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 - Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture. JF - Nat Genet Y1 - 2012 A1 - Estrada, Karol A1 - Styrkarsdottir, Unnur A1 - Evangelou, Evangelos A1 - Hsu, Yi-Hsiang A1 - Duncan, Emma L A1 - Ntzani, Evangelia E A1 - Oei, Ling A1 - Albagha, Omar M E A1 - Amin, Najaf A1 - Kemp, John P A1 - Koller, Daniel L A1 - Li, Guo A1 - Liu, Ching-Ti A1 - Minster, Ryan L A1 - Moayyeri, Alireza A1 - Vandenput, Liesbeth A1 - Willner, Dana A1 - Xiao, Su-Mei A1 - Yerges-Armstrong, Laura M A1 - Zheng, Hou-Feng A1 - Alonso, Nerea A1 - Eriksson, Joel A1 - Kammerer, Candace M A1 - Kaptoge, Stephen K A1 - Leo, Paul J A1 - Thorleifsson, Gudmar A1 - Wilson, Scott G A1 - Wilson, James F A1 - Aalto, Ville A1 - Alen, Markku A1 - Aragaki, Aaron K A1 - Aspelund, Thor A1 - Center, Jacqueline R A1 - Dailiana, Zoe A1 - Duggan, David J A1 - Garcia, Melissa A1 - García-Giralt, Natalia A1 - Giroux, Sylvie A1 - Hallmans, Göran A1 - Hocking, Lynne J A1 - Husted, Lise Bjerre A1 - Jameson, Karen A A1 - Khusainova, Rita A1 - Kim, Ghi Su A1 - Kooperberg, Charles A1 - Koromila, Theodora A1 - Kruk, Marcin A1 - Laaksonen, Marika A1 - LaCroix, Andrea Z A1 - Lee, Seung Hun A1 - Leung, Ping C A1 - Lewis, Joshua R A1 - Masi, Laura A1 - Mencej-Bedrac, Simona A1 - Nguyen, Tuan V A1 - Nogues, Xavier A1 - Patel, Millan S A1 - Prezelj, Janez A1 - Rose, Lynda M A1 - Scollen, Serena A1 - Siggeirsdottir, Kristin A1 - Smith, Albert V A1 - Svensson, Olle A1 - Trompet, Stella A1 - Trummer, Olivia A1 - van Schoor, Natasja M A1 - Woo, Jean A1 - Zhu, Kun A1 - Balcells, Susana A1 - Brandi, Maria Luisa A1 - Buckley, Brendan M A1 - Cheng, Sulin A1 - Christiansen, Claus A1 - Cooper, Cyrus A1 - Dedoussis, George A1 - Ford, Ian A1 - Frost, Morten A1 - Goltzman, David A1 - González-Macías, Jesús A1 - Kähönen, Mika A1 - Karlsson, Magnus A1 - Khusnutdinova, Elza A1 - Koh, Jung-Min A1 - Kollia, Panagoula A1 - Langdahl, Bente Lomholt A1 - Leslie, William D A1 - Lips, Paul A1 - Ljunggren, Osten A1 - Lorenc, Roman S A1 - Marc, Janja A1 - Mellström, Dan A1 - Obermayer-Pietsch, Barbara A1 - Olmos, José M A1 - Pettersson-Kymmer, Ulrika A1 - Reid, David M A1 - Riancho, José A A1 - Ridker, Paul M A1 - Rousseau, François A1 - Slagboom, P Eline A1 - Tang, Nelson L S A1 - Urreizti, Roser A1 - Van Hul, Wim A1 - Viikari, Jorma A1 - Zarrabeitia, María T A1 - Aulchenko, Yurii S A1 - Castano-Betancourt, Martha A1 - Grundberg, Elin A1 - Herrera, Lizbeth A1 - Ingvarsson, Thorvaldur A1 - Johannsdottir, Hrefna A1 - Kwan, Tony A1 - Li, Rui A1 - Luben, Robert A1 - Medina-Gómez, Carolina A1 - Palsson, Stefan Th A1 - Reppe, Sjur A1 - Rotter, Jerome I A1 - Sigurdsson, Gunnar A1 - van Meurs, Joyce B J A1 - Verlaan, Dominique A1 - Williams, Frances M K A1 - Wood, Andrew R A1 - Zhou, Yanhua A1 - Gautvik, Kaare M A1 - Pastinen, Tomi A1 - Raychaudhuri, Soumya A1 - Cauley, Jane A A1 - Chasman, Daniel I A1 - Clark, Graeme R A1 - Cummings, Steven R A1 - Danoy, Patrick A1 - Dennison, Elaine M A1 - Eastell, Richard A1 - Eisman, John A A1 - Gudnason, Vilmundur A1 - Hofman, Albert A1 - Jackson, Rebecca D A1 - Jones, Graeme A1 - Jukema, J Wouter A1 - Khaw, Kay-Tee A1 - Lehtimäki, Terho A1 - Liu, Yongmei A1 - Lorentzon, Mattias A1 - McCloskey, Eugene A1 - Mitchell, Braxton D A1 - Nandakumar, Kannabiran A1 - Nicholson, Geoffrey C A1 - Oostra, Ben A A1 - Peacock, Munro A1 - Pols, Huibert A P A1 - Prince, Richard L A1 - Raitakari, Olli A1 - Reid, Ian R A1 - Robbins, John A1 - Sambrook, Philip N A1 - Sham, Pak Chung A1 - Shuldiner, Alan R A1 - Tylavsky, Frances A A1 - van Duijn, Cornelia M A1 - Wareham, Nick J A1 - Cupples, L Adrienne A1 - Econs, Michael J A1 - Evans, David M A1 - Harris, Tamara B A1 - Kung, Annie Wai Chee A1 - Psaty, Bruce M A1 - Reeve, Jonathan A1 - Spector, Timothy D A1 - Streeten, Elizabeth A A1 - Zillikens, M Carola A1 - Thorsteinsdottir, Unnur A1 - Ohlsson, Claes A1 - Karasik, David A1 - Richards, J Brent A1 - Brown, Matthew A A1 - Stefansson, Kari A1 - Uitterlinden, André G A1 - Ralston, Stuart H A1 - Ioannidis, John P A A1 - Kiel, Douglas P A1 - Rivadeneira, Fernando KW - Bone Density KW - Computational Biology KW - European Continental Ancestry Group KW - Extracellular Matrix Proteins KW - Female KW - Femur Neck KW - Fractures, Bone KW - Gene Expression Profiling KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Genotype KW - Glycoproteins KW - Humans KW - Intercellular Signaling Peptides and Proteins KW - Low Density Lipoprotein Receptor-Related Protein-5 KW - Lumbar Vertebrae KW - Male KW - Mitochondrial Membrane Transport Proteins KW - Osteoporosis KW - Phosphoproteins KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci KW - Risk Factors KW - Spectrin AB -

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

VL - 44 IS - 5 ER - TY - JOUR T1 - A systematic mapping approach of 16q12.2/FTO and BMI in more than 20,000 African Americans narrows in on the underlying functional variation: results from the Population Architecture using Genomics and Epidemiology (PAGE) study. JF - PLoS Genet Y1 - 2013 A1 - Peters, Ulrike A1 - North, Kari E A1 - Sethupathy, Praveen A1 - Buyske, Steve A1 - Haessler, Jeff A1 - Jiao, Shuo A1 - Fesinmeyer, Megan D A1 - Jackson, Rebecca D A1 - Kuller, Lew H A1 - Rajkovic, Aleksandar A1 - Lim, Unhee A1 - Cheng, Iona A1 - Schumacher, Fred A1 - Wilkens, Lynne A1 - Li, Rongling A1 - Monda, Keri A1 - Ehret, Georg A1 - Nguyen, Khanh-Dung H A1 - Cooper, Richard A1 - Lewis, Cora E A1 - Leppert, Mark A1 - Irvin, Marguerite R A1 - Gu, C Charles A1 - Houston, Denise A1 - Bůzková, Petra A1 - Ritchie, Marylyn A1 - Matise, Tara C A1 - Le Marchand, Loïc A1 - Hindorff, Lucia A A1 - Crawford, Dana C A1 - Haiman, Christopher A A1 - Kooperberg, Charles KW - Adaptor Proteins, Signal Transducing KW - Adult KW - African Americans KW - Aged KW - Aged, 80 and over KW - Alleles KW - Body Mass Index KW - Chromosome Mapping KW - Continental Population Groups KW - European Continental Ancestry Group KW - Female KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Linkage Disequilibrium KW - Male KW - Metagenomics KW - Middle Aged KW - Obesity KW - Proteins AB -

