - Postmenopause KW - Sex Distribution KW - United States KW - Uric Acid AB -

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

VL - 177 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23552988?dopt=Abstract ER - TY - JOUR T1 - Effects of smoking on the genetic risk of obesity: the population architecture using genomics and epidemiology study. JF - BMC Med Genet Y1 - 2013 A1 - Fesinmeyer, Megan D A1 - North, Kari E A1 - Lim, Unhee A1 - Bůzková, Petra A1 - Crawford, Dana C A1 - Haessler, Jeffrey A1 - Gross, Myron D A1 - Fowke, Jay H A1 - Goodloe, Robert A1 - Love, Shelley-Ann A1 - Graff, Misa A1 - Carlson, Christopher S A1 - Kuller, Lewis H A1 - Matise, Tara C A1 - Hong, Ching-Ping A1 - Henderson, Brian E A1 - Allen, Melissa A1 - Rohde, Rebecca R A1 - Mayo, Ping A1 - Schnetz-Boutaud, Nathalie A1 - Monroe, Kristine R A1 - Ritchie, Marylyn D A1 - Prentice, Ross L A1 - Kolonel, Lawrence N A1 - Manson, JoAnn E A1 - Pankow, James A1 - Hindorff, Lucia A A1 - Franceschini, Nora A1 - Wilkens, Lynne R A1 - Haiman, Christopher A A1 - Le Marchand, Loïc A1 - Peters, Ulrike KW - Adolescent KW - Adult KW - African Americans KW - Aged KW - Alpha-Ketoglutarate-Dependent Dioxygenase FTO KW - Body Mass Index KW - European Continental Ancestry Group KW - Female KW - Genetic Predisposition to Disease KW - Humans KW - Male KW - Membrane Proteins KW - Middle Aged KW - Obesity KW - Polymorphism, Single Nucleotide KW - Proteins KW - Risk Factors KW - Smoking KW - Young Adult AB -

BACKGROUND: Although smoking behavior is known to affect body mass index (BMI), the potential for smoking to influence genetic associations with BMI is largely unexplored.

METHODS: As part of the 'Population Architecture using Genomics and Epidemiology (PAGE)' Consortium, we investigated interaction between genetic risk factors associated with BMI and smoking for 10 single nucleotide polymorphisms (SNPs) previously identified in genome-wide association studies. We included 6 studies with a total of 56,466 subjects (16,750 African Americans (AA) and 39,716 European Americans (EA)). We assessed effect modification by testing an interaction term for each SNP and smoking (current vs. former/never) in the linear regression and by stratified analyses.

RESULTS: We did not observe strong evidence for interactions and only observed two interactions with p-values <0.1: for rs6548238/TMEM18, the risk allele (C) was associated with BMI only among AA females who were former/never smokers (β = 0.018, p = 0.002), vs. current smokers (β = 0.001, p = 0.95, p(interaction) = 0.10). For rs9939609/FTO, the A allele was more strongly associated with BMI among current smoker EA females (β = 0.017, p = 3.5 x 10(-5)), vs. former/never smokers (β = 0.006, p = 0.05, p(interaction) = 0.08).

CONCLUSIONS: These analyses provide limited evidence that smoking status may modify genetic effects of previously identified genetic risk factors for BMI. Larger studies are needed to follow up our results.

CLINICAL TRIAL REGISTRATION: NCT00000611.

VL - 14 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23311614?dopt=Abstract ER - TY - JOUR T1 - Generalization and dilution of association results from European GWAS in populations of non-European ancestry: the PAGE study. JF - PLoS Biol Y1 - 2013 A1 - Carlson, Christopher S A1 - Matise, Tara C A1 - North, Kari E A1 - Haiman, Christopher A A1 - Fesinmeyer, Megan D A1 - Buyske, Steven A1 - Schumacher, Fredrick R A1 - Peters, Ulrike A1 - Franceschini, Nora A1 - Ritchie, Marylyn D A1 - Duggan, David J A1 - Spencer, Kylee L A1 - Dumitrescu, Logan A1 - Eaton, Charles B A1 - Thomas, Fridtjof A1 - Young, Alicia A1 - Carty, Cara A1 - Heiss, Gerardo A1 - Le Marchand, Loïc A1 - Crawford, Dana C A1 - Hindorff, Lucia A A1 - Kooperberg, Charles L KW - African Americans KW - Asian Americans KW - Body Mass Index KW - Diabetes Mellitus, Type 2 KW - European Continental Ancestry Group KW - Gene Frequency KW - Genetic Predisposition to Disease KW - Genetic Variation KW - Genome-Wide Association Study KW - Hispanic Americans KW - Humans KW - Indians, North American KW - Lipids KW - Metagenomics KW - Oceanic Ancestry Group KW - Polymorphism, Single Nucleotide AB -

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

VL - 11 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24068893?dopt=Abstract ER - TY - JOUR T1 - Genetic risk factors for BMI and obesity in an ethnically diverse population: results from the population architecture using genomics and epidemiology (PAGE) study. JF - Obesity (Silver Spring) Y1 - 2013 A1 - Fesinmeyer, Megan D A1 - North, Kari E A1 - Ritchie, Marylyn D A1 - Lim, Unhee A1 - Franceschini, Nora A1 - Wilkens, Lynne R A1 - Gross, Myron D A1 - Bůzková, Petra A1 - Glenn, Kimberly A1 - Quibrera, P Miguel A1 - Fernandez-Rhodes, Lindsay A1 - Li, Qiong A1 - Fowke, Jay H A1 - Li, Rongling A1 - Carlson, Christopher S A1 - Prentice, Ross L A1 - Kuller, Lewis H A1 - Manson, JoAnn E A1 - Matise, Tara C A1 - Cole, Shelley A A1 - Chen, Christina T L A1 - Howard, Barbara V A1 - Kolonel, Laurence N A1 - Henderson, Brian E A1 - Monroe, Kristine R A1 - Crawford, Dana C A1 - Hindorff, Lucia A A1 - Buyske, Steven A1 - Haiman, Christopher A A1 - Le Marchand, Loïc A1 - Peters, Ulrike KW - Alleles KW - Body Mass Index KW - Ethnic Groups KW - Gene Frequency KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Linkage Disequilibrium KW - Metagenomics KW - Obesity KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Risk Factors AB -

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

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

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

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

VL - 21 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23712987?dopt=Abstract ER - TY - JOUR T1 - Genetic variants associated with fasting glucose and insulin concentrations in an ethnically diverse population: results from the Population Architecture using Genomics and Epidemiology (PAGE) study. JF - BMC Med Genet Y1 - 2013 A1 - Fesinmeyer, Megan D A1 - Meigs, James B A1 - North, Kari E A1 - Schumacher, Fredrick R A1 - Bůzková, Petra A1 - Franceschini, Nora A1 - Haessler, Jeffrey A1 - Goodloe, Robert A1 - Spencer, Kylee L A1 - Voruganti, Venkata Saroja A1 - Howard, Barbara V A1 - Jackson, Rebecca A1 - Kolonel, Laurence N A1 - Liu, Simin A1 - Manson, JoAnn E A1 - Monroe, Kristine R A1 - Mukamal, Kenneth A1 - Dilks, Holli H A1 - Pendergrass, Sarah A A1 - Nato, Andrew A1 - Wan, Peggy A1 - Wilkens, Lynne R A1 - Le Marchand, Loïc A1 - Ambite, Jose Luis A1 - Buyske, Steven A1 - Florez, Jose C A1 - Crawford, Dana C A1 - Hindorff, Lucia A A1 - Haiman, Christopher A A1 - Peters, Ulrike A1 - Pankow, James S KW - Adaptor Proteins, Signal Transducing KW - Adult KW - African Americans KW - Aged KW - Alleles KW - Asian Continental Ancestry Group KW - Blood Glucose KW - Diabetes Mellitus, Type 2 KW - European Continental Ancestry Group KW - Female KW - Gene Frequency KW - Genetic Loci KW - Genome-Wide Association Study KW - Genomics KW - Hispanic Americans KW - Humans KW - Indians, North American KW - Insulin KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Transcription Factor 7-Like 2 Protein AB -

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

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

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

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

VL - 14 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24063630?dopt=Abstract ER - TY - JOUR T1 - A genome-wide association study of early menopause and the combined impact of identified variants. JF - Hum Mol Genet Y1 - 2013 A1 - Perry, John R B A1 - Corre, Tanguy A1 - Esko, Tõnu A1 - Chasman, Daniel I A1 - Fischer, Krista A1 - Franceschini, Nora A1 - He, Chunyan A1 - Kutalik, Zoltán A1 - Mangino, Massimo A1 - Rose, Lynda M A1 - Vernon Smith, Albert A1 - Stolk, Lisette A1 - Sulem, Patrick A1 - Weedon, Michael N A1 - Zhuang, Wei V A1 - Arnold, Alice A1 - Ashworth, Alan A1 - Bergmann, Sven A1 - Buring, Julie E A1 - Burri, Andrea A1 - Chen, Constance A1 - Cornelis, Marilyn C A1 - Couper, David J A1 - Goodarzi, Mark O A1 - Gudnason, Vilmundur A1 - Harris, Tamara A1 - Hofman, Albert A1 - Jones, Michael A1 - Kraft, Peter A1 - Launer, Lenore A1 - Laven, Joop S E A1 - Li, Guo A1 - McKnight, Barbara A1 - Masciullo, Corrado A1 - Milani, Lili A1 - Orr, Nicholas A1 - Psaty, Bruce M A1 - Ridker, Paul M A1 - Rivadeneira, Fernando A1 - Sala, Cinzia A1 - Salumets, Andres A1 - Schoemaker, Minouk A1 - Traglia, Michela A1 - Waeber, Gérard A1 - Chanock, Stephen J A1 - Demerath, Ellen W A1 - Garcia, Melissa A1 - Hankinson, Susan E A1 - Hu, Frank B A1 - Hunter, David J A1 - Lunetta, Kathryn L A1 - Metspalu, Andres A1 - Montgomery, Grant W A1 - Murabito, Joanne M A1 - Newman, Anne B A1 - Ong, Ken K A1 - Spector, Tim D A1 - Stefansson, Kari A1 - Swerdlow, Anthony J A1 - Thorsteinsdottir, Unnur A1 - van Dam, Rob M A1 - Uitterlinden, André G A1 - Visser, Jenny A A1 - Vollenweider, Peter A1 - Toniolo, Daniela A1 - Murray, Anna KW - Case-Control Studies KW - Female KW - Gene Frequency KW - Genome-Wide Association Study KW - Humans KW - Menopause, Premature KW - Polymorphism, Single Nucleotide KW - Primary Ovarian Insufficiency KW - Quantitative Trait Loci KW - Risk AB -

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

VL - 22 IS - 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23307926?dopt=Abstract ER - TY - JOUR T1 - The influence of obesity-related single nucleotide polymorphisms on BMI across the life course: the PAGE study. JF - Diabetes Y1 - 2013 A1 - Graff, Mariaelisa A1 - Gordon-Larsen, Penny A1 - Lim, Unhee A1 - Fowke, Jay H A1 - Love, Shelly-Ann A1 - Fesinmeyer, Megan A1 - Wilkens, Lynne R A1 - Vertilus, Shawyntee A1 - Ritchie, Marilyn D A1 - Prentice, Ross L A1 - Pankow, Jim A1 - Monroe, Kristine A1 - Manson, JoAnn E A1 - Le Marchand, Loïc A1 - Kuller, Lewis H A1 - Kolonel, Laurence N A1 - Hong, Ching P A1 - Henderson, Brian E A1 - Haessler, Jeff A1 - Gross, Myron D A1 - Goodloe, Robert A1 - Franceschini, Nora A1 - Carlson, Christopher S A1 - Buyske, Steven A1 - Bůzková, Petra A1 - Hindorff, Lucia A A1 - Matise, Tara C A1 - Crawford, Dana C A1 - Haiman, Christopher A A1 - Peters, Ulrike A1 - North, Kari E KW - Adolescent KW - Adult KW - Aged KW - Aged, 80 and over KW - Aging KW - Body Mass Index KW - Cohort Studies KW - Cross-Sectional Studies KW - European Continental Ancestry Group KW - Female KW - Genetic Association Studies KW - Health Surveys KW - Humans KW - Male KW - Middle Aged KW - Obesity KW - Polymorphism, Single Nucleotide KW - Proteins KW - United States KW - Young Adult AB -

Evidence is limited as to whether heritable risk of obesity varies throughout adulthood. Among >34,000 European Americans, aged 18-100 years, from multiple U.S. studies in the Population Architecture using Genomics and Epidemiology (PAGE) Consortium, we examined evidence for heterogeneity in the associations of five established obesity risk variants (near FTO, GNPDA2, MTCH2, TMEM18, and NEGR1) with BMI across four distinct epochs of adulthood: 1) young adulthood (ages 18-25 years), adulthood (ages 26-49 years), middle-age adulthood (ages 50-69 years), and older adulthood (ages ≥70 years); or 2) by menopausal status in women and stratification by age 50 years in men. Summary-effect estimates from each meta-analysis were compared for heterogeneity across the life epochs. We found heterogeneity in the association of the FTO (rs8050136) variant with BMI across the four adulthood epochs (P = 0.0006), with larger effects in young adults relative to older adults (β [SE] = 1.17 [0.45] vs. 0.09 [0.09] kg/m², respectively, per A allele) and smaller intermediate effects. We found no evidence for heterogeneity in the association of GNPDA2, MTCH2, TMEM18, and NEGR1 with BMI across adulthood. Genetic predisposition to obesity may have greater effects on body weight in young compared with older adulthood for FTO, suggesting changes by age, generation, or secular trends. Future research should compare and contrast our findings with results using longitudinal data.

VL - 62 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23300277?dopt=Abstract ER - TY - JOUR T1 - Investigation of gene-by-sex interactions for lipid traits in diverse populations from the population architecture using genomics and epidemiology study. JF - BMC Genet Y1 - 2013 A1 - Taylor, Kira C A1 - Carty, Cara L A1 - Dumitrescu, Logan A1 - Bůzková, Petra A1 - Cole, Shelley A A1 - Hindorff, Lucia A1 - Schumacher, Fred R A1 - Wilkens, Lynne R A1 - Shohet, Ralph V A1 - Quibrera, P Miguel A1 - Johnson, Karen C A1 - Henderson, Brian E A1 - Haessler, Jeff A1 - Franceschini, Nora A1 - Eaton, Charles B A1 - Duggan, David J A1 - Cochran, Barbara A1 - Cheng, Iona A1 - Carlson, Chris S A1 - Brown-Gentry, Kristin A1 - Anderson, Garnet A1 - Ambite, Jose Luis A1 - Haiman, Christopher A1 - Le Marchand, Loïc A1 - Kooperberg, Charles A1 - Crawford, Dana C A1 - Buyske, Steven A1 - North, Kari E A1 - Fornage, Myriam KW - Female KW - Genetic Heterogeneity KW - Genome, Human KW - Genome-Wide Association Study KW - Humans KW - Lipids KW - Male KW - Polymorphism, Single Nucleotide KW - Population Groups AB -

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

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

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

VL - 14 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23634756?dopt=Abstract ER - TY - JOUR T1 - Lack of associations of ten candidate coronary heart disease risk genetic variants and subclinical atherosclerosis in four US populations: the Population Architecture using Genomics and Epidemiology (PAGE) study. JF - Atherosclerosis Y1 - 2013 A1 - Zhang, Lili A1 - Bůzková, Petra A1 - Wassel, Christina L A1 - Roman, Mary J A1 - North, Kari E A1 - Crawford, Dana C A1 - Boston, Jonathan A1 - Brown-Gentry, Kristin D A1 - Cole, Shelley A A1 - Deelman, Ewa A1 - Goodloe, Robert A1 - Wilson, Sarah A1 - Heiss, Gerardo A1 - Jenny, Nancy S A1 - Jorgensen, Neal W A1 - Matise, Tara C A1 - McClellan, Bob E A1 - Nato, Alejandro Q A1 - Ritchie, Marylyn D A1 - Franceschini, Nora A1 - Kao, W H Linda KW - African Americans KW - Aged KW - Ankle Brachial Index KW - Asymptomatic Diseases KW - Carotid Artery Diseases KW - Carotid Intima-Media Thickness KW - Coronary Disease KW - European Continental Ancestry Group KW - Female KW - Gene Frequency KW - Genetic Association Studies KW - Genetic Predisposition to Disease KW - Humans KW - Indians, North American KW - Linear Models KW - Logistic Models KW - Male KW - Mexican Americans KW - Middle Aged KW - Odds Ratio KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Predictive Value of Tests KW - Risk Assessment KW - Risk Factors KW - United States AB -

BACKGROUND: A number of genetic variants have been discovered by recent genome-wide association studies for their associations with clinical coronary heart disease (CHD). However, it is unclear whether these variants are also associated with the development of CHD as measured by subclinical atherosclerosis phenotypes, ankle brachial index (ABI), carotid artery intima-media thickness (cIMT) and carotid plaque.

METHODS: Ten CHD risk single nucleotide polymorphisms (SNPs) were genotyped in individuals of European American (EA), African American (AA), American Indian (AI), and Mexican American (MA) ancestry in the Population Architecture using Genomics and Epidemiology (PAGE) study. In each individual study, we performed linear or logistic regression to examine population-specific associations between SNPs and ABI, common and internal cIMT, and plaque. The results from individual studies were meta-analyzed using a fixed effect inverse variance weighted model.

RESULTS: None of the ten SNPs was significantly associated with ABI and common or internal cIMT, after Bonferroni correction. In the sample of 13,337 EA, 3809 AA, and 5353 AI individuals with carotid plaque measurement, the GCKR SNP rs780094 was significantly associated with the presence of plaque in AI only (OR = 1.32, 95% confidence interval: 1.17, 1.49, P = 1.08 × 10(-5)), but not in the other populations (P = 0.90 in EA and P = 0.99 in AA). A 9p21 region SNP, rs1333049, was nominally associated with plaque in EA (OR = 1.07, P = 0.02) and in AI (OR = 1.10, P = 0.05).

CONCLUSIONS: We identified a significant association between rs780094 and plaque in AI populations, which needs to be replicated in future studies. There was little evidence that the index CHD risk variants identified through genome-wide association studies in EA influence the development of CHD through subclinical atherosclerosis as assessed by cIMT and ABI across ancestries.

VL - 228 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23587283?dopt=Abstract ER - TY - JOUR T1 - No evidence of interaction between known lipid-associated genetic variants and smoking in the multi-ethnic PAGE population. JF - Hum Genet Y1 - 2013 A1 - Dumitrescu, Logan A1 - Carty, Cara L A1 - Franceschini, Nora A1 - Hindorff, Lucia A A1 - Cole, Shelley A A1 - Bůzková, Petra A1 - Schumacher, Fredrick R A1 - Eaton, Charles B A1 - Goodloe, Robert J A1 - Duggan, David J A1 - Haessler, Jeff A1 - Cochran, Barbara A1 - Henderson, Brian E A1 - Cheng, Iona A1 - Johnson, Karen C A1 - Carlson, Chris S A1 - Love, Shelly-Anne A1 - Brown-Gentry, Kristin A1 - Nato, Alejandro Q A1 - Quibrera, Miguel A1 - Shohet, Ralph V A1 - Ambite, Jose Luis A1 - Wilkens, Lynne R A1 - Le Marchand, Loïc A1 - Haiman, Christopher A A1 - Buyske, Steven A1 - Kooperberg, Charles A1 - North, Kari E A1 - Fornage, Myriam A1 - Crawford, Dana C KW - Cholesterol, HDL KW - Cholesterol, LDL KW - Cohort Studies KW - Ethnic Groups KW - Female KW - Gene Frequency KW - Gene-Environment Interaction KW - Genetics, Population KW - Genome-Wide Association Study KW - Humans KW - Lipid Metabolism KW - Male KW - Polymorphism, Single Nucleotide KW - Prevalence KW - Smoking KW - Triglycerides KW - Young Adult AB -

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

VL - 132 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24100633?dopt=Abstract ER - TY - JOUR T1 - Post-genome-wide association study challenges for lipid traits: describing age as a modifier of gene-lipid associations in the Population Architecture using Genomics and Epidemiology (PAGE) study. JF - Ann Hum Genet Y1 - 2013 A1 - Dumitrescu, Logan A1 - Carty, Cara L A1 - Franceschini, Nora A1 - Hindorff, Lucia A A1 - Cole, Shelley A A1 - Bůzková, Petra A1 - Schumacher, Fredrick R A1 - Eaton, Charles B A1 - Goodloe, Robert J A1 - Duggan, David J A1 - Haessler, Jeff A1 - Cochran, Barbara A1 - Henderson, Brian E A1 - Cheng, Iona A1 - Johnson, Karen C A1 - Carlson, Chris S A1 - Love, Shelly-Ann A1 - Brown-Gentry, Kristin A1 - Nato, Alejandro Q A1 - Quibrera, Miguel A1 - Anderson, Garnet A1 - Shohet, Ralph V A1 - Ambite, Jose Luis A1 - Wilkens, Lynne R A1 - Marchand, Loic Le A1 - Haiman, Christopher A A1 - Buyske, Steven A1 - Kooperberg, Charles A1 - North, Kari E A1 - Fornage, Myriam A1 - Crawford, Dana C KW - Adult KW - Aged KW - European Continental Ancestry Group KW - Female KW - Genetic Association Studies KW - Genome-Wide Association Study KW - Humans KW - Lipids KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci KW - Quantitative Trait, Heritable KW - Risk Factors AB -

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

VL - 77 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23808484?dopt=Abstract ER - TY - JOUR T1 - Trans-ethnic fine-mapping of lipid loci identifies population-specific signals and allelic heterogeneity that increases the trait variance explained. JF - PLoS Genet Y1 - 2013 A1 - Wu, Ying A1 - Waite, Lindsay L A1 - Jackson, Anne U A1 - Sheu, Wayne H-H A1 - Buyske, Steven A1 - Absher, Devin A1 - Arnett, Donna K A1 - Boerwinkle, Eric A1 - Bonnycastle, Lori L A1 - Carty, Cara L A1 - Cheng, Iona A1 - Cochran, Barbara A1 - Croteau-Chonka, Damien C A1 - Dumitrescu, Logan A1 - Eaton, Charles B A1 - Franceschini, Nora A1 - Guo, Xiuqing A1 - Henderson, Brian E A1 - Hindorff, Lucia A A1 - Kim, Eric A1 - Kinnunen, Leena A1 - Komulainen, Pirjo A1 - Lee, Wen-Jane A1 - Le Marchand, Loïc A1 - Lin, Yi A1 - Lindström, Jaana A1 - Lingaas-Holmen, Oddgeir A1 - Mitchell, Sabrina L A1 - Narisu, Narisu A1 - Robinson, Jennifer G A1 - Schumacher, Fred A1 - Stančáková, Alena A1 - Sundvall, Jouko A1 - Sung, Yun-Ju A1 - Swift, Amy J A1 - Wang, Wen-Chang A1 - Wilkens, Lynne A1 - Wilsgaard, Tom A1 - Young, Alicia M A1 - Adair, Linda S A1 - Ballantyne, Christie M A1 - Bůzková, Petra A1 - Chakravarti, Aravinda A1 - Collins, Francis S A1 - Duggan, David A1 - Feranil, Alan B A1 - Ho, Low-Tone A1 - Hung, Yi-Jen A1 - Hunt, Steven C A1 - Hveem, Kristian A1 - Juang, Jyh-Ming J A1 - Kesäniemi, Antero Y A1 - Kuusisto, Johanna A1 - Laakso, Markku A1 - Lakka, Timo A A1 - Lee, I-Te A1 - Leppert, Mark F A1 - Matise, Tara C A1 - Moilanen, Leena A1 - Njølstad, Inger A1 - Peters, Ulrike A1 - Quertermous, Thomas A1 - Rauramaa, Rainer A1 - Rotter, Jerome I A1 - Saramies, Jouko A1 - Tuomilehto, Jaakko A1 - Uusitupa, Matti A1 - Wang, Tzung-Dau A1 - Boehnke, Michael A1 - Haiman, Christopher A A1 - Chen, Yii-der I A1 - Kooperberg, Charles A1 - Assimes, Themistocles L A1 - Crawford, Dana C A1 - Hsiung, Chao A A1 - North, Kari E A1 - Mohlke, Karen L KW - African Americans KW - Apolipoproteins A KW - Cholesterol, HDL KW - Cholesterol, LDL KW - European Continental Ancestry Group KW - Genome-Wide Association Study KW - Humans KW - Lipoproteins, HDL KW - Lipoproteins, LDL KW - Proprotein Convertases KW - Serine Endopeptidases KW - Triglycerides AB -

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

VL - 9 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23555291?dopt=Abstract ER - TY - JOUR T1 - ADAM19 and HTR4 variants and pulmonary function: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study. JF - Circ Cardiovasc Genet Y1 - 2014 A1 - London, Stephanie J A1 - Gao, Wei A1 - Gharib, Sina A A1 - Hancock, Dana B A1 - Wilk, Jemma B A1 - House, John S A1 - Gibbs, Richard A A1 - Muzny, Donna M A1 - Lumley, Thomas A1 - Franceschini, Nora A1 - North, Kari E A1 - Psaty, Bruce M A1 - Kovar, Christie L A1 - Coresh, Josef A1 - Zhou, Yanhua A1 - Heckbert, Susan R A1 - Brody, Jennifer A A1 - Morrison, Alanna C A1 - Dupuis, Josée KW - ADAM Proteins KW - Aged KW - Aged, 80 and over KW - Aging KW - Cohort Studies KW - Female KW - Genetic Variation KW - Genome-Wide Association Study KW - Genomics KW - Heart Diseases KW - Humans KW - Lung KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Sequence Analysis, DNA AB -

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

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

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

VL - 7 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24951661?dopt=Abstract ER - TY - JOUR T1 - Genetic diversity is a predictor of mortality in humans. JF - BMC Genet Y1 - 2014 A1 - Bihlmeyer, Nathan A A1 - Brody, Jennifer A A1 - Smith, Albert Vernon A1 - Lunetta, Kathryn L A1 - Nalls, Mike A1 - Smith, Jennifer A A1 - Tanaka, Toshiko A1 - Davies, Gail A1 - Yu, Lei A1 - Mirza, Saira Saeed A1 - Teumer, Alexander A1 - Coresh, Josef A1 - Pankow, James S A1 - Franceschini, Nora A1 - Scaria, Anish A1 - Oshima, Junko A1 - Psaty, Bruce M A1 - Gudnason, Vilmundur A1 - Eiriksdottir, Gudny A1 - Harris, Tamara B A1 - Li, Hanyue A1 - Karasik, David A1 - Kiel, Douglas P A1 - Garcia, Melissa A1 - Liu, Yongmei A1 - Faul, Jessica D A1 - Kardia, Sharon Lr A1 - Zhao, Wei A1 - Ferrucci, Luigi A1 - Allerhand, Michael A1 - Liewald, David C A1 - Redmond, Paul A1 - Starr, John M A1 - De Jager, Philip L A1 - Evans, Denis A A1 - Direk, Nese A1 - Ikram, Mohammed Arfan A1 - Uitterlinden, Andre A1 - Homuth, Georg A1 - Lorbeer, Roberto A1 - Grabe, Hans J A1 - Launer, Lenore A1 - Murabito, Joanne M A1 - Singleton, Andrew B A1 - Weir, David R A1 - Bandinelli, Stefania A1 - Deary, Ian J A1 - Bennett, David A A1 - Tiemeier, Henning A1 - Kocher, Thomas A1 - Lumley, Thomas A1 - Arking, Dan E KW - Genome-Wide Association Study KW - Heterozygote KW - Humans KW - Mortality KW - Polymorphism, Single Nucleotide KW - Proportional Hazards Models AB -

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

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

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

VL - 15 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25543667?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association analysis identifies six new loci associated with forced vital capacity. JF - Nat Genet Y1 - 2014 A1 - Loth, Daan W A1 - Soler Artigas, Maria A1 - Gharib, Sina A A1 - Wain, Louise V A1 - Franceschini, Nora A1 - Koch, Beate A1 - Pottinger, Tess D A1 - Smith, Albert Vernon A1 - Duan, Qing A1 - Oldmeadow, Chris A1 - Lee, Mi Kyeong A1 - Strachan, David P A1 - James, Alan L A1 - Huffman, Jennifer E A1 - Vitart, Veronique A1 - Ramasamy, Adaikalavan A1 - Wareham, Nicholas J A1 - Kaprio, Jaakko A1 - Wang, Xin-Qun A1 - Trochet, Holly A1 - Kähönen, Mika A1 - Flexeder, Claudia A1 - Albrecht, Eva A1 - Lopez, Lorna M A1 - de Jong, Kim A1 - Thyagarajan, Bharat A1 - Alves, Alexessander Couto A1 - Enroth, Stefan A1 - Omenaas, Ernst A1 - Joshi, Peter K A1 - Fall, Tove A1 - Viñuela, Ana A1 - Launer, Lenore J A1 - Loehr, Laura R A1 - Fornage, Myriam A1 - Li, Guo A1 - Wilk, Jemma B A1 - Tang, Wenbo A1 - Manichaikul, Ani A1 - Lahousse, Lies A1 - Harris, Tamara B A1 - North, Kari E A1 - Rudnicka, Alicja R A1 - Hui, Jennie A1 - Gu, Xiangjun A1 - Lumley, Thomas A1 - Wright, Alan F A1 - Hastie, Nicholas D A1 - Campbell, Susan A1 - Kumar, Rajesh A1 - Pin, Isabelle A1 - Scott, Robert A A1 - Pietiläinen, Kirsi H A1 - Surakka, Ida A1 - Liu, Yongmei A1 - Holliday, Elizabeth G A1 - Schulz, Holger A1 - Heinrich, Joachim A1 - Davies, Gail A1 - Vonk, Judith M A1 - Wojczynski, Mary A1 - Pouta, Anneli A1 - Johansson, Asa A1 - Wild, Sarah H A1 - Ingelsson, Erik A1 - Rivadeneira, Fernando A1 - Völzke, Henry A1 - Hysi, Pirro G A1 - Eiriksdottir, Gudny A1 - Morrison, Alanna C A1 - Rotter, Jerome I A1 - Gao, Wei A1 - Postma, Dirkje S A1 - White, Wendy B A1 - Rich, Stephen S A1 - Hofman, Albert A1 - Aspelund, Thor A1 - Couper, David A1 - Smith, Lewis J A1 - Psaty, Bruce M A1 - Lohman, Kurt A1 - Burchard, Esteban G A1 - Uitterlinden, André G A1 - Garcia, Melissa A1 - Joubert, Bonnie R A1 - McArdle, Wendy L A1 - Musk, A Bill A1 - Hansel, Nadia A1 - Heckbert, Susan R A1 - Zgaga, Lina A1 - van Meurs, Joyce B J A1 - Navarro, Pau A1 - Rudan, Igor A1 - Oh, Yeon-Mok A1 - Redline, Susan A1 - Jarvis, Deborah L A1 - Zhao, Jing Hua A1 - Rantanen, Taina A1 - O'Connor, George T A1 - Ripatti, Samuli A1 - Scott, Rodney J A1 - Karrasch, Stefan A1 - Grallert, Harald A1 - Gaddis, Nathan C A1 - Starr, John M A1 - Wijmenga, Cisca A1 - Minster, Ryan L A1 - Lederer, David J A1 - Pekkanen, Juha A1 - Gyllensten, Ulf A1 - Campbell, Harry A1 - Morris, Andrew P A1 - Gläser, Sven A1 - Hammond, Christopher J A1 - Burkart, Kristin M A1 - Beilby, John A1 - Kritchevsky, Stephen B A1 - Gudnason, Vilmundur A1 - Hancock, Dana B A1 - Williams, O Dale A1 - Polasek, Ozren A1 - Zemunik, Tatijana A1 - Kolcic, Ivana A1 - Petrini, Marcy F A1 - Wjst, Matthias A1 - Kim, Woo Jin A1 - Porteous, David J A1 - Scotland, Generation A1 - Smith, Blair H A1 - Viljanen, Anne A1 - Heliövaara, Markku A1 - Attia, John R A1 - Sayers, Ian A1 - Hampel, Regina A1 - Gieger, Christian A1 - Deary, Ian J A1 - Boezen, H Marike A1 - Newman, Anne A1 - Jarvelin, Marjo-Riitta A1 - Wilson, James F A1 - Lind, Lars A1 - Stricker, Bruno H A1 - Teumer, Alexander A1 - Spector, Timothy D A1 - Melén, Erik A1 - Peters, Marjolein J A1 - Lange, Leslie A A1 - Barr, R Graham A1 - Bracke, Ken R A1 - Verhamme, Fien M A1 - Sung, Joohon A1 - Hiemstra, Pieter S A1 - Cassano, Patricia A A1 - Sood, Akshay A1 - Hayward, Caroline A1 - Dupuis, Josée A1 - Hall, Ian P A1 - Brusselle, Guy G A1 - Tobin, Martin D A1 - London, Stephanie J KW - Cohort Studies KW - Databases, Genetic KW - Follow-Up Studies KW - Forced Expiratory Volume KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genome, Human KW - Genome-Wide Association Study KW - Humans KW - Lung Diseases KW - Meta-Analysis as Topic KW - Polymorphism, Single Nucleotide KW - Prognosis KW - Quantitative Trait Loci KW - Respiratory Function Tests KW - Spirometry KW - Vital Capacity AB -

