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

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

%B Diabetes %V 61 %P 1642-7 %8 2012 Jun %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/22474029?dopt=Abstract %R 10.2337/db11-1296 %0 Journal Article %J Nat Genet %D 2012 %T Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture. %A Estrada, Karol %A Styrkarsdottir, Unnur %A Evangelou, Evangelos %A Hsu, Yi-Hsiang %A Duncan, Emma L %A Ntzani, Evangelia E %A Oei, Ling %A Albagha, Omar M E %A Amin, Najaf %A Kemp, John P %A Koller, Daniel L %A Li, Guo %A Liu, Ching-Ti %A Minster, Ryan L %A Moayyeri, Alireza %A Vandenput, Liesbeth %A Willner, Dana %A Xiao, Su-Mei %A Yerges-Armstrong, Laura M %A Zheng, Hou-Feng %A Alonso, Nerea %A Eriksson, Joel %A Kammerer, Candace M %A Kaptoge, Stephen K %A Leo, Paul J %A Thorleifsson, Gudmar %A Wilson, Scott G %A Wilson, James F %A Aalto, Ville %A Alen, Markku %A Aragaki, Aaron K %A Aspelund, Thor %A Center, Jacqueline R %A Dailiana, Zoe %A Duggan, David J %A Garcia, Melissa %A García-Giralt, Natalia %A Giroux, Sylvie %A Hallmans, Göran %A Hocking, Lynne J %A Husted, Lise Bjerre %A Jameson, Karen A %A Khusainova, Rita %A Kim, Ghi Su %A Kooperberg, Charles %A Koromila, Theodora %A Kruk, Marcin %A Laaksonen, Marika %A LaCroix, Andrea Z %A Lee, Seung Hun %A Leung, Ping C %A Lewis, Joshua R %A Masi, Laura %A Mencej-Bedrac, Simona %A Nguyen, Tuan V %A Nogues, Xavier %A Patel, Millan S %A Prezelj, Janez %A Rose, Lynda M %A Scollen, Serena %A Siggeirsdottir, Kristin %A Smith, Albert V %A Svensson, Olle %A Trompet, Stella %A Trummer, Olivia %A van Schoor, Natasja M %A Woo, Jean %A Zhu, Kun %A Balcells, Susana %A Brandi, Maria Luisa %A Buckley, Brendan M %A Cheng, Sulin %A Christiansen, Claus %A Cooper, Cyrus %A Dedoussis, George %A Ford, Ian %A Frost, Morten %A Goltzman, David %A González-Macías, Jesús %A Kähönen, Mika %A Karlsson, Magnus %A Khusnutdinova, Elza %A Koh, Jung-Min %A Kollia, Panagoula %A Langdahl, Bente Lomholt %A Leslie, William D %A Lips, Paul %A Ljunggren, Osten %A Lorenc, Roman S %A Marc, Janja %A Mellström, Dan %A Obermayer-Pietsch, Barbara %A Olmos, José M %A Pettersson-Kymmer, Ulrika %A Reid, David M %A Riancho, José A %A Ridker, Paul M %A Rousseau, François %A Slagboom, P Eline %A Tang, Nelson L S %A Urreizti, Roser %A Van Hul, Wim %A Viikari, Jorma %A Zarrabeitia, María T %A Aulchenko, Yurii S %A Castano-Betancourt, Martha %A Grundberg, Elin %A Herrera, Lizbeth %A Ingvarsson, Thorvaldur %A Johannsdottir, Hrefna %A Kwan, Tony %A Li, Rui %A Luben, Robert %A Medina-Gómez, Carolina %A Palsson, Stefan Th %A Reppe, Sjur %A Rotter, Jerome I %A Sigurdsson, Gunnar %A van Meurs, Joyce B J %A Verlaan, Dominique %A Williams, Frances M K %A Wood, Andrew R %A Zhou, Yanhua %A Gautvik, Kaare M %A Pastinen, Tomi %A Raychaudhuri, Soumya %A Cauley, Jane A %A Chasman, Daniel I %A Clark, Graeme R %A Cummings, Steven R %A Danoy, Patrick %A Dennison, Elaine M %A Eastell, Richard %A Eisman, John A %A Gudnason, Vilmundur %A Hofman, Albert %A Jackson, Rebecca D %A Jones, Graeme %A Jukema, J Wouter %A Khaw, Kay-Tee %A Lehtimäki, Terho %A Liu, Yongmei %A Lorentzon, Mattias %A McCloskey, Eugene %A Mitchell, Braxton D %A Nandakumar, Kannabiran %A Nicholson, Geoffrey C %A Oostra, Ben A %A Peacock, Munro %A Pols, Huibert A P %A Prince, Richard L %A Raitakari, Olli %A Reid, Ian R %A Robbins, John %A Sambrook, Philip N %A Sham, Pak Chung %A Shuldiner, Alan R %A Tylavsky, Frances A %A van Duijn, Cornelia M %A Wareham, Nick J %A Cupples, L Adrienne %A Econs, Michael J %A Evans, David M %A Harris, Tamara B %A Kung, Annie Wai Chee %A Psaty, Bruce M %A Reeve, Jonathan %A Spector, Timothy D %A Streeten, Elizabeth A %A Zillikens, M Carola %A Thorsteinsdottir, Unnur %A Ohlsson, Claes %A Karasik, David %A Richards, J Brent %A Brown, Matthew A %A Stefansson, Kari %A Uitterlinden, André G %A Ralston, Stuart H %A Ioannidis, John P A %A Kiel, Douglas P %A Rivadeneira, Fernando %K Bone Density %K Computational Biology %K European Continental Ancestry Group %K Extracellular Matrix Proteins %K Female %K Femur Neck %K Fractures, Bone %K Gene Expression Profiling %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genotype %K Glycoproteins %K Humans %K Intercellular Signaling Peptides and Proteins %K Low Density Lipoprotein Receptor-Related Protein-5 %K Lumbar Vertebrae %K Male %K Mitochondrial Membrane Transport Proteins %K Osteoporosis %K Phosphoproteins %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %K Risk Factors %K Spectrin %X