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

VL - 9 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23341774?dopt=Abstract ER - TY - JOUR T1 - Association of low-frequency and rare coding-sequence variants with blood lipids and coronary heart disease in 56,000 whites and blacks. JF - Am J Hum Genet Y1 - 2014 A1 - Peloso, Gina M A1 - Auer, Paul L A1 - Bis, Joshua C A1 - Voorman, Arend A1 - Morrison, Alanna C A1 - Stitziel, Nathan O A1 - Brody, Jennifer A A1 - Khetarpal, Sumeet A A1 - Crosby, Jacy R A1 - Fornage, Myriam A1 - Isaacs, Aaron A1 - Jakobsdottir, Johanna A1 - Feitosa, Mary F A1 - Davies, Gail A1 - Huffman, Jennifer E A1 - Manichaikul, Ani A1 - Davis, Brian A1 - Lohman, Kurt A1 - Joon, Aron Y A1 - Smith, Albert V A1 - Grove, Megan L A1 - Zanoni, Paolo A1 - Redon, Valeska A1 - Demissie, Serkalem A1 - Lawson, Kim A1 - Peters, Ulrike A1 - Carlson, Christopher A1 - Jackson, Rebecca D A1 - Ryckman, Kelli K A1 - Mackey, Rachel H A1 - Robinson, Jennifer G A1 - Siscovick, David S A1 - Schreiner, Pamela J A1 - Mychaleckyj, Josyf C A1 - Pankow, James S A1 - Hofman, Albert A1 - Uitterlinden, André G A1 - Harris, Tamara B A1 - Taylor, Kent D A1 - Stafford, Jeanette M A1 - Reynolds, Lindsay M A1 - Marioni, Riccardo E A1 - Dehghan, Abbas A1 - Franco, Oscar H A1 - Patel, Aniruddh P A1 - Lu, Yingchang A1 - Hindy, George A1 - Gottesman, Omri A1 - Bottinger, Erwin P A1 - Melander, Olle A1 - Orho-Melander, Marju A1 - Loos, Ruth J F A1 - Duga, Stefano A1 - Merlini, Piera Angelica A1 - Farrall, Martin A1 - Goel, Anuj A1 - Asselta, Rosanna A1 - Girelli, Domenico A1 - Martinelli, Nicola A1 - Shah, Svati H A1 - Kraus, William E A1 - Li, Mingyao A1 - Rader, Daniel J A1 - Reilly, Muredach P A1 - McPherson, Ruth A1 - Watkins, Hugh A1 - Ardissino, Diego A1 - Zhang, Qunyuan A1 - Wang, Judy A1 - Tsai, Michael Y A1 - Taylor, Herman A A1 - Correa, Adolfo A1 - Griswold, Michael E A1 - Lange, Leslie A A1 - Starr, John M A1 - Rudan, Igor A1 - Eiriksdottir, Gudny A1 - Launer, Lenore J A1 - Ordovas, Jose M A1 - Levy, Daniel A1 - Chen, Y-D Ida A1 - Reiner, Alexander P A1 - Hayward, Caroline A1 - Polasek, Ozren A1 - Deary, Ian J A1 - Borecki, Ingrid B A1 - Liu, Yongmei A1 - Gudnason, Vilmundur A1 - Wilson, James G A1 - van Duijn, Cornelia M A1 - Kooperberg, Charles A1 - Rich, Stephen S A1 - Psaty, Bruce M A1 - Rotter, Jerome I A1 - O'Donnell, Christopher J A1 - Rice, Kenneth A1 - Boerwinkle, Eric A1 - Kathiresan, Sekar A1 - Cupples, L Adrienne KW - 1-Alkyl-2-acetylglycerophosphocholine Esterase KW - Adult KW - African Continental Ancestry Group KW - Aged KW - Alleles KW - Animals KW - Cholesterol, HDL KW - Cholesterol, LDL KW - Cohort Studies KW - Coronary Disease KW - European Continental Ancestry Group KW - Female KW - Gene Frequency KW - Genetic Association Studies KW - Genetic Code KW - Genetic Variation KW - Humans KW - Linear Models KW - Male KW - Mice KW - Mice, Inbred C57BL KW - Microtubule-Associated Proteins KW - Middle Aged KW - Phenotype KW - Sequence Analysis, DNA KW - Subtilisins KW - Triglycerides AB -

Low-frequency coding DNA sequence variants in the proprotein convertase subtilisin/kexin type 9 gene (PCSK9) lower plasma low-density lipoprotein cholesterol (LDL-C), protect against risk of coronary heart disease (CHD), and have prompted the development of a new class of therapeutics. It is uncertain whether the PCSK9 example represents a paradigm or an isolated exception. We used the "Exome Array" to genotype >200,000 low-frequency and rare coding sequence variants across the genome in 56,538 individuals (42,208 European ancestry [EA] and 14,330 African ancestry [AA]) and tested these variants for association with LDL-C, high-density lipoprotein cholesterol (HDL-C), and triglycerides. Although we did not identify new genes associated with LDL-C, we did identify four low-frequency (frequencies between 0.1% and 2%) variants (ANGPTL8 rs145464906 [c.361C>T; p.Gln121*], PAFAH1B2 rs186808413 [c.482C>T; p.Ser161Leu], COL18A1 rs114139997 [c.331G>A; p.Gly111Arg], and PCSK7 rs142953140 [c.1511G>A; p.Arg504His]) with large effects on HDL-C and/or triglycerides. None of these four variants was associated with risk for CHD, suggesting that examples of low-frequency coding variants with robust effects on both lipids and CHD will be limited.

VL - 94 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24507774?dopt=Abstract ER - TY - JOUR T1 - Evidence of heterogeneity by race/ethnicity in genetic determinants of QT interval. JF - Epidemiology Y1 - 2014 A1 - Seyerle, Amanda A A1 - Young, Alicia M A1 - Jeff, Janina M A1 - Melton, Phillip E A1 - Jorgensen, Neal W A1 - Lin, Yi A1 - Carty, Cara L A1 - Deelman, Ewa A1 - Heckbert, Susan R A1 - Hindorff, Lucia A A1 - Jackson, Rebecca D A1 - Martin, Lisa W A1 - Okin, Peter M A1 - Perez, Marco V A1 - Psaty, Bruce M A1 - Soliman, Elsayed Z A1 - Whitsel, Eric A A1 - North, Kari E A1 - Laston, Sandra A1 - Kooperberg, Charles A1 - Avery, Christy L KW - Aged KW - Continental Population Groups KW - Electrocardiography KW - Female KW - Genetic Predisposition to Disease KW - Haplotypes KW - Humans KW - Long QT Syndrome KW - Male KW - Middle Aged KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci KW - Quantitative Trait, Heritable KW - Risk Factors AB -

BACKGROUND: QT interval (QT) prolongation is an established risk factor for ventricular tachyarrhythmia and sudden cardiac death. Previous genome-wide association studies in populations of the European descent have identified multiple genetic loci that influence QT, but few have examined these loci in ethnically diverse populations.

METHODS: Here, we examine the direction, magnitude, and precision of effect sizes for 21 previously reported SNPs from 12 QT loci, in populations of European (n = 16,398), African (n = 5,437), American Indian (n = 5,032), Hispanic (n = 1,143), and Asian (n = 932) descent as part of the Population Architecture using Genomics and Epidemiology (PAGE) study. Estimates obtained from linear regression models stratified by race/ethnicity were combined using inverse-variance weighted meta-analysis. Heterogeneity was evaluated using Cochran's Q test.

RESULTS: Of 21 SNPs, 7 showed consistent direction of effect across all 5 populations, and an additional 9 had estimated effects that were consistent across 4 populations. Despite consistent direction of effect, 9 of 16 SNPs had evidence (P < 0.05) of heterogeneity by race/ethnicity. For these 9 SNPs, linkage disequilibrium plots often indicated substantial variation in linkage disequilibrium patterns among the various racial/ethnic groups, as well as possible allelic heterogeneity.

CONCLUSIONS: These results emphasize the importance of analyzing racial/ethnic groups separately in genetic studies. Furthermore, they underscore the possible utility of trans-ethnic studies to pinpoint underlying casual variants influencing heritable traits such as QT.

VL - 25 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25166880?dopt=Abstract ER - TY - JOUR T1 - Quantifying rare, deleterious variation in 12 human cytochrome P450 drug-metabolism genes in a large-scale exome dataset. JF - Hum Mol Genet Y1 - 2014 A1 - Gordon, Adam S A1 - Tabor, Holly K A1 - Johnson, Andrew D A1 - Snively, Beverly M A1 - Assimes, Themistocles L A1 - Auer, Paul L A1 - Ioannidis, John P A A1 - Peters, Ulrike A1 - Robinson, Jennifer G A1 - Sucheston, Lara E A1 - Wang, Danxin A1 - Sotoodehnia, Nona A1 - Rotter, Jerome I A1 - Psaty, Bruce M A1 - Jackson, Rebecca D A1 - Herrington, David M A1 - O'Donnell, Christopher J A1 - Reiner, Alexander P A1 - Rich, Stephen S A1 - Rieder, Mark J A1 - Bamshad, Michael J A1 - Nickerson, Deborah A KW - Cytochrome P-450 Enzyme System KW - Databases, Genetic KW - European Continental Ancestry Group KW - Exome KW - Humans KW - Pharmaceutical Preparations KW - Pharmacogenetics KW - Polymorphism, Genetic AB -

The study of genetic influences on drug response and efficacy ('pharmacogenetics') has existed for over 50 years. Yet, we still lack a complete picture of how genetic variation, both common and rare, affects each individual's responses to medications. Exome sequencing is a promising alternative method for pharmacogenetic discovery as it provides information on both common and rare variation in large numbers of individuals. Using exome data from 2203 AA and 4300 Caucasian individuals through the NHLBI Exome Sequencing Project, we conducted a survey of coding variation within 12 Cytochrome P450 (CYP) genes that are collectively responsible for catalyzing nearly 75% of all known Phase I drug oxidation reactions. In addition to identifying many polymorphisms with known pharmacogenetic effects, we discovered over 730 novel nonsynonymous alleles across the 12 CYP genes of interest. These alleles include many with diverse functional effects such as premature stop codons, aberrant splicesites and mutations at conserved active site residues. Our analysis considering both novel, predicted functional alleles as well as known, actionable CYP alleles reveals that rare, deleterious variation contributes markedly to the overall burden of pharmacogenetic alleles within the populations considered, and that the contribution of rare variation to this burden is over three times greater in AA individuals as compared with Caucasians. While most of these impactful alleles are individually rare, 7.6-11.7% of individuals interrogated in the study carry at least one newly described potentially deleterious alleles in a major drug-metabolizing CYP.