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

VL - 46 IS - 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24929828?dopt=Abstract ER - TY - JOUR T1 - Large-scale genome-wide association studies and meta-analyses of longitudinal change in adult lung function. JF - PLoS One Y1 - 2014 A1 - Tang, Wenbo A1 - Kowgier, Matthew A1 - Loth, Daan W A1 - Soler Artigas, Maria A1 - Joubert, Bonnie R A1 - Hodge, Emily A1 - Gharib, Sina A A1 - Smith, Albert V A1 - Ruczinski, Ingo A1 - Gudnason, Vilmundur A1 - Mathias, Rasika A A1 - Harris, Tamara B A1 - Hansel, Nadia N A1 - Launer, Lenore J A1 - Barnes, Kathleen C A1 - Hansen, Joyanna G A1 - Albrecht, Eva A1 - Aldrich, Melinda C A1 - Allerhand, Michael A1 - Barr, R Graham A1 - Brusselle, Guy G A1 - Couper, David J A1 - Curjuric, Ivan A1 - Davies, Gail A1 - Deary, Ian J A1 - Dupuis, Josée A1 - Fall, Tove A1 - Foy, Millennia A1 - Franceschini, Nora A1 - Gao, Wei A1 - Gläser, Sven A1 - Gu, Xiangjun A1 - Hancock, Dana B A1 - Heinrich, Joachim A1 - Hofman, Albert A1 - Imboden, Medea A1 - Ingelsson, Erik A1 - James, Alan A1 - Karrasch, Stefan A1 - Koch, Beate A1 - Kritchevsky, Stephen B A1 - Kumar, Ashish A1 - Lahousse, Lies A1 - Li, Guo A1 - Lind, Lars A1 - Lindgren, Cecilia A1 - Liu, Yongmei A1 - Lohman, Kurt A1 - Lumley, Thomas A1 - McArdle, Wendy L A1 - Meibohm, Bernd A1 - Morris, Andrew P A1 - Morrison, Alanna C A1 - Musk, Bill A1 - North, Kari E A1 - Palmer, Lyle J A1 - Probst-Hensch, Nicole M A1 - Psaty, Bruce M A1 - Rivadeneira, Fernando A1 - Rotter, Jerome I A1 - Schulz, Holger A1 - Smith, Lewis J A1 - Sood, Akshay A1 - Starr, John M A1 - Strachan, David P A1 - Teumer, Alexander A1 - Uitterlinden, André G A1 - Völzke, Henry A1 - Voorman, Arend A1 - Wain, Louise V A1 - Wells, Martin T A1 - Wilk, Jemma B A1 - Williams, O Dale A1 - Heckbert, Susan R A1 - Stricker, Bruno H A1 - London, Stephanie J A1 - Fornage, Myriam A1 - Tobin, Martin D A1 - O'Connor, George T A1 - Hall, Ian P A1 - Cassano, Patricia A KW - Adult KW - Chromosomes, Human, Pair 11 KW - Female KW - Gene Expression Regulation KW - Genetic Loci KW - Genome-Wide Association Study KW - Humans KW - Longitudinal Studies KW - Male KW - Respiration AB -

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

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

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

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

VL - 9 IS - 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24983941?dopt=Abstract ER - TY - JOUR T1 - Loss-of-function mutations in APOC3, triglycerides, and coronary disease. JF - N Engl J Med Y1 - 2014 A1 - Crosby, Jacy A1 - Peloso, Gina M A1 - Auer, Paul L A1 - Crosslin, David R A1 - Stitziel, Nathan O A1 - Lange, Leslie A A1 - Lu, Yingchang A1 - Tang, Zheng-Zheng A1 - Zhang, He A1 - Hindy, George A1 - Masca, Nicholas A1 - Stirrups, Kathleen A1 - Kanoni, Stavroula A1 - Do, Ron A1 - Jun, Goo A1 - Hu, Youna A1 - Kang, Hyun Min A1 - Xue, Chenyi A1 - Goel, Anuj A1 - Farrall, Martin A1 - Duga, Stefano A1 - Merlini, Pier Angelica A1 - Asselta, Rosanna A1 - Girelli, Domenico A1 - Olivieri, Oliviero A1 - Martinelli, Nicola A1 - Yin, Wu A1 - Reilly, Dermot A1 - Speliotes, Elizabeth A1 - Fox, Caroline S A1 - Hveem, Kristian A1 - Holmen, Oddgeir L A1 - Nikpay, Majid A1 - Farlow, Deborah N A1 - Assimes, Themistocles L A1 - Franceschini, Nora A1 - Robinson, Jennifer A1 - North, Kari E A1 - Martin, Lisa W A1 - DePristo, Mark A1 - Gupta, Namrata A1 - Escher, Stefan A A1 - Jansson, Jan-Håkan A1 - Van Zuydam, Natalie A1 - Palmer, Colin N A A1 - Wareham, Nicholas A1 - Koch, Werner A1 - Meitinger, Thomas A1 - Peters, Annette A1 - Lieb, Wolfgang A1 - Erbel, Raimund A1 - König, Inke R A1 - Kruppa, Jochen A1 - Degenhardt, Franziska A1 - Gottesman, Omri A1 - Bottinger, Erwin P A1 - O'Donnell, Christopher J A1 - Psaty, Bruce M A1 - Ballantyne, Christie M A1 - Abecasis, Goncalo A1 - Ordovas, Jose M A1 - Melander, Olle A1 - Watkins, Hugh A1 - Orho-Melander, Marju A1 - Ardissino, Diego A1 - Loos, Ruth J F A1 - McPherson, Ruth A1 - Willer, Cristen J A1 - Erdmann, Jeanette A1 - Hall, Alistair S A1 - Samani, Nilesh J A1 - Deloukas, Panos A1 - Schunkert, Heribert A1 - Wilson, James G A1 - Kooperberg, Charles A1 - Rich, Stephen S A1 - Tracy, Russell P A1 - Lin, Dan-Yu A1 - Altshuler, David A1 - Gabriel, Stacey A1 - Nickerson, Deborah A A1 - Jarvik, Gail P A1 - Cupples, L Adrienne A1 - Reiner, Alex P A1 - Boerwinkle, Eric A1 - Kathiresan, Sekar KW - African Continental Ancestry Group KW - Apolipoprotein C-III KW - Coronary Disease KW - European Continental Ancestry Group KW - Exome KW - Genotype KW - Heterozygote KW - Humans KW - Liver KW - Mutation KW - Risk Factors KW - Sequence Analysis, DNA KW - Triglycerides AB -

BACKGROUND: Plasma triglyceride levels are heritable and are correlated with the risk of coronary heart disease. Sequencing of the protein-coding regions of the human genome (the exome) has the potential to identify rare mutations that have a large effect on phenotype.

METHODS: We sequenced the protein-coding regions of 18,666 genes in each of 3734 participants of European or African ancestry in the Exome Sequencing Project. We conducted tests to determine whether rare mutations in coding sequence, individually or in aggregate within a gene, were associated with plasma triglyceride levels. For mutations associated with triglyceride levels, we subsequently evaluated their association with the risk of coronary heart disease in 110,970 persons.

RESULTS: An aggregate of rare mutations in the gene encoding apolipoprotein C3 (APOC3) was associated with lower plasma triglyceride levels. Among the four mutations that drove this result, three were loss-of-function mutations: a nonsense mutation (R19X) and two splice-site mutations (IVS2+1G→A and IVS3+1G→T). The fourth was a missense mutation (A43T). Approximately 1 in 150 persons in the study was a heterozygous carrier of at least one of these four mutations. Triglyceride levels in the carriers were 39% lower than levels in noncarriers (P<1×10(-20)), and circulating levels of APOC3 in carriers were 46% lower than levels in noncarriers (P=8×10(-10)). The risk of coronary heart disease among 498 carriers of any rare APOC3 mutation was 40% lower than the risk among 110,472 noncarriers (odds ratio, 0.60; 95% confidence interval, 0.47 to 0.75; P=4×10(-6)).

CONCLUSIONS: Rare mutations that disrupt APOC3 function were associated with lower levels of plasma triglycerides and APOC3. Carriers of these mutations were found to have a reduced risk of coronary heart disease. (Funded by the National Heart, Lung, and Blood Institute and others.).

VL - 371 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24941081?dopt=Abstract ER - TY - JOUR T1 - Meta-analysis of loci associated with age at natural menopause in African-American women. JF - Hum Mol Genet Y1 - 2014 A1 - Chen, Christina T L A1 - Liu, Ching-Ti A1 - Chen, Gary K A1 - Andrews, Jeanette S A1 - Arnold, Alice M A1 - Dreyfus, Jill A1 - Franceschini, Nora A1 - Garcia, Melissa E A1 - Kerr, Kathleen F A1 - Li, Guo A1 - Lohman, Kurt K A1 - Musani, Solomon K A1 - Nalls, Michael A A1 - Raffel, Leslie J A1 - Smith, Jennifer A1 - Ambrosone, Christine B A1 - Bandera, Elisa V A1 - Bernstein, Leslie A1 - Britton, Angela A1 - Brzyski, Robert G A1 - Cappola, Anne A1 - Carlson, Christopher S A1 - Couper, David A1 - Deming, Sandra L A1 - Goodarzi, Mark O A1 - Heiss, Gerardo A1 - John, Esther M A1 - Lu, Xiaoning A1 - Le Marchand, Loïc A1 - Marciante, Kristin A1 - McKnight, Barbara A1 - Millikan, Robert A1 - Nock, Nora L A1 - Olshan, Andrew F A1 - Press, Michael F A1 - Vaiyda, Dhananjay A1 - Woods, Nancy F A1 - Taylor, Herman A A1 - Zhao, Wei A1 - Zheng, Wei A1 - Evans, Michele K A1 - Harris, Tamara B A1 - Henderson, Brian E A1 - Kardia, Sharon L R A1 - Kooperberg, Charles A1 - Liu, Yongmei A1 - Mosley, Thomas H A1 - Psaty, Bruce A1 - Wellons, Melissa A1 - Windham, Beverly G A1 - Zonderman, Alan B A1 - Cupples, L Adrienne A1 - Demerath, Ellen W A1 - Haiman, Christopher A1 - Murabito, Joanne M A1 - Rajkovic, Aleksandar KW - African Americans KW - Age Factors KW - Chromosomes, Human KW - European Continental Ancestry Group KW - Female KW - Genetic Loci KW - Genetic Variation KW - Genome-Wide Association Study KW - Humans KW - Menopause KW - United States AB -

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

VL - 23 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24493794?dopt=Abstract ER - TY - JOUR T1 - Sequencing of 2 subclinical atherosclerosis candidate regions in 3669 individuals: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study. JF - Circ Cardiovasc Genet Y1 - 2014 A1 - Bis, Joshua C A1 - White, Charles C A1 - Franceschini, Nora A1 - Brody, Jennifer A1 - Zhang, Xiaoling A1 - Muzny, Donna A1 - Santibanez, Jireh A1 - Gibbs, Richard A1 - Liu, Xiaoming A1 - Lin, Honghuang A1 - Boerwinkle, Eric A1 - Psaty, Bruce M A1 - North, Kari E A1 - Cupples, L Adrienne A1 - O'Donnell, Christopher J KW - Aged KW - Aged, 80 and over KW - Aging KW - Atherosclerosis KW - Class Ib Phosphatidylinositol 3-Kinase KW - Cohort Studies KW - European Continental Ancestry Group KW - Female KW - Genetic Variation KW - Genome-Wide Association Study KW - Genomics KW - Humans KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Sequence Analysis, DNA KW - Sodium-Phosphate Cotransporter Proteins, Type I AB -

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

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

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

VL - 7 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24951662?dopt=Abstract ER - TY - JOUR T1 - Whole-exome sequencing identifies rare and low-frequency coding variants associated with LDL cholesterol. JF - Am J Hum Genet Y1 - 2014 A1 - Lange, Leslie A A1 - Hu, Youna A1 - Zhang, He A1 - Xue, Chenyi A1 - Schmidt, Ellen M A1 - Tang, Zheng-Zheng A1 - Bizon, Chris A1 - Lange, Ethan M A1 - Smith, Joshua D A1 - Turner, Emily H A1 - Jun, Goo A1 - Kang, Hyun Min A1 - Peloso, Gina A1 - Auer, Paul A1 - Li, Kuo-Ping A1 - Flannick, Jason A1 - Zhang, Ji A1 - Fuchsberger, Christian A1 - Gaulton, Kyle A1 - Lindgren, Cecilia A1 - Locke, Adam A1 - Manning, Alisa A1 - Sim, Xueling A1 - Rivas, Manuel A A1 - Holmen, Oddgeir L A1 - Gottesman, Omri A1 - Lu, Yingchang A1 - Ruderfer, Douglas A1 - Stahl, Eli A A1 - Duan, Qing A1 - Li, Yun A1 - Durda, Peter A1 - Jiao, Shuo A1 - Isaacs, Aaron A1 - Hofman, Albert A1 - Bis, Joshua C A1 - Correa, Adolfo A1 - Griswold, Michael E A1 - Jakobsdottir, Johanna A1 - Smith, Albert V A1 - Schreiner, Pamela J A1 - Feitosa, Mary F A1 - Zhang, Qunyuan A1 - Huffman, Jennifer E A1 - Crosby, Jacy A1 - Wassel, Christina L A1 - Do, Ron A1 - Franceschini, Nora A1 - Martin, Lisa W A1 - Robinson, Jennifer G A1 - Assimes, Themistocles L A1 - Crosslin, David R A1 - Rosenthal, Elisabeth A A1 - Tsai, Michael A1 - Rieder, Mark J A1 - Farlow, Deborah N A1 - Folsom, Aaron R A1 - Lumley, Thomas A1 - Fox, Ervin R A1 - Carlson, Christopher S A1 - Peters, Ulrike A1 - Jackson, Rebecca D A1 - van Duijn, Cornelia M A1 - Uitterlinden, André G A1 - Levy, Daniel A1 - Rotter, Jerome I A1 - Taylor, Herman A A1 - Gudnason, Vilmundur A1 - Siscovick, David S A1 - Fornage, Myriam A1 - Borecki, Ingrid B A1 - Hayward, Caroline A1 - Rudan, Igor A1 - Chen, Y Eugene A1 - Bottinger, Erwin P A1 - Loos, Ruth J F A1 - Sætrom, Pål A1 - Hveem, Kristian A1 - Boehnke, Michael A1 - Groop, Leif A1 - McCarthy, Mark A1 - Meitinger, Thomas A1 - Ballantyne, Christie M A1 - Gabriel, Stacey B A1 - O'Donnell, Christopher J A1 - Post, Wendy S A1 - North, Kari E A1 - Reiner, Alexander P A1 - Boerwinkle, Eric A1 - Psaty, Bruce M A1 - Altshuler, David A1 - Kathiresan, Sekar A1 - Lin, Dan-Yu A1 - Jarvik, Gail P A1 - Cupples, L Adrienne A1 - Kooperberg, Charles A1 - Wilson, James G A1 - Nickerson, Deborah A A1 - Abecasis, Goncalo R A1 - Rich, Stephen S A1 - Tracy, Russell P A1 - Willer, Cristen J KW - Adult KW - Aged KW - Apolipoproteins E KW - Cholesterol, LDL KW - Cohort Studies KW - Dyslipidemias KW - Exome KW - Female KW - Follow-Up Studies KW - Gene Frequency KW - Genetic Code KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Lipase KW - Male KW - Middle Aged KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Proprotein Convertase 9 KW - Proprotein Convertases KW - Receptors, LDL KW - Sequence Analysis, DNA KW - Serine Endopeptidases AB -

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

VL - 94 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24507775?dopt=Abstract ER - TY - JOUR T1 - Genome-Wide Association Study for Incident Myocardial Infarction and Coronary Heart Disease in Prospective Cohort Studies: The CHARGE Consortium. JF - PLoS One Y1 - 2016 A1 - Dehghan, Abbas A1 - Bis, Joshua C A1 - White, Charles C A1 - Smith, Albert Vernon A1 - Morrison, Alanna C A1 - Cupples, L Adrienne A1 - Trompet, Stella A1 - Chasman, Daniel I A1 - Lumley, Thomas A1 - Völker, Uwe A1 - Buckley, Brendan M A1 - Ding, Jingzhong A1 - Jensen, Majken K A1 - Folsom, Aaron R A1 - Kritchevsky, Stephen B A1 - Girman, Cynthia J A1 - Ford, Ian A1 - Dörr, Marcus A1 - Salomaa, Veikko A1 - Uitterlinden, André G A1 - Eiriksdottir, Gudny A1 - Vasan, Ramachandran S A1 - Franceschini, Nora A1 - Carty, Cara L A1 - Virtamo, Jarmo A1 - Demissie, Serkalem A1 - Amouyel, Philippe A1 - Arveiler, Dominique A1 - Heckbert, Susan R A1 - Ferrieres, Jean A1 - Ducimetiere, Pierre A1 - Smith, Nicholas L A1 - Wang, Ying A A1 - Siscovick, David S A1 - Rice, Kenneth M A1 - Wiklund, Per-Gunnar A1 - Taylor, Kent D A1 - Evans, Alun A1 - Kee, Frank A1 - Rotter, Jerome I A1 - Karvanen, Juha A1 - Kuulasmaa, Kari A1 - Heiss, Gerardo A1 - Kraft, Peter A1 - Launer, Lenore J A1 - Hofman, Albert A1 - Markus, Marcello R P A1 - Rose, Lynda M A1 - Silander, Kaisa A1 - Wagner, Peter A1 - Benjamin, Emelia J A1 - Lohman, Kurt A1 - Stott, David J A1 - Rivadeneira, Fernando A1 - Harris, Tamara B A1 - Levy, Daniel A1 - Liu, Yongmei A1 - Rimm, Eric B A1 - Jukema, J Wouter A1 - Völzke, Henry A1 - Ridker, Paul M A1 - Blankenberg, Stefan A1 - Franco, Oscar H A1 - Gudnason, Vilmundur A1 - Psaty, Bruce M A1 - Boerwinkle, Eric A1 - O'Donnell, Christopher J KW - Aged KW - Cohort Studies KW - Cooperative Behavior KW - Coronary Artery Disease KW - Female KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Male KW - Middle Aged KW - Myocardial Infarction KW - Polymorphism, Single Nucleotide KW - Prospective Studies AB -

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

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

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

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

VL - 11 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26950853?dopt=Abstract ER - TY - JOUR T1 - A genome-wide association study meta-analysis of clinical fracture in 10,012 African American women. JF - Bone Rep Y1 - 2016 A1 - Taylor, Kira C A1 - Evans, Daniel S A1 - Edwards, Digna R Velez A1 - Edwards, Todd L A1 - Sofer, Tamar A1 - Li, Guo A1 - Liu, Youfang A1 - Franceschini, Nora A1 - Jackson, Rebecca D A1 - Giri, Ayush A1 - Donneyong, Macarius A1 - Psaty, Bruce A1 - Rotter, Jerome I A1 - LaCroix, Andrea Z A1 - Jordan, Joanne M A1 - Robbins, John A A1 - Lewis, Beth A1 - Stefanick, Marcia L A1 - Liu, Yongmei A1 - Garcia, Melissa A1 - Harris, Tamara A1 - Cauley, Jane A A1 - North, Kari E AB -

BACKGROUND: Osteoporosis is a major public health problem associated with excess disability and mortality. It is estimated that 50-70% of the variation in osteoporotic fracture risk is attributable to genetic factors. The purpose of this hypothesis-generating study was to identify possible genetic determinants of fracture among African American (AA) women in a GWAS meta-analysis.

METHODS: Data on clinical fractures (all fractures except fingers, toes, face, skull or sternum) were analyzed among AA female participants in the Women's Health Initiative (WHI) (N = 8155), Cardiovascular Health Study (CHS) (N = 504), BioVU (N = 704), Health ABC (N = 651), and the Johnston County Osteoarthritis Project (JoCoOA) (N = 291). Affymetrix (WHI) and Illumina (Health ABC, JoCoOA, BioVU, CHS) GWAS panels were used for genotyping, and a 1:1 ratio of YRI:CEU HapMap haplotypes was used as an imputation reference panel. We used Cox proportional hazard models or logistic regression to evaluate the association of ~ 2.5 million SNPs with fracture risk, adjusting for ancestry, age, and geographic region where applicable. We conducted a fixed-effects, inverse variance-weighted meta-analysis. Genome-wide significance was set at P < 5 × 10- 8.

RESULTS: One SNP, rs12775980 in an intron of SVIL on chromosome 10p11.2, reached genome-wide significance (P = 4.0 × 10- 8). Although this SNP has a low minor allele frequency (0.03), there was no evidence for heterogeneity of effects across the studies (I2 = 0). This locus was not reported in any previous osteoporosis-related GWA studies. We also interrogated previously reported GWA-significant loci associated with fracture or bone mineral density in our data. One locus (SMOC1) generalized, but overall there was not substantial evidence of generalization. Possible reasons for the lack of generalization are discussed.

CONCLUSION: This GWAS meta-analysis of fractures in African American women identified a potentially novel locus in the supervillin gene, which encodes a platelet-associated factor and was previously associated with platelet thrombus formation in African Americans. If validated in other populations of African descent, these findings suggest potential new mechanisms involved in fracture that may be particularly important among African Americans.

VL - 5 ER - TY - JOUR T1 - Meta-analysis identifies common and rare variants influencing blood pressure and overlapping with metabolic trait loci. JF - Nat Genet Y1 - 2016 A1 - Liu, Chunyu A1 - Kraja, Aldi T A1 - Smith, Jennifer A A1 - Brody, Jennifer A A1 - Franceschini, Nora A1 - Bis, Joshua C A1 - Rice, Kenneth A1 - Morrison, Alanna C A1 - Lu, Yingchang A1 - Weiss, Stefan A1 - Guo, Xiuqing A1 - Palmas, Walter A1 - Martin, Lisa W A1 - Chen, Yii-Der Ida A1 - Surendran, Praveen A1 - Drenos, Fotios A1 - Cook, James P A1 - Auer, Paul L A1 - Chu, Audrey Y A1 - Giri, Ayush A1 - Zhao, Wei A1 - Jakobsdottir, Johanna A1 - Lin, Li-An A1 - Stafford, Jeanette M A1 - Amin, Najaf A1 - Mei, Hao A1 - Yao, Jie A1 - Voorman, Arend A1 - Larson, Martin G A1 - Grove, Megan L A1 - Smith, Albert V A1 - Hwang, Shih-Jen A1 - Chen, Han A1 - Huan, Tianxiao A1 - Kosova, Gulum A1 - Stitziel, Nathan O A1 - Kathiresan, Sekar A1 - Samani, Nilesh A1 - Schunkert, Heribert A1 - Deloukas, Panos A1 - Li, Man A1 - Fuchsberger, Christian A1 - Pattaro, Cristian A1 - Gorski, Mathias A1 - Kooperberg, Charles A1 - Papanicolaou, George J A1 - Rossouw, Jacques E A1 - Faul, Jessica D A1 - Kardia, Sharon L R A1 - Bouchard, Claude A1 - Raffel, Leslie J A1 - Uitterlinden, André G A1 - Franco, Oscar H A1 - Vasan, Ramachandran S A1 - O'Donnell, Christopher J A1 - Taylor, Kent D A1 - Liu, Kiang A1 - Bottinger, Erwin P A1 - Gottesman, Omri A1 - Daw, E Warwick A1 - Giulianini, Franco A1 - Ganesh, Santhi A1 - Salfati, Elias A1 - Harris, Tamara B A1 - Launer, Lenore J A1 - Dörr, Marcus A1 - Felix, Stephan B A1 - Rettig, Rainer A1 - Völzke, Henry A1 - Kim, Eric A1 - Lee, Wen-Jane A1 - Lee, I-Te A1 - Sheu, Wayne H-H A1 - Tsosie, Krystal S A1 - Edwards, Digna R Velez A1 - Liu, Yongmei A1 - Correa, Adolfo A1 - Weir, David R A1 - Völker, Uwe A1 - Ridker, Paul M A1 - Boerwinkle, Eric A1 - Gudnason, Vilmundur A1 - Reiner, Alexander P A1 - van Duijn, Cornelia M A1 - Borecki, Ingrid B A1 - Edwards, Todd L A1 - Chakravarti, Aravinda A1 - Rotter, Jerome I A1 - Psaty, Bruce M A1 - Loos, Ruth J F A1 - Fornage, Myriam A1 - Ehret, Georg B A1 - Newton-Cheh, Christopher A1 - Levy, Daniel A1 - Chasman, Daniel I AB -

Meta-analyses of association results for blood pressure using exome-centric single-variant and gene-based tests identified 31 new loci in a discovery stage among 146,562 individuals, with follow-up and meta-analysis in 180,726 additional individuals (total n = 327,288). These blood pressure-associated loci are enriched for known variants for cardiometabolic traits. Associations were also observed for the aggregation of rare and low-frequency missense variants in three genes, NPR1, DBH, and PTPMT1. In addition, blood pressure associations at 39 previously reported loci were confirmed. The identified variants implicate biological pathways related to cardiometabolic traits, vascular function, and development. Several new variants are inferred to have roles in transcription or as hubs in protein-protein interaction networks. Genetic risk scores constructed from the identified variants were strongly associated with coronary disease and myocardial infarction. This large collection of blood pressure-associated loci suggests new therapeutic strategies for hypertension, emphasizing a link with cardiometabolic risk.

VL - 48 IS - 10 ER - TY - JOUR T1 - Multiethnic Exome-Wide Association Study of Subclinical Atherosclerosis. JF - Circ Cardiovasc Genet Y1 - 2016 A1 - Natarajan, Pradeep A1 - Bis, Joshua C A1 - Bielak, Lawrence F A1 - Cox, Amanda J A1 - Dörr, Marcus A1 - Feitosa, Mary F A1 - Franceschini, Nora A1 - Guo, Xiuqing A1 - Hwang, Shih-Jen A1 - Isaacs, Aaron A1 - Jhun, Min A A1 - Kavousi, Maryam A1 - Li-Gao, Ruifang A1 - Lyytikäinen, Leo-Pekka A1 - Marioni, Riccardo E A1 - Schminke, Ulf A1 - Stitziel, Nathan O A1 - Tada, Hayato A1 - van Setten, Jessica A1 - Smith, Albert V A1 - Vojinovic, Dina A1 - Yanek, Lisa R A1 - Yao, Jie A1 - Yerges-Armstrong, Laura M A1 - Amin, Najaf A1 - Baber, Usman A1 - Borecki, Ingrid B A1 - Carr, J Jeffrey A1 - Chen, Yii-Der Ida A1 - Cupples, L Adrienne A1 - de Jong, Pim A A1 - de Koning, Harry A1 - de Vos, Bob D A1 - Demirkan, Ayse A1 - Fuster, Valentin A1 - Franco, Oscar H A1 - Goodarzi, Mark O A1 - Harris, Tamara B A1 - Heckbert, Susan R A1 - Heiss, Gerardo A1 - Hoffmann, Udo A1 - Hofman, Albert A1 - Išgum, Ivana A1 - Jukema, J Wouter A1 - Kähönen, Mika A1 - Kardia, Sharon L R A1 - Kral, Brian G A1 - Launer, Lenore J A1 - Massaro, Joseph A1 - Mehran, Roxana A1 - Mitchell, Braxton D A1 - Mosley, Thomas H A1 - de Mutsert, Renée A1 - Newman, Anne B A1 - Nguyen, Khanh-Dung A1 - North, Kari E A1 - O'Connell, Jeffrey R A1 - Oudkerk, Matthijs A1 - Pankow, James S A1 - Peloso, Gina M A1 - Post, Wendy A1 - Province, Michael A A1 - Raffield, Laura M A1 - Raitakari, Olli T A1 - Reilly, Dermot F A1 - Rivadeneira, Fernando A1 - Rosendaal, Frits A1 - Sartori, Samantha A1 - Taylor, Kent D A1 - Teumer, Alexander A1 - Trompet, Stella A1 - Turner, Stephen T A1 - Uitterlinden, André G A1 - Vaidya, Dhananjay A1 - van der Lugt, Aad A1 - Völker, Uwe A1 - Wardlaw, Joanna M A1 - Wassel, Christina L A1 - Weiss, Stefan A1 - Wojczynski, Mary K A1 - Becker, Diane M A1 - Becker, Lewis C A1 - Boerwinkle, Eric A1 - Bowden, Donald W A1 - Deary, Ian J A1 - Dehghan, Abbas A1 - Felix, Stephan B A1 - Gudnason, Vilmundur A1 - Lehtimäki, Terho A1 - Mathias, Rasika A1 - Mook-Kanamori, Dennis O A1 - Psaty, Bruce M A1 - Rader, Daniel J A1 - Rotter, Jerome I A1 - Wilson, James G A1 - van Duijn, Cornelia M A1 - Völzke, Henry A1 - Kathiresan, Sekar A1 - Peyser, Patricia A A1 - O'Donnell, Christopher J AB -

BACKGROUND: -The burden of subclinical atherosclerosis in asymptomatic individuals is heritable and associated with elevated risk of developing clinical coronary heart disease (CHD). We sought to identify genetic variants in protein-coding regions associated with subclinical atherosclerosis and the risk of subsequent CHD.

METHODS AND RESULTS: -We studied a total of 25,109 European ancestry and African-American participants with coronary artery calcification (CAC) measured by cardiac computed tomography and 52,869 with common carotid intima media thickness (CIMT) measured by ultrasonography within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Participants were genotyped for 247,870 DNA sequence variants (231,539 in exons) across the genome. A meta-analysis of exome-wide association studies was performed across cohorts for CAC and CIMT. APOB p.Arg3527Gln was associated with four-fold excess CAC (P = 3×10(-10)). The APOE ε2 allele (p.Arg176Cys) was associated with both 22.3% reduced CAC (P = 1×10(-12)) and 1.4% reduced CIMT (P = 4×10(-14)) in carriers compared with non-carriers. In secondary analyses conditioning on LDL cholesterol concentration, the ε2 protective association with CAC, although attenuated, remained strongly significant. Additionally, the presence of ε2 was associated with reduced risk for CHD (OR 0.77; P = 1×10(-11)).

CONCLUSIONS: -Exome-wide association meta-analysis demonstrates that protein-coding variants in APOB and APOE associate with subclinical atherosclerosis. APOE ε2 represents the first significant association for multiple subclinical atherosclerosis traits across multiple ethnicities as well as clinical CHD.

ER - TY - JOUR T1 - Rare Exome Sequence Variants in CLCN6 Reduce Blood Pressure Levels and Hypertension Risk. JF - Circ Cardiovasc Genet Y1 - 2016 A1 - Yu, Bing A1 - Pulit, Sara L A1 - Hwang, Shih-Jen A1 - Brody, Jennifer A A1 - Amin, Najaf A1 - Auer, Paul L A1 - Bis, Joshua C A1 - Boerwinkle, Eric A1 - Burke, Gregory L A1 - Chakravarti, Aravinda A1 - Correa, Adolfo A1 - Dreisbach, Albert W A1 - Franco, Oscar H A1 - Ehret, Georg B A1 - Franceschini, Nora A1 - Hofman, Albert A1 - Lin, Dan-Yu A1 - Metcalf, Ginger A A1 - Musani, Solomon K A1 - Muzny, Donna A1 - Palmas, Walter A1 - Raffel, Leslie A1 - Reiner, Alex A1 - Rice, Ken A1 - Rotter, Jerome I A1 - Veeraraghavan, Narayanan A1 - Fox, Ervin A1 - Guo, Xiuqing A1 - North, Kari E A1 - Gibbs, Richard A A1 - van Duijn, Cornelia M A1 - Psaty, Bruce M A1 - Levy, Daniel A1 - Newton-Cheh, Christopher A1 - Morrison, Alanna C AB -

BACKGROUND: Rare genetic variants influence blood pressure (BP).

METHODS AND RESULTS: Whole-exome sequencing was performed on DNA samples from 17 956 individuals of European ancestry and African ancestry (14 497, first-stage discovery and 3459, second-stage discovery) to examine the effect of rare variants on hypertension and 4 BP traits: systolic BP, diastolic BP, pulse pressure, and mean arterial pressure. Tests of ≈170 000 common variants (minor allele frequency, ≥1%; statistical significance, P≤2.9×10(-7)) and gene-based tests of rare variants (minor allele frequency, <1%; ≈17 000 genes; statistical significance, P≤1.5×10(-6)) were evaluated for each trait and ancestry, followed by multiethnic meta-analyses. In the first-stage discovery, rare coding variants (splicing, stop-gain, stop-loss, nonsynonymous variants, or indels) in CLCN6 were associated with lower diastolic BP (cumulative minor allele frequency, 1.3%; β=-3.20; P=4.1×10(-6)) and were independent of a nearby common variant (rs17367504) previously associated with BP. CLCN6 rare variants were also associated with lower systolic BP (β=-4.11; P=2.8×10(-4)), mean arterial pressure (β=-3.50; P=8.9×10(-6)), and reduced hypertension risk (odds ratio, 0.72; P=0.017). Meta-analysis of the 2-stage discovery samples showed that CLCN6 was associated with lower diastolic BP at exome-wide significance (cumulative minor allele frequency, 1.1%; β=-3.30; P=5.0×10(-7)).

CONCLUSIONS: These findings implicate the effect of rare coding variants in CLCN6 in BP variation and offer new insights into BP regulation.