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

%B Nat Genet %V 44 %P 491-501 %8 2012 Apr 15 %G eng %N 5 %R 10.1038/ng.2249 %0 Journal Article %J PLoS Genet %D 2013 %T A systematic mapping approach of 16q12.2/FTO and BMI in more than 20,000 African Americans narrows in on the underlying functional variation: results from the Population Architecture using Genomics and Epidemiology (PAGE) study. %A Peters, Ulrike %A North, Kari E %A Sethupathy, Praveen %A Buyske, Steve %A Haessler, Jeff %A Jiao, Shuo %A Fesinmeyer, Megan D %A Jackson, Rebecca D %A Kuller, Lew H %A Rajkovic, Aleksandar %A Lim, Unhee %A Cheng, Iona %A Schumacher, Fred %A Wilkens, Lynne %A Li, Rongling %A Monda, Keri %A Ehret, Georg %A Nguyen, Khanh-Dung H %A Cooper, Richard %A Lewis, Cora E %A Leppert, Mark %A Irvin, Marguerite R %A Gu, C Charles %A Houston, Denise %A Bůzková, Petra %A Ritchie, Marylyn %A Matise, Tara C %A Le Marchand, Loïc %A Hindorff, Lucia A %A Crawford, Dana C %A Haiman, Christopher A %A Kooperberg, Charles %K Adaptor Proteins, Signal Transducing %K Adult %K African Americans %K Aged %K Aged, 80 and over %K Alleles %K Body Mass Index %K Chromosome Mapping %K Continental Population Groups %K European Continental Ancestry Group %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Linkage Disequilibrium %K Male %K Metagenomics %K Middle Aged %K Obesity %K Proteins %X

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

%B PLoS Genet %V 9 %P e1003171 %8 2013 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/23341774?dopt=Abstract %R 10.1371/journal.pgen.1003171 %0 Journal Article %J Am J Hum Genet %D 2014 %T Association of low-frequency and rare coding-sequence variants with blood lipids and coronary heart disease in 56,000 whites and blacks. %A Peloso, Gina M %A Auer, Paul L %A Bis, Joshua C %A Voorman, Arend %A Morrison, Alanna C %A Stitziel, Nathan O %A Brody, Jennifer A %A Khetarpal, Sumeet A %A Crosby, Jacy R %A Fornage, Myriam %A Isaacs, Aaron %A Jakobsdottir, Johanna %A Feitosa, Mary F %A Davies, Gail %A Huffman, Jennifer E %A Manichaikul, Ani %A Davis, Brian %A Lohman, Kurt %A Joon, Aron Y %A Smith, Albert V %A Grove, Megan L %A Zanoni, Paolo %A Redon, Valeska %A Demissie, Serkalem %A Lawson, Kim %A Peters, Ulrike %A Carlson, Christopher %A Jackson, Rebecca D %A Ryckman, Kelli K %A Mackey, Rachel H %A Robinson, Jennifer G %A Siscovick, David S %A Schreiner, Pamela J %A Mychaleckyj, Josyf C %A Pankow, James S %A Hofman, Albert %A Uitterlinden, André G %A Harris, Tamara B %A Taylor, Kent D %A Stafford, Jeanette M %A Reynolds, Lindsay M %A Marioni, Riccardo E %A Dehghan, Abbas %A Franco, Oscar H %A Patel, Aniruddh P %A Lu, Yingchang %A Hindy, George %A Gottesman, Omri %A Bottinger, Erwin P %A Melander, Olle %A Orho-Melander, Marju %A Loos, Ruth J F %A Duga, Stefano %A Merlini, Piera Angelica %A Farrall, Martin %A Goel, Anuj %A Asselta, Rosanna %A Girelli, Domenico %A Martinelli, Nicola %A Shah, Svati H %A Kraus, William E %A Li, Mingyao %A Rader, Daniel J %A Reilly, Muredach P %A McPherson, Ruth %A Watkins, Hugh %A Ardissino, Diego %A Zhang, Qunyuan %A Wang, Judy %A Tsai, Michael Y %A Taylor, Herman A %A Correa, Adolfo %A Griswold, Michael E %A Lange, Leslie A %A Starr, John M %A Rudan, Igor %A Eiriksdottir, Gudny %A Launer, Lenore J %A Ordovas, Jose M %A Levy, Daniel %A Chen, Y-D Ida %A Reiner, Alexander P %A Hayward, Caroline %A Polasek, Ozren %A Deary, Ian J %A Borecki, Ingrid B %A Liu, Yongmei %A Gudnason, Vilmundur %A Wilson, James G %A van Duijn, Cornelia M %A Kooperberg, Charles %A Rich, Stephen S %A Psaty, Bruce M %A Rotter, Jerome I %A O'Donnell, Christopher J %A Rice, Kenneth %A Boerwinkle, Eric %A Kathiresan, Sekar %A Cupples, L Adrienne %K 1-Alkyl-2-acetylglycerophosphocholine Esterase %K Adult %K African Continental Ancestry Group %K Aged %K Alleles %K Animals %K Cholesterol, HDL %K Cholesterol, LDL %K Cohort Studies %K Coronary Disease %K European Continental Ancestry Group %K Female %K Gene Frequency %K Genetic Association Studies %K Genetic Code %K Genetic Variation %K Humans %K Linear Models %K Male %K Mice %K Mice, Inbred C57BL %K Microtubule-Associated Proteins %K Middle Aged %K Phenotype %K Sequence Analysis, DNA %K Subtilisins %K Triglycerides %X

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.

%B Am J Hum Genet %V 94 %P 223-32 %8 2014 Feb 06 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/24507774?dopt=Abstract %R 10.1016/j.ajhg.2014.01.009 %0 Journal Article %J Epidemiology %D 2014 %T Evidence of heterogeneity by race/ethnicity in genetic determinants of QT interval. %A Seyerle, Amanda A %A Young, Alicia M %A Jeff, Janina M %A Melton, Phillip E %A Jorgensen, Neal W %A Lin, Yi %A Carty, Cara L %A Deelman, Ewa %A Heckbert, Susan R %A Hindorff, Lucia A %A Jackson, Rebecca D %A Martin, Lisa W %A Okin, Peter M %A Perez, Marco V %A Psaty, Bruce M %A Soliman, Elsayed Z %A Whitsel, Eric A %A North, Kari E %A Laston, Sandra %A Kooperberg, Charles %A Avery, Christy L %K Aged %K Continental Population Groups %K Electrocardiography %K Female %K Genetic Predisposition to Disease %K Haplotypes %K Humans %K Long QT Syndrome %K Male %K Middle Aged %K Phenotype %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %K Quantitative Trait, Heritable %K Risk Factors %X

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.

%B Epidemiology %V 25 %P 790-8 %8 2014 Nov %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/25166880?dopt=Abstract %R 10.1097/EDE.0000000000000168 %0 Journal Article %J Hum Mol Genet %D 2014 %T Quantifying rare, deleterious variation in 12 human cytochrome P450 drug-metabolism genes in a large-scale exome dataset. %A Gordon, Adam S %A Tabor, Holly K %A Johnson, Andrew D %A Snively, Beverly M %A Assimes, Themistocles L %A Auer, Paul L %A Ioannidis, John P A %A Peters, Ulrike %A Robinson, Jennifer G %A Sucheston, Lara E %A Wang, Danxin %A Sotoodehnia, Nona %A Rotter, Jerome I %A Psaty, Bruce M %A Jackson, Rebecca D %A Herrington, David M %A O'Donnell, Christopher J %A Reiner, Alexander P %A Rich, Stephen S %A Rieder, Mark J %A Bamshad, Michael J %A Nickerson, Deborah A %K Cytochrome P-450 Enzyme System %K Databases, Genetic %K European Continental Ancestry Group %K Exome %K Humans %K Pharmaceutical Preparations %K Pharmacogenetics %K Polymorphism, Genetic %X

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.