VL - 23 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24282029?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 - Association of exome sequences with plasma C-reactive protein levels in >9000 participants. JF - Hum Mol Genet Y1 - 2015 A1 - Schick, Ursula M A1 - Auer, Paul L A1 - Bis, Joshua C A1 - Lin, Honghuang A1 - Wei, Peng A1 - Pankratz, Nathan A1 - Lange, Leslie A A1 - Brody, Jennifer A1 - Stitziel, Nathan O A1 - Kim, Daniel S A1 - Carlson, Christopher S A1 - Fornage, Myriam A1 - Haessler, Jeffery A1 - Hsu, Li A1 - Jackson, Rebecca D A1 - Kooperberg, Charles A1 - Leal, Suzanne M A1 - Psaty, Bruce M A1 - Boerwinkle, Eric A1 - Tracy, Russell A1 - Ardissino, Diego A1 - Shah, Svati A1 - Willer, Cristen A1 - Loos, Ruth A1 - Melander, Olle A1 - McPherson, Ruth A1 - Hovingh, Kees A1 - Reilly, Muredach A1 - Watkins, Hugh A1 - Girelli, Domenico A1 - Fontanillas, Pierre A1 - Chasman, Daniel I A1 - Gabriel, Stacey B A1 - Gibbs, Richard A1 - Nickerson, Deborah A A1 - Kathiresan, Sekar A1 - Peters, Ulrike A1 - Dupuis, Josée A1 - Wilson, James G A1 - Rich, Stephen S A1 - Morrison, Alanna C A1 - Benjamin, Emelia J A1 - Gross, Myron D A1 - Reiner, Alex P KW - Adult KW - African Americans KW - C-Reactive Protein KW - Cardiovascular Diseases KW - Cohort Studies KW - European Continental Ancestry Group KW - Exome KW - Female KW - Gene Frequency KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Hepatocyte Nuclear Factor 1-alpha KW - Humans KW - Male KW - Plasma KW - Polymorphism, Single Nucleotide KW - Receptors, Interleukin-6 KW - Risk Factors AB -

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

VL - 24 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25187575?dopt=Abstract ER - TY - JOUR T1 - Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction. JF - Nature Y1 - 2015 A1 - Do, Ron A1 - Stitziel, Nathan O A1 - Won, Hong-Hee A1 - Jørgensen, Anders Berg A1 - Duga, Stefano A1 - Angelica Merlini, Pier A1 - Kiezun, Adam A1 - Farrall, Martin A1 - Goel, Anuj A1 - Zuk, Or A1 - Guella, Illaria A1 - Asselta, Rosanna A1 - Lange, Leslie A A1 - Peloso, Gina M A1 - Auer, Paul L A1 - Girelli, Domenico A1 - Martinelli, Nicola A1 - Farlow, Deborah N A1 - DePristo, Mark A A1 - Roberts, Robert A1 - Stewart, Alexander F R A1 - Saleheen, Danish A1 - Danesh, John A1 - Epstein, Stephen E A1 - Sivapalaratnam, Suthesh A1 - Hovingh, G Kees A1 - Kastelein, John J A1 - Samani, Nilesh J A1 - Schunkert, Heribert A1 - Erdmann, Jeanette A1 - Shah, Svati H A1 - Kraus, William E A1 - Davies, Robert A1 - Nikpay, Majid A1 - Johansen, Christopher T A1 - Wang, Jian A1 - Hegele, Robert A A1 - Hechter, Eliana A1 - März, Winfried A1 - Kleber, Marcus E A1 - Huang, Jie A1 - Johnson, Andrew D A1 - Li, Mingyao A1 - Burke, Greg L A1 - Gross, Myron A1 - Liu, Yongmei A1 - Assimes, Themistocles L A1 - Heiss, Gerardo A1 - Lange, Ethan M A1 - Folsom, Aaron R A1 - Taylor, Herman A A1 - Olivieri, Oliviero A1 - Hamsten, Anders A1 - Clarke, Robert A1 - Reilly, Dermot F A1 - Yin, Wu A1 - Rivas, Manuel A A1 - Donnelly, Peter A1 - Rossouw, Jacques E A1 - Psaty, Bruce M A1 - Herrington, David M A1 - Wilson, James G A1 - Rich, Stephen S A1 - Bamshad, Michael J A1 - Tracy, Russell P A1 - Cupples, L Adrienne A1 - Rader, Daniel J A1 - Reilly, Muredach P A1 - Spertus, John A A1 - Cresci, Sharon A1 - Hartiala, Jaana A1 - Tang, W H Wilson A1 - Hazen, Stanley L A1 - Allayee, Hooman A1 - Reiner, Alex P A1 - Carlson, Christopher S A1 - Kooperberg, Charles A1 - Jackson, Rebecca D A1 - Boerwinkle, Eric A1 - Lander, Eric S A1 - Schwartz, Stephen M A1 - Siscovick, David S A1 - McPherson, Ruth A1 - Tybjaerg-Hansen, Anne A1 - Abecasis, Goncalo R A1 - Watkins, Hugh A1 - Nickerson, Deborah A A1 - Ardissino, Diego A1 - Sunyaev, Shamil R A1 - O'Donnell, Christopher J A1 - Altshuler, David A1 - Gabriel, Stacey A1 - Kathiresan, Sekar KW - Age Factors KW - Age of Onset KW - Alleles KW - Apolipoproteins A KW - Case-Control Studies KW - Cholesterol, LDL KW - Coronary Artery Disease KW - Exome KW - Female KW - Genetic Predisposition to Disease KW - Genetics, Population KW - Heterozygote KW - Humans KW - Male KW - Middle Aged KW - Mutation KW - Myocardial Infarction KW - National Heart, Lung, and Blood Institute (U.S.) KW - Receptors, LDL KW - Triglycerides KW - United States AB -

Myocardial infarction (MI), a leading cause of death around the world, displays a complex pattern of inheritance. When MI occurs early in life, genetic inheritance is a major component to risk. Previously, rare mutations in low-density lipoprotein (LDL) genes have been shown to contribute to MI risk in individual families, whereas common variants at more than 45 loci have been associated with MI risk in the population. Here we evaluate how rare mutations contribute to early-onset MI risk in the population. We sequenced the protein-coding regions of 9,793 genomes from patients with MI at an early age (≤50 years in males and ≤60 years in females) along with MI-free controls. We identified two genes in which rare coding-sequence mutations were more frequent in MI cases versus controls at exome-wide significance. At low-density lipoprotein receptor (LDLR), carriers of rare non-synonymous mutations were at 4.2-fold increased risk for MI; carriers of null alleles at LDLR were at even higher risk (13-fold difference). Approximately 2% of early MI cases harbour a rare, damaging mutation in LDLR; this estimate is similar to one made more than 40 years ago using an analysis of total cholesterol. Among controls, about 1 in 217 carried an LDLR coding-sequence mutation and had plasma LDL cholesterol > 190 mg dl(-1). At apolipoprotein A-V (APOA5), carriers of rare non-synonymous mutations were at 2.2-fold increased risk for MI. When compared with non-carriers, LDLR mutation carriers had higher plasma LDL cholesterol, whereas APOA5 mutation carriers had higher plasma triglycerides. Recent evidence has connected MI risk with coding-sequence mutations at two genes functionally related to APOA5, namely lipoprotein lipase and apolipoprotein C-III (refs 18, 19). Combined, these observations suggest that, as well as LDL cholesterol, disordered metabolism of triglyceride-rich lipoproteins contributes to MI risk.

VL - 518 IS - 7537 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25487149?dopt=Abstract ER - TY - JOUR T1 - Rare and Coding Region Genetic Variants Associated With Risk of Ischemic Stroke: The NHLBI Exome Sequence Project. JF - JAMA Neurol Y1 - 2015 A1 - Auer, Paul L A1 - Nalls, Mike A1 - Meschia, James F A1 - Worrall, Bradford B A1 - Longstreth, W T A1 - Seshadri, Sudha A1 - Kooperberg, Charles A1 - Burger, Kathleen M A1 - Carlson, Christopher S A1 - Carty, Cara L A1 - Chen, Wei-Min A1 - Cupples, L Adrienne A1 - DeStefano, Anita L A1 - Fornage, Myriam A1 - Hardy, John A1 - Hsu, Li A1 - Jackson, Rebecca D A1 - Jarvik, Gail P A1 - Kim, Daniel S A1 - Lakshminarayan, Kamakshi A1 - Lange, Leslie A A1 - Manichaikul, Ani A1 - Quinlan, Aaron R A1 - Singleton, Andrew B A1 - Thornton, Timothy A A1 - Nickerson, Deborah A A1 - Peters, Ulrike A1 - Rich, Stephen S KW - Aged KW - Brain Ischemia KW - Exome KW - Female KW - Genetic Predisposition to Disease KW - Genetic Variation KW - Genome-Wide Association Study KW - Humans KW - Male KW - Middle Aged KW - Muscle Proteins KW - National Heart, Lung, and Blood Institute (U.S.) KW - Nuclear Proteins KW - Open Reading Frames KW - Palmitoyl-CoA Hydrolase KW - Stroke KW - United States AB -

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

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

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

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

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

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

VL - 72 IS - 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25961151?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 - 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 - 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 - Common Coding Variants in Are Associated With the Nav1.8 Late Current and Cardiac Conduction. JF - Circ Genom Precis Med Y1 - 2018 A1 - Macri, Vincenzo A1 - Brody, Jennifer A A1 - Arking, Dan E A1 - Hucker, William J A1 - Yin, Xiaoyan A1 - Lin, Honghuang A1 - Mills, Robert W A1 - Sinner, Moritz F A1 - Lubitz, Steven A A1 - Liu, Ching-Ti A1 - Morrison, Alanna C A1 - Alonso, Alvaro A1 - Li, Ning A1 - Fedorov, Vadim V A1 - Janssen, Paul M A1 - Bis, Joshua C A1 - Heckbert, Susan R A1 - Dolmatova, Elena V A1 - Lumley, Thomas A1 - Sitlani, Colleen M A1 - Cupples, L Adrienne A1 - Pulit, Sara L A1 - Newton-Cheh, Christopher A1 - Barnard, John A1 - Smith, Jonathan D A1 - Van Wagoner, David R A1 - Chung, Mina K A1 - Vlahakes, Gus J A1 - O'Donnell, Christopher J A1 - Rotter, Jerome I A1 - Margulies, Kenneth B A1 - Morley, Michael P A1 - Cappola, Thomas P A1 - Benjamin, Emelia J A1 - Muzny, Donna A1 - Gibbs, Richard A A1 - Jackson, Rebecca D A1 - Magnani, Jared W A1 - Herndon, Caroline N A1 - Rich, Stephen S A1 - Psaty, Bruce M A1 - Milan, David J A1 - Boerwinkle, Eric A1 - Mohler, Peter J A1 - Sotoodehnia, Nona A1 - Ellinor, Patrick T AB -

BACKGROUND: Genetic variants at the / locus are strongly associated with electrocardiographic PR and QRS intervals. While is the canonical cardiac sodium channel gene, the role of in cardiac conduction is less well characterized.