VL - 9 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26658788?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 - Trans-ethnic Meta-analysis and Functional Annotation Illuminates the Genetic Architecture of Fasting Glucose and Insulin. JF - Am J Hum Genet Y1 - 2016 A1 - Liu, Ching-Ti A1 - Raghavan, Sridharan A1 - Maruthur, Nisa A1 - Kabagambe, Edmond Kato A1 - Hong, Jaeyoung A1 - Ng, Maggie C Y A1 - Hivert, Marie-France A1 - Lu, Yingchang A1 - An, Ping A1 - Bentley, Amy R A1 - Drolet, Anne M A1 - Gaulton, Kyle J A1 - Guo, Xiuqing A1 - Armstrong, Loren L A1 - Irvin, Marguerite R A1 - Li, Man A1 - Lipovich, Leonard A1 - Rybin, Denis V A1 - Taylor, Kent D A1 - Agyemang, Charles A1 - Palmer, Nicholette D A1 - Cade, Brian E A1 - Chen, Wei-Min A1 - Dauriz, Marco A1 - Delaney, Joseph A C A1 - Edwards, Todd L A1 - Evans, Daniel S A1 - Evans, Michele K A1 - Lange, Leslie A A1 - Leong, Aaron A1 - Liu, Jingmin A1 - Liu, Yongmei A1 - Nayak, Uma A1 - Patel, Sanjay R A1 - Porneala, Bianca C A1 - Rasmussen-Torvik, Laura J A1 - Snijder, Marieke B A1 - Stallings, Sarah C A1 - Tanaka, Toshiko A1 - Yanek, Lisa R A1 - Zhao, Wei A1 - Becker, Diane M A1 - Bielak, Lawrence F A1 - Biggs, Mary L A1 - Bottinger, Erwin P A1 - Bowden, Donald W A1 - Chen, Guanjie A1 - Correa, Adolfo A1 - Couper, David J A1 - Crawford, Dana C A1 - Cushman, Mary A1 - Eicher, John D A1 - Fornage, Myriam A1 - Franceschini, Nora A1 - Fu, Yi-Ping A1 - Goodarzi, Mark O A1 - Gottesman, Omri A1 - Hara, Kazuo A1 - Harris, Tamara B A1 - Jensen, Richard A A1 - Johnson, Andrew D A1 - Jhun, Min A A1 - Karter, Andrew J A1 - Keller, Margaux F A1 - Kho, Abel N A1 - Kizer, Jorge R A1 - Krauss, Ronald M A1 - Langefeld, Carl D A1 - Li, Xiaohui A1 - Liang, Jingling A1 - Liu, Simin A1 - Lowe, William L A1 - Mosley, Thomas H A1 - North, Kari E A1 - Pacheco, Jennifer A A1 - Peyser, Patricia A A1 - Patrick, Alan L A1 - Rice, Kenneth M A1 - Selvin, Elizabeth A1 - Sims, Mario A1 - Smith, Jennifer A A1 - Tajuddin, Salman M A1 - Vaidya, Dhananjay A1 - Wren, Mary P A1 - Yao, Jie A1 - Zhu, Xiaofeng A1 - Ziegler, Julie T A1 - Zmuda, Joseph M A1 - Zonderman, Alan B A1 - Zwinderman, Aeilko H A1 - Adeyemo, Adebowale A1 - Boerwinkle, Eric A1 - Ferrucci, Luigi A1 - Hayes, M Geoffrey A1 - Kardia, Sharon L R A1 - Miljkovic, Iva A1 - Pankow, James S A1 - Rotimi, Charles N A1 - Sale, Michèle M A1 - Wagenknecht, Lynne E A1 - Arnett, Donna K A1 - Chen, Yii-Der Ida A1 - Nalls, Michael A A1 - Province, Michael A A1 - Kao, W H Linda A1 - Siscovick, David S A1 - Psaty, Bruce M A1 - Wilson, James G A1 - Loos, Ruth J F A1 - Dupuis, Josée A1 - Rich, Stephen S A1 - Florez, Jose C A1 - Rotter, Jerome I A1 - Morris, Andrew P A1 - Meigs, James B AB -

Knowledge of the genetic basis of the type 2 diabetes (T2D)-related quantitative traits fasting glucose (FG) and insulin (FI) in African ancestry (AA) individuals has been limited. In non-diabetic subjects of AA (n = 20,209) and European ancestry (EA; n = 57,292), we performed trans-ethnic (AA+EA) fine-mapping of 54 established EA FG or FI loci with detailed functional annotation, assessed their relevance in AA individuals, and sought previously undescribed loci through trans-ethnic (AA+EA) meta-analysis. We narrowed credible sets of variants driving association signals for 22/54 EA-associated loci; 18/22 credible sets overlapped with active islet-specific enhancers or transcription factor (TF) binding sites, and 21/22 contained at least one TF motif. Of the 54 EA-associated loci, 23 were shared between EA and AA. Replication with an additional 10,096 AA individuals identified two previously undescribed FI loci, chrX FAM133A (rs213676) and chr5 PELO (rs6450057). Trans-ethnic analyses with regulatory annotation illuminate the genetic architecture of glycemic traits and suggest gene regulation as a target to advance precision medicine for T2D. Our approach to utilize state-of-the-art functional annotation and implement trans-ethnic association analysis for discovery and fine-mapping offers a framework for further follow-up and characterization of GWAS signals of complex trait loci.

VL - 99 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/27321945?dopt=Abstract ER - TY - JOUR T1 - Whole-Exome Sequencing Identifies Loci Associated with Blood Cell Traits and Reveals a Role for Alternative GFI1B Splice Variants in Human Hematopoiesis. JF - Am J Hum Genet Y1 - 2016 A1 - Polfus, Linda M A1 - Khajuria, Rajiv K A1 - Schick, Ursula M A1 - Pankratz, Nathan A1 - Pazoki, Raha A1 - Brody, Jennifer A A1 - Chen, Ming-Huei A1 - Auer, Paul L A1 - Floyd, James S A1 - Huang, Jie A1 - Lange, Leslie A1 - van Rooij, Frank J A A1 - Gibbs, Richard A A1 - Metcalf, Ginger A1 - Muzny, Donna A1 - Veeraraghavan, Narayanan A1 - Walter, Klaudia A1 - Chen, Lu A1 - Yanek, Lisa A1 - Becker, Lewis C A1 - Peloso, Gina M A1 - Wakabayashi, Aoi A1 - Kals, Mart A1 - Metspalu, Andres A1 - Esko, Tõnu A1 - Fox, Keolu A1 - Wallace, Robert A1 - Franceschini, Nora A1 - Matijevic, Nena A1 - Rice, Kenneth M A1 - Bartz, Traci M A1 - Lyytikäinen, Leo-Pekka A1 - Kähönen, Mika A1 - Lehtimäki, Terho A1 - Raitakari, Olli T A1 - Li-Gao, Ruifang A1 - Mook-Kanamori, Dennis O A1 - Lettre, Guillaume A1 - van Duijn, Cornelia M A1 - Franco, Oscar H A1 - Rich, Stephen S A1 - Rivadeneira, Fernando A1 - Hofman, Albert A1 - Uitterlinden, André G A1 - Wilson, James G A1 - Psaty, Bruce M A1 - Soranzo, Nicole A1 - Dehghan, Abbas A1 - Boerwinkle, Eric A1 - Zhang, Xiaoling A1 - Johnson, Andrew D A1 - O'Donnell, Christopher J A1 - Johnsen, Jill M A1 - Reiner, Alexander P A1 - Ganesh, Santhi K A1 - Sankaran, Vijay G VL - 99 IS - 3 ER - TY - JOUR T1 - Genetic loci associated with chronic obstructive pulmonary disease overlap with loci for lung function and pulmonary fibrosis. JF - Nat Genet Y1 - 2017 A1 - Hobbs, Brian D A1 - de Jong, Kim A1 - Lamontagne, Maxime A1 - Bossé, Yohan A1 - Shrine, Nick A1 - Artigas, Maria Soler A1 - Wain, Louise V A1 - Hall, Ian P A1 - Jackson, Victoria E A1 - Wyss, Annah B A1 - London, Stephanie J A1 - North, Kari E A1 - Franceschini, Nora A1 - Strachan, David P A1 - Beaty, Terri H A1 - Hokanson, John E A1 - Crapo, James D A1 - Castaldi, Peter J A1 - Chase, Robert P A1 - Bartz, Traci M A1 - Heckbert, Susan R A1 - Psaty, Bruce M A1 - Gharib, Sina A A1 - Zanen, Pieter A1 - Lammers, Jan W A1 - Oudkerk, Matthijs A1 - Groen, H J A1 - Locantore, Nicholas A1 - Tal-Singer, Ruth A1 - Rennard, Stephen I A1 - Vestbo, Jørgen A1 - Timens, Wim A1 - Paré, Peter D A1 - Latourelle, Jeanne C A1 - Dupuis, Josée A1 - O'Connor, George T A1 - Wilk, Jemma B A1 - Kim, Woo Jin A1 - Lee, Mi Kyeong A1 - Oh, Yeon-Mok A1 - Vonk, Judith M A1 - de Koning, Harry J A1 - Leng, Shuguang A1 - Belinsky, Steven A A1 - Tesfaigzi, Yohannes A1 - Manichaikul, Ani A1 - Wang, Xin-Qun A1 - Rich, Stephen S A1 - Barr, R Graham A1 - Sparrow, David A1 - Litonjua, Augusto A A1 - Bakke, Per A1 - Gulsvik, Amund A1 - Lahousse, Lies A1 - Brusselle, Guy G A1 - Stricker, Bruno H A1 - Uitterlinden, André G A1 - Ampleford, Elizabeth J A1 - Bleecker, Eugene R A1 - Woodruff, Prescott G A1 - Meyers, Deborah A A1 - Qiao, Dandi A1 - Lomas, David A A1 - Yim, Jae-Joon A1 - Kim, Deog Kyeom A1 - Hawrylkiewicz, Iwona A1 - Sliwinski, Pawel A1 - Hardin, Megan A1 - Fingerlin, Tasha E A1 - Schwartz, David A A1 - Postma, Dirkje S A1 - MacNee, William A1 - Tobin, Martin D A1 - Silverman, Edwin K A1 - Boezen, H Marike A1 - Cho, Michael H AB -

Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality worldwide. We performed a genetic association study in 15,256 cases and 47,936 controls, with replication of select top results (P < 5 × 10(-6)) in 9,498 cases and 9,748 controls. In the combined meta-analysis, we identified 22 loci associated at genome-wide significance, including 13 new associations with COPD. Nine of these 13 loci have been associated with lung function in general population samples, while 4 (EEFSEC, DSP, MTCL1, and SFTPD) are new. We noted two loci shared with pulmonary fibrosis (FAM13A and DSP) but that had opposite risk alleles for COPD. None of our loci overlapped with genome-wide associations for asthma, although one locus has been implicated in joint susceptibility to asthma and obesity. We also identified genetic correlation between COPD and asthma. Our findings highlight new loci associated with COPD, demonstrate the importance of specific loci associated with lung function to COPD, and identify potential regions of genetic overlap between COPD and other respiratory diseases.

VL - 49 IS - 3 ER - TY - JOUR T1 - Genome-wide meta-analysis associates HLA-DQA1/DRB1 and LPA and lifestyle factors with human longevity. JF - Nat Commun Y1 - 2017 A1 - Joshi, Peter K A1 - Pirastu, Nicola A1 - Kentistou, Katherine A A1 - Fischer, Krista A1 - Hofer, Edith A1 - Schraut, Katharina E A1 - Clark, David W A1 - Nutile, Teresa A1 - Barnes, Catriona L K A1 - Timmers, Paul R H J A1 - Shen, Xia A1 - Gandin, Ilaria A1 - McDaid, Aaron F A1 - Hansen, Thomas Folkmann A1 - Gordon, Scott D A1 - Giulianini, Franco A1 - Boutin, Thibaud S A1 - Abdellaoui, Abdel A1 - Zhao, Wei A1 - Medina-Gómez, Carolina A1 - Bartz, Traci M A1 - Trompet, Stella A1 - Lange, Leslie A A1 - Raffield, Laura A1 - van der Spek, Ashley A1 - Galesloot, Tessel E A1 - Proitsi, Petroula A1 - Yanek, Lisa R A1 - Bielak, Lawrence F A1 - Payton, Antony A1 - Murgia, Federico A1 - Concas, Maria Pina A1 - Biino, Ginevra A1 - Tajuddin, Salman M A1 - Seppälä, Ilkka A1 - Amin, Najaf A1 - Boerwinkle, Eric A1 - Børglum, Anders D A1 - Campbell, Archie A1 - Demerath, Ellen W A1 - Demuth, Ilja A1 - Faul, Jessica D A1 - Ford, Ian A1 - Gialluisi, Alessandro A1 - Gögele, Martin A1 - Graff, Mariaelisa A1 - Hingorani, Aroon A1 - Hottenga, Jouke-Jan A1 - Hougaard, David M A1 - Hurme, Mikko A A1 - Ikram, M Arfan A1 - Jylhä, Marja A1 - Kuh, Diana A1 - Ligthart, Lannie A1 - Lill, Christina M A1 - Lindenberger, Ulman A1 - Lumley, Thomas A1 - Mägi, Reedik A1 - Marques-Vidal, Pedro A1 - Medland, Sarah E A1 - Milani, Lili A1 - Nagy, Reka A1 - Ollier, William E R A1 - Peyser, Patricia A A1 - Pramstaller, Peter P A1 - Ridker, Paul M A1 - Rivadeneira, Fernando A1 - Ruggiero, Daniela A1 - Saba, Yasaman A1 - Schmidt, Reinhold A1 - Schmidt, Helena A1 - Slagboom, P Eline A1 - Smith, Blair H A1 - Smith, Jennifer A A1 - Sotoodehnia, Nona A1 - Steinhagen-Thiessen, Elisabeth A1 - van Rooij, Frank J A A1 - Verbeek, André L A1 - Vermeulen, Sita H A1 - Vollenweider, Peter A1 - Wang, Yunpeng A1 - Werge, Thomas A1 - Whitfield, John B A1 - Zonderman, Alan B A1 - Lehtimäki, Terho A1 - Evans, Michele K A1 - Pirastu, Mario A1 - Fuchsberger, Christian A1 - Bertram, Lars A1 - Pendleton, Neil A1 - Kardia, Sharon L R A1 - Ciullo, Marina A1 - Becker, Diane M A1 - Wong, Andrew A1 - Psaty, Bruce M A1 - van Duijn, Cornelia M A1 - Wilson, James G A1 - Jukema, J Wouter A1 - Kiemeney, Lambertus A1 - Uitterlinden, André G A1 - Franceschini, Nora A1 - North, Kari E A1 - Weir, David R A1 - Metspalu, Andres A1 - Boomsma, Dorret I A1 - Hayward, Caroline A1 - Chasman, Daniel A1 - Martin, Nicholas G A1 - Sattar, Naveed A1 - Campbell, Harry A1 - Esko, Tõnu A1 - Kutalik, Zoltán A1 - Wilson, James F AB -

Genomic analysis of longevity offers the potential to illuminate the biology of human aging. Here, using genome-wide association meta-analysis of 606,059 parents' survival, we discover two regions associated with longevity (HLA-DQA1/DRB1 and LPA). We also validate previous suggestions that APOE, CHRNA3/5, CDKN2A/B, SH2B3 and FOXO3A influence longevity. Next we show that giving up smoking, educational attainment, openness to new experience and high-density lipoprotein (HDL) cholesterol levels are most positively genetically correlated with lifespan while susceptibility to coronary artery disease (CAD), cigarettes smoked per day, lung cancer, insulin resistance and body fat are most negatively correlated. We suggest that the effect of education on lifespan is principally mediated through smoking while the effect of obesity appears to act via CAD. Using instrumental variables, we suggest that an increase of one body mass index unit reduces lifespan by 7 months while 1 year of education adds 11 months to expected lifespan.Variability in human longevity is genetically influenced. Using genetic data of parental lifespan, the authors identify associations at HLA-DQA/DRB1 and LPA and find that genetic variants that increase educational attainment have a positive effect on lifespan whereas increasing BMI negatively affects lifespan.

VL - 8 IS - 1 ER - TY - JOUR T1 - New Blood Pressure-Associated Loci Identified in Meta-Analyses of 475 000 Individuals. JF - Circ Cardiovasc Genet Y1 - 2017 A1 - Kraja, Aldi T A1 - Cook, James P A1 - Warren, Helen R A1 - Surendran, Praveen A1 - Liu, Chunyu A1 - Evangelou, Evangelos A1 - Manning, Alisa K A1 - Grarup, Niels A1 - Drenos, Fotios A1 - Sim, Xueling A1 - Smith, Albert Vernon A1 - Amin, Najaf A1 - Blakemore, Alexandra I F A1 - Bork-Jensen, Jette A1 - Brandslund, Ivan A1 - Farmaki, Aliki-Eleni A1 - Fava, Cristiano A1 - Ferreira, Teresa A1 - Herzig, Karl-Heinz A1 - Giri, Ayush A1 - Giulianini, Franco A1 - Grove, Megan L A1 - Guo, Xiuqing A1 - Harris, Sarah E A1 - Have, Christian T A1 - Havulinna, Aki S A1 - Zhang, He A1 - Jørgensen, Marit E A1 - Käräjämäki, AnneMari A1 - Kooperberg, Charles A1 - Linneberg, Allan A1 - Little, Louis A1 - Liu, Yongmei A1 - Bonnycastle, Lori L A1 - Lu, Yingchang A1 - Mägi, Reedik A1 - Mahajan, Anubha A1 - Malerba, Giovanni A1 - Marioni, Riccardo E A1 - Mei, Hao A1 - Menni, Cristina A1 - Morrison, Alanna C A1 - Padmanabhan, Sandosh A1 - Palmas, Walter A1 - Poveda, Alaitz A1 - Rauramaa, Rainer A1 - Rayner, Nigel William A1 - Riaz, Muhammad A1 - Rice, Ken A1 - Richard, Melissa A A1 - Smith, Jennifer A A1 - Southam, Lorraine A1 - Stančáková, Alena A1 - Stirrups, Kathleen E A1 - Tragante, Vinicius A1 - Tuomi, Tiinamaija A1 - Tzoulaki, Ioanna A1 - Varga, Tibor V A1 - Weiss, Stefan A1 - Yiorkas, Andrianos M A1 - Young, Robin A1 - Zhang, Weihua A1 - Barnes, Michael R A1 - Cabrera, Claudia P A1 - Gao, He A1 - Boehnke, Michael A1 - Boerwinkle, Eric A1 - Chambers, John C A1 - Connell, John M A1 - Christensen, Cramer K A1 - de Boer, Rudolf A A1 - Deary, Ian J A1 - Dedoussis, George A1 - Deloukas, Panos A1 - Dominiczak, Anna F A1 - Dörr, Marcus A1 - Joehanes, Roby A1 - Edwards, Todd L A1 - Esko, Tõnu A1 - Fornage, Myriam A1 - Franceschini, Nora A1 - Franks, Paul W A1 - Gambaro, Giovanni A1 - Groop, Leif A1 - Hallmans, Göran A1 - Hansen, Torben A1 - Hayward, Caroline A1 - Heikki, Oksa A1 - Ingelsson, Erik A1 - Tuomilehto, Jaakko A1 - Jarvelin, Marjo-Riitta A1 - Kardia, Sharon L R A1 - Karpe, Fredrik A1 - Kooner, Jaspal S A1 - Lakka, Timo A A1 - Langenberg, Claudia A1 - Lind, Lars A1 - Loos, Ruth J F A1 - Laakso, Markku A1 - McCarthy, Mark I A1 - Melander, Olle A1 - Mohlke, Karen L A1 - Morris, Andrew P A1 - Palmer, Colin N A A1 - Pedersen, Oluf A1 - Polasek, Ozren A1 - Poulter, Neil R A1 - Province, Michael A A1 - Psaty, Bruce M A1 - Ridker, Paul M A1 - Rotter, Jerome I A1 - Rudan, Igor A1 - Salomaa, Veikko A1 - Samani, Nilesh J A1 - Sever, Peter J A1 - Skaaby, Tea A1 - Stafford, Jeanette M A1 - Starr, John M A1 - van der Harst, Pim A1 - van der Meer, Peter A1 - van Duijn, Cornelia M A1 - Vergnaud, Anne-Claire A1 - Gudnason, Vilmundur A1 - Wareham, Nicholas J A1 - Wilson, James G A1 - Willer, Cristen J A1 - Witte, Daniel R A1 - Zeggini, Eleftheria A1 - Saleheen, Danish A1 - Butterworth, Adam S A1 - Danesh, John A1 - Asselbergs, Folkert W A1 - Wain, Louise V A1 - Ehret, Georg B A1 - Chasman, Daniel I A1 - Caulfield, Mark J A1 - Elliott, Paul A1 - Lindgren, Cecilia M A1 - Levy, Daniel A1 - Newton-Cheh, Christopher A1 - Munroe, Patricia B A1 - Howson, Joanna M M AB -

BACKGROUND: Genome-wide association studies have recently identified >400 loci that harbor DNA sequence variants that influence blood pressure (BP). Our earlier studies identified and validated 56 single nucleotide variants (SNVs) associated with BP from meta-analyses of exome chip genotype data. An additional 100 variants yielded suggestive evidence of association.

METHODS AND RESULTS: Here, we augment the sample with 140 886 European individuals from the UK Biobank, in whom 77 of the 100 suggestive SNVs were available for association analysis with systolic BP or diastolic BP or pulse pressure. We performed 2 meta-analyses, one in individuals of European, South Asian, African, and Hispanic descent (pan-ancestry, ≈475 000), and the other in the subset of individuals of European descent (≈423 000). Twenty-one SNVs were genome-wide significant (P<5×10-8) for BP, of which 4 are new BP loci: rs9678851 (missense, SLC4A1AP), rs7437940 (AFAP1), rs13303 (missense, STAB1), and rs1055144 (7p15.2). In addition, we identified a potentially independent novel BP-associated SNV, rs3416322 (missense, SYNPO2L) at a known locus, uncorrelated with the previously reported SNVs. Two SNVs are associated with expression levels of nearby genes, and SNVs at 3 loci are associated with other traits. One SNV with a minor allele frequency <0.01, (rs3025380 at DBH) was genome-wide significant.

CONCLUSIONS: We report 4 novel loci associated with BP regulation, and 1 independent variant at an established BP locus. This analysis highlights several candidate genes with variation that alter protein function or gene expression for potential follow-up.

VL - 10 IS - 5 ER - TY - JOUR T1 - Single-trait and multi-trait genome-wide association analyses identify novel loci for blood pressure in African-ancestry populations. JF - PLoS Genet Y1 - 2017 A1 - Liang, Jingjing A1 - Le, Thu H A1 - Edwards, Digna R Velez A1 - Tayo, Bamidele O A1 - Gaulton, Kyle J A1 - Smith, Jennifer A A1 - Lu, Yingchang A1 - Jensen, Richard A A1 - Chen, Guanjie A1 - Yanek, Lisa R A1 - Schwander, Karen A1 - Tajuddin, Salman M A1 - Sofer, Tamar A1 - Kim, Wonji A1 - Kayima, James A1 - McKenzie, Colin A A1 - Fox, Ervin A1 - Nalls, Michael A A1 - Young, J Hunter A1 - Sun, Yan V A1 - Lane, Jacqueline M A1 - Cechova, Sylvia A1 - Zhou, Jie A1 - Tang, Hua A1 - Fornage, Myriam A1 - Musani, Solomon K A1 - Wang, Heming A1 - Lee, Juyoung A1 - Adeyemo, Adebowale A1 - Dreisbach, Albert W A1 - Forrester, Terrence A1 - Chu, Pei-Lun A1 - Cappola, Anne A1 - Evans, Michele K A1 - Morrison, Alanna C A1 - Martin, Lisa W A1 - Wiggins, Kerri L A1 - Hui, Qin A1 - Zhao, Wei A1 - Jackson, Rebecca D A1 - Ware, Erin B A1 - Faul, Jessica D A1 - Reiner, Alex P A1 - Bray, Michael A1 - Denny, Joshua C A1 - Mosley, Thomas H A1 - Palmas, Walter A1 - Guo, Xiuqing A1 - Papanicolaou, George J A1 - Penman, Alan D A1 - Polak, Joseph F A1 - Rice, Kenneth A1 - Taylor, Ken D A1 - Boerwinkle, Eric A1 - Bottinger, Erwin P A1 - Liu, Kiang A1 - Risch, Neil A1 - Hunt, Steven C A1 - Kooperberg, Charles A1 - Zonderman, Alan B A1 - Laurie, Cathy C A1 - Becker, Diane M A1 - Cai, Jianwen A1 - Loos, Ruth J F A1 - Psaty, Bruce M A1 - Weir, David R A1 - Kardia, Sharon L R A1 - Arnett, Donna K A1 - Won, Sungho A1 - Edwards, Todd L A1 - Redline, Susan A1 - Cooper, Richard S A1 - Rao, D C A1 - Rotter, Jerome I A1 - Rotimi, Charles A1 - Levy, Daniel A1 - Chakravarti, Aravinda A1 - Zhu, Xiaofeng A1 - Franceschini, Nora KW - African Americans KW - Animals KW - Basic Helix-Loop-Helix Transcription Factors KW - Blood Pressure KW - Cadherins KW - Case-Control Studies KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Humans KW - Hypertension KW - Male KW - Membrane Proteins KW - Mice KW - Multifactorial Inheritance KW - Polymorphism, Single Nucleotide AB -

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

VL - 13 IS - 5 ER - TY - JOUR T1 - Trans-ethnic fine-mapping of genetic loci for body mass index in the diverse ancestral populations of the Population Architecture using Genomics and Epidemiology (PAGE) Study reveals evidence for multiple signals at established loci. JF - Hum Genet Y1 - 2017 A1 - Fernandez-Rhodes, Lindsay A1 - Gong, Jian A1 - Haessler, Jeffrey A1 - Franceschini, Nora A1 - Graff, Mariaelisa A1 - Nishimura, Katherine K A1 - Wang, Yujie A1 - Highland, Heather M A1 - Yoneyama, Sachiko A1 - Bush, William S A1 - Goodloe, Robert A1 - Ritchie, Marylyn D A1 - Crawford, Dana A1 - Gross, Myron A1 - Fornage, Myriam A1 - Bůzková, Petra A1 - Tao, Ran A1 - Isasi, Carmen A1 - Avilés-Santa, Larissa A1 - Daviglus, Martha A1 - Mackey, Rachel H A1 - Houston, Denise A1 - Gu, C Charles A1 - Ehret, Georg A1 - Nguyen, Khanh-Dung H A1 - Lewis, Cora E A1 - Leppert, Mark A1 - Irvin, Marguerite R A1 - Lim, Unhee A1 - Haiman, Christopher A A1 - Le Marchand, Loïc A1 - Schumacher, Fredrick A1 - Wilkens, Lynne A1 - Lu, Yingchang A1 - Bottinger, Erwin P A1 - Loos, Ruth J L A1 - Sheu, Wayne H-H A1 - Guo, Xiuqing A1 - Lee, Wen-Jane A1 - Hai, Yang A1 - Hung, Yi-Jen A1 - Absher, Devin A1 - Wu, I-Chien A1 - Taylor, Kent D A1 - Lee, I-Te A1 - Liu, Yeheng A1 - Wang, Tzung-Dau A1 - Quertermous, Thomas A1 - Juang, Jyh-Ming J A1 - Rotter, Jerome I A1 - Assimes, Themistocles A1 - Hsiung, Chao A A1 - Chen, Yii-Der Ida A1 - Prentice, Ross A1 - Kuller, Lewis H A1 - Manson, JoAnn E A1 - Kooperberg, Charles A1 - Smokowski, Paul A1 - Robinson, Whitney R A1 - Gordon-Larsen, Penny A1 - Li, Rongling A1 - Hindorff, Lucia A1 - Buyske, Steven A1 - Matise, Tara C A1 - Peters, Ulrike A1 - North, Kari E KW - Body Mass Index KW - Ethnic Groups KW - Genetics, Population KW - Humans KW - Obesity AB -

Most body mass index (BMI) genetic loci have been identified in studies of primarily European ancestries. The effect of these loci in other racial/ethnic groups is less clear. Thus, we aimed to characterize the generalizability of 170 established BMI variants, or their proxies, to diverse US populations and trans-ethnically fine-map 36 BMI loci using a sample of >102,000 adults of African, Hispanic/Latino, Asian, European and American Indian/Alaskan Native descent from the Population Architecture using Genomics and Epidemiology Study. We performed linear regression of the natural log of BMI (18.5-70 kg/m(2)) on the additive single nucleotide polymorphisms (SNPs) at BMI loci on the MetaboChip (Illumina, Inc.), adjusting for age, sex, population stratification, study site, or relatedness. We then performed fixed-effect meta-analyses and a Bayesian trans-ethnic meta-analysis to empirically cluster by allele frequency differences. Finally, we approximated conditional and joint associations to test for the presence of secondary signals. We noted directional consistency with the previously reported risk alleles beyond what would have been expected by chance (binomial p < 0.05). Nearly, a quarter of the previously described BMI index SNPs and 29 of 36 densely-genotyped BMI loci on the MetaboChip replicated/generalized in trans-ethnic analyses. We observed multiple signals at nine loci, including the description of seven loci with novel multiple signals. This study supports the generalization of most common genetic loci to diverse ancestral populations and emphasizes the importance of dense multiethnic genomic data in refining the functional variation at genetic loci of interest and describing several loci with multiple underlying genetic variants.

VL - 136 IS - 6 ER - TY - JOUR T1 - Genome-wide association study and meta-analysis identify loci associated with ventricular and supraventricular ectopy. JF - Sci Rep Y1 - 2018 A1 - Napier, Melanie D A1 - Franceschini, Nora A1 - Gondalia, Rahul A1 - Stewart, James D A1 - Méndez-Giráldez, Rául A1 - Sitlani, Colleen M A1 - Seyerle, Amanda A A1 - Highland, Heather M A1 - Li, Yun A1 - Wilhelmsen, Kirk C A1 - Yan, Song A1 - Duan, Qing A1 - Roach, Jeffrey A1 - Yao, Jie A1 - Guo, Xiuqing A1 - Taylor, Kent D A1 - Heckbert, Susan R A1 - Rotter, Jerome I A1 - North, Kari E A1 - Reiner, Alexander P A1 - Zhang, Zhu-Ming A1 - Tinker, Lesley F A1 - Liao, Duanping A1 - Laurie, Cathy C A1 - Gogarten, Stephanie M A1 - Lin, Henry J A1 - Brody, Jennifer A A1 - Bartz, Traci M A1 - Psaty, Bruce M A1 - Sotoodehnia, Nona A1 - Soliman, Elsayed Z A1 - Avery, Christy L A1 - Whitsel, Eric A AB -

The genetic basis of supraventricular and ventricular ectopy (SVE, VE) remains largely uncharacterized, despite established genetic mechanisms of arrhythmogenesis. To identify novel genetic variants associated with SVE/VE in ancestrally diverse human populations, we conducted a genome-wide association study of electrocardiographically identified SVE and VE in five cohorts including approximately 43,000 participants of African, European and Hispanic/Latino ancestry. In thirteen ancestry-stratified subgroups, we tested multivariable-adjusted associations of SVE and VE with single nucleotide polymorphism (SNP) dosage. We combined subgroup-specific association estimates in inverse variance-weighted, fixed-effects and Bayesian meta-analyses. We also combined fixed-effects meta-analytic t-test statistics for SVE and VE in multi-trait SNP association analyses. No loci reached genome-wide significance in trans-ethnic meta-analyses. However, we found genome-wide significant SNPs intronic to an apoptosis-enhancing gene previously associated with QRS interval duration (FAF1; lead SNP rs7545860; effect allele frequency = 0.02; P = 2.0 × 10) in multi-trait analysis among European ancestry participants and near a locus encoding calcium-dependent glycoproteins (DSC3; lead SNP rs8086068; effect allele frequency = 0.17) in meta-analysis of SVE (P = 4.0 × 10) and multi-trait analysis (P = 2.9 × 10) among African ancestry participants. The novel findings suggest several mechanisms by which genetic variation may predispose to ectopy in humans and highlight the potential value of leveraging pleiotropy in future studies of ectopy-related phenotypes.