%B Hum Mol Genet %V 23 %P 1957-63 %8 2014 Apr 15 %G eng %N 8 %1 http://www.ncbi.nlm.nih.gov/pubmed/24282029?dopt=Abstract %R 10.1093/hmg/ddt588 %0 Journal Article %J Am J Hum Genet %D 2014 %T Whole-exome sequencing identifies rare and low-frequency coding variants associated with LDL cholesterol. %A Lange, Leslie A %A Hu, Youna %A Zhang, He %A Xue, Chenyi %A Schmidt, Ellen M %A Tang, Zheng-Zheng %A Bizon, Chris %A Lange, Ethan M %A Smith, Joshua D %A Turner, Emily H %A Jun, Goo %A Kang, Hyun Min %A Peloso, Gina %A Auer, Paul %A Li, Kuo-Ping %A Flannick, Jason %A Zhang, Ji %A Fuchsberger, Christian %A Gaulton, Kyle %A Lindgren, Cecilia %A Locke, Adam %A Manning, Alisa %A Sim, Xueling %A Rivas, Manuel A %A Holmen, Oddgeir L %A Gottesman, Omri %A Lu, Yingchang %A Ruderfer, Douglas %A Stahl, Eli A %A Duan, Qing %A Li, Yun %A Durda, Peter %A Jiao, Shuo %A Isaacs, Aaron %A Hofman, Albert %A Bis, Joshua C %A Correa, Adolfo %A Griswold, Michael E %A Jakobsdottir, Johanna %A Smith, Albert V %A Schreiner, Pamela J %A Feitosa, Mary F %A Zhang, Qunyuan %A Huffman, Jennifer E %A Crosby, Jacy %A Wassel, Christina L %A Do, Ron %A Franceschini, Nora %A Martin, Lisa W %A Robinson, Jennifer G %A Assimes, Themistocles L %A Crosslin, David R %A Rosenthal, Elisabeth A %A Tsai, Michael %A Rieder, Mark J %A Farlow, Deborah N %A Folsom, Aaron R %A Lumley, Thomas %A Fox, Ervin R %A Carlson, Christopher S %A Peters, Ulrike %A Jackson, Rebecca D %A van Duijn, Cornelia M %A Uitterlinden, André G %A Levy, Daniel %A Rotter, Jerome I %A Taylor, Herman A %A Gudnason, Vilmundur %A Siscovick, David S %A Fornage, Myriam %A Borecki, Ingrid B %A Hayward, Caroline %A Rudan, Igor %A Chen, Y Eugene %A Bottinger, Erwin P %A Loos, Ruth J F %A Sætrom, Pål %A Hveem, Kristian %A Boehnke, Michael %A Groop, Leif %A McCarthy, Mark %A Meitinger, Thomas %A Ballantyne, Christie M %A Gabriel, Stacey B %A O'Donnell, Christopher J %A Post, Wendy S %A North, Kari E %A Reiner, Alexander P %A Boerwinkle, Eric %A Psaty, Bruce M %A Altshuler, David %A Kathiresan, Sekar %A Lin, Dan-Yu %A Jarvik, Gail P %A Cupples, L Adrienne %A Kooperberg, Charles %A Wilson, James G %A Nickerson, Deborah A %A Abecasis, Goncalo R %A Rich, Stephen S %A Tracy, Russell P %A Willer, Cristen J %K Adult %K Aged %K Apolipoproteins E %K Cholesterol, LDL %K Cohort Studies %K Dyslipidemias %K Exome %K Female %K Follow-Up Studies %K Gene Frequency %K Genetic Code %K Genome-Wide Association Study %K Genotype %K Humans %K Lipase %K Male %K Middle Aged %K Phenotype %K Polymorphism, Single Nucleotide %K Proprotein Convertase 9 %K Proprotein Convertases %K Receptors, LDL %K Sequence Analysis, DNA %K Serine Endopeptidases %X

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

%B Am J Hum Genet %V 94 %P 233-45 %8 2014 Feb 06 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/24507775?dopt=Abstract %R 10.1016/j.ajhg.2014.01.010 %0 Journal Article %J Hum Mol Genet %D 2015 %T Association of exome sequences with plasma C-reactive protein levels in >9000 participants. %A Schick, Ursula M %A Auer, Paul L %A Bis, Joshua C %A Lin, Honghuang %A Wei, Peng %A Pankratz, Nathan %A Lange, Leslie A %A Brody, Jennifer %A Stitziel, Nathan O %A Kim, Daniel S %A Carlson, Christopher S %A Fornage, Myriam %A Haessler, Jeffery %A Hsu, Li %A Jackson, Rebecca D %A Kooperberg, Charles %A Leal, Suzanne M %A Psaty, Bruce M %A Boerwinkle, Eric %A Tracy, Russell %A Ardissino, Diego %A Shah, Svati %A Willer, Cristen %A Loos, Ruth %A Melander, Olle %A McPherson, Ruth %A Hovingh, Kees %A Reilly, Muredach %A Watkins, Hugh %A Girelli, Domenico %A Fontanillas, Pierre %A Chasman, Daniel I %A Gabriel, Stacey B %A Gibbs, Richard %A Nickerson, Deborah A %A Kathiresan, Sekar %A Peters, Ulrike %A Dupuis, Josée %A Wilson, James G %A Rich, Stephen S %A Morrison, Alanna C %A Benjamin, Emelia J %A Gross, Myron D %A Reiner, Alex P %K Adult %K African Americans %K C-Reactive Protein %K Cardiovascular Diseases %K Cohort Studies %K European Continental Ancestry Group %K Exome %K Female %K Gene Frequency %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Hepatocyte Nuclear Factor 1-alpha %K Humans %K Male %K Plasma %K Polymorphism, Single Nucleotide %K Receptors, Interleukin-6 %K Risk Factors %X