METHODS: We sequenced the locus in 3699 European-ancestry individuals to identify variants associated with cardiac conduction, and replicated our findings in 21,000 individuals of European ancestry. We examined association with expression in human atrial tissue. We explored the biophysical effect of variation on channel function using cellular electrophysiology.

RESULTS: We identified 2 intronic single nucleotide polymorphisms in high linkage disequilibrium (  =0.86) with each other to be the strongest signals for PR (rs10428132, β=-4.74, =1.52×10) and QRS intervals (rs6599251, QRS β=-0.73; =1.2×10), respectively. Although these variants were not associated with or expression in human atrial tissue (n=490), they were in high linkage disequilibrium (  ≥0.72) with a common missense variant, rs6795970 (V1073A). In total, we identified 7 missense variants, 4 of which (I962V, P1045T, V1073A, and L1092P) were associated with cardiac conduction. These 4 missense variants cluster in the cytoplasmic linker of the second and third domains of the SCN10A protein and together form 6 common haplotypes. Using cellular electrophysiology, we found that haplotypes associated with shorter PR intervals had a significantly larger percentage of late current compared with wild-type (I962V+V1073A+L1092P, 20.2±3.3%, =0.03, and I962V+V1073A, 22.4±0.8%, =0.0004 versus wild-type 11.7±1.6%), and the haplotype associated with the longest PR interval had a significantly smaller late current percentage (P1045T, 6.4±1.2%, =0.03).

CONCLUSIONS: Our findings suggest an association between genetic variation in , the late sodium current, and alterations in cardiac conduction.

VL - 11 IS - 5 ER - TY - JOUR T1 - Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes. JF - Nat Genet Y1 - 2018 A1 - Malik, Rainer A1 - Chauhan, Ganesh A1 - Traylor, Matthew A1 - Sargurupremraj, Muralidharan A1 - Okada, Yukinori A1 - Mishra, Aniket A1 - Rutten-Jacobs, Loes A1 - Giese, Anne-Katrin A1 - van der Laan, Sander W A1 - Gretarsdottir, Solveig A1 - Anderson, Christopher D A1 - Chong, Michael A1 - Adams, Hieab H H A1 - Ago, Tetsuro A1 - Almgren, Peter A1 - Amouyel, Philippe A1 - Ay, Hakan A1 - Bartz, Traci M A1 - Benavente, Oscar R A1 - Bevan, Steve A1 - Boncoraglio, Giorgio B A1 - Brown, Robert D A1 - Butterworth, Adam S A1 - Carrera, Caty A1 - Carty, Cara L A1 - Chasman, Daniel I A1 - Chen, Wei-Min A1 - Cole, John W A1 - Correa, Adolfo A1 - Cotlarciuc, Ioana A1 - Cruchaga, Carlos A1 - Danesh, John A1 - de Bakker, Paul I W A1 - DeStefano, Anita L A1 - den Hoed, Marcel A1 - Duan, Qing A1 - Engelter, Stefan T A1 - Falcone, Guido J A1 - Gottesman, Rebecca F A1 - Grewal, Raji P A1 - Gudnason, Vilmundur A1 - Gustafsson, Stefan A1 - Haessler, Jeffrey A1 - Harris, Tamara B A1 - Hassan, Ahamad A1 - Havulinna, Aki S A1 - Heckbert, Susan R A1 - Holliday, Elizabeth G A1 - Howard, George A1 - Hsu, Fang-Chi A1 - Hyacinth, Hyacinth I A1 - Ikram, M Arfan A1 - Ingelsson, Erik A1 - Irvin, Marguerite R A1 - Jian, Xueqiu A1 - Jimenez-Conde, Jordi A1 - Johnson, Julie A A1 - Jukema, J Wouter A1 - Kanai, Masahiro A1 - Keene, Keith L A1 - Kissela, Brett M A1 - Kleindorfer, Dawn O A1 - Kooperberg, Charles A1 - Kubo, Michiaki A1 - Lange, Leslie A A1 - Langefeld, Carl D A1 - Langenberg, Claudia A1 - Launer, Lenore J A1 - Lee, Jin-Moo A1 - Lemmens, Robin A1 - Leys, Didier A1 - Lewis, Cathryn M A1 - Lin, Wei-Yu A1 - Lindgren, Arne G A1 - Lorentzen, Erik A1 - Magnusson, Patrik K A1 - Maguire, Jane A1 - Manichaikul, Ani A1 - McArdle, Patrick F A1 - Meschia, James F A1 - Mitchell, Braxton D A1 - Mosley, Thomas H A1 - Nalls, Michael A A1 - Ninomiya, Toshiharu A1 - O'Donnell, Martin J A1 - Psaty, Bruce M A1 - Pulit, Sara L A1 - Rannikmae, Kristiina A1 - Reiner, Alexander P A1 - Rexrode, Kathryn M A1 - Rice, Kenneth A1 - Rich, Stephen S A1 - Ridker, Paul M A1 - Rost, Natalia S A1 - Rothwell, Peter M A1 - Rotter, Jerome I A1 - Rundek, Tatjana A1 - Sacco, Ralph L A1 - Sakaue, Saori A1 - Sale, Michèle M A1 - Salomaa, Veikko A1 - Sapkota, Bishwa R A1 - Schmidt, Reinhold A1 - Schmidt, Carsten O A1 - Schminke, Ulf A1 - Sharma, Pankaj A1 - Slowik, Agnieszka A1 - Sudlow, Cathie L M A1 - Tanislav, Christian A1 - Tatlisumak, Turgut A1 - Taylor, Kent D A1 - Thijs, Vincent N S A1 - Thorleifsson, Gudmar A1 - Thorsteinsdottir, Unnur A1 - Tiedt, Steffen A1 - Trompet, Stella A1 - Tzourio, Christophe A1 - van Duijn, Cornelia M A1 - Walters, Matthew A1 - Wareham, Nicholas J A1 - Wassertheil-Smoller, Sylvia A1 - Wilson, James G A1 - Wiggins, Kerri L A1 - Yang, Qiong A1 - Yusuf, Salim A1 - Bis, Joshua C A1 - Pastinen, Tomi A1 - Ruusalepp, Arno A1 - Schadt, Eric E A1 - Koplev, Simon A1 - Björkegren, Johan L M A1 - Codoni, Veronica A1 - Civelek, Mete A1 - Smith, Nicholas L A1 - Trégouët, David A A1 - Christophersen, Ingrid E A1 - Roselli, Carolina A1 - Lubitz, Steven A A1 - Ellinor, Patrick T A1 - Tai, E Shyong A1 - Kooner, Jaspal S A1 - Kato, Norihiro A1 - He, Jiang A1 - van der Harst, Pim A1 - Elliott, Paul A1 - Chambers, John C A1 - Takeuchi, Fumihiko A1 - Johnson, Andrew D A1 - Sanghera, Dharambir K A1 - Melander, Olle A1 - Jern, Christina A1 - Strbian, Daniel A1 - Fernandez-Cadenas, Israel A1 - Longstreth, W T A1 - Rolfs, Arndt A1 - Hata, Jun A1 - Woo, Daniel A1 - Rosand, Jonathan A1 - Paré, Guillaume A1 - Hopewell, Jemma C A1 - Saleheen, Danish A1 - Stefansson, Kari A1 - Worrall, Bradford B A1 - Kittner, Steven J A1 - Seshadri, Sudha A1 - Fornage, Myriam A1 - Markus, Hugh S A1 - Howson, Joanna M M A1 - Kamatani, Yoichiro A1 - Debette, Stephanie A1 - Dichgans, Martin A1 - Malik, Rainer A1 - Chauhan, Ganesh A1 - Traylor, Matthew A1 - Sargurupremraj, Muralidharan A1 - Okada, Yukinori A1 - Mishra, Aniket A1 - Rutten-Jacobs, Loes A1 - Giese, Anne-Katrin A1 - van der Laan, Sander W A1 - Gretarsdottir, Solveig A1 - Anderson, Christopher D A1 - Chong, Michael A1 - Adams, Hieab H H A1 - Ago, Tetsuro A1 - Almgren, Peter A1 - Amouyel, Philippe A1 - Ay, Hakan A1 - Bartz, Traci M A1 - Benavente, Oscar R A1 - Bevan, Steve A1 - Boncoraglio, Giorgio B A1 - Brown, Robert D A1 - Butterworth, Adam S A1 - Carrera, Caty A1 - Carty, Cara L A1 - Chasman, Daniel I A1 - Chen, Wei-Min A1 - Cole, John W A1 - Correa, Adolfo A1 - Cotlarciuc, Ioana A1 - Cruchaga, Carlos A1 - Danesh, John A1 - de Bakker, Paul I W A1 - DeStefano, Anita L A1 - Hoed, Marcel den A1 - Duan, Qing A1 - Engelter, Stefan T A1 - Falcone, Guido J A1 - Gottesman, Rebecca F A1 - Grewal, Raji P A1 - Gudnason, Vilmundur A1 - Gustafsson, Stefan A1 - Haessler, Jeffrey A1 - Harris, Tamara B A1 - Hassan, Ahamad A1 - Havulinna, Aki S A1 - Heckbert, Susan R A1 - Holliday, Elizabeth G A1 - Howard, George A1 - Hsu, Fang-Chi A1 - Hyacinth, Hyacinth I A1 - Ikram, M Arfan A1 - Ingelsson, Erik A1 - Irvin, Marguerite R A1 - Jian, Xueqiu A1 - Jimenez-Conde, Jordi A1 - Johnson, Julie A A1 - Jukema, J Wouter A1 - Kanai, Masahiro A1 - Keene, Keith L A1 - Kissela, Brett M A1 - Kleindorfer, Dawn O A1 - Kooperberg, Charles A1 - Kubo, Michiaki A1 - Lange, Leslie A A1 - Langefeld, Carl D A1 - Langenberg, Claudia A1 - Launer, Lenore J A1 - Lee, Jin-Moo A1 - Lemmens, Robin A1 - Leys, Didier A1 - Lewis, Cathryn M A1 - Lin, Wei-Yu A1 - Lindgren, Arne G A1 - Lorentzen, Erik A1 - Magnusson, Patrik K A1 - Maguire, Jane A1 - Manichaikul, Ani A1 - McArdle, Patrick F A1 - Meschia, James F A1 - Mitchell, Braxton D A1 - Mosley, Thomas H A1 - Nalls, Michael A A1 - Ninomiya, Toshiharu A1 - O'Donnell, Martin J A1 - Psaty, Bruce M A1 - Pulit, Sara L A1 - Rannikmae, Kristiina A1 - Reiner, Alexander P A1 - Rexrode, Kathryn M A1 - Rice, Kenneth A1 - Rich, Stephen S A1 - Ridker, Paul M A1 - Rost, Natalia S A1 - Rothwell, Peter M A1 - Rotter, Jerome I A1 - Rundek, Tatjana A1 - Sacco, Ralph L A1 - Sakaue, Saori A1 - Sale, Michèle M A1 - Salomaa, Veikko A1 - Sapkota, Bishwa R A1 - Schmidt, Reinhold A1 - Schmidt, Carsten O A1 - Schminke, Ulf A1 - Sharma, Pankaj A1 - Slowik, Agnieszka A1 - Sudlow, Cathie L M A1 - Tanislav, Christian A1 - Tatlisumak, Turgut A1 - Taylor, Kent D A1 - Thijs, Vincent N S A1 - Thorleifsson, Gudmar A1 - Thorsteinsdottir, Unnur A1 - Tiedt, Steffen A1 - Trompet, Stella A1 - Tzourio, Christophe A1 - van Duijn, Cornelia M A1 - Walters, Matthew A1 - Wareham, Nicholas J A1 - Wassertheil-Smoller, Sylvia A1 - Wilson, James G A1 - Wiggins, Kerri L A1 - Yang, Qiong A1 - Yusuf, Salim A1 - Amin, Najaf A1 - Aparicio, Hugo S A1 - Arnett, Donna K A1 - Attia, John A1 - Beiser, Alexa S A1 - Berr, Claudine A1 - Buring, Julie E A1 - Bustamante, Mariana A1 - Caso, Valeria A1 - Cheng, Yu-Ching A1 - Choi, Seung Hoan A1 - Chowhan, Ayesha A1 - Cullell, Natalia A1 - Dartigues, Jean-François A1 - Delavaran, Hossein A1 - Delgado, Pilar A1 - Dörr, Marcus A1 - Engström, Gunnar A1 - Ford, Ian A1 - Gurpreet, Wander S A1 - Hamsten, Anders A1 - Heitsch, Laura A1 - Hozawa, Atsushi A1 - Ibanez, Laura A1 - Ilinca, Andreea A1 - Ingelsson, Martin A1 - Iwasaki, Motoki A1 - Jackson, Rebecca D A1 - Jood, Katarina A1 - Jousilahti, Pekka A1 - Kaffashian, Sara A1 - Kalra, Lalit A1 - Kamouchi, Masahiro A1 - Kitazono, Takanari A1 - Kjartansson, Olafur A1 - Kloss, Manja A1 - Koudstaal, Peter J A1 - Krupinski, Jerzy A1 - Labovitz, Daniel L A1 - Laurie, Cathy C A1 - Levi, Christopher R A1 - Li, Linxin A1 - Lind, Lars A1 - Lindgren, Cecilia M A1 - Lioutas, Vasileios A1 - Liu, Yong Mei A1 - Lopez, Oscar L A1 - Makoto, Hirata A1 - Martinez-Majander, Nicolas A1 - Matsuda, Koichi A1 - Minegishi, Naoko A1 - Montaner, Joan A1 - Morris, Andrew P A1 - Muiño, Elena A1 - Müller-Nurasyid, Martina A1 - Norrving, Bo A1 - Ogishima, Soichi A1 - Parati, Eugenio A A1 - Peddareddygari, Leema Reddy A1 - Pedersen, Nancy L A1 - Pera, Joanna A1 - Perola, Markus A1 - Pezzini, Alessandro A1 - Pileggi, Silvana A1 - Rabionet, Raquel A1 - Riba-Llena, Iolanda A1 - Ribasés, Marta A1 - Romero, Jose R A1 - Roquer, Jaume A1 - Rudd, Anthony G A1 - Sarin, Antti-Pekka A1 - Sarju, Ralhan A1 - Sarnowski, Chloe A1 - Sasaki, Makoto A1 - Satizabal, Claudia L A1 - Satoh, Mamoru A1 - Sattar, Naveed A1 - Sawada, Norie A1 - Sibolt, Gerli A1 - Sigurdsson, Ásgeir A1 - Smith, Albert A1 - Sobue, Kenji A1 - Soriano-Tárraga, Carolina A1 - Stanne, Tara A1 - Stine, O Colin A1 - Stott, David J A1 - Strauch, Konstantin A1 - Takai, Takako A1 - Tanaka, Hideo A1 - Tanno, Kozo A1 - Teumer, Alexander A1 - Tomppo, Liisa A1 - Torres-Aguila, Nuria P A1 - Touze, Emmanuel A1 - Tsugane, Shoichiro A1 - Uitterlinden, André G A1 - Valdimarsson, Einar M A1 - van der Lee, Sven J A1 - Völzke, Henry A1 - Wakai, Kenji A1 - Weir, David A1 - Williams, Stephen R A1 - Wolfe, Charles D A A1 - Wong, Quenna A1 - Xu, Huichun A1 - Yamaji, Taiki A1 - Sanghera, Dharambir K A1 - Melander, Olle A1 - Jern, Christina A1 - Strbian, Daniel A1 - Fernandez-Cadenas, Israel A1 - Longstreth, W T A1 - Rolfs, Arndt A1 - Hata, Jun A1 - Woo, Daniel A1 - Rosand, Jonathan A1 - Paré, Guillaume A1 - Hopewell, Jemma C A1 - Saleheen, Danish A1 - Stefansson, Kari A1 - Worrall, Bradford B A1 - Kittner, Steven J A1 - Seshadri, Sudha A1 - Fornage, Myriam A1 - Markus, Hugh S A1 - Howson, Joanna M M A1 - Kamatani, Yoichiro A1 - Debette, Stephanie A1 - Dichgans, Martin AB -