VL - 8 IS - 1 ER - TY - JOUR T1 - GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes. JF - Nat Commun Y1 - 2018 A1 - Franceschini, Nora A1 - Giambartolomei, Claudia A1 - de Vries, Paul S A1 - Finan, Chris A1 - Bis, Joshua C A1 - Huntley, Rachael P A1 - Lovering, Ruth C A1 - Tajuddin, Salman M A1 - Winkler, Thomas W A1 - Graff, Misa A1 - Kavousi, Maryam A1 - Dale, Caroline A1 - Smith, Albert V A1 - Hofer, Edith A1 - van Leeuwen, Elisabeth M A1 - Nolte, Ilja M A1 - Lu, Lingyi A1 - Scholz, Markus A1 - Sargurupremraj, Muralidharan A1 - Pitkänen, Niina A1 - Franzén, Oscar A1 - Joshi, Peter K A1 - Noordam, Raymond A1 - Marioni, Riccardo E A1 - Hwang, Shih-Jen A1 - Musani, Solomon K A1 - Schminke, Ulf A1 - Palmas, Walter A1 - Isaacs, Aaron A1 - Correa, Adolfo A1 - Zonderman, Alan B A1 - Hofman, Albert A1 - Teumer, Alexander A1 - Cox, Amanda J A1 - Uitterlinden, André G A1 - Wong, Andrew A1 - Smit, Andries J A1 - Newman, Anne B A1 - Britton, Annie A1 - Ruusalepp, Arno A1 - Sennblad, Bengt A1 - Hedblad, Bo A1 - Pasaniuc, Bogdan A1 - Penninx, Brenda W A1 - Langefeld, Carl D A1 - Wassel, Christina L A1 - Tzourio, Christophe A1 - Fava, Cristiano A1 - Baldassarre, Damiano A1 - O'Leary, Daniel H A1 - Teupser, Daniel A1 - Kuh, Diana A1 - Tremoli, Elena A1 - Mannarino, Elmo A1 - Grossi, Enzo A1 - Boerwinkle, Eric A1 - Schadt, Eric E A1 - Ingelsson, Erik A1 - Veglia, Fabrizio A1 - Rivadeneira, Fernando A1 - Beutner, Frank A1 - Chauhan, Ganesh A1 - Heiss, Gerardo A1 - Snieder, Harold A1 - Campbell, Harry A1 - Völzke, Henry A1 - Markus, Hugh S A1 - Deary, Ian J A1 - Jukema, J Wouter A1 - de Graaf, Jacqueline A1 - Price, Jacqueline A1 - Pott, Janne A1 - Hopewell, Jemma C A1 - Liang, Jingjing A1 - Thiery, Joachim A1 - Engmann, Jorgen A1 - Gertow, Karl A1 - Rice, Kenneth A1 - Taylor, Kent D A1 - Dhana, Klodian A1 - Kiemeney, Lambertus A L M A1 - Lind, Lars A1 - Raffield, Laura M A1 - Launer, Lenore J A1 - Holdt, Lesca M A1 - Dörr, Marcus A1 - Dichgans, Martin A1 - Traylor, Matthew A1 - Sitzer, Matthias A1 - Kumari, Meena A1 - Kivimaki, Mika A1 - Nalls, Mike A A1 - Melander, Olle A1 - Raitakari, Olli A1 - Franco, Oscar H A1 - Rueda-Ochoa, Oscar L A1 - Roussos, Panos A1 - Whincup, Peter H A1 - Amouyel, Philippe A1 - Giral, Philippe A1 - Anugu, Pramod A1 - Wong, Quenna A1 - Malik, Rainer A1 - Rauramaa, Rainer A1 - Burkhardt, Ralph A1 - Hardy, Rebecca A1 - Schmidt, Reinhold A1 - de Mutsert, Renée A1 - Morris, Richard W A1 - Strawbridge, Rona J A1 - Wannamethee, S Goya A1 - Hägg, Sara A1 - Shah, Sonia A1 - McLachlan, Stela A1 - Trompet, Stella A1 - Seshadri, Sudha A1 - Kurl, Sudhir A1 - Heckbert, Susan R A1 - Ring, Susan A1 - Harris, Tamara B A1 - Lehtimäki, Terho A1 - Galesloot, Tessel E A1 - Shah, Tina A1 - de Faire, Ulf A1 - Plagnol, Vincent A1 - Rosamond, Wayne D A1 - Post, Wendy A1 - Zhu, Xiaofeng A1 - Zhang, Xiaoling A1 - Guo, Xiuqing A1 - Saba, Yasaman A1 - Dehghan, Abbas A1 - Seldenrijk, Adrie A1 - Morrison, Alanna C A1 - Hamsten, Anders A1 - Psaty, Bruce M A1 - van Duijn, Cornelia M A1 - Lawlor, Deborah A A1 - Mook-Kanamori, Dennis O A1 - Bowden, Donald W A1 - Schmidt, Helena A1 - Wilson, James F A1 - Wilson, James G A1 - Rotter, Jerome I A1 - Wardlaw, Joanna M A1 - Deanfield, John A1 - Halcox, Julian A1 - Lyytikäinen, Leo-Pekka A1 - Loeffler, Markus A1 - Evans, Michele K A1 - Debette, Stephanie A1 - Humphries, Steve E A1 - Völker, Uwe A1 - Gudnason, Vilmundur A1 - Hingorani, Aroon D A1 - Björkegren, Johan L M A1 - Casas, Juan P A1 - O'Donnell, Christopher J KW - ADAMTS9 Protein KW - Amino Acid Oxidoreductases KW - Carotid Intima-Media Thickness KW - Coronary Disease KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Lod Score KW - Plaque, Atherosclerotic KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci KW - Risk Factors AB -

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

VL - 9 IS - 1 ER - TY - JOUR T1 - A Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure. JF - Am J Hum Genet Y1 - 2018 A1 - Sung, Yun J A1 - Winkler, Thomas W A1 - de Las Fuentes, Lisa A1 - Bentley, Amy R A1 - Brown, Michael R A1 - Kraja, Aldi T A1 - Schwander, Karen A1 - Ntalla, Ioanna A1 - Guo, Xiuqing A1 - Franceschini, Nora A1 - Lu, Yingchang A1 - Cheng, Ching-Yu A1 - Sim, Xueling A1 - Vojinovic, Dina A1 - Marten, Jonathan A1 - Musani, Solomon K A1 - Li, Changwei A1 - Feitosa, Mary F A1 - Kilpeläinen, Tuomas O A1 - Richard, Melissa A A1 - Noordam, Raymond A1 - Aslibekyan, Stella A1 - Aschard, Hugues A1 - Bartz, Traci M A1 - Dorajoo, Rajkumar A1 - Liu, Yongmei A1 - Manning, Alisa K A1 - Rankinen, Tuomo A1 - Smith, Albert Vernon A1 - Tajuddin, Salman M A1 - Tayo, Bamidele O A1 - Warren, Helen R A1 - Zhao, Wei A1 - Zhou, Yanhua A1 - Matoba, Nana A1 - Sofer, Tamar A1 - Alver, Maris A1 - Amini, Marzyeh A1 - Boissel, Mathilde A1 - Chai, Jin Fang A1 - Chen, Xu A1 - Divers, Jasmin A1 - Gandin, Ilaria A1 - Gao, Chuan A1 - Giulianini, Franco A1 - Goel, Anuj A1 - Harris, Sarah E A1 - Hartwig, Fernando Pires A1 - Horimoto, Andrea R V R A1 - Hsu, Fang-Chi A1 - Jackson, Anne U A1 - Kähönen, Mika A1 - Kasturiratne, Anuradhani A1 - Kuhnel, Brigitte A1 - Leander, Karin A1 - Lee, Wen-Jane A1 - Lin, Keng-Hung A1 - 'an Luan, Jian A1 - McKenzie, Colin A A1 - Meian, He A1 - Nelson, Christopher P A1 - Rauramaa, Rainer A1 - Schupf, Nicole A1 - Scott, Robert A A1 - Sheu, Wayne H H A1 - Stančáková, Alena A1 - Takeuchi, Fumihiko A1 - van der Most, Peter J A1 - Varga, Tibor V A1 - Wang, Heming A1 - Wang, Yajuan A1 - Ware, Erin B A1 - Weiss, Stefan A1 - Wen, Wanqing A1 - Yanek, Lisa R A1 - Zhang, Weihua A1 - Zhao, Jing Hua A1 - Afaq, Saima A1 - Alfred, Tamuno A1 - Amin, Najaf A1 - Arking, Dan A1 - Aung, Tin A1 - Barr, R Graham A1 - Bielak, Lawrence F A1 - Boerwinkle, Eric A1 - Bottinger, Erwin P A1 - Braund, Peter S A1 - Brody, Jennifer A A1 - Broeckel, Ulrich A1 - Cabrera, Claudia P A1 - Cade, Brian A1 - Caizheng, Yu A1 - Campbell, Archie A1 - Canouil, Mickaël A1 - Chakravarti, Aravinda A1 - Chauhan, Ganesh A1 - Christensen, Kaare A1 - Cocca, Massimiliano A1 - Collins, Francis S A1 - Connell, John M A1 - de Mutsert, Renée A1 - de Silva, H Janaka A1 - Debette, Stephanie A1 - Dörr, Marcus A1 - Duan, Qing A1 - Eaton, Charles B A1 - Ehret, Georg A1 - Evangelou, Evangelos A1 - Faul, Jessica D A1 - Fisher, Virginia A A1 - Forouhi, Nita G A1 - Franco, Oscar H A1 - Friedlander, Yechiel A1 - Gao, He A1 - Gigante, Bruna A1 - Graff, Misa A1 - Gu, C Charles A1 - Gu, Dongfeng A1 - Gupta, Preeti A1 - Hagenaars, Saskia P A1 - Harris, Tamara B A1 - He, Jiang A1 - Heikkinen, Sami A1 - Heng, Chew-Kiat A1 - Hirata, Makoto A1 - Hofman, Albert A1 - Howard, Barbara V A1 - Hunt, Steven A1 - Irvin, Marguerite R A1 - Jia, Yucheng A1 - Joehanes, Roby A1 - Justice, Anne E A1 - Katsuya, Tomohiro A1 - Kaufman, Joel A1 - Kerrison, Nicola D A1 - Khor, Chiea Chuen A1 - Koh, Woon-Puay A1 - Koistinen, Heikki A A1 - Komulainen, Pirjo A1 - Kooperberg, Charles A1 - Krieger, Jose E A1 - Kubo, Michiaki A1 - Kuusisto, Johanna A1 - Langefeld, Carl D A1 - Langenberg, Claudia A1 - Launer, Lenore J A1 - Lehne, Benjamin A1 - Lewis, Cora E A1 - Li, Yize A1 - Lim, Sing Hui A1 - Lin, Shiow A1 - Liu, Ching-Ti A1 - Liu, Jianjun A1 - Liu, Jingmin A1 - Liu, Kiang A1 - Liu, Yeheng A1 - Loh, Marie A1 - Lohman, Kurt K A1 - Long, Jirong A1 - Louie, Tin A1 - Mägi, Reedik A1 - Mahajan, Anubha A1 - Meitinger, Thomas A1 - Metspalu, Andres A1 - Milani, Lili A1 - Momozawa, Yukihide A1 - Morris, Andrew P A1 - Mosley, Thomas H A1 - Munson, Peter A1 - Murray, Alison D A1 - Nalls, Mike A A1 - Nasri, Ubaydah A1 - Norris, Jill M A1 - North, Kari A1 - Ogunniyi, Adesola A1 - Padmanabhan, Sandosh A1 - Palmas, Walter R A1 - Palmer, Nicholette D A1 - Pankow, James S A1 - Pedersen, Nancy L A1 - Peters, Annette A1 - Peyser, Patricia A A1 - Polasek, Ozren A1 - Raitakari, Olli T A1 - Renstrom, Frida A1 - Rice, Treva K A1 - Ridker, Paul M A1 - Robino, Antonietta A1 - Robinson, Jennifer G A1 - Rose, Lynda M A1 - Rudan, Igor A1 - Sabanayagam, Charumathi A1 - Salako, Babatunde L A1 - Sandow, Kevin A1 - Schmidt, Carsten O A1 - Schreiner, Pamela J A1 - Scott, William R A1 - Seshadri, Sudha A1 - Sever, Peter A1 - Sitlani, Colleen M A1 - Smith, Jennifer A A1 - Snieder, Harold A1 - Starr, John M A1 - Strauch, Konstantin A1 - Tang, Hua A1 - Taylor, Kent D A1 - Teo, Yik Ying A1 - Tham, Yih Chung A1 - Uitterlinden, André G A1 - Waldenberger, Melanie A1 - Wang, Lihua A1 - Wang, Ya X A1 - Wei, Wen Bin A1 - Williams, Christine A1 - Wilson, Gregory A1 - Wojczynski, Mary K A1 - Yao, Jie A1 - Yuan, Jian-Min A1 - Zonderman, Alan B A1 - Becker, Diane M A1 - Boehnke, Michael A1 - Bowden, Donald W A1 - Chambers, John C A1 - Chen, Yii-Der Ida A1 - de Faire, Ulf A1 - Deary, Ian J A1 - Esko, Tõnu A1 - Farrall, Martin A1 - Forrester, Terrence A1 - Franks, Paul W A1 - Freedman, Barry I A1 - Froguel, Philippe A1 - Gasparini, Paolo A1 - Gieger, Christian A1 - Horta, Bernardo Lessa A1 - Hung, Yi-Jen A1 - Jonas, Jost B A1 - Kato, Norihiro A1 - Kooner, Jaspal S A1 - Laakso, Markku A1 - Lehtimäki, Terho A1 - Liang, Kae-Woei A1 - Magnusson, Patrik K E A1 - Newman, Anne B A1 - Oldehinkel, Albertine J A1 - Pereira, Alexandre C A1 - Redline, Susan A1 - Rettig, Rainer A1 - Samani, Nilesh J A1 - Scott, James A1 - Shu, Xiao-Ou A1 - van der Harst, Pim A1 - Wagenknecht, Lynne E A1 - Wareham, Nicholas J A1 - Watkins, Hugh A1 - Weir, David R A1 - Wickremasinghe, Ananda R A1 - Wu, Tangchun A1 - Zheng, Wei A1 - Kamatani, Yoichiro A1 - Laurie, Cathy C A1 - Bouchard, Claude A1 - Cooper, Richard S A1 - Evans, Michele K A1 - Gudnason, Vilmundur A1 - Kardia, Sharon L R A1 - Kritchevsky, Stephen B A1 - Levy, Daniel A1 - O'Connell, Jeff R A1 - Psaty, Bruce M A1 - van Dam, Rob M A1 - Sims, Mario A1 - Arnett, Donna K A1 - Mook-Kanamori, Dennis O A1 - Kelly, Tanika N A1 - Fox, Ervin R A1 - Hayward, Caroline A1 - Fornage, Myriam A1 - Rotimi, Charles N A1 - Province, Michael A A1 - van Duijn, Cornelia M A1 - Tai, E Shyong A1 - Wong, Tien Yin A1 - Loos, Ruth J F A1 - Reiner, Alex P A1 - Rotter, Jerome I A1 - Zhu, Xiaofeng A1 - Bierut, Laura J A1 - Gauderman, W James A1 - Caulfield, Mark J A1 - Elliott, Paul A1 - Rice, Kenneth A1 - Munroe, Patricia B A1 - Morrison, Alanna C A1 - Cupples, L Adrienne A1 - Rao, Dabeeru C A1 - Chasman, Daniel I AB -

Genome-wide association analysis advanced understanding of blood pressure (BP), a major risk factor for vascular conditions such as coronary heart disease and stroke. Accounting for smoking behavior may help identify BP loci and extend our knowledge of its genetic architecture. We performed genome-wide association meta-analyses of systolic and diastolic BP incorporating gene-smoking interactions in 610,091 individuals. Stage 1 analysis examined ∼18.8 million SNPs and small insertion/deletion variants in 129,913 individuals from four ancestries (European, African, Asian, and Hispanic) with follow-up analysis of promising variants in 480,178 additional individuals from five ancestries. We identified 15 loci that were genome-wide significant (p < 5 × 10) in stage 1 and formally replicated in stage 2. A combined stage 1 and 2 meta-analysis identified 66 additional genome-wide significant loci (13, 35, and 18 loci in European, African, and trans-ancestry, respectively). A total of 56 known BP loci were also identified by our results (p < 5 × 10). Of the newly identified loci, ten showed significant interaction with smoking status, but none of them were replicated in stage 2. Several loci were identified in African ancestry, highlighting the importance of genetic studies in diverse populations. The identified loci show strong evidence for regulatory features and support shared pathophysiology with cardiometabolic and addiction traits. They also highlight a role in BP regulation for biological candidates such as modulators of vascular structure and function (CDKN1B, BCAR1-CFDP1, PXDN, EEA1), ciliopathies (SDCCAG8, RPGRIP1L), telomere maintenance (TNKS, PINX1, AKTIP), and central dopaminergic signaling (MSRA, EBF2).

VL - 102 IS - 3 ER - TY - JOUR T1 - Meta-analysis of exome array data identifies six novel genetic loci for lung function. JF - Wellcome Open Res Y1 - 2018 A1 - Jackson, Victoria E A1 - Latourelle, Jeanne C A1 - Wain, Louise V A1 - Smith, Albert V A1 - Grove, Megan L A1 - Bartz, Traci M A1 - Obeidat, Ma'en A1 - Province, Michael A A1 - Gao, Wei A1 - Qaiser, Beenish A1 - Porteous, David J A1 - Cassano, Patricia A A1 - Ahluwalia, Tarunveer S A1 - Grarup, Niels A1 - Li, Jin A1 - Altmaier, Elisabeth A1 - Marten, Jonathan A1 - Harris, Sarah E A1 - Manichaikul, Ani A1 - Pottinger, Tess D A1 - Li-Gao, Ruifang A1 - Lind-Thomsen, Allan A1 - Mahajan, Anubha A1 - Lahousse, Lies A1 - Imboden, Medea A1 - Teumer, Alexander A1 - Prins, Bram A1 - Lyytikäinen, Leo-Pekka A1 - Eiriksdottir, Gudny A1 - Franceschini, Nora A1 - Sitlani, Colleen M A1 - Brody, Jennifer A A1 - Bossé, Yohan A1 - Timens, Wim A1 - Kraja, Aldi A1 - Loukola, Anu A1 - Tang, Wenbo A1 - Liu, Yongmei A1 - Bork-Jensen, Jette A1 - Justesen, Johanne M A1 - Linneberg, Allan A1 - Lange, Leslie A A1 - Rawal, Rajesh A1 - Karrasch, Stefan A1 - Huffman, Jennifer E A1 - Smith, Blair H A1 - Davies, Gail A1 - Burkart, Kristin M A1 - Mychaleckyj, Josyf C A1 - Bonten, Tobias N A1 - Enroth, Stefan A1 - Lind, Lars A1 - Brusselle, Guy G A1 - Kumar, Ashish A1 - Stubbe, Beate A1 - Kähönen, Mika A1 - Wyss, Annah B A1 - Psaty, Bruce M A1 - Heckbert, Susan R A1 - Hao, Ke A1 - Rantanen, Taina A1 - Kritchevsky, Stephen B A1 - Lohman, Kurt A1 - Skaaby, Tea A1 - Pisinger, Charlotta A1 - Hansen, Torben A1 - Schulz, Holger A1 - Polasek, Ozren A1 - Campbell, Archie A1 - Starr, John M A1 - Rich, Stephen S A1 - Mook-Kanamori, Dennis O A1 - Johansson, Asa A1 - Ingelsson, Erik A1 - Uitterlinden, André G A1 - Weiss, Stefan A1 - Raitakari, Olli T A1 - Gudnason, Vilmundur A1 - North, Kari E A1 - Gharib, Sina A A1 - Sin, Don D A1 - Taylor, Kent D A1 - O'Connor, George T A1 - Kaprio, Jaakko A1 - Harris, Tamara B A1 - Pederson, Oluf A1 - Vestergaard, Henrik A1 - Wilson, James G A1 - Strauch, Konstantin A1 - Hayward, Caroline A1 - Kerr, Shona A1 - Deary, Ian J A1 - Barr, R Graham A1 - de Mutsert, Renée A1 - Gyllensten, Ulf A1 - Morris, Andrew P A1 - Ikram, M Arfan A1 - Probst-Hensch, Nicole A1 - Gläser, Sven A1 - Zeggini, Eleftheria A1 - Lehtimäki, Terho A1 - Strachan, David P A1 - Dupuis, Josée A1 - Morrison, Alanna C A1 - Hall, Ian P A1 - Tobin, Martin D A1 - London, Stephanie J AB -

Over 90 regions of the genome have been associated with lung function to date, many of which have also been implicated in chronic obstructive pulmonary disease. We carried out meta-analyses of exome array data and three lung function measures: forced expiratory volume in one second (FEV ), forced vital capacity (FVC) and the ratio of FEV to FVC (FEV /FVC). These analyses by the SpiroMeta and CHARGE consortia included 60,749 individuals of European ancestry from 23 studies, and 7,721 individuals of African Ancestry from 5 studies in the discovery stage, with follow-up in up to 111,556 independent individuals. We identified significant (P<2·8x10 ) associations with six SNPs: a nonsynonymous variant in , which is predicted to be damaging, three intronic SNPs ( and ) and two intergenic SNPs near to and Expression quantitative trait loci analyses found evidence for regulation of gene expression at three signals and implicated several genes, including and . Further interrogation of these loci could provide greater understanding of the determinants of lung function and pulmonary disease.

VL - 3 ER - TY - JOUR T1 - Multiethnic meta-analysis identifies ancestry-specific and cross-ancestry loci for pulmonary function. JF - Nat Commun Y1 - 2018 A1 - Wyss, Annah B A1 - Sofer, Tamar A1 - Lee, Mi Kyeong A1 - Terzikhan, Natalie A1 - Nguyen, Jennifer N A1 - Lahousse, Lies A1 - Latourelle, Jeanne C A1 - Smith, Albert Vernon A1 - Bartz, Traci M A1 - Feitosa, Mary F A1 - Gao, Wei A1 - Ahluwalia, Tarunveer S A1 - Tang, Wenbo A1 - Oldmeadow, Christopher A1 - Duan, Qing A1 - de Jong, Kim A1 - Wojczynski, Mary K A1 - Wang, Xin-Qun A1 - Noordam, Raymond A1 - Hartwig, Fernando Pires A1 - Jackson, Victoria E A1 - Wang, Tianyuan A1 - Obeidat, Ma'en A1 - Hobbs, Brian D A1 - Huan, Tianxiao A1 - Gui, Hongsheng A1 - Parker, Margaret M A1 - Hu, Donglei A1 - Mogil, Lauren S A1 - Kichaev, Gleb A1 - Jin, Jianping A1 - Graff, Mariaelisa A1 - Harris, Tamara B A1 - Kalhan, Ravi A1 - Heckbert, Susan R A1 - Paternoster, Lavinia A1 - Burkart, Kristin M A1 - Liu, Yongmei A1 - Holliday, Elizabeth G A1 - Wilson, James G A1 - Vonk, Judith M A1 - Sanders, Jason L A1 - Barr, R Graham A1 - de Mutsert, Renée A1 - Menezes, Ana Maria Baptista A1 - Adams, Hieab H H A1 - van den Berge, Maarten A1 - Joehanes, Roby A1 - Levin, Albert M A1 - Liberto, Jennifer A1 - Launer, Lenore J A1 - Morrison, Alanna C A1 - Sitlani, Colleen M A1 - Celedón, Juan C A1 - Kritchevsky, Stephen B A1 - Scott, Rodney J A1 - Christensen, Kaare A1 - Rotter, Jerome I A1 - Bonten, Tobias N A1 - Wehrmeister, Fernando César A1 - Bossé, Yohan A1 - Xiao, Shujie A1 - Oh, Sam A1 - Franceschini, Nora A1 - Brody, Jennifer A A1 - Kaplan, Robert C A1 - Lohman, Kurt A1 - McEvoy, Mark A1 - Province, Michael A A1 - Rosendaal, Frits R A1 - Taylor, Kent D A1 - Nickle, David C A1 - Williams, L Keoki A1 - Burchard, Esteban G A1 - Wheeler, Heather E A1 - Sin, Don D A1 - Gudnason, Vilmundur A1 - North, Kari E A1 - Fornage, Myriam A1 - Psaty, Bruce M A1 - Myers, Richard H A1 - O'Connor, George A1 - Hansen, Torben A1 - Laurie, Cathy C A1 - Cassano, Patricia A A1 - Sung, Joohon A1 - Kim, Woo Jin A1 - Attia, John R A1 - Lange, Leslie A1 - Boezen, H Marike A1 - Thyagarajan, Bharat A1 - Rich, Stephen S A1 - Mook-Kanamori, Dennis O A1 - Horta, Bernardo Lessa A1 - Uitterlinden, André G A1 - Im, Hae Kyung A1 - Cho, Michael H A1 - Brusselle, Guy G A1 - Gharib, Sina A A1 - Dupuis, Josée A1 - Manichaikul, Ani A1 - London, Stephanie J AB -

Nearly 100 loci have been identified for pulmonary function, almost exclusively in studies of European ancestry populations. We extend previous research by meta-analyzing genome-wide association studies of 1000 Genomes imputed variants in relation to pulmonary function in a multiethnic population of 90,715 individuals of European (N = 60,552), African (N = 8429), Asian (N = 9959), and Hispanic/Latino (N = 11,775) ethnicities. We identify over 50 additional loci at genome-wide significance in ancestry-specific or multiethnic meta-analyses. Using recent fine-mapping methods incorporating functional annotation, gene expression, and differences in linkage disequilibrium between ethnicities, we further shed light on potential causal variants and genes at known and newly identified loci. Several of the novel genes encode proteins with predicted or established drug targets, including KCNK2 and CDK12. Our study highlights the utility of multiethnic and integrative genomics approaches to extend existing knowledge of the genetics of lung function and clinical relevance of implicated loci.

VL - 9 IS - 1 ER - TY - JOUR T1 - Novel genetic associations for blood pressure identified via gene-alcohol interaction in up to 570K individuals across multiple ancestries. JF - PLoS One Y1 - 2018 A1 - Feitosa, Mary F A1 - Kraja, Aldi T A1 - Chasman, Daniel I A1 - Sung, Yun J A1 - Winkler, Thomas W A1 - Ntalla, Ioanna A1 - Guo, Xiuqing A1 - Franceschini, Nora A1 - Cheng, Ching-Yu A1 - Sim, Xueling A1 - Vojinovic, Dina A1 - Marten, Jonathan A1 - Musani, Solomon K A1 - Li, Changwei A1 - Bentley, Amy R A1 - Brown, Michael R A1 - Schwander, Karen A1 - Richard, Melissa A A1 - Noordam, Raymond A1 - Aschard, Hugues A1 - Bartz, Traci M A1 - Bielak, Lawrence F A1 - Dorajoo, Rajkumar A1 - Fisher, Virginia A1 - Hartwig, Fernando P A1 - Horimoto, Andrea R V R A1 - Lohman, Kurt K A1 - Manning, Alisa K A1 - Rankinen, Tuomo A1 - Smith, Albert V A1 - Tajuddin, Salman M A1 - Wojczynski, Mary K A1 - Alver, Maris A1 - Boissel, Mathilde A1 - Cai, Qiuyin A1 - Campbell, Archie A1 - Chai, Jin Fang A1 - Chen, Xu A1 - Divers, Jasmin A1 - Gao, Chuan A1 - Goel, Anuj A1 - Hagemeijer, Yanick A1 - Harris, Sarah E A1 - He, Meian A1 - Hsu, Fang-Chi A1 - Jackson, Anne U A1 - Kähönen, Mika A1 - Kasturiratne, Anuradhani A1 - Komulainen, Pirjo A1 - Kuhnel, Brigitte A1 - Laguzzi, Federica A1 - Luan, Jian'an A1 - Matoba, Nana A1 - Nolte, Ilja M A1 - Padmanabhan, Sandosh A1 - Riaz, Muhammad A1 - Rueedi, Rico A1 - Robino, Antonietta A1 - Said, M Abdullah A1 - Scott, Robert A A1 - Sofer, Tamar A1 - Stančáková, Alena A1 - Takeuchi, Fumihiko A1 - Tayo, Bamidele O A1 - van der Most, Peter J A1 - Varga, Tibor V A1 - Vitart, Veronique A1 - Wang, Yajuan A1 - Ware, Erin B A1 - Warren, Helen R A1 - Weiss, Stefan A1 - Wen, Wanqing A1 - Yanek, Lisa R A1 - Zhang, Weihua A1 - Zhao, Jing Hua A1 - Afaq, Saima A1 - Amin, Najaf A1 - Amini, Marzyeh A1 - Arking, Dan E A1 - Aung, Tin A1 - Boerwinkle, Eric A1 - Borecki, Ingrid A1 - Broeckel, Ulrich A1 - Brown, Morris A1 - Brumat, Marco A1 - Burke, Gregory L A1 - Canouil, Mickaël A1 - Chakravarti, Aravinda A1 - Charumathi, Sabanayagam A1 - Ida Chen, Yii-Der A1 - Connell, John M A1 - Correa, Adolfo A1 - de Las Fuentes, Lisa A1 - de Mutsert, Renée A1 - de Silva, H Janaka A1 - Deng, Xuan A1 - Ding, Jingzhong A1 - Duan, Qing A1 - Eaton, Charles B A1 - Ehret, Georg A1 - Eppinga, Ruben N A1 - Evangelou, Evangelos A1 - Faul, Jessica D A1 - Felix, Stephan B A1 - Forouhi, Nita G A1 - Forrester, Terrence A1 - Franco, Oscar H A1 - Friedlander, Yechiel A1 - Gandin, Ilaria A1 - Gao, He A1 - Ghanbari, Mohsen A1 - Gigante, Bruna A1 - Gu, C Charles A1 - Gu, Dongfeng A1 - Hagenaars, Saskia P A1 - Hallmans, Göran A1 - Harris, Tamara B A1 - He, Jiang A1 - Heikkinen, Sami A1 - Heng, Chew-Kiat A1 - Hirata, Makoto A1 - Howard, Barbara V A1 - Ikram, M Arfan A1 - John, Ulrich A1 - Katsuya, Tomohiro A1 - Khor, Chiea Chuen A1 - Kilpeläinen, Tuomas O A1 - Koh, Woon-Puay A1 - Krieger, Jose E A1 - Kritchevsky, Stephen B A1 - Kubo, Michiaki A1 - Kuusisto, Johanna A1 - Lakka, Timo A A1 - Langefeld, Carl D A1 - Langenberg, Claudia A1 - Launer, Lenore J A1 - Lehne, Benjamin A1 - Lewis, Cora E A1 - Li, Yize A1 - Lin, Shiow A1 - Liu, Jianjun A1 - Liu, Jingmin A1 - Loh, Marie A1 - Louie, Tin A1 - Mägi, Reedik A1 - McKenzie, Colin A A1 - Meitinger, Thomas A1 - Metspalu, Andres A1 - Milaneschi, Yuri A1 - Milani, Lili A1 - Mohlke, Karen L A1 - Momozawa, Yukihide A1 - Nalls, Mike A A1 - Nelson, Christopher P A1 - Sotoodehnia, Nona A1 - Norris, Jill M A1 - O'Connell, Jeff R A1 - Palmer, Nicholette D A1 - Perls, Thomas A1 - Pedersen, Nancy L A1 - Peters, Annette A1 - Peyser, Patricia A A1 - Poulter, Neil A1 - Raffel, Leslie J A1 - Raitakari, Olli T A1 - Roll, Kathryn A1 - Rose, Lynda M A1 - Rosendaal, Frits R A1 - Rotter, Jerome I A1 - Schmidt, Carsten O A1 - Schreiner, Pamela J A1 - Schupf, Nicole A1 - Scott, William R A1 - Sever, Peter S A1 - Shi, Yuan A1 - Sidney, Stephen A1 - Sims, Mario A1 - Sitlani, Colleen M A1 - Smith, Jennifer A A1 - Snieder, Harold A1 - Starr, John M A1 - Strauch, Konstantin A1 - Stringham, Heather M A1 - Tan, Nicholas Y Q A1 - Tang, Hua A1 - Taylor, Kent D A1 - Teo, Yik Ying A1 - Tham, Yih Chung A1 - Turner, Stephen T A1 - Uitterlinden, André G A1 - Vollenweider, Peter A1 - Waldenberger, Melanie A1 - Wang, Lihua A1 - Wang, Ya Xing A1 - Wei, Wen Bin A1 - Williams, Christine A1 - Yao, Jie A1 - Yu, Caizheng A1 - Yuan, Jian-Min A1 - Zhao, Wei A1 - Zonderman, Alan B A1 - Becker, Diane M A1 - Boehnke, Michael A1 - Bowden, Donald W A1 - Chambers, John C A1 - Deary, Ian J A1 - Esko, Tõnu A1 - Farrall, Martin A1 - Franks, Paul W A1 - Freedman, Barry I A1 - Froguel, Philippe A1 - Gasparini, Paolo A1 - Gieger, Christian A1 - Jonas, Jost Bruno A1 - Kamatani, Yoichiro A1 - Kato, Norihiro A1 - Kooner, Jaspal S A1 - Kutalik, Zoltán A1 - Laakso, Markku A1 - Laurie, Cathy C A1 - Leander, Karin A1 - Lehtimäki, Terho A1 - Study, Lifelines Cohort A1 - Magnusson, Patrik K E A1 - Oldehinkel, Albertine J A1 - Penninx, Brenda W J H A1 - Polasek, Ozren A1 - Porteous, David J A1 - Rauramaa, Rainer A1 - Samani, Nilesh J A1 - Scott, James A1 - Shu, Xiao-Ou A1 - van der Harst, Pim A1 - Wagenknecht, Lynne E A1 - Wareham, Nicholas J A1 - Watkins, Hugh A1 - Weir, David R A1 - Wickremasinghe, Ananda R A1 - Wu, Tangchun A1 - Zheng, Wei A1 - Bouchard, Claude A1 - Christensen, Kaare A1 - Evans, Michele K A1 - Gudnason, Vilmundur A1 - Horta, Bernardo L A1 - Kardia, Sharon L R A1 - Liu, Yongmei A1 - Pereira, Alexandre C A1 - Psaty, Bruce M A1 - Ridker, Paul M A1 - van Dam, Rob M A1 - Gauderman, W James A1 - Zhu, Xiaofeng A1 - Mook-Kanamori, Dennis O A1 - Fornage, Myriam A1 - Rotimi, Charles N A1 - Cupples, L Adrienne A1 - Kelly, Tanika N A1 - Fox, Ervin R A1 - Hayward, Caroline A1 - van Duijn, Cornelia M A1 - Tai, E Shyong A1 - Wong, Tien Yin A1 - Kooperberg, Charles A1 - Palmas, Walter A1 - Rice, Kenneth A1 - Morrison, Alanna C A1 - Elliott, Paul A1 - Caulfield, Mark J A1 - Munroe, Patricia B A1 - Rao, Dabeeru C A1 - Province, Michael A A1 - Levy, Daniel AB -

Heavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in ≈131K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P < 1.0 x 10-5). In Stage 2, these SNVs were tested for independent external replication in ≈440K individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2,159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 x 10-8). For African ancestry samples, we detected 18 potentially novel BP loci (P < 5.0 x 10-8) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2) have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension.