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

%B Hum Mol Genet %V 24 %P 559-71 %8 2015 Jan 15 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/25187575?dopt=Abstract %R 10.1093/hmg/ddu450 %0 Journal Article %J Nature %D 2015 %T Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction. %A Do, Ron %A Stitziel, Nathan O %A Won, Hong-Hee %A Jørgensen, Anders Berg %A Duga, Stefano %A Angelica Merlini, Pier %A Kiezun, Adam %A Farrall, Martin %A Goel, Anuj %A Zuk, Or %A Guella, Illaria %A Asselta, Rosanna %A Lange, Leslie A %A Peloso, Gina M %A Auer, Paul L %A Girelli, Domenico %A Martinelli, Nicola %A Farlow, Deborah N %A DePristo, Mark A %A Roberts, Robert %A Stewart, Alexander F R %A Saleheen, Danish %A Danesh, John %A Epstein, Stephen E %A Sivapalaratnam, Suthesh %A Hovingh, G Kees %A Kastelein, John J %A Samani, Nilesh J %A Schunkert, Heribert %A Erdmann, Jeanette %A Shah, Svati H %A Kraus, William E %A Davies, Robert %A Nikpay, Majid %A Johansen, Christopher T %A Wang, Jian %A Hegele, Robert A %A Hechter, Eliana %A März, Winfried %A Kleber, Marcus E %A Huang, Jie %A Johnson, Andrew D %A Li, Mingyao %A Burke, Greg L %A Gross, Myron %A Liu, Yongmei %A Assimes, Themistocles L %A Heiss, Gerardo %A Lange, Ethan M %A Folsom, Aaron R %A Taylor, Herman A %A Olivieri, Oliviero %A Hamsten, Anders %A Clarke, Robert %A Reilly, Dermot F %A Yin, Wu %A Rivas, Manuel A %A Donnelly, Peter %A Rossouw, Jacques E %A Psaty, Bruce M %A Herrington, David M %A Wilson, James G %A Rich, Stephen S %A Bamshad, Michael J %A Tracy, Russell P %A Cupples, L Adrienne %A Rader, Daniel J %A Reilly, Muredach P %A Spertus, John A %A Cresci, Sharon %A Hartiala, Jaana %A Tang, W H Wilson %A Hazen, Stanley L %A Allayee, Hooman %A Reiner, Alex P %A Carlson, Christopher S %A Kooperberg, Charles %A Jackson, Rebecca D %A Boerwinkle, Eric %A Lander, Eric S %A Schwartz, Stephen M %A Siscovick, David S %A McPherson, Ruth %A Tybjaerg-Hansen, Anne %A Abecasis, Goncalo R %A Watkins, Hugh %A Nickerson, Deborah A %A Ardissino, Diego %A Sunyaev, Shamil R %A O'Donnell, Christopher J %A Altshuler, David %A Gabriel, Stacey %A Kathiresan, Sekar %K Age Factors %K Age of Onset %K Alleles %K Apolipoproteins A %K Case-Control Studies %K Cholesterol, LDL %K Coronary Artery Disease %K Exome %K Female %K Genetic Predisposition to Disease %K Genetics, Population %K Heterozygote %K Humans %K Male %K Middle Aged %K Mutation %K Myocardial Infarction %K National Heart, Lung, and Blood Institute (U.S.) %K Receptors, LDL %K Triglycerides %K United States %X

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.

%B Nature %V 518 %P 102-6 %8 2015 Feb 5 %G eng %N 7537 %1 http://www.ncbi.nlm.nih.gov/pubmed/25487149?dopt=Abstract %R 10.1038/nature13917 %0 Journal Article %J JAMA Neurol %D 2015 %T Rare and Coding Region Genetic Variants Associated With Risk of Ischemic Stroke: The NHLBI Exome Sequence Project. %A Auer, Paul L %A Nalls, Mike %A Meschia, James F %A Worrall, Bradford B %A Longstreth, W T %A Seshadri, Sudha %A Kooperberg, Charles %A Burger, Kathleen M %A Carlson, Christopher S %A Carty, Cara L %A Chen, Wei-Min %A Cupples, L Adrienne %A DeStefano, Anita L %A Fornage, Myriam %A Hardy, John %A Hsu, Li %A Jackson, Rebecca D %A Jarvik, Gail P %A Kim, Daniel S %A Lakshminarayan, Kamakshi %A Lange, Leslie A %A Manichaikul, Ani %A Quinlan, Aaron R %A Singleton, Andrew B %A Thornton, Timothy A %A Nickerson, Deborah A %A Peters, Ulrike %A Rich, Stephen S %K Aged %K Brain Ischemia %K Exome %K Female %K Genetic Predisposition to Disease %K Genetic Variation %K Genome-Wide Association Study %K Humans %K Male %K Middle Aged %K Muscle Proteins %K National Heart, Lung, and Blood Institute (U.S.) %K Nuclear Proteins %K Open Reading Frames %K Palmitoyl-CoA Hydrolase %K Stroke %K United States %X

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

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

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

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

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

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

%B JAMA Neurol %V 72 %P 781-8 %8 2015 Jul %G eng %N 7 %1 http://www.ncbi.nlm.nih.gov/pubmed/25961151?dopt=Abstract %R 10.1001/jamaneurol.2015.0582 %0 Journal Article %J Bone Rep %D 2016 %T A genome-wide association study meta-analysis of clinical fracture in 10,012 African American women. %A Taylor, Kira C %A Evans, Daniel S %A Edwards, Digna R Velez %A Edwards, Todd L %A Sofer, Tamar %A Li, Guo %A Liu, Youfang %A Franceschini, Nora %A Jackson, Rebecca D %A Giri, Ayush %A Donneyong, Macarius %A Psaty, Bruce %A Rotter, Jerome I %A LaCroix, Andrea Z %A Jordan, Joanne M %A Robbins, John A %A Lewis, Beth %A Stefanick, Marcia L %A Liu, Yongmei %A Garcia, Melissa %A Harris, Tamara %A Cauley, Jane A %A North, Kari E %X

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.