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

VL - 50 IS - 4 ER - TY - JOUR T1 - Genomic and transcriptomic association studies identify 16 novel susceptibility loci for venous thromboembolism. JF - Blood Y1 - 2019 A1 - Lindström, Sara A1 - Wang, Lu A1 - Smith, Erin N A1 - Gordon, William A1 - van Hylckama Vlieg, Astrid A1 - de Andrade, Mariza A1 - Brody, Jennifer A A1 - Pattee, Jack W A1 - Haessler, Jeffrey A1 - Brumpton, Ben M A1 - Chasman, Daniel I A1 - Suchon, Pierre A1 - Chen, Ming-Huei A1 - Turman, Constance A1 - Germain, Marine A1 - Wiggins, Kerri L A1 - MacDonald, James A1 - Braekkan, Sigrid K A1 - Armasu, Sebastian M A1 - Pankratz, Nathan A1 - Jackson, Rebecca D A1 - Nielsen, Jonas B A1 - Giulianini, Franco A1 - Puurunen, Marja K A1 - Ibrahim, Manal A1 - Heckbert, Susan R A1 - Damrauer, Scott M A1 - Natarajan, Pradeep A1 - Klarin, Derek A1 - de Vries, Paul S A1 - Sabater-Lleal, Maria A1 - Huffman, Jennifer E A1 - Bammler, Theo K A1 - Frazer, Kelly A A1 - McCauley, Bryan M A1 - Taylor, Kent A1 - Pankow, James S A1 - Reiner, Alexander P A1 - Gabrielsen, Maiken E A1 - Deleuze, Jean-Francois A1 - O'Donnell, Chris J A1 - Kim, Jihye A1 - McKnight, Barbara A1 - Kraft, Peter A1 - Hansen, John-Bjarne A1 - Rosendaal, Frits R A1 - Heit, John A A1 - Psaty, Bruce M A1 - Tang, Weihong A1 - Kooperberg, Charles A1 - Hveem, Kristian A1 - Ridker, Paul M A1 - Morange, Pierre-Emmanuel A1 - Johnson, Andrew D A1 - Kabrhel, Christopher A1 - Trégouët, David-Alexandre A1 - Smith, Nicholas L AB -

Venous thromboembolism (VTE) is a significant contributor to morbidity and mortality. To advance our understanding of the biology contributing to VTE, we conducted a genome-wide association study (GWAS) of VTE and a transcriptome-wide association study (TWAS) based on imputed gene expression from whole blood and liver. We meta-analyzed GWAS data from 18 studies for 30 234 VTE cases and 172 122 controls and assessed the association between 12 923 718 genetic variants and VTE. We generated variant prediction scores of gene expression from whole blood and liver tissue and assessed them for association with VTE. Mendelian randomization analyses were conducted for traits genetically associated with novel VTE loci. We identified 34 independent genetic signals for VTE risk from GWAS meta-analysis, of which 14 are newly reported associations. This included 11 newly associated genetic loci (C1orf198, PLEK, OSMR-AS1, NUGGC/SCARA5, GRK5, MPHOSPH9, ARID4A, PLCG2, SMG6, EIF5A, and STX10) of which 6 replicated, and 3 new independent signals in 3 known genes. Further, TWAS identified 5 additional genetic loci with imputed gene expression levels differing between cases and controls in whole blood (SH2B3, SPSB1, RP11-747H7.3, RP4-737E23.2) and in liver (ERAP1). At some GWAS loci, we found suggestive evidence that the VTE association signal for novel and previously known regions colocalized with expression quantitative trait locus signals. Mendelian randomization analyses suggested that blood traits may contribute to the underlying risk of VTE. To conclude, we identified 16 novel susceptibility loci for VTE; for some loci, the association signals are likely mediated through gene expression of nearby genes.