VL - 13 IS - 6 ER - TY - JOUR T1 - Associations of autozygosity with a broad range of human phenotypes. JF - Nat Commun Y1 - 2019 A1 - Clark, David W A1 - Okada, Yukinori A1 - Moore, Kristjan H S A1 - Mason, Dan A1 - Pirastu, Nicola A1 - Gandin, Ilaria A1 - Mattsson, Hannele A1 - Barnes, Catriona L K A1 - Lin, Kuang A1 - Zhao, Jing Hua A1 - Deelen, Patrick A1 - Rohde, Rebecca A1 - Schurmann, Claudia A1 - Guo, Xiuqing A1 - Giulianini, Franco A1 - Zhang, Weihua A1 - Medina-Gómez, Carolina A1 - Karlsson, Robert A1 - Bao, Yanchun A1 - Bartz, Traci M A1 - Baumbach, Clemens A1 - Biino, Ginevra A1 - Bixley, Matthew J A1 - Brumat, Marco A1 - Chai, Jin-Fang A1 - Corre, Tanguy A1 - Cousminer, Diana L A1 - Dekker, Annelot M A1 - Eccles, David A A1 - van Eijk, Kristel R A1 - Fuchsberger, Christian A1 - Gao, He A1 - Germain, Marine A1 - Gordon, Scott D A1 - de Haan, Hugoline G A1 - Harris, Sarah E A1 - Hofer, Edith A1 - Huerta-Chagoya, Alicia A1 - Igartua, Catherine A1 - Jansen, Iris E A1 - Jia, Yucheng A1 - Kacprowski, Tim A1 - Karlsson, Torgny A1 - Kleber, Marcus E A1 - Li, Shengchao Alfred A1 - Li-Gao, Ruifang A1 - Mahajan, Anubha A1 - Matsuda, Koichi A1 - Meidtner, Karina A1 - Meng, Weihua A1 - Montasser, May E A1 - van der Most, Peter J A1 - Munz, Matthias A1 - Nutile, Teresa A1 - Palviainen, Teemu A1 - Prasad, Gauri A1 - Prasad, Rashmi B A1 - Priyanka, Tallapragada Divya Sri A1 - Rizzi, Federica A1 - Salvi, Erika A1 - Sapkota, Bishwa R A1 - Shriner, Daniel A1 - Skotte, Line A1 - Smart, Melissa C A1 - Smith, Albert Vernon A1 - van der Spek, Ashley A1 - Spracklen, Cassandra N A1 - Strawbridge, Rona J A1 - Tajuddin, Salman M A1 - Trompet, Stella A1 - Turman, Constance A1 - Verweij, Niek A1 - Viberti, Clara A1 - Wang, Lihua A1 - Warren, Helen R A1 - Wootton, Robyn E A1 - Yanek, Lisa R A1 - Yao, Jie A1 - Yousri, Noha A A1 - Zhao, Wei A1 - Adeyemo, Adebowale A A1 - Afaq, Saima A1 - Aguilar-Salinas, Carlos Alberto A1 - Akiyama, Masato A1 - Albert, Matthew L A1 - Allison, Matthew A A1 - Alver, Maris A1 - Aung, Tin A1 - Azizi, Fereidoun A1 - Bentley, Amy R A1 - Boeing, Heiner A1 - Boerwinkle, Eric A1 - Borja, Judith B A1 - de Borst, Gert J A1 - Bottinger, Erwin P A1 - Broer, Linda A1 - Campbell, Harry A1 - Chanock, Stephen A1 - Chee, Miao-Li A1 - Chen, Guanjie A1 - Chen, Yii-der I A1 - Chen, Zhengming A1 - Chiu, Yen-Feng A1 - Cocca, Massimiliano A1 - Collins, Francis S A1 - Concas, Maria Pina A1 - Corley, Janie A1 - Cugliari, Giovanni A1 - van Dam, Rob M A1 - Damulina, Anna A1 - Daneshpour, Maryam S A1 - Day, Felix R A1 - Delgado, Graciela E A1 - Dhana, Klodian A1 - Doney, Alexander S F A1 - Dörr, Marcus A1 - Doumatey, Ayo P A1 - Dzimiri, Nduna A1 - Ebenesersdóttir, S Sunna A1 - Elliott, Joshua A1 - Elliott, Paul A1 - Ewert, Ralf A1 - Felix, Janine F A1 - Fischer, Krista A1 - Freedman, Barry I A1 - Girotto, Giorgia A1 - Goel, Anuj A1 - Gögele, Martin A1 - Goodarzi, Mark O A1 - Graff, Mariaelisa A1 - Granot-Hershkovitz, Einat A1 - Grodstein, Francine A1 - Guarrera, Simonetta A1 - Gudbjartsson, Daniel F A1 - Guity, Kamran A1 - Gunnarsson, Bjarni A1 - Guo, Yu A1 - Hagenaars, Saskia P A1 - Haiman, Christopher A A1 - Halevy, Avner A1 - Harris, Tamara B A1 - Hedayati, Mehdi A1 - van Heel, David A A1 - Hirata, Makoto A1 - Höfer, Imo A1 - Hsiung, Chao Agnes A1 - Huang, Jinyan A1 - Hung, Yi-Jen A1 - Ikram, M Arfan A1 - Jagadeesan, Anuradha A1 - Jousilahti, Pekka A1 - Kamatani, Yoichiro A1 - Kanai, Masahiro A1 - Kerrison, Nicola D A1 - Kessler, Thorsten A1 - Khaw, Kay-Tee A1 - Khor, Chiea Chuen A1 - de Kleijn, Dominique P V A1 - Koh, Woon-Puay A1 - Kolcic, Ivana A1 - Kraft, Peter A1 - Krämer, Bernhard K A1 - Kutalik, Zoltán A1 - Kuusisto, Johanna A1 - Langenberg, Claudia A1 - Launer, Lenore J A1 - Lawlor, Deborah A A1 - Lee, I-Te A1 - Lee, Wen-Jane A1 - Lerch, Markus M A1 - Li, Liming A1 - Liu, Jianjun A1 - Loh, Marie A1 - London, Stephanie J A1 - Loomis, Stephanie A1 - Lu, Yingchang A1 - Luan, Jian'an A1 - Mägi, Reedik A1 - Manichaikul, Ani W A1 - Manunta, Paolo A1 - Másson, Gísli A1 - Matoba, Nana A1 - Mei, Xue W A1 - Meisinger, Christa A1 - Meitinger, Thomas A1 - Mezzavilla, Massimo A1 - Milani, Lili A1 - Millwood, Iona Y A1 - Momozawa, Yukihide A1 - Moore, Amy A1 - Morange, Pierre-Emmanuel A1 - Moreno-Macias, Hortensia A1 - Mori, Trevor A A1 - Morrison, Alanna C A1 - Muka, Taulant A1 - Murakami, Yoshinori A1 - Murray, Alison D A1 - de Mutsert, Renée A1 - Mychaleckyj, Josyf C A1 - Nalls, Mike A A1 - Nauck, Matthias A1 - Neville, Matt J A1 - Nolte, Ilja M A1 - Ong, Ken K A1 - Orozco, Lorena A1 - Padmanabhan, Sandosh A1 - Pálsson, Gunnar A1 - Pankow, James S A1 - Pattaro, Cristian A1 - Pattie, Alison A1 - Polasek, Ozren A1 - Poulter, Neil A1 - Pramstaller, Peter P A1 - Quintana-Murci, Lluis A1 - Räikkönen, Katri A1 - Ralhan, Sarju A1 - Rao, Dabeeru C A1 - van Rheenen, Wouter A1 - Rich, Stephen S A1 - Ridker, Paul M A1 - Rietveld, Cornelius A A1 - Robino, Antonietta A1 - van Rooij, Frank J A A1 - Ruggiero, Daniela A1 - Saba, Yasaman A1 - Sabanayagam, Charumathi A1 - Sabater-Lleal, Maria A1 - Sala, Cinzia Felicita A1 - Salomaa, Veikko A1 - Sandow, Kevin A1 - Schmidt, Helena A1 - Scott, Laura J A1 - Scott, William R A1 - Sedaghati-Khayat, Bahareh A1 - Sennblad, Bengt A1 - van Setten, Jessica A1 - Sever, Peter J A1 - Sheu, Wayne H-H A1 - Shi, Yuan A1 - Shrestha, Smeeta A1 - Shukla, Sharvari Rahul A1 - Sigurdsson, Jon K A1 - Sikka, Timo Tonis A1 - Singh, Jai Rup A1 - Smith, Blair H A1 - Stančáková, Alena A1 - Stanton, Alice A1 - Starr, John M A1 - Stefansdottir, Lilja A1 - Straker, Leon A1 - Sulem, Patrick A1 - Sveinbjornsson, Gardar A1 - Swertz, Morris A A1 - Taylor, Adele M A1 - Taylor, Kent D A1 - Terzikhan, Natalie A1 - Tham, Yih-Chung A1 - Thorleifsson, Gudmar A1 - Thorsteinsdottir, Unnur A1 - Tillander, Annika A1 - Tracy, Russell P A1 - Tusié-Luna, Teresa A1 - Tzoulaki, Ioanna A1 - Vaccargiu, Simona A1 - Vangipurapu, Jagadish A1 - Veldink, Jan H A1 - Vitart, Veronique A1 - Völker, Uwe A1 - Vuoksimaa, Eero A1 - Wakil, Salma M A1 - Waldenberger, Melanie A1 - Wander, Gurpreet S A1 - Wang, Ya Xing A1 - Wareham, Nicholas J A1 - Wild, Sarah A1 - Yajnik, Chittaranjan S A1 - Yuan, Jian-Min A1 - Zeng, Lingyao A1 - Zhang, Liang A1 - Zhou, Jie A1 - Amin, Najaf A1 - Asselbergs, Folkert W A1 - Bakker, Stephan J L A1 - Becker, Diane M A1 - Lehne, Benjamin A1 - Bennett, David A A1 - van den Berg, Leonard H A1 - Berndt, Sonja I A1 - Bharadwaj, Dwaipayan A1 - Bielak, Lawrence F A1 - Bochud, Murielle A1 - Boehnke, Mike A1 - Bouchard, Claude A1 - Bradfield, Jonathan P A1 - Brody, Jennifer A A1 - Campbell, Archie A1 - Carmi, Shai A1 - Caulfield, Mark J A1 - Cesarini, David A1 - Chambers, John C A1 - Chandak, Giriraj Ratan A1 - Cheng, Ching-Yu A1 - Ciullo, Marina A1 - Cornelis, Marilyn A1 - Cusi, Daniele A1 - Smith, George Davey A1 - Deary, Ian J A1 - Dorajoo, Rajkumar A1 - van Duijn, Cornelia M A1 - Ellinghaus, David A1 - Erdmann, Jeanette A1 - Eriksson, Johan G A1 - Evangelou, Evangelos A1 - Evans, Michele K A1 - Faul, Jessica D A1 - Feenstra, Bjarke A1 - Feitosa, Mary A1 - Foisy, Sylvain A1 - Franke, Andre A1 - Friedlander, Yechiel A1 - Gasparini, Paolo A1 - Gieger, Christian A1 - Gonzalez, Clicerio A1 - Goyette, Philippe A1 - Grant, Struan F A A1 - Griffiths, Lyn R A1 - Groop, Leif A1 - Gudnason, Vilmundur A1 - Gyllensten, Ulf A1 - Hakonarson, Hakon A1 - Hamsten, Anders A1 - van der Harst, Pim A1 - Heng, Chew-Kiat A1 - Hicks, Andrew A A1 - Hochner, Hagit A1 - Huikuri, Heikki A1 - Hunt, Steven C A1 - Jaddoe, Vincent W V A1 - De Jager, Philip L A1 - Johannesson, Magnus A1 - Johansson, Asa A1 - Jonas, Jost B A1 - Jukema, J Wouter A1 - Junttila, Juhani A1 - Kaprio, Jaakko A1 - Kardia, Sharon L R A1 - Karpe, Fredrik A1 - Kumari, Meena A1 - Laakso, Markku A1 - van der Laan, Sander W A1 - Lahti, Jari A1 - Laudes, Matthias A1 - Lea, Rodney A A1 - Lieb, Wolfgang A1 - Lumley, Thomas A1 - Martin, Nicholas G A1 - März, Winfried A1 - Matullo, Giuseppe A1 - McCarthy, Mark I A1 - Medland, Sarah E A1 - Merriman, Tony R A1 - Metspalu, Andres A1 - Meyer, Brian F A1 - Mohlke, Karen L A1 - Montgomery, Grant W A1 - Mook-Kanamori, Dennis A1 - Munroe, Patricia B A1 - North, Kari E A1 - Nyholt, Dale R A1 - O'Connell, Jeffery R A1 - Ober, Carole A1 - Oldehinkel, Albertine J A1 - Palmas, Walter A1 - Palmer, Colin A1 - Pasterkamp, Gerard G A1 - Patin, Etienne A1 - Pennell, Craig E A1 - Perusse, Louis A1 - Peyser, Patricia A A1 - Pirastu, Mario A1 - Polderman, Tinca J C A1 - Porteous, David J A1 - Posthuma, Danielle A1 - Psaty, Bruce M A1 - Rioux, John D A1 - Rivadeneira, Fernando A1 - Rotimi, Charles A1 - Rotter, Jerome I A1 - Rudan, Igor A1 - den Ruijter, Hester M A1 - Sanghera, Dharambir K A1 - Sattar, Naveed A1 - Schmidt, Reinhold A1 - Schulze, Matthias B A1 - Schunkert, Heribert A1 - Scott, Robert A A1 - Shuldiner, Alan R A1 - Sim, Xueling A1 - Small, Neil A1 - Smith, Jennifer A A1 - Sotoodehnia, Nona A1 - Tai, E-Shyong A1 - Teumer, Alexander A1 - Timpson, Nicholas J A1 - Toniolo, Daniela A1 - Trégouët, David-Alexandre A1 - Tuomi, Tiinamaija A1 - Vollenweider, Peter A1 - Wang, Carol A A1 - Weir, David R A1 - Whitfield, John B A1 - Wijmenga, Cisca A1 - Wong, Tien-Yin A1 - Wright, John A1 - Yang, Jingyun A1 - Yu, Lei A1 - Zemel, Babette S A1 - Zonderman, Alan B A1 - Perola, Markus A1 - Magnusson, Patrik K E A1 - Uitterlinden, André G A1 - Kooner, Jaspal S A1 - Chasman, Daniel I A1 - Loos, Ruth J F A1 - Franceschini, Nora A1 - Franke, Lude A1 - Haley, Chris S A1 - Hayward, Caroline A1 - Walters, Robin G A1 - Perry, John R B A1 - Esko, Tõnu A1 - Helgason, Agnar A1 - Stefansson, Kari A1 - Joshi, Peter K A1 - Kubo, Michiaki A1 - Wilson, James F AB -

In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (F) for >1.4 million individuals, we show that F is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: F equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44-66%] in the odds of having children. Finally, the effects of F are confirmed within full-sibling pairs, where the variation in F is independent of all environmental confounding.

VL - 10 IS - 1 ER - TY - JOUR T1 - Multi-Ancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions. JF - Am J Epidemiol Y1 - 2019 A1 - de Vries, Paul S A1 - Brown, Michael R A1 - Bentley, Amy R A1 - Sung, Yun J A1 - Winkler, Thomas W A1 - Ntalla, Ioanna A1 - Schwander, Karen A1 - Kraja, Aldi T A1 - Guo, Xiuqing A1 - Franceschini, Nora A1 - Cheng, Ching-Yu A1 - Sim, Xueling A1 - Vojinovic, Dina A1 - Huffman, Jennifer E A1 - Musani, Solomon K A1 - Li, Changwei A1 - Feitosa, Mary F A1 - Richard, Melissa A A1 - Noordam, Raymond A1 - Aschard, Hugues A1 - Bartz, Traci M A1 - Bielak, Lawrence F A1 - Deng, Xuan A1 - Dorajoo, Rajkumar A1 - Lohman, Kurt K A1 - Manning, Alisa K A1 - Rankinen, Tuomo A1 - Smith, Albert V A1 - Tajuddin, Salman M A1 - Evangelou, Evangelos A1 - Graff, Mariaelisa A1 - Alver, Maris A1 - Boissel, Mathilde A1 - Chai, Jin Fang A1 - Chen, Xu A1 - Divers, Jasmin A1 - Gandin, Ilaria A1 - Gao, Chuan A1 - Goel, Anuj A1 - Hagemeijer, Yanick A1 - Harris, Sarah E A1 - Hartwig, Fernando P A1 - He, Meian A1 - Horimoto, Andrea R V R A1 - Hsu, Fang-Chi A1 - Jackson, Anne U A1 - Kasturiratne, Anuradhani A1 - Komulainen, Pirjo A1 - Kuhnel, Brigitte A1 - Laguzzi, Federica A1 - Lee, Joseph H A1 - Luan, Jian'an A1 - Lyytikäinen, Leo-Pekka A1 - Matoba, Nana A1 - Nolte, Ilja M A1 - Pietzner, Maik A1 - Riaz, Muhammad A1 - Said, M Abdullah A1 - Scott, Robert A A1 - Sofer, Tamar A1 - Stančáková, Alena A1 - Takeuchi, Fumihiko A1 - Tayo, Bamidele O A1 - van der Most, Peter J A1 - Varga, Tibor V A1 - Wang, Yajuan A1 - Ware, Erin B A1 - Wen, Wanqing A1 - Yanek, Lisa R A1 - Zhang, Weihua A1 - Zhao, Jing Hua A1 - Afaq, Saima A1 - Amin, Najaf A1 - Amini, Marzyeh A1 - Arking, Dan E A1 - Aung, Tin A1 - Ballantyne, Christie A1 - Boerwinkle, Eric A1 - Broeckel, Ulrich A1 - Campbell, Archie A1 - Canouil, Mickaël A1 - Charumathi, Sabanayagam A1 - Chen, Yii-Der Ida A1 - Connell, John M A1 - de Faire, Ulf A1 - de Las Fuentes, Lisa A1 - de Mutsert, Renée A1 - de Silva, H Janaka A1 - Ding, Jingzhong A1 - Dominiczak, Anna F A1 - Duan, Qing A1 - Eaton, Charles B A1 - Eppinga, Ruben N A1 - Faul, Jessica D A1 - Fisher, Virginia A1 - Forrester, Terrence A1 - Franco, Oscar H A1 - Friedlander, Yechiel A1 - Ghanbari, Mohsen A1 - Giulianini, Franco A1 - Grabe, Hans J A1 - Grove, Megan L A1 - Gu, C Charles A1 - Harris, Tamara B A1 - Heikkinen, Sami A1 - Heng, Chew-Kiat A1 - Hirata, Makoto A1 - Hixson, James E A1 - Howard, Barbara V A1 - Ikram, M Arfan A1 - Jacobs, David R A1 - Johnson, Craig A1 - Jonas, Jost Bruno A1 - Kammerer, Candace M A1 - Katsuya, Tomohiro A1 - Khor, Chiea Chuen A1 - Kilpeläinen, Tuomas O A1 - Koh, Woon-Puay A1 - Koistinen, Heikki A A1 - Kolcic, Ivana A1 - Kooperberg, Charles A1 - Krieger, Jose E A1 - Kritchevsky, Steve B A1 - Kubo, Michiaki A1 - Kuusisto, Johanna A1 - Lakka, Timo A A1 - Langefeld, Carl D A1 - Langenberg, Claudia A1 - Launer, Lenore J A1 - Lehne, Benjamin A1 - Lemaitre, Rozenn N A1 - Li, Yize A1 - Liang, Jingjing A1 - Liu, Jianjun A1 - Liu, Kiang A1 - Loh, Marie A1 - Louie, Tin A1 - Mägi, Reedik A1 - Manichaikul, Ani W A1 - McKenzie, Colin A A1 - Meitinger, Thomas A1 - Metspalu, Andres A1 - Milaneschi, Yuri A1 - Milani, Lili A1 - Mohlke, Karen L A1 - Mosley, Thomas H A1 - Mukamal, Kenneth J A1 - Nalls, Mike A A1 - Nauck, Matthias A1 - Nelson, Christopher P A1 - Sotoodehnia, Nona A1 - O'Connell, Jeff R A1 - Palmer, Nicholette D A1 - Pazoki, Raha A1 - Pedersen, Nancy L A1 - Peters, Annette A1 - Peyser, Patricia A A1 - Polasek, Ozren A1 - Poulter, Neil A1 - Raffel, Leslie J A1 - Raitakari, Olli T A1 - Reiner, Alex P A1 - Rice, Treva K A1 - Rich, Stephen S A1 - Robino, Antonietta A1 - Robinson, Jennifer G A1 - Rose, Lynda M A1 - Rudan, Igor A1 - Schmidt, Carsten O A1 - Schreiner, Pamela J A1 - Scott, William R A1 - Sever, Peter A1 - Shi, Yuan A1 - Sidney, Stephen A1 - Sims, Mario A1 - Smith, Blair H A1 - Smith, Jennifer A A1 - Snieder, Harold A1 - Starr, John M A1 - Strauch, Konstantin A1 - Tan, Nicholas A1 - Taylor, Kent D A1 - Teo, Yik Ying A1 - Tham, Yih Chung A1 - Uitterlinden, André G A1 - van Heemst, Diana A1 - Vuckovic, Dragana A1 - Waldenberger, Melanie A1 - Wang, Lihua A1 - Wang, Yujie A1 - Wang, Zhe A1 - Wei, Wen Bin A1 - Williams, Christine A1 - Wilson, Gregory A1 - Wojczynski, Mary K A1 - Yao, Jie A1 - Yu, Bing A1 - Yu, Caizheng A1 - Yuan, Jian-Min A1 - Zhao, Wei A1 - Zonderman, Alan B A1 - Becker, Diane M A1 - Boehnke, Michael A1 - Bowden, Donald W A1 - Chambers, John C A1 - Deary, Ian J A1 - Esko, Tõnu A1 - Farrall, Martin A1 - Franks, Paul W A1 - Freedman, Barry I A1 - Froguel, Philippe A1 - Gasparini, Paolo A1 - Gieger, Christian A1 - Horta, Bernardo L A1 - Kamatani, Yoichiro A1 - Kato, Norihiro A1 - Kooner, Jaspal S A1 - Laakso, Markku A1 - Leander, Karin A1 - Lehtimäki, Terho A1 - Magnusson, Patrik K E A1 - Penninx, Brenda A1 - Pereira, Alexandre C A1 - Rauramaa, Rainer A1 - Samani, Nilesh J A1 - Scott, James A1 - Shu, Xiao-Ou A1 - van der Harst, Pim A1 - Wagenknecht, Lynne E A1 - Wang, Ya Xing A1 - Wareham, Nicholas J A1 - Watkins, Hugh A1 - Weir, David R A1 - Wickremasinghe, Ananda R A1 - Zheng, Wei A1 - Elliott, Paul A1 - North, Kari E A1 - Bouchard, Claude A1 - Evans, Michele K A1 - Gudnason, Vilmundur A1 - Liu, Ching-Ti A1 - Liu, Yongmei A1 - Psaty, Bruce M A1 - Ridker, Paul M A1 - van Dam, Rob M A1 - Kardia, Sharon L R A1 - Zhu, Xiaofeng A1 - Rotimi, Charles N A1 - Mook-Kanamori, Dennis O A1 - Fornage, Myriam A1 - Kelly, Tanika N A1 - Fox, Ervin R A1 - Hayward, Caroline A1 - van Duijn, Cornelia M A1 - Tai, E Shyong A1 - Wong, Tien Yin A1 - Liu, Jingmin A1 - Rotter, Jerome I A1 - Gauderman, W James A1 - Province, Michael A A1 - Munroe, Patricia B A1 - Rice, Kenneth A1 - Chasman, Daniel I A1 - Cupples, L Adrienne A1 - Rao, Dabeeru C A1 - Morrison, Alanna C AB -

An individual's lipid profile is influenced by genetic variants and alcohol consumption, but the contribution of interactions between these exposures has not been studied. We therefore incorporated gene-alcohol interactions into a multi-ancestry genome-wide association study of levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. We included 45 studies in Stage 1 (genome-wide discovery) and 66 studies in Stage 2 (focused follow-up), for a total of 394,584 individuals from five ancestry groups. Genetic main and interaction effects were jointly assessed by a 2 degrees of freedom (DF) test, and a 1 DF test was used to assess the interaction effects alone. Variants at 495 loci were at least suggestively associated (P < 1 × 10-6) with lipid levels in Stage 1 and were evaluated in Stage 2, followed by combined analyses of Stage 1 and Stage 2. In the combined analysis of Stage 1 and Stage 2, 147 independent loci were associated with lipid levels at P < 5 × 10-8 using 2 DF tests, of which 18 were novel. No genome-wide significant associations were found testing the interaction effect alone. The novel loci included several genes (PCSK5, VEGFB, and A1CF) with a putative role in lipid metabolism based on existing evidence from cellular and experimental models.

ER - TY - JOUR T1 - Multi-ancestry genome-wide gene-smoking interaction study of 387,272 individuals identifies new loci associated with serum lipids. JF - Nat Genet Y1 - 2019 A1 - Bentley, Amy R A1 - Sung, Yun J A1 - Brown, Michael R A1 - Winkler, Thomas W A1 - Kraja, Aldi T A1 - Ntalla, Ioanna A1 - Schwander, Karen A1 - Chasman, Daniel I A1 - Lim, Elise A1 - Deng, Xuan A1 - Guo, Xiuqing A1 - Liu, Jingmin A1 - Lu, Yingchang A1 - Cheng, Ching-Yu A1 - Sim, Xueling A1 - Vojinovic, Dina A1 - Huffman, Jennifer E A1 - Musani, Solomon K A1 - Li, Changwei A1 - Feitosa, Mary F A1 - Richard, Melissa A A1 - Noordam, Raymond A1 - Baker, Jenna A1 - Chen, Guanjie A1 - Aschard, Hugues A1 - Bartz, Traci M A1 - Ding, Jingzhong A1 - Dorajoo, Rajkumar A1 - Manning, Alisa K A1 - Rankinen, Tuomo A1 - Smith, Albert V A1 - Tajuddin, Salman M A1 - Zhao, Wei A1 - Graff, Mariaelisa A1 - Alver, Maris A1 - Boissel, Mathilde A1 - Chai, Jin Fang A1 - Chen, Xu A1 - Divers, Jasmin A1 - Evangelou, Evangelos A1 - Gao, Chuan A1 - Goel, Anuj A1 - Hagemeijer, Yanick A1 - Harris, Sarah E A1 - Hartwig, Fernando P A1 - He, Meian A1 - Horimoto, Andrea R V R A1 - Hsu, Fang-Chi A1 - Hung, Yi-Jen A1 - Jackson, Anne U A1 - Kasturiratne, Anuradhani A1 - Komulainen, Pirjo A1 - Kuhnel, Brigitte A1 - Leander, Karin A1 - Lin, Keng-Hung A1 - Luan, Jian'an A1 - Lyytikäinen, Leo-Pekka A1 - Matoba, Nana A1 - Nolte, Ilja M A1 - Pietzner, Maik A1 - Prins, Bram A1 - Riaz, Muhammad A1 - Robino, Antonietta A1 - Said, M Abdullah A1 - Schupf, Nicole A1 - Scott, Robert A A1 - Sofer, Tamar A1 - Stančáková, Alena A1 - Takeuchi, Fumihiko A1 - Tayo, Bamidele O A1 - van der Most, Peter J A1 - Varga, Tibor V A1 - Wang, Tzung-Dau A1 - Wang, Yajuan A1 - Ware, Erin B A1 - Wen, Wanqing A1 - Xiang, Yong-Bing A1 - Yanek, Lisa R A1 - Zhang, Weihua A1 - Zhao, Jing Hua A1 - Adeyemo, Adebowale A1 - Afaq, Saima A1 - Amin, Najaf A1 - Amini, Marzyeh A1 - Arking, Dan E A1 - Arzumanyan, Zorayr A1 - Aung, Tin A1 - Ballantyne, Christie A1 - Barr, R Graham A1 - Bielak, Lawrence F A1 - Boerwinkle, Eric A1 - Bottinger, Erwin P A1 - Broeckel, Ulrich A1 - Brown, Morris A1 - Cade, Brian E A1 - Campbell, Archie A1 - Canouil, Mickaël A1 - Charumathi, Sabanayagam A1 - Chen, Yii-Der Ida A1 - Christensen, Kaare A1 - Concas, Maria Pina A1 - Connell, John M A1 - de Las Fuentes, Lisa A1 - de Silva, H Janaka A1 - de Vries, Paul S A1 - Doumatey, Ayo A1 - Duan, Qing A1 - Eaton, Charles B A1 - Eppinga, Ruben N A1 - Faul, Jessica D A1 - Floyd, James S A1 - Forouhi, Nita G A1 - Forrester, Terrence A1 - Friedlander, Yechiel A1 - Gandin, Ilaria A1 - Gao, He A1 - Ghanbari, Mohsen A1 - Gharib, Sina A A1 - Gigante, Bruna A1 - Giulianini, Franco A1 - Grabe, Hans J A1 - Gu, C Charles A1 - Harris, Tamara B A1 - Heikkinen, Sami A1 - Heng, Chew-Kiat A1 - Hirata, Makoto A1 - Hixson, James E A1 - Ikram, M Arfan A1 - Jia, Yucheng A1 - Joehanes, Roby A1 - Johnson, Craig A1 - Jonas, Jost Bruno A1 - Justice, Anne E A1 - Katsuya, Tomohiro A1 - Khor, Chiea Chuen A1 - Kilpeläinen, Tuomas O A1 - Koh, Woon-Puay A1 - Kolcic, Ivana A1 - Kooperberg, Charles A1 - Krieger, Jose E A1 - Kritchevsky, Stephen B A1 - Kubo, Michiaki A1 - Kuusisto, Johanna A1 - Lakka, Timo A A1 - Langefeld, Carl D A1 - Langenberg, Claudia A1 - Launer, Lenore J A1 - Lehne, Benjamin A1 - Lewis, Cora E A1 - Li, Yize A1 - Liang, Jingjing A1 - Lin, Shiow A1 - Liu, Ching-Ti A1 - Liu, Jianjun A1 - Liu, Kiang A1 - Loh, Marie A1 - Lohman, Kurt K A1 - Louie, Tin A1 - Luzzi, Anna A1 - Mägi, Reedik A1 - Mahajan, Anubha A1 - Manichaikul, Ani W A1 - McKenzie, Colin A A1 - Meitinger, Thomas A1 - Metspalu, Andres A1 - Milaneschi, Yuri A1 - Milani, Lili A1 - Mohlke, Karen L A1 - Momozawa, Yukihide A1 - Morris, Andrew P A1 - Murray, Alison D A1 - Nalls, Mike A A1 - Nauck, Matthias A1 - Nelson, Christopher P A1 - North, Kari E A1 - O'Connell, Jeffrey R A1 - Palmer, Nicholette D A1 - Papanicolau, George J A1 - Pedersen, Nancy L A1 - Peters, Annette A1 - Peyser, Patricia A A1 - Polasek, Ozren A1 - Poulter, Neil A1 - Raitakari, Olli T A1 - Reiner, Alex P A1 - Renstrom, Frida A1 - Rice, Treva K A1 - Rich, Stephen S A1 - Robinson, Jennifer G A1 - Rose, Lynda M A1 - Rosendaal, Frits R A1 - Rudan, Igor A1 - Schmidt, Carsten O A1 - Schreiner, Pamela J A1 - Scott, William R A1 - Sever, Peter A1 - Shi, Yuan A1 - Sidney, Stephen A1 - Sims, Mario A1 - Smith, Jennifer A A1 - Snieder, Harold A1 - Starr, John M A1 - Strauch, Konstantin A1 - Stringham, Heather M A1 - Tan, Nicholas Y Q A1 - Tang, Hua A1 - Taylor, Kent D A1 - Teo, Yik Ying A1 - Tham, Yih Chung A1 - Tiemeier, Henning A1 - Turner, Stephen T A1 - Uitterlinden, André G A1 - van Heemst, Diana A1 - Waldenberger, Melanie A1 - Wang, Heming A1 - Wang, Lan A1 - Wang, Lihua A1 - Wei, Wen Bin A1 - Williams, Christine A A1 - Wilson, Gregory A1 - Wojczynski, Mary K A1 - Yao, Jie A1 - Young, Kristin A1 - Yu, Caizheng A1 - Yuan, Jian-Min A1 - Zhou, Jie A1 - Zonderman, Alan B A1 - Becker, Diane M A1 - Boehnke, Michael A1 - Bowden, Donald W A1 - Chambers, John C A1 - Cooper, Richard S A1 - de Faire, Ulf A1 - Deary, Ian J A1 - Elliott, Paul A1 - Esko, Tõnu A1 - Farrall, Martin A1 - Franks, Paul W A1 - Freedman, Barry I A1 - Froguel, Philippe A1 - Gasparini, Paolo A1 - Gieger, Christian A1 - Horta, Bernardo L A1 - Juang, Jyh-Ming Jimmy A1 - Kamatani, Yoichiro A1 - Kammerer, Candace M A1 - Kato, Norihiro A1 - Kooner, Jaspal S A1 - Laakso, Markku A1 - Laurie, Cathy C A1 - Lee, I-Te A1 - Lehtimäki, Terho A1 - Magnusson, Patrik K E A1 - Oldehinkel, Albertine J A1 - Penninx, Brenda W J H A1 - Pereira, Alexandre C A1 - Rauramaa, Rainer A1 - Redline, Susan A1 - Samani, Nilesh J A1 - Scott, James A1 - Shu, Xiao-Ou A1 - van der Harst, Pim A1 - Wagenknecht, Lynne E A1 - Wang, Jun-Sing A1 - Wang, Ya Xing A1 - Wareham, Nicholas J A1 - Watkins, Hugh A1 - Weir, David R A1 - Wickremasinghe, Ananda R A1 - Wu, Tangchun A1 - Zeggini, Eleftheria A1 - Zheng, Wei A1 - Bouchard, Claude A1 - Evans, Michele K A1 - Gudnason, Vilmundur A1 - Kardia, Sharon L R A1 - Liu, Yongmei A1 - Psaty, Bruce M A1 - Ridker, Paul M A1 - van Dam, Rob M A1 - Mook-Kanamori, Dennis O A1 - Fornage, Myriam A1 - Province, Michael A A1 - Kelly, Tanika N A1 - Fox, Ervin R A1 - Hayward, Caroline A1 - van Duijn, Cornelia M A1 - Tai, E Shyong A1 - Wong, Tien Yin A1 - Loos, Ruth J F A1 - Franceschini, Nora A1 - Rotter, Jerome I A1 - Zhu, Xiaofeng A1 - Bierut, Laura J A1 - Gauderman, W James A1 - Rice, Kenneth A1 - Munroe, Patricia B A1 - Morrison, Alanna C A1 - Rao, Dabeeru C A1 - Rotimi, Charles N A1 - Cupples, L Adrienne AB -

The concentrations of high- and low-density-lipoprotein cholesterol and triglycerides are influenced by smoking, but it is unknown whether genetic associations with lipids may be modified by smoking. We conducted a multi-ancestry genome-wide gene-smoking interaction study in 133,805 individuals with follow-up in an additional 253,467 individuals. Combined meta-analyses identified 13 new loci associated with lipids, some of which were detected only because association differed by smoking status. Additionally, we demonstrate the importance of including diverse populations, particularly in studies of interactions with lifestyle factors, where genomic and lifestyle differences by ancestry may contribute to novel findings.