%B Bone Rep %V 5 %P 233-242 %8 2016 Dec %G eng %R 10.1016/j.bonr.2016.08.005 %0 Journal Article %J J Am Soc Nephrol %D 2016 %T SOS2 and ACP1 Loci Identified through Large-Scale Exome Chip Analysis Regulate Kidney Development and Function. %A Li, Man %A Li, Yong %A Weeks, Olivia %A Mijatovic, Vladan %A Teumer, Alexander %A Huffman, Jennifer E %A Tromp, Gerard %A Fuchsberger, Christian %A Gorski, Mathias %A Lyytikäinen, Leo-Pekka %A Nutile, Teresa %A Sedaghat, Sanaz %A Sorice, Rossella %A Tin, Adrienne %A Yang, Qiong %A Ahluwalia, Tarunveer S %A Arking, Dan E %A Bihlmeyer, Nathan A %A Böger, Carsten A %A Carroll, Robert J %A Chasman, Daniel I %A Cornelis, Marilyn C %A Dehghan, Abbas %A Faul, Jessica D %A Feitosa, Mary F %A Gambaro, Giovanni %A Gasparini, Paolo %A Giulianini, Franco %A Heid, Iris %A Huang, Jinyan %A Imboden, Medea %A Jackson, Anne U %A Jeff, Janina %A Jhun, Min A %A Katz, Ronit %A Kifley, Annette %A Kilpeläinen, Tuomas O %A Kumar, Ashish %A Laakso, Markku %A Li-Gao, Ruifang %A Lohman, Kurt %A Lu, Yingchang %A Mägi, Reedik %A Malerba, Giovanni %A Mihailov, Evelin %A Mohlke, Karen L %A Mook-Kanamori, Dennis O %A Robino, Antonietta %A Ruderfer, Douglas %A Salvi, Erika %A Schick, Ursula M %A Schulz, Christina-Alexandra %A Smith, Albert V %A Smith, Jennifer A %A Traglia, Michela %A Yerges-Armstrong, Laura M %A Zhao, Wei %A Goodarzi, Mark O %A Kraja, Aldi T %A Liu, Chunyu %A Wessel, Jennifer %A Boerwinkle, Eric %A Borecki, Ingrid B %A Bork-Jensen, Jette %A Bottinger, Erwin P %A Braga, Daniele %A Brandslund, Ivan %A Brody, Jennifer A %A Campbell, Archie %A Carey, David J %A Christensen, Cramer %A Coresh, Josef %A Crook, Errol %A Curhan, Gary C %A Cusi, Daniele %A de Boer, Ian H %A de Vries, Aiko P J %A Denny, Joshua C %A Devuyst, Olivier %A Dreisbach, Albert W %A Endlich, Karlhans %A Esko, Tõnu %A Franco, Oscar H %A Fulop, Tibor %A Gerhard, Glenn S %A Glümer, Charlotte %A Gottesman, Omri %A Grarup, Niels %A Gudnason, Vilmundur %A Harris, Tamara B %A Hayward, Caroline %A Hocking, Lynne %A Hofman, Albert %A Hu, Frank B %A Husemoen, Lise Lotte N %A Jackson, Rebecca D %A Jørgensen, Torben %A Jørgensen, Marit E %A Kähönen, Mika %A Kardia, Sharon L R %A König, Wolfgang %A Kooperberg, Charles %A Kriebel, Jennifer %A Launer, Lenore J %A Lauritzen, Torsten %A Lehtimäki, Terho %A Levy, Daniel %A Linksted, Pamela %A Linneberg, Allan %A Liu, Yongmei %A Loos, Ruth J F %A Lupo, Antonio %A Meisinger, Christine %A Melander, Olle %A Metspalu, Andres %A Mitchell, Paul %A Nauck, Matthias %A Nürnberg, Peter %A Orho-Melander, Marju %A Parsa, Afshin %A Pedersen, Oluf %A Peters, Annette %A Peters, Ulrike %A Polasek, Ozren %A Porteous, David %A Probst-Hensch, Nicole M %A Psaty, Bruce M %A Qi, Lu %A Raitakari, Olli T %A Reiner, Alex P %A Rettig, Rainer %A Ridker, Paul M %A Rivadeneira, Fernando %A Rossouw, Jacques E %A Schmidt, Frank %A Siscovick, David %A Soranzo, Nicole %A Strauch, Konstantin %A Toniolo, Daniela %A Turner, Stephen T %A Uitterlinden, André G %A Ulivi, Sheila %A Velayutham, Dinesh %A Völker, Uwe %A Völzke, Henry %A Waldenberger, Melanie %A Wang, Jie Jin %A Weir, David R %A Witte, Daniel %A Kuivaniemi, Helena %A Fox, Caroline S %A Franceschini, Nora %A Goessling, Wolfram %A Köttgen, Anna %A Chu, Audrey Y %X

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.

%B J Am Soc Nephrol %8 2016 Dec 05 %G eng %R 10.1681/ASN.2016020131 %0 Journal Article %J PLoS Genet %D 2017 %T Single-trait and multi-trait genome-wide association analyses identify novel loci for blood pressure in African-ancestry populations. %A Liang, Jingjing %A Le, Thu H %A Edwards, Digna R Velez %A Tayo, Bamidele O %A Gaulton, Kyle J %A Smith, Jennifer A %A Lu, Yingchang %A Jensen, Richard A %A Chen, Guanjie %A Yanek, Lisa R %A Schwander, Karen %A Tajuddin, Salman M %A Sofer, Tamar %A Kim, Wonji %A Kayima, James %A McKenzie, Colin A %A Fox, Ervin %A Nalls, Michael A %A Young, J Hunter %A Sun, Yan V %A Lane, Jacqueline M %A Cechova, Sylvia %A Zhou, Jie %A Tang, Hua %A Fornage, Myriam %A Musani, Solomon K %A Wang, Heming %A Lee, Juyoung %A Adeyemo, Adebowale %A Dreisbach, Albert W %A Forrester, Terrence %A Chu, Pei-Lun %A Cappola, Anne %A Evans, Michele K %A Morrison, Alanna C %A Martin, Lisa W %A Wiggins, Kerri L %A Hui, Qin %A Zhao, Wei %A Jackson, Rebecca D %A Ware, Erin B %A Faul, Jessica D %A Reiner, Alex P %A Bray, Michael %A Denny, Joshua C %A Mosley, Thomas H %A Palmas, Walter %A Guo, Xiuqing %A Papanicolaou, George J %A Penman, Alan D %A Polak, Joseph F %A Rice, Kenneth %A Taylor, Ken D %A Boerwinkle, Eric %A Bottinger, Erwin P %A Liu, Kiang %A Risch, Neil %A Hunt, Steven C %A Kooperberg, Charles %A Zonderman, Alan B %A Laurie, Cathy C %A Becker, Diane M %A Cai, Jianwen %A Loos, Ruth J F %A Psaty, Bruce M %A Weir, David R %A Kardia, Sharon L R %A Arnett, Donna K %A Won, Sungho %A Edwards, Todd L %A Redline, Susan %A Cooper, Richard S %A Rao, D C %A Rotter, Jerome I %A Rotimi, Charles %A Levy, Daniel %A Chakravarti, Aravinda %A Zhu, Xiaofeng %A Franceschini, Nora %K African Americans %K Animals %K Basic Helix-Loop-Helix Transcription Factors %K Blood Pressure %K Cadherins %K Case-Control Studies %K Female %K Genetic Loci %K Genome-Wide Association Study %K Humans %K Hypertension %K Male %K Membrane Proteins %K Mice %K Multifactorial Inheritance %K Polymorphism, Single Nucleotide %X