VL - 134 IS - 19 ER - TY - JOUR T1 - Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction. JF - Nat Commun Y1 - 2020 A1 - Ntalla, Ioanna A1 - Weng, Lu-Chen A1 - Cartwright, James H A1 - Hall, Amelia Weber A1 - Sveinbjornsson, Gardar A1 - Tucker, Nathan R A1 - Choi, Seung Hoan A1 - Chaffin, Mark D A1 - Roselli, Carolina A1 - Barnes, Michael R A1 - Mifsud, Borbala A1 - Warren, Helen R A1 - Hayward, Caroline A1 - Marten, Jonathan A1 - Cranley, James J A1 - Concas, Maria Pina A1 - Gasparini, Paolo A1 - Boutin, Thibaud A1 - Kolcic, Ivana A1 - Polasek, Ozren A1 - Rudan, Igor A1 - Araujo, Nathalia M A1 - Lima-Costa, Maria Fernanda A1 - Ribeiro, Antonio Luiz P A1 - Souza, Renan P A1 - Tarazona-Santos, Eduardo A1 - Giedraitis, Vilmantas A1 - Ingelsson, Erik A1 - Mahajan, Anubha A1 - Morris, Andrew P A1 - del Greco M, Fabiola A1 - Foco, Luisa A1 - Gögele, Martin A1 - Hicks, Andrew A A1 - Cook, James P A1 - Lind, Lars A1 - Lindgren, Cecilia M A1 - Sundström, Johan A1 - Nelson, Christopher P A1 - Riaz, Muhammad B A1 - Samani, Nilesh J A1 - Sinagra, Gianfranco A1 - Ulivi, Sheila A1 - Kähönen, Mika A1 - Mishra, Pashupati P A1 - Mononen, Nina A1 - Nikus, Kjell A1 - Caulfield, Mark J A1 - Dominiczak, Anna A1 - Padmanabhan, Sandosh A1 - Montasser, May E A1 - O'Connell, Jeff R A1 - Ryan, Kathleen A1 - Shuldiner, Alan R A1 - Aeschbacher, Stefanie A1 - Conen, David A1 - Risch, Lorenz A1 - Thériault, Sébastien A1 - Hutri-Kähönen, Nina A1 - Lehtimäki, Terho A1 - Lyytikäinen, Leo-Pekka A1 - Raitakari, Olli T A1 - Barnes, Catriona L K A1 - Campbell, Harry A1 - Joshi, Peter K A1 - Wilson, James F A1 - Isaacs, Aaron A1 - Kors, Jan A A1 - van Duijn, Cornelia M A1 - Huang, Paul L A1 - Gudnason, Vilmundur A1 - Harris, Tamara B A1 - Launer, Lenore J A1 - Smith, Albert V A1 - Bottinger, Erwin P A1 - Loos, Ruth J F A1 - Nadkarni, Girish N A1 - Preuss, Michael H A1 - Correa, Adolfo A1 - Mei, Hao A1 - Wilson, James A1 - Meitinger, Thomas A1 - Müller-Nurasyid, Martina A1 - Peters, Annette A1 - Waldenberger, Melanie A1 - Mangino, Massimo A1 - Spector, Timothy D A1 - Rienstra, Michiel A1 - van de Vegte, Yordi J A1 - van der Harst, Pim A1 - Verweij, Niek A1 - Kääb, Stefan A1 - Schramm, Katharina A1 - Sinner, Moritz F A1 - Strauch, Konstantin A1 - Cutler, Michael J A1 - Fatkin, Diane A1 - London, Barry A1 - Olesen, Morten A1 - Roden, Dan M A1 - Benjamin Shoemaker, M A1 - Gustav Smith, J A1 - Biggs, Mary L A1 - Bis, Joshua C A1 - Brody, Jennifer A A1 - Psaty, Bruce M A1 - Rice, Kenneth A1 - Sotoodehnia, Nona A1 - De Grandi, Alessandro A1 - Fuchsberger, Christian A1 - Pattaro, Cristian A1 - Pramstaller, Peter P A1 - Ford, Ian A1 - Wouter Jukema, J A1 - Macfarlane, Peter W A1 - Trompet, Stella A1 - Dörr, Marcus A1 - Felix, Stephan B A1 - Völker, Uwe A1 - Weiss, Stefan A1 - Havulinna, Aki S A1 - Jula, Antti A1 - Sääksjärvi, Katri A1 - Salomaa, Veikko A1 - Guo, Xiuqing A1 - Heckbert, Susan R A1 - Lin, Henry J A1 - Rotter, Jerome I A1 - Taylor, Kent D A1 - Yao, Jie A1 - de Mutsert, Renée A1 - Maan, Arie C A1 - Mook-Kanamori, Dennis O A1 - Noordam, Raymond A1 - Cucca, Francesco A1 - Ding, Jun A1 - Lakatta, Edward G A1 - Qian, Yong A1 - Tarasov, Kirill V A1 - Levy, Daniel A1 - Lin, Honghuang A1 - Newton-Cheh, Christopher H A1 - Lunetta, Kathryn L A1 - Murray, Alison D A1 - Porteous, David J A1 - Smith, Blair H A1 - Stricker, Bruno H A1 - Uitterlinden, Andre A1 - van den Berg, Marten E A1 - Haessler, Jeffrey A1 - Jackson, Rebecca D A1 - Kooperberg, Charles A1 - Peters, Ulrike A1 - Reiner, Alexander P A1 - Whitsel, Eric A A1 - Alonso, Alvaro A1 - Arking, Dan E A1 - Boerwinkle, Eric A1 - Ehret, Georg B A1 - Soliman, Elsayed Z A1 - Avery, Christy L A1 - Gogarten, Stephanie M A1 - Kerr, Kathleen F A1 - Laurie, Cathy C A1 - Seyerle, Amanda A A1 - Stilp, Adrienne A1 - Assa, Solmaz A1 - Abdullah Said, M A1 - Yldau van der Ende, M A1 - Lambiase, Pier D A1 - Orini, Michele A1 - Ramirez, Julia A1 - Van Duijvenboden, Stefan A1 - Arnar, David O A1 - Gudbjartsson, Daniel F A1 - Holm, Hilma A1 - Sulem, Patrick A1 - Thorleifsson, Gudmar A1 - Thorolfsdottir, Rosa B A1 - Thorsteinsdottir, Unnur A1 - Benjamin, Emelia J A1 - Tinker, Andrew A1 - Stefansson, Kari A1 - Ellinor, Patrick T A1 - Jamshidi, Yalda A1 - Lubitz, Steven A A1 - Munroe, Patricia B AB -

The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N = 293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease.

VL - 11 IS - 1 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 - 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 - Cross-Ancestry Investigation of Venous Thromboembolism Genomic Predictors. JF - Circulation Y1 - 2022 A1 - Thibord, Florian A1 - Klarin, Derek A1 - Brody, Jennifer A A1 - Chen, Ming-Huei A1 - Levin, Michael G A1 - Chasman, Daniel I A1 - Goode, Ellen L A1 - Hveem, Kristian A1 - Teder-Laving, Maris A1 - Martinez-Perez, Angel A1 - Aïssi, Dylan A1 - Daian-Bacq, Delphine A1 - Ito, Kaoru A1 - Natarajan, Pradeep A1 - Lutsey, Pamela L A1 - Nadkarni, Girish N A1 - de Vries, Paul S A1 - Cuellar-Partida, Gabriel A1 - Wolford, Brooke N A1 - Pattee, Jack W A1 - Kooperberg, Charles A1 - Braekkan, Sigrid K A1 - Li-Gao, Ruifang A1 - Saut, Noémie A1 - Sept, Corriene A1 - Germain, Marine A1 - Judy, Renae L A1 - Wiggins, Kerri L A1 - Ko, Darae A1 - O'Donnell, Christopher J A1 - Taylor, Kent D A1 - Giulianini, Franco A1 - de Andrade, Mariza A1 - Nøst, Therese H A1 - Boland, Anne A1 - Empana, Jean-Philippe A1 - Koyama, Satoshi A1 - Gilliland, Thomas A1 - Do, Ron A1 - Huffman, Jennifer E A1 - Wang, Xin A1 - Zhou, Wei A1 - Manuel Soria, Jose A1 - Carlos Souto, Juan A1 - Pankratz, Nathan A1 - Haessler, Jeffery A1 - Hindberg, Kristian A1 - Rosendaal, Frits R A1 - Turman, Constance A1 - Olaso, Robert A1 - Kember, Rachel L A1 - Bartz, Traci M A1 - Lynch, Julie A A1 - Heckbert, Susan R A1 - Armasu, Sebastian M A1 - Brumpton, Ben A1 - Smadja, David M A1 - Jouven, Xavier A1 - Komuro, Issei A1 - Clapham, Katharine R A1 - Loos, Ruth J F A1 - Willer, Cristen J A1 - Sabater-Lleal, Maria A1 - Pankow, James S A1 - Reiner, Alexander P A1 - Morelli, Vania M A1 - Ridker, Paul M A1 - Vlieg, Astrid van Hylckama A1 - Deleuze, Jean-Francois A1 - Kraft, Peter A1 - Rader, Daniel J A1 - Min Lee, Kyung A1 - Psaty, Bruce M A1 - Heidi Skogholt, Anne A1 - Emmerich, Joseph A1 - Suchon, Pierre A1 - Rich, Stephen S A1 - Vy, Ha My T A1 - Tang, Weihong A1 - Jackson, Rebecca D A1 - Hansen, John-Bjarne A1 - Morange, Pierre-Emmanuel A1 - Kabrhel, Christopher A1 - Trégouët, David-Alexandre A1 - Damrauer, Scott M A1 - Johnson, Andrew D A1 - Smith, Nicholas L KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Genomics KW - Humans KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci KW - Thrombosis KW - Venous Thromboembolism AB -