VL - 51 IS - 4 ER - TY - JOUR T1 - Multi-ancestry sleep-by-SNP interaction analysis in 126,926 individuals reveals lipid loci stratified by sleep duration. JF - Nat Commun Y1 - 2019 A1 - Noordam, Raymond A1 - Bos, Maxime M A1 - Wang, Heming A1 - Winkler, Thomas W A1 - Bentley, Amy R A1 - Kilpeläinen, Tuomas O A1 - de Vries, Paul S A1 - Sung, Yun Ju A1 - Schwander, Karen A1 - Cade, Brian E A1 - Manning, Alisa A1 - Aschard, Hugues A1 - Brown, Michael R A1 - Chen, Han A1 - Franceschini, Nora A1 - Musani, Solomon K A1 - Richard, Melissa A1 - Vojinovic, Dina A1 - Aslibekyan, Stella A1 - Bartz, Traci M A1 - de Las Fuentes, Lisa A1 - Feitosa, Mary A1 - Horimoto, Andrea R A1 - Ilkov, Marjan A1 - Kho, Minjung A1 - Kraja, Aldi A1 - Li, Changwei A1 - Lim, Elise A1 - Liu, Yongmei A1 - Mook-Kanamori, Dennis O A1 - Rankinen, Tuomo A1 - Tajuddin, Salman M A1 - van der Spek, Ashley A1 - Wang, Zhe A1 - Marten, Jonathan A1 - Laville, Vincent A1 - Alver, Maris A1 - Evangelou, Evangelos A1 - Graff, Maria E A1 - He, Meian A1 - Kuhnel, Brigitte A1 - Lyytikäinen, Leo-Pekka A1 - Marques-Vidal, Pedro A1 - Nolte, Ilja M A1 - Palmer, Nicholette D A1 - Rauramaa, Rainer A1 - Shu, Xiao-Ou A1 - Snieder, Harold A1 - Weiss, Stefan A1 - Wen, Wanqing A1 - Yanek, Lisa R A1 - Adolfo, Correa A1 - Ballantyne, Christie A1 - Bielak, Larry A1 - Biermasz, Nienke R A1 - Boerwinkle, Eric A1 - Dimou, Niki A1 - Eiriksdottir, Gudny A1 - Gao, Chuan A1 - Gharib, Sina A A1 - Gottlieb, Daniel J A1 - Haba-Rubio, José A1 - Harris, Tamara B A1 - Heikkinen, Sami A1 - Heinzer, Raphael A1 - Hixson, James E A1 - Homuth, Georg A1 - Ikram, M Arfan A1 - Komulainen, Pirjo A1 - Krieger, Jose E A1 - Lee, Jiwon A1 - Liu, Jingmin A1 - Lohman, Kurt K A1 - Luik, Annemarie I A1 - Mägi, Reedik A1 - Martin, Lisa W A1 - Meitinger, Thomas A1 - Metspalu, Andres A1 - Milaneschi, Yuri A1 - Nalls, Mike A A1 - O'Connell, Jeff A1 - Peters, Annette A1 - Peyser, Patricia A1 - Raitakari, Olli T A1 - Reiner, Alex P A1 - Rensen, Patrick C N A1 - Rice, Treva K A1 - Rich, Stephen S A1 - Roenneberg, Till A1 - Rotter, Jerome I A1 - Schreiner, Pamela J A1 - Shikany, James A1 - Sidney, Stephen S A1 - Sims, Mario A1 - Sitlani, Colleen M A1 - Sofer, Tamar A1 - Strauch, Konstantin A1 - Swertz, Morris A A1 - Taylor, Kent D A1 - Uitterlinden, André G A1 - van Duijn, Cornelia M A1 - Völzke, Henry A1 - Waldenberger, Melanie A1 - Wallance, Robert B A1 - van Dijk, Ko Willems A1 - Yu, Caizheng A1 - Zonderman, Alan B A1 - Becker, Diane M A1 - Elliott, Paul A1 - Esko, Tõnu A1 - Gieger, Christian A1 - Grabe, Hans J A1 - Lakka, Timo A A1 - Lehtimäki, Terho A1 - North, Kari E A1 - Penninx, Brenda W J H A1 - Vollenweider, Peter A1 - Wagenknecht, Lynne E A1 - Wu, Tangchun A1 - Xiang, Yong-Bing A1 - Zheng, Wei A1 - Arnett, Donna K A1 - Bouchard, Claude A1 - Evans, Michele K A1 - Gudnason, Vilmundur A1 - Kardia, Sharon A1 - Kelly, Tanika N A1 - Kritchevsky, Stephen B A1 - Loos, Ruth J F A1 - Pereira, Alexandre C A1 - Province, Mike A1 - Psaty, Bruce M A1 - Rotimi, Charles A1 - Zhu, Xiaofeng A1 - Amin, Najaf A1 - Cupples, L Adrienne A1 - Fornage, Myriam A1 - Fox, Ervin F A1 - Guo, Xiuqing A1 - Gauderman, W James A1 - Rice, Kenneth A1 - Kooperberg, Charles A1 - Munroe, Patricia B A1 - Liu, Ching-Ti A1 - Morrison, Alanna C A1 - Rao, Dabeeru C A1 - van Heemst, Diana A1 - Redline, Susan AB -

Both short and long sleep are associated with an adverse lipid profile, likely through different biological pathways. To elucidate the biology of sleep-associated adverse lipid profile, we conduct multi-ancestry genome-wide sleep-SNP interaction analyses on three lipid traits (HDL-c, LDL-c and triglycerides). In the total study sample (discovery + replication) of 126,926 individuals from 5 different ancestry groups, when considering either long or short total sleep time interactions in joint analyses, we identify 49 previously unreported lipid loci, and 10 additional previously unreported lipid loci in a restricted sample of European-ancestry cohorts. In addition, we identify new gene-sleep interactions for known lipid loci such as LPL and PCSK9. The previously unreported lipid loci have a modest explained variance in lipid levels: most notable, gene-short-sleep interactions explain 4.25% of the variance in triglyceride level. Collectively, these findings contribute to our understanding of the biological mechanisms involved in sleep-associated adverse lipid profiles.

VL - 10 IS - 1 ER - TY - JOUR T1 - Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity. JF - Nat Commun Y1 - 2019 A1 - Kilpeläinen, Tuomas O A1 - Bentley, Amy R A1 - Noordam, Raymond A1 - Sung, Yun Ju A1 - Schwander, Karen A1 - Winkler, Thomas W A1 - Jakupović, Hermina A1 - Chasman, Daniel I A1 - Manning, Alisa A1 - Ntalla, Ioanna A1 - Aschard, Hugues A1 - Brown, Michael R A1 - de Las Fuentes, Lisa A1 - Franceschini, Nora A1 - Guo, Xiuqing A1 - Vojinovic, Dina A1 - Aslibekyan, Stella A1 - Feitosa, Mary F A1 - Kho, Minjung A1 - Musani, Solomon K A1 - Richard, Melissa A1 - Wang, Heming A1 - Wang, Zhe A1 - Bartz, Traci M A1 - Bielak, Lawrence F A1 - Campbell, Archie A1 - Dorajoo, Rajkumar A1 - Fisher, Virginia A1 - Hartwig, Fernando P A1 - Horimoto, Andrea R V R A1 - Li, Changwei A1 - Lohman, Kurt K A1 - Marten, Jonathan A1 - Sim, Xueling A1 - Smith, Albert V A1 - Tajuddin, Salman M A1 - Alver, Maris A1 - Amini, Marzyeh A1 - Boissel, Mathilde A1 - Chai, Jin Fang A1 - Chen, Xu A1 - Divers, Jasmin A1 - Evangelou, Evangelos A1 - Gao, Chuan A1 - Graff, Mariaelisa A1 - Harris, Sarah E A1 - He, Meian A1 - Hsu, Fang-Chi A1 - Jackson, Anne U A1 - Zhao, Jing Hua A1 - Kraja, Aldi T A1 - Kuhnel, Brigitte A1 - Laguzzi, Federica A1 - Lyytikäinen, Leo-Pekka A1 - Nolte, Ilja M A1 - Rauramaa, Rainer A1 - Riaz, Muhammad A1 - Robino, Antonietta A1 - Rueedi, Rico A1 - Stringham, Heather M A1 - Takeuchi, Fumihiko A1 - van der Most, Peter J A1 - Varga, Tibor V A1 - Verweij, Niek A1 - Ware, Erin B A1 - Wen, Wanqing A1 - Li, Xiaoyin A1 - Yanek, Lisa R A1 - Amin, Najaf A1 - Arnett, Donna K A1 - Boerwinkle, Eric A1 - Brumat, Marco A1 - Cade, Brian A1 - Canouil, Mickaël A1 - Chen, Yii-Der Ida A1 - Concas, Maria Pina A1 - Connell, John A1 - de Mutsert, Renée A1 - de Silva, H Janaka A1 - de Vries, Paul S A1 - Demirkan, Ayse A1 - Ding, Jingzhong A1 - Eaton, Charles B A1 - Faul, Jessica D A1 - Friedlander, Yechiel A1 - Gabriel, Kelley P A1 - Ghanbari, Mohsen A1 - Giulianini, Franco A1 - Gu, Chi Charles A1 - Gu, Dongfeng A1 - Harris, Tamara B A1 - He, Jiang A1 - Heikkinen, Sami A1 - Heng, Chew-Kiat A1 - Hunt, Steven C A1 - Ikram, M Arfan A1 - Jonas, Jost B A1 - Koh, Woon-Puay A1 - Komulainen, Pirjo A1 - Krieger, Jose E A1 - Kritchevsky, Stephen B A1 - Kutalik, Zoltán A1 - Kuusisto, Johanna A1 - Langefeld, Carl D A1 - Langenberg, Claudia A1 - Launer, Lenore J A1 - Leander, Karin A1 - Lemaitre, Rozenn N A1 - Lewis, Cora E A1 - Liang, Jingjing A1 - Liu, Jianjun A1 - Mägi, Reedik A1 - Manichaikul, Ani A1 - Meitinger, Thomas A1 - Metspalu, Andres A1 - Milaneschi, Yuri A1 - Mohlke, Karen L A1 - Mosley, Thomas H A1 - Murray, Alison D A1 - Nalls, Mike A A1 - Nang, Ei-Ei Khaing A1 - Nelson, Christopher P A1 - Nona, Sotoodehnia A1 - Norris, Jill M A1 - Nwuba, Chiamaka Vivian A1 - O'Connell, Jeff A1 - Palmer, Nicholette D A1 - Papanicolau, George J A1 - Pazoki, Raha A1 - Pedersen, Nancy L A1 - Peters, Annette A1 - Peyser, Patricia A A1 - Polasek, Ozren A1 - Porteous, David J A1 - Poveda, Alaitz A1 - Raitakari, Olli T A1 - Rich, Stephen S A1 - Risch, Neil A1 - Robinson, Jennifer G A1 - Rose, Lynda M A1 - Rudan, Igor A1 - Schreiner, Pamela J A1 - Scott, Robert A A1 - Sidney, Stephen S A1 - Sims, Mario A1 - Smith, Jennifer A A1 - Snieder, Harold A1 - Sofer, Tamar A1 - Starr, John M A1 - Sternfeld, Barbara A1 - Strauch, Konstantin A1 - Tang, Hua A1 - Taylor, Kent D A1 - Tsai, Michael Y A1 - Tuomilehto, Jaakko A1 - Uitterlinden, André G A1 - van der Ende, M Yldau A1 - van Heemst, Diana A1 - Voortman, Trudy A1 - Waldenberger, Melanie A1 - Wennberg, Patrik A1 - Wilson, Gregory A1 - Xiang, Yong-Bing A1 - Yao, Jie A1 - Yu, Caizheng A1 - Yuan, Jian-Min A1 - Zhao, Wei A1 - Zonderman, Alan B A1 - Becker, Diane M A1 - Boehnke, Michael A1 - Bowden, Donald W A1 - de Faire, Ulf A1 - Deary, Ian J A1 - Elliott, Paul A1 - Esko, Tõnu A1 - Freedman, Barry I A1 - Froguel, Philippe A1 - Gasparini, Paolo A1 - Gieger, Christian A1 - Kato, Norihiro A1 - Laakso, Markku A1 - Lakka, Timo A A1 - Lehtimäki, Terho A1 - Magnusson, Patrik K E A1 - Oldehinkel, Albertine J A1 - Penninx, Brenda W J H A1 - Samani, Nilesh J A1 - Shu, Xiao-Ou A1 - van der Harst, Pim A1 - van Vliet-Ostaptchouk, Jana V A1 - Vollenweider, Peter A1 - Wagenknecht, Lynne E A1 - Wang, Ya X A1 - Wareham, Nicholas J A1 - Weir, David R A1 - Wu, Tangchun A1 - Zheng, Wei A1 - Zhu, Xiaofeng A1 - Evans, Michele K A1 - Franks, Paul W A1 - Gudnason, Vilmundur A1 - Hayward, Caroline A1 - Horta, Bernardo L A1 - Kelly, Tanika N A1 - Liu, Yongmei A1 - North, Kari E A1 - Pereira, Alexandre C A1 - Ridker, Paul M A1 - Tai, E Shyong A1 - van Dam, Rob M A1 - Fox, Ervin R A1 - Kardia, Sharon L R A1 - Liu, Ching-Ti A1 - Mook-Kanamori, Dennis O A1 - Province, Michael A A1 - Redline, Susan A1 - van Duijn, Cornelia M A1 - Rotter, Jerome I A1 - Kooperberg, Charles B A1 - Gauderman, W James A1 - Psaty, Bruce M A1 - Rice, Kenneth A1 - Munroe, Patricia B A1 - Fornage, Myriam A1 - Cupples, L Adrienne A1 - Rotimi, Charles N A1 - Morrison, Alanna C A1 - Rao, Dabeeru C A1 - Loos, Ruth J F KW - Adolescent KW - Adult KW - African Continental Ancestry Group KW - Aged KW - Aged, 80 and over KW - Asian Continental Ancestry Group KW - Brazil KW - Calcium-Binding Proteins KW - Cholesterol KW - Cholesterol, HDL KW - Cholesterol, LDL KW - European Continental Ancestry Group KW - Exercise KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Genotype KW - Hispanic Americans KW - Humans KW - LIM-Homeodomain Proteins KW - Lipid Metabolism KW - Lipids KW - Male KW - Membrane Proteins KW - Microtubule-Associated Proteins KW - Middle Aged KW - Muscle Proteins KW - Nerve Tissue Proteins KW - Transcription Factors KW - Triglycerides KW - Young Adult AB -

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

VL - 10 IS - 1 ER - TY - JOUR T1 - Role of Rare and Low-Frequency Variants in Gene-Alcohol Interactions on Plasma Lipid Levels. JF - Circ Genom Precis Med Y1 - 2020 A1 - Wang, Zhe A1 - Chen, Han A1 - Bartz, Traci M A1 - Bielak, Lawrence F A1 - Chasman, Daniel I A1 - Feitosa, Mary F A1 - Franceschini, Nora A1 - Guo, Xiuqing A1 - Lim, Elise A1 - Noordam, Raymond A1 - Richard, Melissa A A1 - Wang, Heming A1 - Cade, Brian A1 - Cupples, L Adrienne A1 - de Vries, Paul S A1 - Giulanini, Franco A1 - Lee, Jiwon A1 - Lemaitre, Rozenn N A1 - Martin, Lisa W A1 - Reiner, Alex P A1 - Rich, Stephen S A1 - Schreiner, Pamela J A1 - Sidney, Stephen A1 - Sitlani, Colleen M A1 - Smith, Jennifer A A1 - Willems van Dijk, Ko A1 - Yao, Jie A1 - Zhao, Wei A1 - Fornage, Myriam A1 - Kardia, Sharon L R A1 - Kooperberg, Charles A1 - Liu, Ching-Ti A1 - Mook-Kanamori, Dennis O A1 - Province, Michael A A1 - Psaty, Bruce M A1 - Redline, Susan A1 - Ridker, Paul M A1 - Rotter, Jerome I A1 - Boerwinkle, Eric A1 - Morrison, Alanna C AB -

BACKGROUND: Alcohol intake influences plasma lipid levels, and such effects may be moderated by genetic variants. We aimed to characterize the role of aggregated rare and low-frequency protein-coding variants in gene by alcohol consumption interactions associated with fasting plasma lipid levels.

METHODS: In the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, fasting plasma triglycerides and high- and low-density lipoprotein cholesterol were measured in 34 153 individuals with European ancestry from 5 discovery studies and 32 277 individuals from 6 replication studies. Rare and low-frequency functional protein-coding variants (minor allele frequency, ≤5%) measured by an exome array were aggregated by genes and evaluated by a gene-environment interaction test and a joint test of genetic main and gene-environment interaction effects. Two dichotomous self-reported alcohol consumption variables, current drinker, defined as any recurrent drinking behavior, and regular drinker, defined as the subset of current drinkers who consume at least 2 drinks per week, were considered.

RESULTS: We discovered and replicated 21 gene-lipid associations at 13 known lipid loci through the joint test. Eight loci (, , , , , , , and ) remained significant after conditioning on the common index single-nucleotide polymorphism identified by previous genome-wide association studies, suggesting an independent role for rare and low-frequency variants at these loci. One significant gene-alcohol interaction on triglycerides in a novel locus was significantly discovered (=6.65×10 for the interaction test) and replicated at nominal significance level (=0.013) in .

CONCLUSIONS: In conclusion, this study applied new gene-based statistical approaches and suggested that rare and low-frequency genetic variants interacted with alcohol consumption on lipid levels.

VL - 13 IS - 4 ER - TY - JOUR T1 - Genetic insights into biological mechanisms governing human ovarian ageing. JF - Nature Y1 - 2021 A1 - Ruth, Katherine S A1 - Day, Felix R A1 - Hussain, Jazib A1 - Martínez-Marchal, Ana A1 - Aiken, Catherine E A1 - Azad, Ajuna A1 - Thompson, Deborah J A1 - Knoblochova, Lucie A1 - Abe, Hironori A1 - Tarry-Adkins, Jane L A1 - Gonzalez, Javier Martin A1 - Fontanillas, Pierre A1 - Claringbould, Annique A1 - Bakker, Olivier B A1 - Sulem, Patrick A1 - Walters, Robin G A1 - Terao, Chikashi A1 - Turon, Sandra A1 - Horikoshi, Momoko A1 - Lin, Kuang A1 - Onland-Moret, N Charlotte A1 - Sankar, Aditya A1 - Hertz, Emil Peter Thrane A1 - Timshel, Pascal N A1 - Shukla, Vallari A1 - Borup, Rehannah A1 - Olsen, Kristina W A1 - Aguilera, Paula A1 - Ferrer-Roda, Mònica A1 - Huang, Yan A1 - Stankovic, Stasa A1 - Timmers, Paul R H J A1 - Ahearn, Thomas U A1 - Alizadeh, Behrooz Z A1 - Naderi, Elnaz A1 - Andrulis, Irene L A1 - Arnold, Alice M A1 - Aronson, Kristan J A1 - Augustinsson, Annelie A1 - Bandinelli, Stefania A1 - Barbieri, Caterina M A1 - Beaumont, Robin N A1 - Becher, Heiko A1 - Beckmann, Matthias W A1 - Benonisdottir, Stefania A1 - Bergmann, Sven A1 - Bochud, Murielle A1 - Boerwinkle, Eric A1 - Bojesen, Stig E A1 - Bolla, Manjeet K A1 - Boomsma, Dorret I A1 - Bowker, Nicholas A1 - Brody, Jennifer A A1 - Broer, Linda A1 - Buring, Julie E A1 - Campbell, Archie A1 - Campbell, Harry A1 - Castelao, Jose E A1 - Catamo, Eulalia A1 - Chanock, Stephen J A1 - Chenevix-Trench, Georgia A1 - Ciullo, Marina A1 - Corre, Tanguy A1 - Couch, Fergus J A1 - Cox, Angela A1 - Crisponi, Laura A1 - Cross, Simon S A1 - Cucca, Francesco A1 - Czene, Kamila A1 - Smith, George Davey A1 - de Geus, Eco J C N A1 - de Mutsert, Renée A1 - De Vivo, Immaculata A1 - Demerath, Ellen W A1 - Dennis, Joe A1 - Dunning, Alison M A1 - Dwek, Miriam A1 - Eriksson, Mikael A1 - Esko, Tõnu A1 - Fasching, Peter A A1 - Faul, Jessica D A1 - Ferrucci, Luigi A1 - Franceschini, Nora A1 - Frayling, Timothy M A1 - Gago-Dominguez, Manuela A1 - Mezzavilla, Massimo A1 - García-Closas, Montserrat A1 - Gieger, Christian A1 - Giles, Graham G A1 - Grallert, Harald A1 - Gudbjartsson, Daniel F A1 - Gudnason, Vilmundur A1 - Guénel, Pascal A1 - Haiman, Christopher A A1 - Håkansson, Niclas A1 - Hall, Per A1 - Hayward, Caroline A1 - He, Chunyan A1 - He, Wei A1 - Heiss, Gerardo A1 - Høffding, Miya K A1 - Hopper, John L A1 - Hottenga, Jouke J A1 - Hu, Frank A1 - Hunter, David A1 - Ikram, Mohammad A A1 - Jackson, Rebecca D A1 - Joaquim, Micaella D R A1 - John, Esther M A1 - Joshi, Peter K A1 - Karasik, David A1 - Kardia, Sharon L R A1 - Kartsonaki, Christiana A1 - Karlsson, Robert A1 - Kitahara, Cari M A1 - Kolcic, Ivana A1 - Kooperberg, Charles A1 - Kraft, Peter A1 - Kurian, Allison W A1 - Kutalik, Zoltán A1 - La Bianca, Martina A1 - Lachance, Genevieve A1 - Langenberg, Claudia A1 - Launer, Lenore J A1 - Laven, Joop S E A1 - Lawlor, Deborah A A1 - Le Marchand, Loïc A1 - Li, Jingmei A1 - Lindblom, Annika A1 - Lindström, Sara A1 - Lindstrom, Tricia A1 - Linet, Martha A1 - Liu, Yongmei A1 - Liu, Simin A1 - Luan, Jian'an A1 - Mägi, Reedik A1 - Magnusson, Patrik K E A1 - Mangino, Massimo A1 - Mannermaa, Arto A1 - Marco, Brumat A1 - Marten, Jonathan A1 - Martin, Nicholas G A1 - Mbarek, Hamdi A1 - McKnight, Barbara A1 - Medland, Sarah E A1 - Meisinger, Christa A1 - Meitinger, Thomas A1 - Menni, Cristina A1 - Metspalu, Andres A1 - Milani, Lili A1 - Milne, Roger L A1 - Montgomery, Grant W A1 - Mook-Kanamori, Dennis O A1 - Mulas, Antonella A1 - Mulligan, Anna M A1 - Murray, Alison A1 - Nalls, Mike A A1 - Newman, Anne A1 - Noordam, Raymond A1 - Nutile, Teresa A1 - Nyholt, Dale R A1 - Olshan, Andrew F A1 - Olsson, Håkan A1 - Painter, Jodie N A1 - Patel, Alpa V A1 - Pedersen, Nancy L A1 - Perjakova, Natalia A1 - Peters, Annette A1 - Peters, Ulrike A1 - Pharoah, Paul D P A1 - Polasek, Ozren A1 - Porcu, Eleonora A1 - Psaty, Bruce M A1 - Rahman, Iffat A1 - Rennert, Gad A1 - Rennert, Hedy S A1 - Ridker, Paul M A1 - Ring, Susan M A1 - Robino, Antonietta A1 - Rose, Lynda M A1 - Rosendaal, Frits R A1 - Rossouw, Jacques A1 - Rudan, Igor A1 - Rueedi, Rico A1 - Ruggiero, Daniela A1 - Sala, Cinzia F A1 - Saloustros, Emmanouil A1 - Sandler, Dale P A1 - Sanna, Serena A1 - Sawyer, Elinor J A1 - Sarnowski, Chloe A1 - Schlessinger, David A1 - Schmidt, Marjanka K A1 - Schoemaker, Minouk J A1 - Schraut, Katharina E A1 - Scott, Christopher A1 - Shekari, Saleh A1 - Shrikhande, Amruta A1 - Smith, Albert V A1 - Smith, Blair H A1 - Smith, Jennifer A A1 - Sorice, Rossella A1 - Southey, Melissa C A1 - Spector, Tim D A1 - Spinelli, John J A1 - Stampfer, Meir A1 - Stöckl, Doris A1 - van Meurs, Joyce B J A1 - Strauch, Konstantin A1 - Styrkarsdottir, Unnur A1 - Swerdlow, Anthony J A1 - Tanaka, Toshiko A1 - Teras, Lauren R A1 - Teumer, Alexander A1 - Þorsteinsdottir, Unnur A1 - Timpson, Nicholas J A1 - Toniolo, Daniela A1 - Traglia, Michela A1 - Troester, Melissa A A1 - Truong, Thérèse A1 - Tyrrell, Jessica A1 - Uitterlinden, André G A1 - Ulivi, Sheila A1 - Vachon, Celine M A1 - Vitart, Veronique A1 - Völker, Uwe A1 - Vollenweider, Peter A1 - Völzke, Henry A1 - Wang, Qin A1 - Wareham, Nicholas J A1 - Weinberg, Clarice R A1 - Weir, David R A1 - Wilcox, Amber N A1 - van Dijk, Ko Willems A1 - Willemsen, Gonneke A1 - Wilson, James F A1 - Wolffenbuttel, Bruce H R A1 - Wolk, Alicja A1 - Wood, Andrew R A1 - Zhao, Wei A1 - Zygmunt, Marek A1 - Chen, Zhengming A1 - Li, Liming A1 - Franke, Lude A1 - Burgess, Stephen A1 - Deelen, Patrick A1 - Pers, Tune H A1 - Grøndahl, Marie Louise A1 - Andersen, Claus Yding A1 - Pujol, Anna A1 - Lopez-Contreras, Andres J A1 - Daniel, Jeremy A A1 - Stefansson, Kari A1 - Chang-Claude, Jenny A1 - van der Schouw, Yvonne T A1 - Lunetta, Kathryn L A1 - Chasman, Daniel I A1 - Easton, Douglas F A1 - Visser, Jenny A A1 - Ozanne, Susan E A1 - Namekawa, Satoshi H A1 - Solc, Petr A1 - Murabito, Joanne M A1 - Ong, Ken K A1 - Hoffmann, Eva R A1 - Murray, Anna A1 - Roig, Ignasi A1 - Perry, John R B AB -

Reproductive longevity is essential for fertility and influences healthy ageing in women, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.

VL - 596 IS - 7872 ER - TY - JOUR T1 - Multi-Ancestry Genome-wide Association Study Accounting for Gene-Psychosocial Factor Interactions Identifies Novel Loci for Blood Pressure Traits. JF - HGG Adv Y1 - 2021 A1 - Sun, Daokun A1 - Richard, Melissa A1 - Musani, Solomon K A1 - Sung, Yun Ju A1 - Winkler, Thomas W A1 - Schwander, Karen A1 - Chai, Jin Fang A1 - Guo, Xiuqing A1 - Kilpeläinen, Tuomas O A1 - Vojinovic, Dina A1 - Aschard, Hugues A1 - Bartz, Traci M A1 - Bielak, Lawrence F A1 - Brown, Michael R A1 - Chitrala, Kumaraswamy A1 - Hartwig, Fernando P A1 - Horimoto, Andrea R V R A1 - Liu, Yongmei A1 - Manning, Alisa K A1 - Noordam, Raymond A1 - Smith, Albert V A1 - Harris, Sarah E A1 - Kuhnel, Brigitte A1 - Lyytikäinen, Leo-Pekka A1 - Nolte, Ilja M A1 - Rauramaa, Rainer A1 - van der Most, Peter J A1 - Wang, Rujia A1 - Ware, Erin B A1 - Weiss, Stefan A1 - Wen, Wanqing A1 - Yanek, Lisa R A1 - Arking, Dan E A1 - Arnett, Donna K A1 - Barac, Ana A1 - Boerwinkle, Eric A1 - Broeckel, Ulrich A1 - Chakravarti, Aravinda A1 - Chen, Yii-Der Ida A1 - Cupples, L Adrienne A1 - Davigulus, Martha L A1 - de Las Fuentes, Lisa A1 - de Mutsert, Renée A1 - de Vries, Paul S A1 - Delaney, Joseph A C A1 - Roux, Ana V Diez A1 - Dörr, Marcus A1 - Faul, Jessica D A1 - Fretts, Amanda M A1 - Gallo, Linda C A1 - Grabe, Hans Jörgen A1 - Gu, C Charles A1 - Harris, Tamara B A1 - Hartman, Catharina C A A1 - Heikkinen, Sami A1 - Ikram, M Arfan A1 - Isasi, Carmen A1 - Johnson, W Craig A1 - Jonas, Jost Bruno A1 - Kaplan, Robert C A1 - Komulainen, Pirjo A1 - Krieger, Jose E A1 - Levy, Daniel A1 - Liu, Jianjun A1 - Lohman, Kurt A1 - Luik, Annemarie I A1 - Martin, Lisa W A1 - Meitinger, Thomas A1 - Milaneschi, Yuri A1 - O'Connell, Jeff R A1 - Palmas, Walter R A1 - Peters, Annette A1 - Peyser, Patricia A A1 - Pulkki-Råback, Laura A1 - Raffel, Leslie J A1 - Reiner, Alex P A1 - Rice, Kenneth A1 - Robinson, Jennifer G A1 - Rosendaal, Frits R A1 - Schmidt, Carsten Oliver A1 - Schreiner, Pamela J A1 - Schwettmann, Lars A1 - Shikany, James M A1 - Shu, Xiao-Ou A1 - Sidney, Stephen A1 - Sims, Mario A1 - Smith, Jennifer A A1 - Sotoodehnia, Nona A1 - Strauch, Konstantin A1 - Tai, E Shyong A1 - Taylor, Kent A1 - Uitterlinden, André G A1 - van Duijn, Cornelia M A1 - Waldenberger, Melanie A1 - Wee, Hwee-Lin A1 - Wei, Wen-Bin A1 - Wilson, Gregory A1 - Xuan, Deng A1 - Yao, Jie A1 - Zeng, Donglin A1 - Zhao, Wei A1 - Zhu, Xiaofeng A1 - Zonderman, Alan B A1 - Becker, Diane M A1 - Deary, Ian J A1 - Gieger, Christian A1 - Lakka, Timo A A1 - Lehtimäki, Terho A1 - North, Kari E A1 - Oldehinkel, Albertine J A1 - Penninx, Brenda W J H A1 - Snieder, Harold A1 - Wang, Ya-Xing A1 - Weir, David R A1 - Zheng, Wei A1 - Evans, Michele K A1 - Gauderman, W James A1 - Gudnason, Vilmundur A1 - Horta, Bernardo L A1 - Liu, Ching-Ti A1 - Mook-Kanamori, Dennis O A1 - Morrison, Alanna C A1 - Pereira, Alexandre C A1 - Psaty, Bruce M A1 - Amin, Najaf A1 - Fox, Ervin R A1 - Kooperberg, Charles A1 - Sim, Xueling A1 - Bierut, Laura A1 - Rotter, Jerome I A1 - Kardia, Sharon L R A1 - Franceschini, Nora A1 - Rao, Dabeeru C A1 - Fornage, Myriam AB -

Psychological and social factors are known to influence blood pressure (BP) and risk of hypertension and associated cardiovascular diseases. To identify novel BP loci, we carried out genome-wide association meta-analyses of systolic, diastolic, pulse, and mean arterial BP taking into account the interaction effects of genetic variants with three psychosocial factors: depressive symptoms, anxiety symptoms, and social support. Analyses were performed using a two-stage design in a sample of up to 128,894 adults from 5 ancestry groups. In the combined meta-analyses of Stages 1 and 2, we identified 59 loci (p value <5e-8), including nine novel BP loci. The novel associations were observed mostly with pulse pressure, with fewer observed with mean arterial pressure. Five novel loci were identified in African ancestry, and all but one showed patterns of interaction with at least one psychosocial factor. Functional annotation of the novel loci supports a major role for genes implicated in the immune response (), synaptic function and neurotransmission (), as well as genes previously implicated in neuropsychiatric or stress-related disorders (). These findings underscore the importance of considering psychological and social factors in gene discovery for BP, especially in non-European populations.