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

%B PLoS Genet %V 13 %P e1006728 %8 2017 May %G eng %N 5 %R 10.1371/journal.pgen.1006728 %0 Journal Article %J Circ Genom Precis Med %D 2018 %T Common Coding Variants in Are Associated With the Nav1.8 Late Current and Cardiac Conduction. %A Macri, Vincenzo %A Brody, Jennifer A %A Arking, Dan E %A Hucker, William J %A Yin, Xiaoyan %A Lin, Honghuang %A Mills, Robert W %A Sinner, Moritz F %A Lubitz, Steven A %A Liu, Ching-Ti %A Morrison, Alanna C %A Alonso, Alvaro %A Li, Ning %A Fedorov, Vadim V %A Janssen, Paul M %A Bis, Joshua C %A Heckbert, Susan R %A Dolmatova, Elena V %A Lumley, Thomas %A Sitlani, Colleen M %A Cupples, L Adrienne %A Pulit, Sara L %A Newton-Cheh, Christopher %A Barnard, John %A Smith, Jonathan D %A Van Wagoner, David R %A Chung, Mina K %A Vlahakes, Gus J %A O'Donnell, Christopher J %A Rotter, Jerome I %A Margulies, Kenneth B %A Morley, Michael P %A Cappola, Thomas P %A Benjamin, Emelia J %A Muzny, Donna %A Gibbs, Richard A %A Jackson, Rebecca D %A Magnani, Jared W %A Herndon, Caroline N %A Rich, Stephen S %A Psaty, Bruce M %A Milan, David J %A Boerwinkle, Eric %A Mohler, Peter J %A Sotoodehnia, Nona %A Ellinor, Patrick T %X

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.