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

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

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

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

VL - 146 IS - 16 ER - TY - JOUR T1 - The Value of Rare Genetic Variation in the Prediction of Common Obesity in European Ancestry Populations. JF - Front Endocrinol (Lausanne) Y1 - 2022 A1 - Wang, Zhe A1 - Choi, Shing Wan A1 - Chami, Nathalie A1 - Boerwinkle, Eric A1 - Fornage, Myriam A1 - Redline, Susan A1 - Bis, Joshua C A1 - Brody, Jennifer A A1 - Psaty, Bruce M A1 - Kim, Wonji A1 - McDonald, Merry-Lynn N A1 - Regan, Elizabeth A A1 - Silverman, Edwin K A1 - Liu, Ching-Ti A1 - Vasan, Ramachandran S A1 - Kalyani, Rita R A1 - Mathias, Rasika A A1 - Yanek, Lisa R A1 - Arnett, Donna K A1 - Justice, Anne E A1 - North, Kari E A1 - Kaplan, Robert A1 - Heckbert, Susan R A1 - de Andrade, Mariza A1 - Guo, Xiuqing A1 - Lange, Leslie A A1 - Rich, Stephen S A1 - Rotter, Jerome I A1 - Ellinor, Patrick T A1 - Lubitz, Steven A A1 - Blangero, John A1 - Shoemaker, M Benjamin A1 - Darbar, Dawood A1 - Gladwin, Mark T A1 - Albert, Christine M A1 - Chasman, Daniel I A1 - Jackson, Rebecca D A1 - Kooperberg, Charles A1 - Reiner, Alexander P A1 - O'Reilly, Paul F A1 - Loos, Ruth J F KW - Gene Frequency KW - Genetic Variation KW - Genome-Wide Association Study KW - Humans KW - Obesity KW - Whole Genome Sequencing AB -

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

VL - 13 ER - TY - JOUR T1 - Genetic architecture of spatial electrical biomarkers for cardiac arrhythmia and relationship with cardiovascular disease. JF - Nat Commun Y1 - 2023 A1 - Young, William J A1 - Haessler, Jeffrey A1 - Benjamins, Jan-Walter A1 - Repetto, Linda A1 - Yao, Jie A1 - Isaacs, Aaron A1 - Harper, Andrew R A1 - Ramirez, Julia A1 - Garnier, Sophie A1 - Van Duijvenboden, Stefan A1 - Baldassari, Antoine R A1 - Concas, Maria Pina A1 - Duong, ThuyVy A1 - Foco, Luisa A1 - Isaksen, Jonas L A1 - Mei, Hao A1 - Noordam, Raymond A1 - Nursyifa, Casia A1 - Richmond, Anne A1 - Santolalla, Meddly L A1 - Sitlani, Colleen M A1 - Soroush, Negin A1 - Thériault, Sébastien A1 - Trompet, Stella A1 - Aeschbacher, Stefanie A1 - Ahmadizar, Fariba A1 - Alonso, Alvaro A1 - Brody, Jennifer A A1 - Campbell, Archie A1 - Correa, Adolfo A1 - Darbar, Dawood A1 - De Luca, Antonio A1 - Deleuze, Jean-Francois A1 - Ellervik, Christina A1 - Fuchsberger, Christian A1 - Goel, Anuj A1 - Grace, Christopher A1 - Guo, Xiuqing A1 - Hansen, Torben A1 - Heckbert, Susan R A1 - Jackson, Rebecca D A1 - Kors, Jan A A1 - Lima-Costa, Maria Fernanda A1 - Linneberg, Allan A1 - Macfarlane, Peter W A1 - Morrison, Alanna C A1 - Navarro, Pau A1 - Porteous, David J A1 - Pramstaller, Peter P A1 - Reiner, Alexander P A1 - Risch, Lorenz A1 - Schotten, Ulrich A1 - Shen, Xia A1 - Sinagra, Gianfranco A1 - Soliman, Elsayed Z A1 - Stoll, Monika A1 - Tarazona-Santos, Eduardo A1 - Tinker, Andrew A1 - Trajanoska, Katerina A1 - Villard, Eric A1 - Warren, Helen R A1 - Whitsel, Eric A A1 - Wiggins, Kerri L A1 - Arking, Dan E A1 - Avery, Christy L A1 - Conen, David A1 - Girotto, Giorgia A1 - Grarup, Niels A1 - Hayward, Caroline A1 - Jukema, J Wouter A1 - Mook-Kanamori, Dennis O A1 - Olesen, Morten Salling A1 - Padmanabhan, Sandosh A1 - Psaty, Bruce M A1 - Pattaro, Cristian A1 - Ribeiro, Antonio Luiz P A1 - Rotter, Jerome I A1 - Stricker, Bruno H A1 - van der Harst, Pim A1 - van Duijn, Cornelia M A1 - Verweij, Niek A1 - Wilson, James G A1 - Orini, Michele A1 - Charron, Philippe A1 - Watkins, Hugh A1 - Kooperberg, Charles A1 - Lin, Henry J A1 - Wilson, James F A1 - Kanters, Jørgen K A1 - Sotoodehnia, Nona A1 - Mifsud, Borbala A1 - Lambiase, Pier D A1 - Tereshchenko, Larisa G A1 - Munroe, Patricia B KW - Arrhythmias, Cardiac KW - Atrioventricular Block KW - Biomarkers KW - Cardiovascular Diseases KW - Electrocardiography KW - Genome-Wide Association Study KW - Humans KW - Risk Factors AB -

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

VL - 14 IS - 1 ER - TY - JOUR T1 - Time-to-Event Genome-Wide Association Study for Incident Cardiovascular Disease in People with Type 2 Diabetes Mellitus. JF - medRxiv Y1 - 2023 A1 - Kwak, Soo Heon A1 - Hernandez-Cancela, Ryan B A1 - DiCorpo, Daniel A A1 - Condon, David E A1 - Merino, Jordi A1 - Wu, Peitao A1 - Brody, Jennifer A A1 - Yao, Jie A1 - Guo, Xiuqing A1 - Ahmadizar, Fariba A1 - Meyer, Mariah A1 - Sincan, Murat A1 - Mercader, Josep M A1 - Lee, Sujin A1 - Haessler, Jeffrey A1 - Vy, Ha My T A1 - Lin, Zhaotong A1 - Armstrong, Nicole D A1 - Gu, Shaopeng A1 - Tsao, Noah L A1 - Lange, Leslie A A1 - Wang, Ningyuan A1 - Wiggins, Kerri L A1 - Trompet, Stella A1 - Liu, Simin A1 - Loos, Ruth J F A1 - Judy, Renae A1 - Schroeder, Philip H A1 - Hasbani, Natalie R A1 - Bos, Maxime M A1 - Morrison, Alanna C A1 - Jackson, Rebecca D A1 - Reiner, Alexander P A1 - Manson, JoAnn E A1 - Chaudhary, Ninad S A1 - Carmichael, Lynn K A1 - Chen, Yii-Der Ida A1 - Taylor, Kent D A1 - Ghanbari, Mohsen A1 - van Meurs, Joyce A1 - Pitsillides, Achilleas N A1 - Psaty, Bruce M A1 - Noordam, Raymond A1 - Do, Ron A1 - Park, Kyong Soo A1 - Jukema, J Wouter A1 - Kavousi, Maryam A1 - Correa, Adolfo A1 - Rich, Stephen S A1 - Damrauer, Scott M A1 - Hajek, Catherine A1 - Cho, Nam H A1 - Irvin, Marguerite R A1 - Pankow, James S A1 - Nadkarni, Girish N A1 - Sladek, Robert A1 - Goodarzi, Mark O A1 - Florez, Jose C A1 - Chasman, Daniel I A1 - Heckbert, Susan R A1 - Kooperberg, Charles A1 - Dupuis, Josée A1 - Malhotra, Rajeev A1 - de Vries, Paul S A1 - Liu, Ching-Ti A1 - Rotter, Jerome I A1 - Meigs, James B AB -

BACKGROUND: Type 2 diabetes mellitus (T2D) confers a two- to three-fold increased risk of cardiovascular disease (CVD). However, the mechanisms underlying increased CVD risk among people with T2D are only partially understood. We hypothesized that a genetic association study among people with T2D at risk for developing incident cardiovascular complications could provide insights into molecular genetic aspects underlying CVD.

METHODS: From 16 studies of the Cohorts for Heart & Aging Research in Genomic Epidemiology (CHARGE) Consortium, we conducted a multi-ancestry time-to-event genome-wide association study (GWAS) for incident CVD among people with T2D using Cox proportional hazards models. Incident CVD was defined based on a composite of coronary artery disease (CAD), stroke, and cardiovascular death that occurred at least one year after the diagnosis of T2D. Cohort-level estimated effect sizes were combined using inverse variance weighted fixed effects meta-analysis. We also tested 204 known CAD variants for association with incident CVD among patients with T2D.