VL - 2 IS - 1 ER - TY - JOUR T1 - Multi-ancestry genome-wide gene-sleep interactions identify novel loci for blood pressure. JF - Mol Psychiatry Y1 - 2021 A1 - Wang, Heming A1 - Noordam, Raymond A1 - Cade, Brian E A1 - Schwander, Karen A1 - Winkler, Thomas W A1 - Lee, Jiwon A1 - Sung, Yun Ju A1 - Bentley, Amy R A1 - Manning, Alisa K A1 - Aschard, Hugues A1 - Kilpeläinen, Tuomas O A1 - Ilkov, Marjan A1 - Brown, Michael R A1 - Horimoto, Andrea R A1 - Richard, Melissa A1 - Bartz, Traci M A1 - Vojinovic, Dina A1 - Lim, Elise A1 - Nierenberg, Jovia L A1 - Liu, Yongmei A1 - Chitrala, Kumaraswamynaidu A1 - Rankinen, Tuomo A1 - Musani, Solomon K A1 - Franceschini, Nora A1 - Rauramaa, Rainer A1 - Alver, Maris A1 - Zee, Phyllis C A1 - Harris, Sarah E A1 - van der Most, Peter J A1 - Nolte, Ilja M A1 - Munroe, Patricia B A1 - Palmer, Nicholette D A1 - Kuhnel, Brigitte A1 - Weiss, Stefan A1 - Wen, Wanqing A1 - Hall, Kelly A A1 - Lyytikäinen, Leo-Pekka A1 - O'Connell, Jeff A1 - Eiriksdottir, Gudny A1 - Launer, Lenore J A1 - de Vries, Paul S A1 - Arking, Dan E A1 - Chen, Han A1 - Boerwinkle, Eric A1 - Krieger, Jose E A1 - Schreiner, Pamela J A1 - Sidney, Stephen A1 - Shikany, James M A1 - Rice, Kenneth A1 - Chen, Yii-Der Ida A1 - Gharib, Sina A A1 - Bis, Joshua C A1 - Luik, Annemarie I A1 - Ikram, M Arfan A1 - Uitterlinden, André G A1 - Amin, Najaf A1 - Xu, Hanfei A1 - Levy, Daniel A1 - He, Jiang A1 - Lohman, Kurt K A1 - Zonderman, Alan B A1 - Rice, Treva K A1 - Sims, Mario A1 - Wilson, Gregory A1 - Sofer, Tamar A1 - Rich, Stephen S A1 - Palmas, Walter A1 - Yao, Jie A1 - Guo, Xiuqing A1 - Rotter, Jerome I A1 - Biermasz, Nienke R A1 - Mook-Kanamori, Dennis O A1 - Martin, Lisa W A1 - Barac, Ana A1 - Wallace, Robert B A1 - Gottlieb, Daniel J A1 - Komulainen, Pirjo A1 - Heikkinen, Sami A1 - Mägi, Reedik A1 - Milani, Lili A1 - Metspalu, Andres A1 - Starr, John M A1 - Milaneschi, Yuri A1 - Waken, R J A1 - Gao, Chuan A1 - Waldenberger, Melanie A1 - Peters, Annette A1 - Strauch, Konstantin A1 - Meitinger, Thomas A1 - Roenneberg, Till A1 - Völker, Uwe A1 - Dörr, Marcus A1 - Shu, Xiao-Ou A1 - Mukherjee, Sutapa A1 - Hillman, David R A1 - Kähönen, Mika A1 - Wagenknecht, Lynne E A1 - Gieger, Christian A1 - Grabe, Hans J A1 - Zheng, Wei A1 - Palmer, Lyle J A1 - Lehtimäki, Terho A1 - Gudnason, Vilmundur A1 - Morrison, Alanna C A1 - Pereira, Alexandre C A1 - Fornage, Myriam A1 - Psaty, Bruce M A1 - van Duijn, Cornelia M A1 - Liu, Ching-Ti A1 - Kelly, Tanika N A1 - Evans, Michele K A1 - Bouchard, Claude A1 - Fox, Ervin R A1 - Kooperberg, Charles A1 - Zhu, Xiaofeng A1 - Lakka, Timo A A1 - Esko, Tõnu A1 - North, Kari E A1 - Deary, Ian J A1 - Snieder, Harold A1 - Penninx, Brenda W J H A1 - Gauderman, W James A1 - Rao, Dabeeru C A1 - Redline, Susan A1 - van Heemst, Diana AB -

Long and short sleep duration are associated with elevated blood pressure (BP), possibly through effects on molecular pathways that influence neuroendocrine and vascular systems. To gain new insights into the genetic basis of sleep-related BP variation, we performed genome-wide gene by short or long sleep duration interaction analyses on four BP traits (systolic BP, diastolic BP, mean arterial pressure, and pulse pressure) across five ancestry groups in two stages using 2 degree of freedom (df) joint test followed by 1df test of interaction effects. Primary multi-ancestry analysis in 62,969 individuals in stage 1 identified three novel gene by sleep interactions that were replicated in an additional 59,296 individuals in stage 2 (stage 1 + 2 P < 5 × 10), including rs7955964 (FIGNL2/ANKRD33) that increases BP among long sleepers, and rs73493041 (SNORA26/C9orf170) and rs10406644 (KCTD15/LSM14A) that increase BP among short sleepers (P < 5 × 10). Secondary ancestry-specific analysis identified another novel gene by long sleep interaction at rs111887471 (TRPC3/KIAA1109) in individuals of African ancestry (P = 2 × 10). Combined stage 1 and 2 analyses additionally identified significant gene by long sleep interactions at 10 loci including MKLN1 and RGL3/ELAVL3 previously associated with BP, and significant gene by short sleep interactions at 10 loci including C2orf43 previously associated with BP (P < 10). 2df test also identified novel loci for BP after modeling sleep that has known functions in sleep-wake regulation, nervous and cardiometabolic systems. This study indicates that sleep and primary mechanisms regulating BP may interact to elevate BP level, suggesting novel insights into sleep-related BP regulation.

ER - TY - JOUR T1 - Multiethnic Genome-Wide Association Study of Subclinical Atherosclerosis in Individuals With Type 2 Diabetes. JF - Circ Genom Precis Med Y1 - 2021 A1 - Lu, Yingchang A1 - Dimitrov, Latchezar A1 - Chen, Shyh-Huei A1 - Bielak, Lawrence F A1 - Bis, Joshua C A1 - Feitosa, Mary F A1 - Lu, Lingyi A1 - Kavousi, Maryam A1 - Raffield, Laura M A1 - Smith, Albert V A1 - Wang, Lihua A1 - Weiss, Stefan A1 - Yao, Jie A1 - Zhu, Jiaxi A1 - Gudmundsson, Elias F A1 - Gudmundsdottir, Valborg A1 - Bos, Daniel A1 - Ghanbari, Mohsen A1 - Ikram, M Arfan A1 - Hwang, Shih-Jen A1 - Taylor, Kent D A1 - Budoff, Matthew J A1 - Gislason, Gauti K A1 - O'Donnell, Christopher J A1 - An, Ping A1 - Franceschini, Nora A1 - Freedman, Barry I A1 - Fu, Yi-Ping A1 - Guo, Xiuqing A1 - Heiss, Gerardo A1 - Kardia, Sharon L R A1 - Wilson, James G A1 - Langefeld, Carl D A1 - Schminke, Ulf A1 - Uitterlinden, André G A1 - Lange, Leslie A A1 - Peyser, Patricia A A1 - Gudnason, Vilmundur G A1 - Psaty, Bruce M A1 - Rotter, Jerome I A1 - Bowden, Donald W A1 - Ng, Maggie C Y AB -

BACKGROUND: Coronary artery calcification (CAC) and carotid artery intima-media thickness (cIMT) are measures of subclinical atherosclerosis in asymptomatic individuals and strong risk factors for cardiovascular disease. Type 2 diabetes (T2D) is an independent cardiovascular disease risk factor that accelerates atherosclerosis.

METHODS: We performed meta-analyses of genome-wide association studies in up to 2500 T2D individuals of European ancestry (EA) and 1590 T2D individuals of African ancestry with or without exclusion of prevalent cardiovascular disease, for CAC measured by cardiac computed tomography, and 3608 individuals of EA and 838 individuals of African ancestry with T2D for cIMT measured by ultrasonography within the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium.

RESULTS: We replicated 2 loci (rs9369640 and rs9349379 near and rs10757278 near ) for CAC and one locus for cIMT (rs7412 and rs445925 near ) that were previously reported in the general EA populations. We identified one novel CAC locus (rs8000449 near at 13q13.3) at =2.0×10 in EA. No additional loci were identified with the meta-analyses of EA and African ancestry. The expression quantitative trait loci analysis with nearby expressed genes derived from arterial wall and metabolic tissues from the Genotype-Tissue Expression project pinpoints , encoding a matricellular protein involved in bone formation and bone matrix organization, as the potential candidate gene at this locus. In addition, we found significant associations (<3.1×10) for 3 previously reported coronary artery disease loci for these subclinical atherosclerotic phenotypes (rs2891168 near and rs11170820 near for CAC, and rs7412 near for cIMT).

CONCLUSIONS: Our results provide potential biological mechanisms that could link CAC and cIMT to increased cardiovascular disease risk in individuals with T2D.

VL - 14 IS - 4 ER - TY - JOUR T1 - Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program. JF - Nature Y1 - 2021 A1 - Taliun, Daniel A1 - Harris, Daniel N A1 - Kessler, Michael D A1 - Carlson, Jedidiah A1 - Szpiech, Zachary A A1 - Torres, Raul A1 - Taliun, Sarah A Gagliano A1 - Corvelo, André A1 - Gogarten, Stephanie M A1 - Kang, Hyun Min A1 - Pitsillides, Achilleas N A1 - LeFaive, Jonathon A1 - Lee, Seung-Been A1 - Tian, Xiaowen A1 - Browning, Brian L A1 - Das, Sayantan A1 - Emde, Anne-Katrin A1 - Clarke, Wayne E A1 - Loesch, Douglas P A1 - Shetty, Amol C A1 - Blackwell, Thomas W A1 - Smith, Albert V A1 - Wong, Quenna A1 - Liu, Xiaoming A1 - Conomos, Matthew P A1 - Bobo, Dean M A1 - Aguet, Francois A1 - Albert, Christine A1 - Alonso, Alvaro A1 - Ardlie, Kristin G A1 - Arking, Dan E A1 - Aslibekyan, Stella A1 - Auer, Paul L A1 - Barnard, John A1 - Barr, R Graham A1 - Barwick, Lucas A1 - Becker, Lewis C A1 - Beer, Rebecca L A1 - Benjamin, Emelia J A1 - Bielak, Lawrence F A1 - Blangero, John A1 - Boehnke, Michael A1 - Bowden, Donald W A1 - Brody, Jennifer A A1 - Burchard, Esteban G A1 - Cade, Brian E A1 - Casella, James F A1 - Chalazan, Brandon A1 - Chasman, Daniel I A1 - Chen, Yii-Der Ida A1 - Cho, Michael H A1 - Choi, Seung Hoan A1 - Chung, Mina K A1 - Clish, Clary B A1 - Correa, Adolfo A1 - Curran, Joanne E A1 - Custer, Brian A1 - Darbar, Dawood A1 - Daya, Michelle A1 - de Andrade, Mariza A1 - DeMeo, Dawn L A1 - Dutcher, Susan K A1 - Ellinor, Patrick T A1 - Emery, Leslie S A1 - Eng, Celeste A1 - Fatkin, Diane A1 - Fingerlin, Tasha A1 - Forer, Lukas A1 - Fornage, Myriam A1 - Franceschini, Nora A1 - Fuchsberger, Christian A1 - Fullerton, Stephanie M A1 - Germer, Soren A1 - Gladwin, Mark T A1 - Gottlieb, Daniel J A1 - Guo, Xiuqing A1 - Hall, Michael E A1 - He, Jiang A1 - Heard-Costa, Nancy L A1 - Heckbert, Susan R A1 - Irvin, Marguerite R A1 - Johnsen, Jill M A1 - Johnson, Andrew D A1 - Kaplan, Robert A1 - Kardia, Sharon L R A1 - Kelly, Tanika A1 - Kelly, Shannon A1 - Kenny, Eimear E A1 - Kiel, Douglas P A1 - Klemmer, Robert A1 - Konkle, Barbara A A1 - Kooperberg, Charles A1 - Köttgen, Anna A1 - Lange, Leslie A A1 - Lasky-Su, Jessica A1 - Levy, Daniel A1 - Lin, Xihong A1 - Lin, Keng-Han A1 - Liu, Chunyu A1 - Loos, Ruth J F A1 - Garman, Lori A1 - Gerszten, Robert A1 - Lubitz, Steven A A1 - Lunetta, Kathryn L A1 - Mak, Angel C Y A1 - Manichaikul, Ani A1 - Manning, Alisa K A1 - Mathias, Rasika A A1 - McManus, David D A1 - McGarvey, Stephen T A1 - Meigs, James B A1 - Meyers, Deborah A A1 - Mikulla, Julie L A1 - Minear, Mollie A A1 - Mitchell, Braxton D A1 - Mohanty, Sanghamitra A1 - Montasser, May E A1 - Montgomery, Courtney A1 - Morrison, Alanna C A1 - Murabito, Joanne M A1 - Natale, Andrea A1 - Natarajan, Pradeep A1 - Nelson, Sarah C A1 - North, Kari E A1 - O'Connell, Jeffrey R A1 - Palmer, Nicholette D A1 - Pankratz, Nathan A1 - Peloso, Gina M A1 - Peyser, Patricia A A1 - Pleiness, Jacob A1 - Post, Wendy S A1 - Psaty, Bruce M A1 - Rao, D C A1 - Redline, Susan A1 - Reiner, Alexander P A1 - Roden, Dan A1 - Rotter, Jerome I A1 - Ruczinski, Ingo A1 - Sarnowski, Chloe A1 - Schoenherr, Sebastian A1 - Schwartz, David A A1 - Seo, Jeong-Sun A1 - Seshadri, Sudha A1 - Sheehan, Vivien A A1 - Sheu, Wayne H A1 - Shoemaker, M Benjamin A1 - Smith, Nicholas L A1 - Smith, Jennifer A A1 - Sotoodehnia, Nona A1 - Stilp, Adrienne M A1 - Tang, Weihong A1 - Taylor, Kent D A1 - Telen, Marilyn A1 - Thornton, Timothy A A1 - Tracy, Russell P A1 - Van Den Berg, David J A1 - Vasan, Ramachandran S A1 - Viaud-Martinez, Karine A A1 - Vrieze, Scott A1 - Weeks, Daniel E A1 - Weir, Bruce S A1 - Weiss, Scott T A1 - Weng, Lu-Chen A1 - Willer, Cristen J A1 - Zhang, Yingze A1 - Zhao, Xutong A1 - Arnett, Donna K A1 - Ashley-Koch, Allison E A1 - Barnes, Kathleen C A1 - Boerwinkle, Eric A1 - Gabriel, Stacey A1 - Gibbs, Richard A1 - Rice, Kenneth M A1 - Rich, Stephen S A1 - Silverman, Edwin K A1 - Qasba, Pankaj A1 - Gan, Weiniu A1 - Papanicolaou, George J A1 - Nickerson, Deborah A A1 - Browning, Sharon R A1 - Zody, Michael C A1 - Zöllner, Sebastian A1 - Wilson, James G A1 - Cupples, L Adrienne A1 - Laurie, Cathy C A1 - Jaquish, Cashell E A1 - Hernandez, Ryan D A1 - O'Connor, Timothy D A1 - Abecasis, Goncalo R AB -

The Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases. The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data. The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and Phenotypes). In the first 53,831 TOPMed samples, we detected more than 400 million single-nucleotide and insertion or deletion variants after alignment with the reference genome. Additional previously undescribed variants were detected through assembly of unmapped reads and customized analysis in highly variable loci. Among the more than 400 million detected variants, 97% have frequencies of less than 1% and 46% are singletons that are present in only one individual (53% among unrelated individuals). These rare variants provide insights into mutational processes and recent human evolutionary history. The extensive catalogue of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and noncoding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and reach of genome-wide association studies to include variants down to a frequency of approximately 0.01%.

VL - 590 IS - 7845 ER - TY - JOUR T1 - A System for Phenotype Harmonization in the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program. JF - Am J Epidemiol Y1 - 2021 A1 - Stilp, Adrienne M A1 - Emery, Leslie S A1 - Broome, Jai G A1 - Buth, Erin J A1 - Khan, Alyna T A1 - Laurie, Cecelia A A1 - Wang, Fei Fei A1 - Wong, Quenna A1 - Chen, Dongquan A1 - D'Augustine, Catherine M A1 - Heard-Costa, Nancy L A1 - Hohensee, Chancellor R A1 - Johnson, William Craig A1 - Juarez, Lucia D A1 - Liu, Jingmin A1 - Mutalik, Karen M A1 - Raffield, Laura M A1 - Wiggins, Kerri L A1 - de Vries, Paul S A1 - Kelly, Tanika N A1 - Kooperberg, Charles A1 - Natarajan, Pradeep A1 - Peloso, Gina M A1 - Peyser, Patricia A A1 - Reiner, Alex P A1 - Arnett, Donna K A1 - Aslibekyan, Stella A1 - Barnes, Kathleen C A1 - Bielak, Lawrence F A1 - Bis, Joshua C A1 - Cade, Brian E A1 - Chen, Ming-Huei A1 - Correa, Adolfo A1 - Cupples, L Adrienne A1 - de Andrade, Mariza A1 - Ellinor, Patrick T A1 - Fornage, Myriam A1 - Franceschini, Nora A1 - Gan, Weiniu A1 - Ganesh, Santhi K A1 - Graffelman, Jan A1 - Grove, Megan L A1 - Guo, Xiuqing A1 - Hawley, Nicola L A1 - Hsu, Wan-Ling A1 - Jackson, Rebecca D A1 - Jaquish, Cashell E A1 - Johnson, Andrew D A1 - Kardia, Sharon L R A1 - Kelly, Shannon A1 - Lee, Jiwon A1 - Mathias, Rasika A A1 - McGarvey, Stephen T A1 - Mitchell, Braxton D A1 - Montasser, May E A1 - Morrison, Alanna C A1 - North, Kari E A1 - Nouraie, Seyed Mehdi A1 - Oelsner, Elizabeth C A1 - Pankratz, Nathan A1 - Rich, Stephen S A1 - Rotter, Jerome I A1 - Smith, Jennifer A A1 - Taylor, Kent D A1 - Vasan, Ramachandran S A1 - Weeks, Daniel E A1 - Weiss, Scott T A1 - Wilson, Carla G A1 - Yanek, Lisa R A1 - Psaty, Bruce M A1 - Heckbert, Susan R A1 - Laurie, Cathy C AB -

Genotype-phenotype association studies often combine phenotype data from multiple studies to increase power. Harmonization of the data usually requires substantial effort due to heterogeneity in phenotype definitions, study design, data collection procedures, and data set organization. Here we describe a centralized system for phenotype harmonization that includes input from phenotype domain and study experts, quality control, documentation, reproducible results, and data sharing mechanisms. This system was developed for the National Heart, Lung and Blood Institute's Trans-Omics for Precision Medicine program, which is generating genomic and other omics data for >80 studies with extensive phenotype data. To date, 63 phenotypes have been harmonized across thousands of participants from up to 17 studies per phenotype (participants recruited 1948-2012). We discuss challenges in this undertaking and how they were addressed. The harmonized phenotype data and associated documentation have been submitted to National Institutes of Health data repositories for controlled-access by the scientific community. We also provide materials to facilitate future harmonization efforts by the community, which include (1) the code used to generate the 63 harmonized phenotypes, enabling others to reproduce, modify or extend these harmonizations to additional studies; and (2) results of labeling thousands of phenotype variables with controlled vocabulary terms.

ER - TY - JOUR T1 - Whole genome sequence analyses of eGFR in 23,732 people representing multiple ancestries in the NHLBI trans-omics for precision medicine (TOPMed) consortium. JF - EBioMedicine Y1 - 2021 A1 - Lin, Bridget M A1 - Grinde, Kelsey E A1 - Brody, Jennifer A A1 - Breeze, Charles E A1 - Raffield, Laura M A1 - Mychaleckyj, Josyf C A1 - Thornton, Timothy A A1 - Perry, James A A1 - Baier, Leslie J A1 - de Las Fuentes, Lisa A1 - Guo, Xiuqing A1 - Heavner, Benjamin D A1 - Hanson, Robert L A1 - Hung, Yi-Jen A1 - Qian, Huijun A1 - Hsiung, Chao A A1 - Hwang, Shih-Jen A1 - Irvin, Margaret R A1 - Jain, Deepti A1 - Kelly, Tanika N A1 - Kobes, Sayuko A1 - Lange, Leslie A1 - Lash, James P A1 - Li, Yun A1 - Liu, Xiaoming A1 - Mi, Xuenan A1 - Musani, Solomon K A1 - Papanicolaou, George J A1 - Parsa, Afshin A1 - Reiner, Alex P A1 - Salimi, Shabnam A1 - Sheu, Wayne H-H A1 - Shuldiner, Alan R A1 - Taylor, Kent D A1 - Smith, Albert V A1 - Smith, Jennifer A A1 - Tin, Adrienne A1 - Vaidya, Dhananjay A1 - Wallace, Robert B A1 - Yamamoto, Kenichi A1 - Sakaue, Saori A1 - Matsuda, Koichi A1 - Kamatani, Yoichiro A1 - Momozawa, Yukihide A1 - Yanek, Lisa R A1 - Young, Betsi A A1 - Zhao, Wei A1 - Okada, Yukinori A1 - Abecasis, Gonzalo A1 - Psaty, Bruce M A1 - Arnett, Donna K A1 - Boerwinkle, Eric A1 - Cai, Jianwen A1 - Yii-Der Chen, Ida A1 - Correa, Adolfo A1 - Cupples, L Adrienne A1 - He, Jiang A1 - Kardia, Sharon Lr A1 - Kooperberg, Charles A1 - Mathias, Rasika A A1 - Mitchell, Braxton D A1 - Nickerson, Deborah A A1 - Turner, Steve T A1 - Vasan, Ramachandran S A1 - Rotter, Jerome I A1 - Levy, Daniel A1 - Kramer, Holly J A1 - Köttgen, Anna A1 - Rich, Stephen S A1 - Lin, Dan-Yu A1 - Browning, Sharon R A1 - Franceschini, Nora AB -

BACKGROUND: Genetic factors that influence kidney traits have been understudied for low frequency and ancestry-specific variants.

METHODS: We combined whole genome sequencing (WGS) data from 23,732 participants from 10 NHLBI Trans-Omics for Precision Medicine (TOPMed) Program multi-ethnic studies to identify novel loci for estimated glomerular filtration rate (eGFR). Participants included European, African, East Asian, and Hispanic ancestries. We applied linear mixed models using a genetic relationship matrix estimated from the WGS data and adjusted for age, sex, study, and ethnicity.

FINDINGS: When testing single variants, we identified three novel loci driven by low frequency variants more commonly observed in non-European ancestry (PRKAA2, rs180996919, minor allele frequency [MAF] 0.04%, P = 6.1 × 10; METTL8, rs116951054, MAF 0.09%, P = 4.5 × 10; and MATK, rs539182790, MAF 0.05%, P = 3.4 × 10). We also replicated two known loci for common variants (rs2461702, MAF=0.49, P = 1.2 × 10, nearest gene GATM, and rs71147340, MAF=0.34, P = 3.3 × 10, CDK12). Testing aggregated variants within a gene identified the MAF gene. A statistical approach based on local ancestry helped to identify replication samples for ancestry-specific variants.

INTERPRETATION: This study highlights challenges in studying variants influencing kidney traits that are low frequency in populations and more common in non-European ancestry.

VL - 63 ER - TY - JOUR T1 - Clonal Hematopoiesis of Indeterminate Potential and Kidney Function Decline in the General Population. JF - Am J Kidney Dis Y1 - 2022 A1 - Kestenbaum, Bryan A1 - Bick, Alexander G A1 - Vlasschaert, Caitlyn A1 - Rauh, Michael J A1 - Lanktree, Matthew B A1 - Franceschini, Nora A1 - Shoemaker, Moore B A1 - Harris, Raymond C A1 - Psaty, Bruce M A1 - Köttgen, Anna A1 - Natarajan, Pradeep A1 - Robinson-Cohen, Cassianne AB -

RATIONALE & OBJECTIVE: Clonal hematopoiesis of indeterminate potential (CHIP), defined by the age-related ontogenesis of expanded leukemogenic variants indicative of a genetically distinct clonal leukocyte population, is associated with risk of hematologic malignancy and cardiovascular disease. In experimental models, recapitulation of CHIP promotes kidney interstitial fibrosis with direct tissue infiltration of donor macrophages. We tested the hypothesis that CHIP is associated with kidney function decline in the general population.

STUDY DESIGN: Cohort study.

SETTING & PARTICIPANTS: 12,004 individuals from 3 community-based cohorts in the TOPMed Consortium.

EXPOSURE: CHIP status from whole-genome sequences obtained from DNA extracted from peripheral blood.

OUTCOME: Risk of 30% decline in estimated glomerular filtration rate (eGFR) and percent eGFR decline per year during the follow-up period.

ANALYTICAL APPROACH: Cox proportional hazards models for 30% eGFR decline end point and generalized estimating equations for annualized relative change in eGFR with meta-analysis. Study-specific estimates were combined using fixed-effect meta-analysis.

RESULTS: The median baseline eGFR was 84mL/min/1.73m. The prevalence of CHIP was 6.6%, 9.0%, and 12.2% in persons aged 50-60, 60-70, and>70 years, respectively. Over a median follow-up period of 8 years, for the 30% eGFR outcome 205 events occurred among 1,002 CHIP carriers (2.1 events per 100 person-years) and 2,041 events in persons without CHIP (1.7 events per 100 person-years). In meta-analysis, CHIP was associated with greater risk of a 30% eGFR decline (17% [95% CI, 1%-36%] higher; P=0.04). Differences were not observed between those with baseline eGFR above or below 60mL/min/1.73m, of age above or below 60 years, or with or without diabetes.

LIMITATIONS: Small number of participants with moderate-to-advanced kidney disease and restricted set of CHIP driver variants.

CONCLUSIONS: We report an association between CHIP and eGFR decline in 3 general population cohorts without known kidney disease. Further studies are needed to investigate this novel condition and its potential impact among individuals with overt kidney disease.

ER - TY - JOUR T1 - Correlations between complex human phenotypes vary by genetic background, gender, and environment. JF - Cell Rep Med Y1 - 2022 A1 - Elgart, Michael A1 - Goodman, Matthew O A1 - Isasi, Carmen A1 - Chen, Han A1 - Morrison, Alanna C A1 - de Vries, Paul S A1 - Xu, Huichun A1 - Manichaikul, Ani W A1 - Guo, Xiuqing A1 - Franceschini, Nora A1 - Psaty, Bruce M A1 - Rich, Stephen S A1 - Rotter, Jerome I A1 - Lloyd-Jones, Donald M A1 - Fornage, Myriam A1 - Correa, Adolfo A1 - Heard-Costa, Nancy L A1 - Vasan, Ramachandran S A1 - Hernandez, Ryan A1 - Kaplan, Robert C A1 - Redline, Susan A1 - Sofer, Tamar KW - Female KW - Genetic Background KW - Humans KW - Male KW - Phenotype AB -

We develop a closed-form Haseman-Elston estimator for genetic and environmental correlation coefficients between complex phenotypes, which we term HEc, that is as precise as GCTA yet ∼20× faster. We estimate genetic and environmental correlations between over 7,000 phenotype pairs in subgroups from the Trans-Omics in Precision Medicine (TOPMed) program. We demonstrate substantial differences in both heritabilities and genetic correlations for multiple phenotypes and phenotype pairs between individuals of self-reported Black, Hispanic/Latino, and White backgrounds. We similarly observe differences in many of the genetic and environmental correlations between genders. To estimate the contribution of genetics to the observed phenotypic correlation, we introduce "fractional genetic correlation" as the fraction of phenotypic correlation explained by genetics. Finally, we quantify the enrichment of correlations between phenotypic domains, each of which is comprised of multiple phenotypes. Altogether, we demonstrate that the observed correlations between complex human phenotypes depend on the genetic background of the individuals, their gender, and their environment.

VL - 3 IS - 12 ER - TY - JOUR T1 - A framework for detecting noncoding rare-variant associations of large-scale whole-genome sequencing studies. JF - Nat Methods Y1 - 2022 A1 - Li, Zilin A1 - Li, Xihao A1 - Zhou, Hufeng A1 - Gaynor, Sheila M A1 - Selvaraj, Margaret Sunitha A1 - Arapoglou, Theodore A1 - Quick, Corbin A1 - Liu, Yaowu A1 - Chen, Han A1 - Sun, Ryan A1 - Dey, Rounak A1 - Arnett, Donna K A1 - Auer, Paul L A1 - Bielak, Lawrence F A1 - Bis, Joshua C A1 - Blackwell, Thomas W A1 - Blangero, John A1 - Boerwinkle, Eric A1 - Bowden, Donald W A1 - Brody, Jennifer A A1 - Cade, Brian E A1 - Conomos, Matthew P A1 - Correa, Adolfo A1 - Cupples, L Adrienne A1 - Curran, Joanne E A1 - de Vries, Paul S A1 - Duggirala, Ravindranath A1 - Franceschini, Nora A1 - Freedman, Barry I A1 - Göring, Harald H H A1 - Guo, Xiuqing A1 - Kalyani, Rita R A1 - Kooperberg, Charles A1 - Kral, Brian G A1 - Lange, Leslie A A1 - Lin, Bridget M A1 - Manichaikul, Ani A1 - Manning, Alisa K A1 - Martin, Lisa W A1 - Mathias, Rasika A A1 - Meigs, James B A1 - Mitchell, Braxton D A1 - Montasser, May E A1 - Morrison, Alanna C A1 - Naseri, Take A1 - O'Connell, Jeffrey R A1 - Palmer, Nicholette D A1 - Peyser, Patricia A A1 - Psaty, Bruce M A1 - Raffield, Laura M A1 - Redline, Susan A1 - Reiner, Alexander P A1 - Reupena, Muagututi'a Sefuiva A1 - Rice, Kenneth M A1 - Rich, Stephen S A1 - Smith, Jennifer A A1 - Taylor, Kent D A1 - Taub, Margaret A A1 - Vasan, Ramachandran S A1 - Weeks, Daniel E A1 - Wilson, James G A1 - Yanek, Lisa R A1 - Zhao, Wei A1 - Rotter, Jerome I A1 - Willer, Cristen J A1 - Natarajan, Pradeep A1 - Peloso, Gina M A1 - Lin, Xihong KW - Genetic Variation KW - Genome KW - Genome-Wide Association Study KW - Humans KW - Phenotype KW - Whole Genome Sequencing AB -

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

VL - 19 IS - 12 ER - TY - JOUR T1 - Insights From a Large-Scale Whole-Genome Sequencing Study of Systolic Blood Pressure, Diastolic Blood Pressure, and Hypertension. JF - Hypertension Y1 - 2022 A1 - Kelly, Tanika N A1 - Sun, Xiao A1 - He, Karen Y A1 - Brown, Michael R A1 - Taliun, Sarah A Gagliano A1 - Hellwege, Jacklyn N A1 - Irvin, Marguerite R A1 - Mi, Xuenan A1 - Brody, Jennifer A A1 - Franceschini, Nora A1 - Guo, Xiuqing A1 - Hwang, Shih-Jen A1 - de Vries, Paul S A1 - Gao, Yan A1 - Moscati, Arden A1 - Nadkarni, Girish N A1 - Yanek, Lisa R A1 - Elfassy, Tali A1 - Smith, Jennifer A A1 - Chung, Ren-Hua A1 - Beitelshees, Amber L A1 - Patki, Amit A1 - Aslibekyan, Stella A1 - Blobner, Brandon M A1 - Peralta, Juan M A1 - Assimes, Themistocles L A1 - Palmas, Walter R A1 - Liu, Chunyu A1 - Bress, Adam P A1 - Huang, Zhijie A1 - Becker, Lewis C A1 - Hwa, Chii-Min A1 - O'Connell, Jeffrey R A1 - Carlson, Jenna C A1 - Warren, Helen R A1 - Das, Sayantan A1 - Giri, Ayush A1 - Martin, Lisa W A1 - Craig Johnson, W A1 - Fox, Ervin R A1 - Bottinger, Erwin P A1 - Razavi, Alexander C A1 - Vaidya, Dhananjay A1 - Chuang, Lee-Ming A1 - Chang, Yen-Pei C A1 - Naseri, Take A1 - Jain, Deepti A1 - Kang, Hyun Min A1 - Hung, Adriana M A1 - Srinivasasainagendra, Vinodh A1 - Snively, Beverly M A1 - Gu, Dongfeng A1 - Montasser, May E A1 - Reupena, Muagututi'a Sefuiva A1 - Heavner, Benjamin D A1 - LeFaive, Jonathon A1 - Hixson, James E A1 - Rice, Kenneth M A1 - Wang, Fei Fei A1 - Nielsen, Jonas B A1 - Huang, Jianfeng A1 - Khan, Alyna T A1 - Zhou, Wei A1 - Nierenberg, Jovia L A1 - Laurie, Cathy C A1 - Armstrong, Nicole D A1 - Shi, Mengyao A1 - Pan, Yang A1 - Stilp, Adrienne M A1 - Emery, Leslie A1 - Wong, Quenna A1 - Hawley, Nicola L A1 - Minster, Ryan L A1 - Curran, Joanne E A1 - Munroe, Patricia B A1 - Weeks, Daniel E A1 - North, Kari E A1 - Tracy, Russell P A1 - Kenny, Eimear E A1 - Shimbo, Daichi A1 - Chakravarti, Aravinda A1 - Rich, Stephen S A1 - Reiner, Alex P A1 - Blangero, John A1 - Redline, Susan A1 - Mitchell, Braxton D A1 - Rao, Dabeeru C A1 - Ida Chen, Yii-Der A1 - Kardia, Sharon L R A1 - Kaplan, Robert C A1 - Mathias, Rasika A A1 - He, Jiang A1 - Psaty, Bruce M A1 - Fornage, Myriam A1 - Loos, Ruth J F A1 - Correa, Adolfo A1 - Boerwinkle, Eric A1 - Rotter, Jerome I A1 - Kooperberg, Charles A1 - Edwards, Todd L A1 - Abecasis, Goncalo R A1 - Zhu, Xiaofeng A1 - Levy, Daniel A1 - Arnett, Donna K A1 - Morrison, Alanna C AB -

BACKGROUND: The availability of whole-genome sequencing data in large studies has enabled the assessment of coding and noncoding variants across the allele frequency spectrum for their associations with blood pressure.