%B Circ Genom Precis Med %V 11 %P e001663 %8 2018 May %G eng %N 5 %R 10.1161/CIRCGEN.116.001663 %0 Journal Article %J Nat Genet %D 2018 %T Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes. %A Malik, Rainer %A Chauhan, Ganesh %A Traylor, Matthew %A Sargurupremraj, Muralidharan %A Okada, Yukinori %A Mishra, Aniket %A Rutten-Jacobs, Loes %A Giese, Anne-Katrin %A van der Laan, Sander W %A Gretarsdottir, Solveig %A Anderson, Christopher D %A Chong, Michael %A Adams, Hieab H H %A Ago, Tetsuro %A Almgren, Peter %A Amouyel, Philippe %A Ay, Hakan %A Bartz, Traci M %A Benavente, Oscar R %A Bevan, Steve %A Boncoraglio, Giorgio B %A Brown, Robert D %A Butterworth, Adam S %A Carrera, Caty %A Carty, Cara L %A Chasman, Daniel I %A Chen, Wei-Min %A Cole, John W %A Correa, Adolfo %A Cotlarciuc, Ioana %A Cruchaga, Carlos %A Danesh, John %A de Bakker, Paul I W %A DeStefano, Anita L %A den Hoed, Marcel %A Duan, Qing %A Engelter, Stefan T %A Falcone, Guido J %A Gottesman, Rebecca F %A Grewal, Raji P %A Gudnason, Vilmundur %A Gustafsson, Stefan %A Haessler, Jeffrey %A Harris, Tamara B %A Hassan, Ahamad %A Havulinna, Aki S %A Heckbert, Susan R %A Holliday, Elizabeth G %A Howard, George %A Hsu, Fang-Chi %A Hyacinth, Hyacinth I %A Ikram, M Arfan %A Ingelsson, Erik %A Irvin, Marguerite R %A Jian, Xueqiu %A Jimenez-Conde, Jordi %A Johnson, Julie A %A Jukema, J Wouter %A Kanai, Masahiro %A Keene, Keith L %A Kissela, Brett M %A Kleindorfer, Dawn O %A Kooperberg, Charles %A Kubo, Michiaki %A Lange, Leslie A %A Langefeld, Carl D %A Langenberg, Claudia %A Launer, Lenore J %A Lee, Jin-Moo %A Lemmens, Robin %A Leys, Didier %A Lewis, Cathryn M %A Lin, Wei-Yu %A Lindgren, Arne G %A Lorentzen, Erik %A Magnusson, Patrik K %A Maguire, Jane %A Manichaikul, Ani %A McArdle, Patrick F %A Meschia, James F %A Mitchell, Braxton D %A Mosley, Thomas H %A Nalls, Michael A %A Ninomiya, Toshiharu %A O'Donnell, Martin J %A Psaty, Bruce M %A Pulit, Sara L %A Rannikmae, Kristiina %A Reiner, Alexander P %A Rexrode, Kathryn M %A Rice, Kenneth %A Rich, Stephen S %A Ridker, Paul M %A Rost, Natalia S %A Rothwell, Peter M %A Rotter, Jerome I %A Rundek, Tatjana %A Sacco, Ralph L %A Sakaue, Saori %A Sale, Michèle M %A Salomaa, Veikko %A Sapkota, Bishwa R %A Schmidt, Reinhold %A Schmidt, Carsten O %A Schminke, Ulf %A Sharma, Pankaj %A Slowik, Agnieszka %A Sudlow, Cathie L M %A Tanislav, Christian %A Tatlisumak, Turgut %A Taylor, Kent D %A Thijs, Vincent N S %A Thorleifsson, Gudmar %A Thorsteinsdottir, Unnur %A Tiedt, Steffen %A Trompet, Stella %A Tzourio, Christophe %A van Duijn, Cornelia M %A Walters, Matthew %A Wareham, Nicholas J %A Wassertheil-Smoller, Sylvia %A Wilson, James G %A Wiggins, Kerri L %A Yang, Qiong %A Yusuf, Salim %A Bis, Joshua C %A Pastinen, Tomi %A Ruusalepp, Arno %A Schadt, Eric E %A Koplev, Simon %A Björkegren, Johan L M %A Codoni, Veronica %A Civelek, Mete %A Smith, Nicholas L %A Trégouët, David A %A Christophersen, Ingrid E %A Roselli, Carolina %A Lubitz, Steven A %A Ellinor, Patrick T %A Tai, E Shyong %A Kooner, Jaspal S %A Kato, Norihiro %A He, Jiang %A van der Harst, Pim %A Elliott, Paul %A Chambers, John C %A Takeuchi, Fumihiko %A Johnson, Andrew D %A Sanghera, Dharambir K %A Melander, Olle %A Jern, Christina %A Strbian, Daniel %A Fernandez-Cadenas, Israel %A Longstreth, W T %A Rolfs, Arndt %A Hata, Jun %A Woo, Daniel %A Rosand, Jonathan %A Paré, Guillaume %A Hopewell, Jemma C %A Saleheen, Danish %A Stefansson, Kari %A Worrall, Bradford B %A Kittner, Steven J %A Seshadri, Sudha %A Fornage, Myriam %A Markus, Hugh S %A Howson, Joanna M M %A Kamatani, Yoichiro %A Debette, Stephanie %A Dichgans, Martin %A Malik, Rainer %A Chauhan, Ganesh %A Traylor, Matthew %A Sargurupremraj, Muralidharan %A Okada, Yukinori %A Mishra, Aniket %A Rutten-Jacobs, Loes %A Giese, Anne-Katrin %A van der Laan, Sander W %A Gretarsdottir, Solveig %A Anderson, Christopher D %A Chong, Michael %A Adams, Hieab H H %A Ago, Tetsuro %A Almgren, Peter %A Amouyel, Philippe %A Ay, Hakan %A Bartz, Traci M %A Benavente, Oscar R %A Bevan, Steve %A Boncoraglio, Giorgio B %A Brown, Robert D %A Butterworth, Adam S %A Carrera, Caty %A Carty, Cara L %A Chasman, Daniel I %A Chen, Wei-Min %A Cole, John W %A Correa, Adolfo %A Cotlarciuc, Ioana %A Cruchaga, Carlos %A Danesh, John %A de Bakker, Paul I W %A DeStefano, Anita L %A Hoed, Marcel den %A Duan, Qing %A Engelter, Stefan T %A Falcone, Guido J %A Gottesman, Rebecca F %A Grewal, Raji P %A Gudnason, Vilmundur %A Gustafsson, Stefan %A Haessler, Jeffrey %A Harris, Tamara B %A Hassan, Ahamad %A Havulinna, Aki S %A Heckbert, Susan R %A Holliday, Elizabeth G %A Howard, George %A Hsu, Fang-Chi %A Hyacinth, Hyacinth I %A Ikram, M Arfan %A Ingelsson, Erik %A Irvin, Marguerite R %A Jian, Xueqiu %A Jimenez-Conde, Jordi %A Johnson, Julie A %A Jukema, J Wouter %A Kanai, Masahiro %A Keene, Keith L %A Kissela, Brett M %A Kleindorfer, Dawn O %A Kooperberg, Charles %A Kubo, Michiaki %A Lange, Leslie A %A Langefeld, Carl D %A Langenberg, Claudia %A Launer, Lenore J %A Lee, Jin-Moo %A Lemmens, Robin %A Leys, Didier %A Lewis, Cathryn M %A Lin, Wei-Yu %A Lindgren, Arne G %A Lorentzen, Erik %A Magnusson, Patrik K %A Maguire, Jane %A Manichaikul, Ani %A McArdle, Patrick F %A Meschia, James F %A Mitchell, Braxton D %A Mosley, Thomas H %A Nalls, Michael A %A Ninomiya, Toshiharu %A O'Donnell, Martin J %A Psaty, Bruce M %A Pulit, Sara L %A Rannikmae, Kristiina %A Reiner, Alexander P %A Rexrode, Kathryn M %A Rice, Kenneth %A Rich, Stephen S %A Ridker, Paul M %A Rost, Natalia S %A Rothwell, Peter M %A Rotter, Jerome I %A Rundek, Tatjana %A Sacco, Ralph L %A Sakaue, Saori %A Sale, Michèle M %A Salomaa, Veikko %A Sapkota, Bishwa R %A Schmidt, Reinhold %A Schmidt, Carsten O %A Schminke, Ulf %A Sharma, Pankaj %A Slowik, Agnieszka %A Sudlow, Cathie L M %A Tanislav, Christian %A Tatlisumak, Turgut %A Taylor, Kent D %A Thijs, Vincent N S %A Thorleifsson, Gudmar %A Thorsteinsdottir, Unnur %A Tiedt, Steffen %A Trompet, Stella %A Tzourio, Christophe %A van Duijn, Cornelia M %A Walters, Matthew %A Wareham, Nicholas J %A Wassertheil-Smoller, Sylvia %A Wilson, James G %A Wiggins, Kerri L %A Yang, Qiong %A Yusuf, Salim %A Amin, Najaf %A Aparicio, Hugo S %A Arnett, Donna K %A Attia, John %A Beiser, Alexa S %A Berr, Claudine %A Buring, Julie E %A Bustamante, Mariana %A Caso, Valeria %A Cheng, Yu-Ching %A Choi, Seung Hoan %A Chowhan, Ayesha %A Cullell, Natalia %A Dartigues, Jean-François %A Delavaran, Hossein %A Delgado, Pilar %A Dörr, Marcus %A Engström, Gunnar %A Ford, Ian %A Gurpreet, Wander S %A Hamsten, Anders %A Heitsch, Laura %A Hozawa, Atsushi %A Ibanez, Laura %A Ilinca, Andreea %A Ingelsson, Martin %A Iwasaki, Motoki %A Jackson, Rebecca D %A Jood, Katarina %A Jousilahti, Pekka %A Kaffashian, Sara %A Kalra, Lalit %A Kamouchi, Masahiro %A Kitazono, Takanari %A Kjartansson, Olafur %A Kloss, Manja %A Koudstaal, Peter J %A Krupinski, Jerzy %A Labovitz, Daniel L %A Laurie, Cathy C %A Levi, Christopher R %A Li, Linxin %A Lind, Lars %A Lindgren, Cecilia M %A Lioutas, Vasileios %A Liu, Yong Mei %A Lopez, Oscar L %A Makoto, Hirata %A Martinez-Majander, Nicolas %A Matsuda, Koichi %A Minegishi, Naoko %A Montaner, Joan %A Morris, Andrew P %A Muiño, Elena %A Müller-Nurasyid, Martina %A Norrving, Bo %A Ogishima, Soichi %A Parati, Eugenio A %A Peddareddygari, Leema Reddy %A Pedersen, Nancy L %A Pera, Joanna %A Perola, Markus %A Pezzini, Alessandro %A Pileggi, Silvana %A Rabionet, Raquel %A Riba-Llena, Iolanda %A Ribasés, Marta %A Romero, Jose R %A Roquer, Jaume %A Rudd, Anthony G %A Sarin, Antti-Pekka %A Sarju, Ralhan %A Sarnowski, Chloe %A Sasaki, Makoto %A Satizabal, Claudia L %A Satoh, Mamoru %A Sattar, Naveed %A Sawada, Norie %A Sibolt, Gerli %A Sigurdsson, Ásgeir %A Smith, Albert %A Sobue, Kenji %A Soriano-Tárraga, Carolina %A Stanne, Tara %A Stine, O Colin %A Stott, David J %A Strauch, Konstantin %A Takai, Takako %A Tanaka, Hideo %A Tanno, Kozo %A Teumer, Alexander %A Tomppo, Liisa %A Torres-Aguila, Nuria P %A Touze, Emmanuel %A Tsugane, Shoichiro %A Uitterlinden, André G %A Valdimarsson, Einar M %A van der Lee, Sven J %A Völzke, Henry %A Wakai, Kenji %A Weir, David %A Williams, Stephen R %A Wolfe, Charles D A %A Wong, Quenna %A Xu, Huichun %A Yamaji, Taiki %A Sanghera, Dharambir K %A Melander, Olle %A Jern, Christina %A Strbian, Daniel %A Fernandez-Cadenas, Israel %A Longstreth, W T %A Rolfs, Arndt %A Hata, Jun %A Woo, Daniel %A Rosand, Jonathan %A Paré, Guillaume %A Hopewell, Jemma C %A Saleheen, Danish %A Stefansson, Kari %A Worrall, Bradford B %A Kittner, Steven J %A Seshadri, Sudha %A Fornage, Myriam %A Markus, Hugh S %A Howson, Joanna M M %A Kamatani, Yoichiro %A Debette, Stephanie %A Dichgans, Martin %X

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.