RESULTS: A total of 49,230 participants with T2D were included in the analyses (31,118 European ancestries and 18,112 non-European ancestries) which consisted of 8,956 incident CVD cases over a range of mean follow-up duration between 3.2 and 33.7 years (event rate 18.2%). We identified three novel, distinct genetic loci for incident CVD among individuals with T2D that reached the threshold for genome-wide significance ( <5.0×10 ): rs147138607 (intergenic variant between and ) with a hazard ratio (HR) 1.23, 95% confidence interval (CI) 1.15 - 1.32, =3.6×10 , rs11444867 (intergenic variant near ) with HR 1.89, 95% CI 1.52 - 2.35, =9.9×10 , and rs335407 (intergenic variant between and ) HR 1.25, 95% CI 1.16 - 1.35, =1.5×10 . Among 204 known CAD loci, 32 were associated with incident CVD in people with T2D with <0.05, and 5 were significant after Bonferroni correction ( <0.00024, 0.05/204). A polygenic score of these 204 variants was significantly associated with incident CVD with HR 1.14 (95% CI 1.12 - 1.16) per 1 standard deviation increase ( =1.0×10 ).

CONCLUSIONS: The data point to novel and known genomic regions associated with incident CVD among individuals with T2D.

CLINICAL PERSPECTIVE: We conducted a large-scale multi-ancestry time-to-event GWAS to identify genetic variants associated with CVD among people with T2D. Three variants were significantly associated with incident CVD in people with T2D: rs147138607 (intergenic variant between and ), rs11444867 (intergenic variant near ), and rs335407 (intergenic variant between and ). A polygenic score composed of known CAD variants identified in the general population was significantly associated with the risk of CVD in people with T2D. There are genetic risk factors specific to T2D that could at least partially explain the excess risk of CVD in people with T2D.In addition, we show that people with T2D have enrichment of known CAD association signals which could also explain the excess risk of CVD.

ER - TY - JOUR T1 - Whole Genome Analysis of Venous Thromboembolism: the Trans-Omics for Precision Medicine Program. JF - Circ Genom Precis Med Y1 - 2023 A1 - Seyerle, Amanda A A1 - Laurie, Cecelia A A1 - Coombes, Brandon J A1 - Jain, Deepti A1 - Conomos, Matthew P A1 - Brody, Jennifer A1 - Chen, Ming-Huei A1 - Gogarten, Stephanie M A1 - Beutel, Kathleen M A1 - Gupta, Namrata A1 - Heckbert, Susan R A1 - Jackson, Rebecca D A1 - Johnson, Andrew D A1 - Ko, Darae A1 - Manson, JoAnn E A1 - McKnight, Barbara A1 - Metcalf, Ginger A A1 - Morrison, Alanna C A1 - Reiner, Alexander P A1 - Sofer, Tamar A1 - Tang, Weihong A1 - Wiggins, Kerri L A1 - Boerwinkle, Eric A1 - Andrade, Mariza de A1 - Gabriel, Stacey B A1 - Gibbs, Richard A A1 - Laurie, Cathy C A1 - Psaty, Bruce M A1 - Vasan, Ramachandran S A1 - Rice, Ken A1 - Kooperberg, Charles A1 - Pankow, James S A1 - Smith, Nicholas L A1 - Pankratz, Nathan AB -

Background Risk for venous thromboembolism has a strong genetic component. Whole genome sequencingfrom the Trans-Omics for Precision Medicine program allowed us to look for new associations, particularly rare variants missed by standard genome-wide association studies. Methods The 3793 cases and 7834 controls (11.6% of cases were Black, Hispanic/Latino, or Asian American) were analyzed using a single variant approach and an aggregate gene-based approach using our primary filter (included only loss-of-function and missense variants predicted to be deleterious) and our secondary filter (included all missense variants). Results Single variant analyses identified associations at 5 known loci. Aggregate gene-based analyses identified only (odds ratio, 6.2 for carriers of rare variants; =7.4×10) when using our primary filter. Employing our secondary variant filter led to a smaller effect size at (odds ratio, 3.8; =1.6×10), while excluding variants found only in rare isoforms led to a larger one (odds ratio, 7.5). Different filtering strategies improved the signal for 2 other known genes: became significant (minimum =1.8×10 with the secondary filter), while did not (minimum =4.4×10 with minor allele frequency <0.0005). Results were largely the same when restricting the analyses to include only unprovoked cases; however, one novel gene, , became significant (=4.4×10 using all missense variants with minor allele frequency <0.0005). Conclusions Here, we have demonstrated the importance of using multiple variant filtering strategies, as we detected additional genes when filtering variants based on their predicted deleteriousness, frequency, and presence on the most expressed isoforms. Our primary analyses did not identify new candidate loci; thus larger follow-up studies are needed to replicate the novel locus and to identify additional rare variation associated with venous thromboembolism.

ER - TY - JOUR T1 - WHOLE GENOME SEQUENCING ANALYSIS OF BODY MASS INDEX IDENTIFIES NOVEL AFRICAN ANCESTRY-SPECIFIC RISK ALLELE. JF - medRxiv Y1 - 2023 A1 - Zhang, Xinruo A1 - Brody, Jennifer A A1 - Graff, Mariaelisa A1 - Highland, Heather M A1 - Chami, Nathalie A1 - Xu, Hanfei A1 - Wang, Zhe A1 - Ferrier, Kendra A1 - Chittoor, Geetha A1 - Josyula, Navya S A1 - Li, Xihao A1 - Li, Zilin A1 - Allison, Matthew A A1 - Becker, Diane M A1 - Bielak, Lawrence F A1 - Bis, Joshua C A1 - Boorgula, Meher Preethi A1 - Bowden, Donald W A1 - Broome, Jai G A1 - Buth, Erin J A1 - Carlson, Christopher S A1 - Chang, Kyong-Mi A1 - Chavan, Sameer A1 - Chiu, Yen-Feng A1 - Chuang, Lee-Ming A1 - Conomos, Matthew P A1 - DeMeo, Dawn L A1 - Du, Margaret A1 - Duggirala, Ravindranath A1 - Eng, Celeste A1 - Fohner, Alison E A1 - Freedman, Barry I A1 - Garrett, Melanie E A1 - Guo, Xiuqing A1 - Haiman, Chris A1 - Heavner, Benjamin D A1 - Hidalgo, Bertha A1 - Hixson, James E A1 - Ho, Yuk-Lam A1 - Hobbs, Brian D A1 - Hu, Donglei A1 - Hui, Qin A1 - Hwu, Chii-Min A1 - Jackson, Rebecca D A1 - Jain, Deepti A1 - Kalyani, Rita R A1 - Kardia, Sharon L R A1 - Kelly, Tanika N A1 - Lange, Ethan M A1 - LeNoir, Michael A1 - Li, Changwei A1 - Marchand, Loic Le A1 - McDonald, Merry-Lynn N A1 - McHugh, Caitlin P A1 - Morrison, Alanna C A1 - Naseri, Take A1 - O'Connell, Jeffrey A1 - O'Donnell, Christopher J A1 - Palmer, Nicholette D A1 - Pankow, James S A1 - Perry, James A A1 - Peters, Ulrike A1 - Preuss, Michael H A1 - Rao, D C A1 - Regan, Elizabeth A A1 - Reupena, Sefuiva M A1 - Roden, Dan M A1 - Rodriguez-Santana, Jose A1 - Sitlani, Colleen M A1 - Smith, Jennifer A A1 - Tiwari, Hemant K A1 - Vasan, Ramachandran S A1 - Wang, Zeyuan A1 - Weeks, Daniel E A1 - Wessel, Jennifer A1 - Wiggins, Kerri L A1 - Wilkens, Lynne R A1 - Wilson, Peter W F A1 - Yanek, Lisa R A1 - Yoneda, Zachary T A1 - Zhao, Wei A1 - Zöllner, Sebastian A1 - Arnett, Donna K A1 - Ashley-Koch, Allison E A1 - Barnes, Kathleen C A1 - Blangero, John A1 - Boerwinkle, Eric A1 - Burchard, Esteban G A1 - Carson, April P A1 - Chasman, Daniel I A1 - Chen, Yii-Der Ida A1 - Curran, Joanne E A1 - Fornage, Myriam A1 - Gordeuk, Victor R A1 - He, Jiang A1 - Heckbert, Susan R A1 - Hou, Lifang A1 - Irvin, Marguerite R A1 - Kooperberg, Charles A1 - Minster, Ryan L A1 - Mitchell, Braxton D A1 - Nouraie, Mehdi A1 - Psaty, Bruce M A1 - Raffield, Laura M A1 - Reiner, Alexander P A1 - Rich, Stephen S A1 - Rotter, Jerome I A1 - Shoemaker, M Benjamin A1 - Smith, Nicholas L A1 - Taylor, Kent D A1 - Telen, Marilyn J A1 - Weiss, Scott T A1 - Zhang, Yingze A1 - Costa, Nancy Heard- A1 - Sun, Yan V A1 - Lin, Xihong A1 - Cupples, L Adrienne A1 - Lange, Leslie A A1 - Liu, Ching-Ti A1 - Loos, Ruth J F A1 - North, Kari E A1 - Justice, Anne E AB -

Obesity is a major public health crisis associated with high mortality rates. Previous genome-wide association studies (GWAS) investigating body mass index (BMI) have largely relied on imputed data from European individuals. This study leveraged whole-genome sequencing (WGS) data from 88,873 participants from the Trans-Omics for Precision Medicine (TOPMed) Program, of which 51% were of non-European population groups. We discovered 18 BMI-associated signals ( < 5 × 10 ). Notably, we identified and replicated a novel low frequency single nucleotide polymorphism (SNP) in that was common in individuals of African descent. Using a diverse study population, we further identified two novel secondary signals in known BMI loci and pinpointed two likely causal variants in the and loci. Our work demonstrates the benefits of combining WGS and diverse cohorts in expanding current catalog of variants and genes confer risk for obesity, bringing us one step closer to personalized medicine.

ER -