METHODS: We conducted a multiancestry whole-genome sequencing analysis of blood pressure among 51 456 Trans-Omics for Precision Medicine and Centers for Common Disease Genomics program participants (stage-1). Stage-2 analyses leveraged array data from UK Biobank (N=383 145), Million Veteran Program (N=318 891), and Reasons for Geographic and Racial Differences in Stroke (N=10 643) participants, along with whole-exome sequencing data from UK Biobank (N=199 631) participants.

RESULTS: Two blood pressure signals achieved genome-wide significance in meta-analyses of stage-1 and stage-2 single variant findings (<5×10). Among them, a rare intergenic variant at novel locus, , was associated with lower systolic blood pressure in stage-1 (beta [SE]=-32.6 [6.0]; =4.99×10) but not stage-2 analysis (=0.11). Furthermore, a novel common variant at the known locus was suggestively associated with diastolic blood pressure in stage-1 (beta [SE]=-0.36 [0.07]; =4.18×10) and attained genome-wide significance in stage-2 (beta [SE]=-0.29 [0.03]; =7.28×10). Nineteen additional signals suggestively associated with blood pressure in meta-analysis of single and aggregate rare variant findings (<1×10 and <1×10, respectively).

DISCUSSION: We report one promising but unconfirmed rare variant for blood pressure and, more importantly, contribute insights for future blood pressure sequencing studies. Our findings suggest promise of aggregate analyses to complement single variant analysis strategies and the need for larger, diverse samples, and family studies to enable robust rare variant identification.

ER - TY - JOUR T1 - A multi-ethnic polygenic risk score is associated with hypertension prevalence and progression throughout adulthood. JF - Nat Commun Y1 - 2022 A1 - Kurniansyah, Nuzulul A1 - Goodman, Matthew O A1 - Kelly, Tanika N A1 - Elfassy, Tali A1 - Wiggins, Kerri L A1 - Bis, Joshua C A1 - Guo, Xiuqing A1 - Palmas, Walter A1 - Taylor, Kent D A1 - Lin, Henry J A1 - Haessler, Jeffrey A1 - Gao, Yan A1 - Shimbo, Daichi A1 - Smith, Jennifer A A1 - Yu, Bing A1 - Feofanova, Elena V A1 - Smit, Roelof A J A1 - Wang, Zhe A1 - Hwang, Shih-Jen A1 - Liu, Simin A1 - Wassertheil-Smoller, Sylvia A1 - Manson, JoAnn E A1 - Lloyd-Jones, Donald M A1 - Rich, Stephen S A1 - Loos, Ruth J F A1 - Redline, Susan A1 - Correa, Adolfo A1 - Kooperberg, Charles A1 - Fornage, Myriam A1 - Kaplan, Robert C A1 - Psaty, Bruce M A1 - Rotter, Jerome I A1 - Arnett, Donna K A1 - Morrison, Alanna C A1 - Franceschini, Nora A1 - Levy, Daniel A1 - Sofer, Tamar KW - Adult KW - Diabetes Mellitus, Type 2 KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Hypertension KW - Multifactorial Inheritance KW - Prevalence KW - Risk Factors AB -

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

VL - 13 IS - 1 ER - TY - JOUR T1 - Whole-Exome Sequencing Study Identifies Four Novel Gene Loci Associated with Diabetic Kidney Disease. JF - Hum Mol Genet Y1 - 2022 A1 - Pan, Yang A1 - Sun, Xiao A1 - Mi, Xuenan A1 - Huang, Zhijie A1 - Hsu, Yenchih A1 - Hixson, James E A1 - Munzy, Donna A1 - Metcalf, Ginger A1 - Franceschini, Nora A1 - Tin, Adrienne A1 - Köttgen, Anna A1 - Francis, Michael A1 - Brody, Jennifer A A1 - Kestenbaum, Bryan A1 - Sitlani, Colleen M A1 - Mychaleckyj, Josyf C A1 - Kramer, Holly A1 - Lange, Leslie A A1 - Guo, Xiuqing A1 - Hwang, Shih-Jen A1 - Irvin, Marguerite R A1 - Smith, Jennifer A A1 - Yanek, Lisa R A1 - Vaidya, Dhananjay A1 - Chen, Yii-Der Ida A1 - Fornage, Myriam A1 - Lloyd-Jones, Donald M A1 - Hou, Lifang A1 - Mathias, Rasika A A1 - Mitchell, Braxton D A1 - Peyser, Patricia A A1 - Kardia, Sharon L R A1 - Arnett, Donna K A1 - Correa, Adolfo A1 - Raffield, Laura M A1 - Vasan, Ramachandran S A1 - Cupple, L Adrienne A1 - Levy, Daniel A1 - Kaplan, Robert C A1 - North, Kari E A1 - Rotter, Jerome I A1 - Kooperberg, Charles A1 - Reiner, Alexander P A1 - Psaty, Bruce M A1 - Tracy, Russell P A1 - Gibbs, Richard A A1 - Morrison, Alanna C A1 - Feldman, Harold A1 - Boerwinkle, Eric A1 - He, Jiang A1 - Kelly, Tanika N AB -

Diabetic kidney disease (DKD) is recognized as an important public health challenge. However, its genomic mechanisms are poorly understood. To identify rare variants for DKD, we conducted a whole-exome sequencing (WES) study leveraging large cohorts well-phenotyped for chronic kidney disease (CKD) and diabetes. Our two-stage whole-exome sequencing study included 4372 European and African ancestry participants from the Chronic Renal Insufficiency Cohort (CRIC) and Atherosclerosis Risk in Communities (ARIC) studies (stage-1) and 11 487 multi-ancestry Trans-Omics for Precision Medicine (TOPMed) participants (stage-2). Generalized linear mixed models, which accounted for genetic relatedness and adjusted for age, sex, and ancestry, were used to test associations between single variants and DKD. Gene-based aggregate rare variant analyses were conducted using an optimized sequence kernel association test (SKAT-O) implemented within our mixed model framework. We identified four novel exome-wide significant DKD-related loci through initiating diabetes. In single variant analyses, participants carrying a rare, in-frame insertion in the DIS3L2 gene (rs141560952) exhibited a 193-fold increased odds (95% confidence interval: 33.6, 1105) of DKD compared with non-carriers (P = 3.59 × 10-9). Likewise, each copy of a low-frequency KRT6B splice-site variant (rs425827) conferred a 5.31-fold higher odds (95% confidence interval: 3.06, 9.21) of DKD (P = 2.72 × 10-9). Aggregate gene-based analyses further identified ERAP2 (P = 4.03 × 10-8) and NPEPPS (P = 1.51 × 10-7), which are both expressed in the kidney and implicated in renin-angiotensin-aldosterone system modulated immune response. In the largest WES study of DKD, we identified novel rare variant loci attaining exome-wide significance. These findings provide new insights into the molecular mechanisms underlying DKD.

ER - TY - JOUR T1 - Clonal Hematopoiesis of Indeterminate Potential is Associated with Acute Kidney Injury. JF - medRxiv Y1 - 2023 A1 - Vlasschaert, Caitlyn A1 - Robinson-Cohen, Cassianne A1 - Kestenbaum, Bryan A1 - Silver, Samuel A A1 - Chen, Jian-Chun A1 - Akwo, Elvis A1 - Bhatraju, Pavan K A1 - Zhang, Ming-Zhi A1 - Cao, Shirong A1 - Jiang, Ming A1 - Wang, Yinqiu A1 - Niu, Aolei A1 - Siew, Edward A1 - Kramer, Holly J A1 - Köttgen, Anna A1 - Franceschini, Nora A1 - Psaty, Bruce M A1 - Tracy, Russell P A1 - Alonso, Alvaro A1 - Arking, Dan E A1 - Coresh, Josef A1 - Ballantyne, Christie M A1 - Boerwinkle, Eric A1 - Grams, Morgan A1 - Lanktree, Matthew B A1 - Rauh, Michael J A1 - Harris, Raymond C A1 - Bick, Alexander G AB -

Age is a predominant risk factor for acute kidney injury (AKI), yet the biological mechanisms underlying this risk are largely unknown and to date no genetic mechanisms for AKI have been established. Clonal hematopoiesis of indeterminate potential (CHIP) is a recently recognized biological mechanism conferring risk of several chronic aging diseases including cardiovascular disease, pulmonary disease and liver disease. In CHIP, blood stem cells acquire mutations in myeloid cancer driver genes such as and and the myeloid progeny of these mutated cells contribute to end-organ damage through inflammatory dysregulation. We sought to establish whether CHIP causes acute kidney injury (AKI). To address this question, we first evaluated associations with incident AKI events in three population-based epidemiology cohorts (N = 442,153). We found that CHIP was associated with a greater risk of AKI (adjusted HR 1.26, 95% CI: 1.19-1.34, p<0.0001), which was more pronounced in patients with AKI requiring dialysis (adjusted HR 1.65, 95% CI: 1.24-2.20, p=0.001). The risk was particularly high in the subset of individuals where CHIP was driven by mutations in genes other than (HR: 1.49, 95% CI: 1.37-1.61, p<0.0001). We then examined the association between CHIP and recovery from AKI in the ASSESS-AKI cohort and identified that non- CHIP was more common among those with a non-resolving pattern of injury (HR 2.3, 95% CI: 1.14-4.64, p = 0.03). To gain mechanistic insight, we evaluated the role of -CHIP to AKI in ischemia-reperfusion injury (IRI) and unilateral ureteral obstruction (UUO) mouse models. In both models, we observed more severe AKI and greater post-AKI kidney fibrosis in -CHIP mice. Kidney macrophage infiltration was markedly increased in -CHIP mice and -CHIP mutant renal macrophages displayed greater pro-inflammatory responses. In summary, this work establishes CHIP as a genetic mechanism conferring risk of AKI and impaired kidney function recovery following AKI via an aberrant inflammatory response in CHIP derived renal macrophages.

ER - TY - JOUR T1 - Determinants of mosaic chromosomal alteration fitness. JF - medRxiv Y1 - 2023 A1 - Pershad, Yash A1 - Mack, Taralynn A1 - Poisner, Hannah A1 - Jakubek, Yasminka A A1 - Stilp, Adrienne M A1 - Mitchell, Braxton D A1 - Lewis, Joshua P A1 - Boerwinkle, Eric A1 - Loos, Ruth J A1 - Chami, Nathalie A1 - Wang, Zhe A1 - Barnes, Kathleen A1 - Pankratz, Nathan A1 - Fornage, Myriam A1 - Redline, Susan A1 - Psaty, Bruce M A1 - Bis, Joshua C A1 - Shojaie, Ali A1 - Silverman, Edwin K A1 - Cho, Michael H A1 - Yun, Jeong A1 - DeMeo, Dawn A1 - Levy, Daniel A1 - Johnson, Andrew A1 - Mathias, Rasika A1 - Taub, Margaret A1 - Arnett, Donna A1 - North, Kari A1 - Raffield, Laura M A1 - Carson, April A1 - Doyle, Margaret F A1 - Rich, Stephen S A1 - Rotter, Jerome I A1 - Guo, Xiuqing A1 - Cox, Nancy A1 - Roden, Dan M A1 - Franceschini, Nora A1 - Desai, Pinkal A1 - Reiner, Alex A1 - Auer, Paul L A1 - Scheet, Paul A1 - Jaiswal, Siddhartha A1 - Weinstock, Joshua S A1 - Bick, Alexander G AB -

Clonal hematopoiesis (CH) is characterized by the acquisition of a somatic mutation in a hematopoietic stem cell that results in a clonal expansion. These driver mutations can be single nucleotide variants in cancer driver genes or larger structural rearrangements called mosaic chromosomal alterations (mCAs). The factors that influence the variations in mCA fitness and ultimately result in different clonal expansion rates are not well-understood. We used the Passenger-Approximated Clonal Expansion Rate (PACER) method to estimate clonal expansion rate for 6,381 individuals in the NHLBI TOPMed cohort with gain, loss, and copy-neutral loss of heterozygosity mCAs. Our estimates of mCA fitness were correlated (R = 0.49) with an alternative approach that estimated fitness of mCAs in the UK Biobank using a theoretical probability distribution. Individuals with lymphoid-associated mCAs had a significantly higher white blood cell count and faster clonal expansion rate. In a cross-sectional analysis, genome-wide association study of estimates of mCA expansion rate identified , , and locus variants as modulators of mCA clonal expansion rate.

ER - TY - JOUR T1 - Evaluating the use of blood pressure polygenic risk scores across race/ethnic background groups. JF - Nat Commun Y1 - 2023 A1 - Kurniansyah, Nuzulul A1 - Goodman, Matthew O A1 - Khan, Alyna T A1 - Wang, Jiongming A1 - Feofanova, Elena A1 - Bis, Joshua C A1 - Wiggins, Kerri L A1 - Huffman, Jennifer E A1 - Kelly, Tanika A1 - Elfassy, Tali A1 - Guo, Xiuqing A1 - Palmas, Walter A1 - Lin, Henry J A1 - Hwang, Shih-Jen A1 - Gao, Yan A1 - Young, Kendra A1 - Kinney, Gregory L A1 - Smith, Jennifer A A1 - Yu, Bing A1 - Liu, Simin A1 - Wassertheil-Smoller, Sylvia A1 - Manson, JoAnn E A1 - Zhu, Xiaofeng A1 - Chen, Yii-Der Ida A1 - Lee, I-Te A1 - Gu, C Charles A1 - Lloyd-Jones, Donald M A1 - Zöllner, Sebastian A1 - Fornage, Myriam A1 - Kooperberg, Charles A1 - Correa, Adolfo A1 - Psaty, Bruce M A1 - Arnett, Donna K A1 - Isasi, Carmen R A1 - Rich, Stephen S A1 - Kaplan, Robert C A1 - Redline, Susan A1 - Mitchell, Braxton D A1 - Franceschini, Nora A1 - Levy, Daniel A1 - Rotter, Jerome I A1 - Morrison, Alanna C A1 - Sofer, Tamar KW - Blood Pressure KW - Ethnicity KW - Female KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Male KW - Multifactorial Inheritance KW - Population Health KW - Risk Factors AB -

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

VL - 14 IS - 1 ER - TY - JOUR T1 - Genome-Wide Interaction Analysis with DASH Diet Score Identified Novel Loci for Systolic Blood Pressure. JF - medRxiv Y1 - 2023 A1 - Guirette, Melanie A1 - Lan, Jessie A1 - McKeown, Nicola A1 - Brown, Michael R A1 - Chen, Han A1 - de Vries, Paul S A1 - Kim, Hyunju A1 - Rebholz, Casey M A1 - Morrison, Alanna C A1 - Bartz, Traci M A1 - Fretts, Amanda M A1 - Guo, Xiuqing A1 - Lemaitre, Rozenn N A1 - Liu, Ching-Ti A1 - Noordam, Raymond A1 - de Mutsert, Renée A1 - Rosendaal, Frits R A1 - Wang, Carol A A1 - Beilin, Lawrence A1 - Mori, Trevor A A1 - Oddy, Wendy H A1 - Pennell, Craig E A1 - Chai, Jin Fang A1 - Whitton, Clare A1 - van Dam, Rob M A1 - Liu, Jianjun A1 - Tai, E Shyong A1 - Sim, Xueling A1 - Neuhouser, Marian L A1 - Kooperberg, Charles A1 - Tinker, Lesley A1 - Franceschini, Nora A1 - Huan, Tianxiao A1 - Winkler, Thomas W A1 - Bentley, Amy R A1 - Gauderman, W James A1 - Heerkens, Luc A1 - Tanaka, Toshiko A1 - van Rooij, Jeroen A1 - Munroe, Patricia B A1 - Warren, Helen R A1 - Voortman, Trudy A1 - Chen, Honglei A1 - Rao, D C A1 - Levy, Daniel A1 - Ma, Jiantao AB -

OBJECTIVE: We examined interactions between genotype and a Dietary Approaches to Stop Hypertension (DASH) diet score in relation to systolic blood pressure (SBP).

METHODS: We analyzed up to 9,420,585 biallelic imputed single nucleotide polymorphisms (SNPs) in up to 127,282 individuals of six population groups (91% of European population) from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (CHARGE; n=35,660) and UK Biobank (n=91,622) and performed European population-specific and cross-population meta-analyses.

RESULTS: We identified three loci in European-specific analyses and an additional four loci in cross-population analyses at P for interaction < 5e-8. We observed a consistent interaction between rs117878928 at 15q25.1 (minor allele frequency = 0.03) and the DASH diet score (P for interaction = 4e-8; P for heterogeneity = 0.35) in European population, where the interaction effect size was 0.42±0.09 mm Hg (P for interaction = 9.4e-7) and 0.20±0.06 mm Hg (P for interaction = 0.001) in CHARGE and the UK Biobank, respectively. The 1 Mb region surrounding rs117878928 was enriched with -expression quantitative trait loci (eQTL) variants (P = 4e-273) and -DNA methylation quantitative trait loci (mQTL) variants (P = 1e-300). While the closest gene for rs117878928 is , the highest narrow sense heritability accounted by SNPs potentially interacting with the DASH diet score in this locus was for gene at 15q25.1.

CONCLUSION: We demonstrated gene-DASH diet score interaction effects on SBP in several loci. Studies with larger diverse populations are needed to validate our findings.

ER - TY - JOUR T1 - Multi-ancestry genome-wide study identifies effector genes and druggable pathways for coronary artery calcification. JF - Nat Genet Y1 - 2023 A1 - Kavousi, Maryam A1 - Bos, Maxime M A1 - Barnes, Hanna J A1 - Lino Cardenas, Christian L A1 - Wong, Doris A1 - Lu, Haojie A1 - Hodonsky, Chani J A1 - Landsmeer, Lennart P L A1 - Turner, Adam W A1 - Kho, Minjung A1 - Hasbani, Natalie R A1 - de Vries, Paul S A1 - Bowden, Donald W A1 - Chopade, Sandesh A1 - Deelen, Joris A1 - Benavente, Ernest Diez A1 - Guo, Xiuqing A1 - Hofer, Edith A1 - Hwang, Shih-Jen A1 - Lutz, Sharon M A1 - Lyytikäinen, Leo-Pekka A1 - Slenders, Lotte A1 - Smith, Albert V A1 - Stanislawski, Maggie A A1 - van Setten, Jessica A1 - Wong, Quenna A1 - Yanek, Lisa R A1 - Becker, Diane M A1 - Beekman, Marian A1 - Budoff, Matthew J A1 - Feitosa, Mary F A1 - Finan, Chris A1 - Hilliard, Austin T A1 - Kardia, Sharon L R A1 - Kovacic, Jason C A1 - Kral, Brian G A1 - Langefeld, Carl D A1 - Launer, Lenore J A1 - Malik, Shaista A1 - Hoesein, Firdaus A A Mohamed A1 - Mokry, Michal A1 - Schmidt, Reinhold A1 - Smith, Jennifer A A1 - Taylor, Kent D A1 - Terry, James G A1 - van der Grond, Jeroen A1 - van Meurs, Joyce A1 - Vliegenthart, Rozemarijn A1 - Xu, Jianzhao A1 - Young, Kendra A A1 - Zilhão, Nuno R A1 - Zweiker, Robert A1 - Assimes, Themistocles L A1 - Becker, Lewis C A1 - Bos, Daniel A1 - Carr, J Jeffrey A1 - Cupples, L Adrienne A1 - de Kleijn, Dominique P V A1 - de Winther, Menno A1 - den Ruijter, Hester M A1 - Fornage, Myriam A1 - Freedman, Barry I A1 - Gudnason, Vilmundur A1 - Hingorani, Aroon D A1 - Hokanson, John E A1 - Ikram, M Arfan A1 - Išgum, Ivana A1 - Jacobs, David R A1 - Kähönen, Mika A1 - Lange, Leslie A A1 - Lehtimäki, Terho A1 - Pasterkamp, Gerard A1 - Raitakari, Olli T A1 - Schmidt, Helena A1 - Slagboom, P Eline A1 - Uitterlinden, André G A1 - Vernooij, Meike W A1 - Bis, Joshua C A1 - Franceschini, Nora A1 - Psaty, Bruce M A1 - Post, Wendy S A1 - Rotter, Jerome I A1 - Björkegren, Johan L M A1 - O'Donnell, Christopher J A1 - Bielak, Lawrence F A1 - Peyser, Patricia A A1 - Malhotra, Rajeev A1 - van der Laan, Sander W A1 - Miller, Clint L AB -

Coronary artery calcification (CAC), a measure of subclinical atherosclerosis, predicts future symptomatic coronary artery disease (CAD). Identifying genetic risk factors for CAC may point to new therapeutic avenues for prevention. Currently, there are only four known risk loci for CAC identified from genome-wide association studies (GWAS) in the general population. Here we conducted the largest multi-ancestry GWAS meta-analysis of CAC to date, which comprised 26,909 individuals of European ancestry and 8,867 individuals of African ancestry. We identified 11 independent risk loci, of which eight were new for CAC and five had not been reported for CAD. These new CAC loci are related to bone mineralization, phosphate catabolism and hormone metabolic pathways. Several new loci harbor candidate causal genes supported by multiple lines of functional evidence and are regulators of smooth muscle cell-mediated calcification ex vivo and in vitro. Together, these findings help refine the genetic architecture of CAC and extend our understanding of the biological and potential druggable pathways underlying CAC.

VL - 55 IS - 10 ER - TY - JOUR T1 - A statistical framework for powerful multi-trait rare variant analysis in large-scale whole-genome sequencing studies. JF - bioRxiv Y1 - 2023 A1 - Li, Xihao A1 - Chen, Han A1 - Selvaraj, Margaret Sunitha A1 - Van Buren, Eric A1 - Zhou, Hufeng A1 - Wang, Yuxuan A1 - Sun, Ryan A1 - McCaw, Zachary R A1 - Yu, Zhi A1 - Arnett, Donna K A1 - Bis, Joshua C A1 - Blangero, John A1 - Boerwinkle, Eric A1 - Bowden, Donald W A1 - Brody, Jennifer A A1 - Cade, Brian E A1 - Carson, April P A1 - Carlson, Jenna C A1 - Chami, Nathalie A1 - Chen, Yii-Der Ida A1 - Curran, Joanne E A1 - de Vries, Paul S A1 - Fornage, Myriam A1 - Franceschini, Nora A1 - Freedman, Barry I A1 - Gu, Charles A1 - Heard-Costa, Nancy L A1 - He, Jiang A1 - Hou, Lifang A1 - Hung, Yi-Jen A1 - Irvin, Marguerite R A1 - Kaplan, Robert C A1 - Kardia, Sharon L R A1 - Kelly, Tanika A1 - Konigsberg, Iain A1 - Kooperberg, Charles A1 - Kral, Brian G A1 - Li, Changwei A1 - Loos, Ruth J F A1 - Mahaney, Michael C A1 - Martin, Lisa W A1 - Mathias, Rasika A A1 - Minster, Ryan L A1 - Mitchell, Braxton D A1 - Montasser, May E A1 - Morrison, Alanna C A1 - Palmer, Nicholette D A1 - Peyser, Patricia A A1 - Psaty, Bruce M A1 - Raffield, Laura M A1 - Redline, Susan A1 - Reiner, Alexander P A1 - Rich, Stephen S A1 - Sitlani, Colleen M A1 - Smith, Jennifer A A1 - Taylor, Kent D A1 - Tiwari, Hemant A1 - Vasan, Ramachandran S A1 - Wang, Zhe A1 - Yanek, Lisa R A1 - Yu, Bing A1 - Rice, Kenneth M A1 - Rotter, Jerome I A1 - Peloso, Gina M A1 - Natarajan, Pradeep A1 - Li, Zilin A1 - Liu, Zhonghua A1 - Lin, Xihong AB -

Large-scale whole-genome sequencing (WGS) studies have improved our understanding of the contributions of coding and noncoding rare variants to complex human traits. Leveraging association effect sizes across multiple traits in WGS rare variant association analysis can improve statistical power over single-trait analysis, and also detect pleiotropic genes and regions. Existing multi-trait methods have limited ability to perform rare variant analysis of large-scale WGS data. We propose MultiSTAAR, a statistical framework and computationally-scalable analytical pipeline for functionally-informed multi-trait rare variant analysis in large-scale WGS studies. MultiSTAAR accounts for relatedness, population structure and correlation among phenotypes by jointly analyzing multiple traits, and further empowers rare variant association analysis by incorporating multiple functional annotations. We applied MultiSTAAR to jointly analyze three lipid traits (low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides) in 61,861 multi-ethnic samples from the Trans-Omics for Precision Medicine (TOPMed) Program. We discovered new associations with lipid traits missed by single-trait analysis, including rare variants within an enhancer of and an intergenic region on chromosome 1.

ER - TY - JOUR T1 - Whole genome sequence analysis of apparent treatment resistant hypertension status in participants from the Trans-Omics for Precision Medicine program. JF - Front Genet Y1 - 2023 A1 - Armstrong, Nicole D A1 - Srinivasasainagendra, Vinodh A1 - Ammous, Farah A1 - Assimes, Themistocles L A1 - Beitelshees, Amber L A1 - Brody, Jennifer A1 - Cade, Brian E A1 - Ida Chen, Yii-Der A1 - Chen, Han A1 - de Vries, Paul S A1 - Floyd, James S A1 - Franceschini, Nora A1 - Guo, Xiuqing A1 - Hellwege, Jacklyn N A1 - House, John S A1 - Hwu, Chii-Min A1 - Kardia, Sharon L R A1 - Lange, Ethan M A1 - Lange, Leslie A A1 - McDonough, Caitrin W A1 - Montasser, May E A1 - O'Connell, Jeffrey R A1 - Shuey, Megan M A1 - Sun, Xiao A1 - Tanner, Rikki M A1 - Wang, Zhe A1 - Zhao, Wei A1 - Carson, April P A1 - Edwards, Todd L A1 - Kelly, Tanika N A1 - Kenny, Eimear E A1 - Kooperberg, Charles A1 - Loos, Ruth J F A1 - Morrison, Alanna C A1 - Motsinger-Reif, Alison A1 - Psaty, Bruce M A1 - Rao, Dabeeru C A1 - Redline, Susan A1 - Rich, Stephen S A1 - Rotter, Jerome I A1 - Smith, Jennifer A A1 - Smith, Albert V A1 - Irvin, Marguerite R A1 - Arnett, Donna K AB -

Apparent treatment-resistant hypertension (aTRH) is characterized by the use of four or more antihypertensive (AHT) classes to achieve blood pressure (BP) control. In the current study, we conducted single-variant and gene-based analyses of aTRH among individuals from 12 Trans-Omics for Precision Medicine cohorts with whole-genome sequencing data. Cases were defined as individuals treated for hypertension (HTN) taking three different AHT classes, with average systolic BP ≥ 140 or diastolic BP ≥ 90 mmHg, or four or more medications regardless of BP ( = 1,705). A normotensive control group was defined as individuals with BP < 140/90 mmHg ( = 22,079), not on AHT medication. A second control group comprised individuals who were treatment responsive on one AHT medication with BP < 140/ 90 mmHg ( = 5,424). Logistic regression with kinship adjustment using the Scalable and Accurate Implementation of Generalized mixed models (SAIGE) was performed, adjusting for age, sex, and genetic ancestry. We assessed variants using SKAT-O in rare-variant analyses. Single-variant and gene-based tests were conducted in a pooled multi-ethnicity stratum, as well as self-reported ethnic/racial strata (European and African American). One variant in the known HTN locus, , was a top finding in the multi-ethnic analysis ( = 8.23E-07) for the normotensive control group [rs12476527, odds ratio (95% confidence interval) = 0.80 (0.74-0.88)]. This variant was replicated in the Vanderbilt University Medical Center's DNA repository data. Aggregate gene-based signals included the genes and . Additional work validating these loci in larger, more diverse populations, is warranted to determine whether these regions influence the pathobiology of aTRH.

VL - 14 ER - TY - JOUR T1 - X-chromosome and kidney function: evidence from a multi-trait genetic analysis of 908,697 individuals reveals sex-specific and sex-differential findings in genes regulated by androgen response elements. JF - Nat Commun Y1 - 2024 A1 - Scholz, Markus A1 - Horn, Katrin A1 - Pott, Janne A1 - Wuttke, Matthias A1 - Kühnapfel, Andreas A1 - Nasr, M Kamal A1 - Kirsten, Holger A1 - Li, Yong A1 - Hoppmann, Anselm A1 - Gorski, Mathias A1 - Ghasemi, Sahar A1 - Li, Man A1 - Tin, Adrienne A1 - Chai, Jin-Fang A1 - Cocca, Massimiliano A1 - Wang, Judy A1 - Nutile, Teresa A1 - Akiyama, Masato A1 - Åsvold, Bjørn Olav A1 - Bansal, Nisha A1 - Biggs, Mary L A1 - Boutin, Thibaud A1 - Brenner, Hermann A1 - Brumpton, Ben A1 - Burkhardt, Ralph A1 - Cai, Jianwen A1 - Campbell, Archie A1 - Campbell, Harry A1 - Chalmers, John A1 - Chasman, Daniel I A1 - Chee, Miao Ling A1 - Chee, Miao Li A1 - Chen, Xu A1 - Cheng, Ching-Yu A1 - Cifkova, Renata A1 - Daviglus, Martha A1 - Delgado, Graciela A1 - Dittrich, Katalin A1 - Edwards, Todd L A1 - Endlich, Karlhans A1 - Michael Gaziano, J A1 - Giri, Ayush A1 - Giulianini, Franco A1 - Gordon, Scott D A1 - Gudbjartsson, Daniel F A1 - Hallan, Stein A1 - Hamet, Pavel A1 - Hartman, Catharina A A1 - Hayward, Caroline A1 - Heid, Iris M A1 - Hellwege, Jacklyn N A1 - Holleczek, Bernd A1 - Holm, Hilma A1 - Hutri-Kähönen, Nina A1 - Hveem, Kristian A1 - Isermann, Berend A1 - Jonas, Jost B A1 - Joshi, Peter K A1 - Kamatani, Yoichiro A1 - Kanai, Masahiro A1 - Kastarinen, Mika A1 - Khor, Chiea Chuen A1 - Kiess, Wieland A1 - Kleber, Marcus E A1 - Körner, Antje A1 - Kovacs, Peter A1 - Krajcoviechova, Alena A1 - Kramer, Holly A1 - Krämer, Bernhard K A1 - Kuokkanen, Mikko A1 - Kähönen, Mika A1 - Lange, Leslie A A1 - Lash, James P A1 - Lehtimäki, Terho A1 - Li, Hengtong A1 - Lin, Bridget M A1 - Liu, Jianjun A1 - Loeffler, Markus A1 - Lyytikäinen, Leo-Pekka A1 - Magnusson, Patrik K E A1 - Martin, Nicholas G A1 - Matsuda, Koichi A1 - Milaneschi, Yuri A1 - Mishra, Pashupati P A1 - Mononen, Nina A1 - Montgomery, Grant W A1 - Mook-Kanamori, Dennis O A1 - Mychaleckyj, Josyf C A1 - März, Winfried A1 - Nauck, Matthias A1 - Nikus, Kjell A1 - Nolte, Ilja M A1 - Noordam, Raymond A1 - Okada, Yukinori A1 - Olafsson, Isleifur A1 - Oldehinkel, Albertine J A1 - Penninx, Brenda W J H A1 - Perola, Markus A1 - Pirastu, Nicola A1 - Polasek, Ozren A1 - Porteous, David J A1 - Poulain, Tanja A1 - Psaty, Bruce M A1 - Rabelink, Ton J A1 - Raffield, Laura M A1 - Raitakari, Olli T A1 - Rasheed, Humaira A1 - Reilly, Dermot F A1 - Rice, Kenneth M A1 - Richmond, Anne A1 - Ridker, Paul M A1 - Rotter, Jerome I A1 - Rudan, Igor A1 - Sabanayagam, Charumathi A1 - Salomaa, Veikko A1 - Schneiderman, Neil A1 - Schöttker, Ben A1 - Sims, Mario A1 - Snieder, Harold A1 - Stark, Klaus J A1 - Stefansson, Kari A1 - Stocker, Hannah A1 - Stumvoll, Michael A1 - Sulem, Patrick A1 - Sveinbjornsson, Gardar A1 - Svensson, Per O A1 - Tai, E-Shyong A1 - Taylor, Kent D A1 - Tayo, Bamidele O A1 - Teren, Andrej A1 - Tham, Yih-Chung A1 - Thiery, Joachim A1 - Thio, Chris H L A1 - Thomas, Laurent F A1 - Tremblay, Johanne A1 - Tönjes, Anke A1 - van der Most, Peter J A1 - Vitart, Veronique A1 - Völker, Uwe A1 - Wang, Ya Xing A1 - Wang, Chaolong A1 - Wei, Wen Bin A1 - Whitfield, John B A1 - Wild, Sarah H A1 - Wilson, James F A1 - Winkler, Thomas W A1 - Wong, Tien-Yin A1 - Woodward, Mark A1 - Sim, Xueling A1 - Chu, Audrey Y A1 - Feitosa, Mary F A1 - Thorsteinsdottir, Unnur A1 - Hung, Adriana M A1 - Teumer, Alexander A1 - Franceschini, Nora A1 - Parsa, Afshin A1 - Köttgen, Anna A1 - Schlosser, Pascal A1 - Pattaro, Cristian KW - Androgens KW - Chromosomes, Human, X KW - Female KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Kidney KW - Male KW - Polymorphism, Single Nucleotide KW - Response Elements KW - Tetraspanins AB -

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

VL - 15 IS - 1 ER -