%B Nat Genet %V 50 %P 524-537 %8 2018 Apr %G eng %N 4 %R 10.1038/s41588-018-0058-3 %0 Journal Article %J Blood %D 2019 %T Genomic and transcriptomic association studies identify 16 novel susceptibility loci for venous thromboembolism. %A Lindström, Sara %A Wang, Lu %A Smith, Erin N %A Gordon, William %A van Hylckama Vlieg, Astrid %A de Andrade, Mariza %A Brody, Jennifer A %A Pattee, Jack W %A Haessler, Jeffrey %A Brumpton, Ben M %A Chasman, Daniel I %A Suchon, Pierre %A Chen, Ming-Huei %A Turman, Constance %A Germain, Marine %A Wiggins, Kerri L %A MacDonald, James %A Braekkan, Sigrid K %A Armasu, Sebastian M %A Pankratz, Nathan %A Jackson, Rebecca D %A Nielsen, Jonas B %A Giulianini, Franco %A Puurunen, Marja K %A Ibrahim, Manal %A Heckbert, Susan R %A Damrauer, Scott M %A Natarajan, Pradeep %A Klarin, Derek %A de Vries, Paul S %A Sabater-Lleal, Maria %A Huffman, Jennifer E %A Bammler, Theo K %A Frazer, Kelly A %A McCauley, Bryan M %A Taylor, Kent %A Pankow, James S %A Reiner, Alexander P %A Gabrielsen, Maiken E %A Deleuze, Jean-Francois %A O'Donnell, Chris J %A Kim, Jihye %A McKnight, Barbara %A Kraft, Peter %A Hansen, John-Bjarne %A Rosendaal, Frits R %A Heit, John A %A Psaty, Bruce M %A Tang, Weihong %A Kooperberg, Charles %A Hveem, Kristian %A Ridker, Paul M %A Morange, Pierre-Emmanuel %A Johnson, Andrew D %A Kabrhel, Christopher %A Trégouët, David-Alexandre %A Smith, Nicholas L %X

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.

%B Blood %V 134 %P 1645-1657 %8 2019 Nov 07 %G eng %N 19 %R 10.1182/blood.2019000435 %0 Journal Article %J Nat Commun %D 2020 %T Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction. %A Ntalla, Ioanna %A Weng, Lu-Chen %A Cartwright, James H %A Hall, Amelia Weber %A Sveinbjornsson, Gardar %A Tucker, Nathan R %A Choi, Seung Hoan %A Chaffin, Mark D %A Roselli, Carolina %A Barnes, Michael R %A Mifsud, Borbala %A Warren, Helen R %A Hayward, Caroline %A Marten, Jonathan %A Cranley, James J %A Concas, Maria Pina %A Gasparini, Paolo %A Boutin, Thibaud %A Kolcic, Ivana %A Polasek, Ozren %A Rudan, Igor %A Araujo, Nathalia M %A Lima-Costa, Maria Fernanda %A Ribeiro, Antonio Luiz P %A Souza, Renan P %A Tarazona-Santos, Eduardo %A Giedraitis, Vilmantas %A Ingelsson, Erik %A Mahajan, Anubha %A Morris, Andrew P %A del Greco M, Fabiola %A Foco, Luisa %A Gögele, Martin %A Hicks, Andrew A %A Cook, James P %A Lind, Lars %A Lindgren, Cecilia M %A Sundström, Johan %A Nelson, Christopher P %A Riaz, Muhammad B %A Samani, Nilesh J %A Sinagra, Gianfranco %A Ulivi, Sheila %A Kähönen, Mika %A Mishra, Pashupati P %A Mononen, Nina %A Nikus, Kjell %A Caulfield, Mark J %A Dominiczak, Anna %A Padmanabhan, Sandosh %A Montasser, May E %A O'Connell, Jeff R %A Ryan, Kathleen %A Shuldiner, Alan R %A Aeschbacher, Stefanie %A Conen, David %A Risch, Lorenz %A Thériault, Sébastien %A Hutri-Kähönen, Nina %A Lehtimäki, Terho %A Lyytikäinen, Leo-Pekka %A Raitakari, Olli T %A Barnes, Catriona L K %A Campbell, Harry %A Joshi, Peter K %A Wilson, James F %A Isaacs, Aaron %A Kors, Jan A %A van Duijn, Cornelia M %A Huang, Paul L %A Gudnason, Vilmundur %A Harris, Tamara B %A Launer, Lenore J %A Smith, Albert V %A Bottinger, Erwin P %A Loos, Ruth J F %A Nadkarni, Girish N %A Preuss, Michael H %A Correa, Adolfo %A Mei, Hao %A Wilson, James %A Meitinger, Thomas %A Müller-Nurasyid, Martina %A Peters, Annette %A Waldenberger, Melanie %A Mangino, Massimo %A Spector, Timothy D %A Rienstra, Michiel %A van de Vegte, Yordi J %A van der Harst, Pim %A Verweij, Niek %A Kääb, Stefan %A Schramm, Katharina %A Sinner, Moritz F %A Strauch, Konstantin %A Cutler, Michael J %A Fatkin, Diane %A London, Barry %A Olesen, Morten %A Roden, Dan M %A Benjamin Shoemaker, M %A Gustav Smith, J %A Biggs, Mary L %A Bis, Joshua C %A Brody, Jennifer A %A Psaty, Bruce M %A Rice, Kenneth %A Sotoodehnia, Nona %A De Grandi, Alessandro %A Fuchsberger, Christian %A Pattaro, Cristian %A Pramstaller, Peter P %A Ford, Ian %A Wouter Jukema, J %A Macfarlane, Peter W %A Trompet, Stella %A Dörr, Marcus %A Felix, Stephan B %A Völker, Uwe %A Weiss, Stefan %A Havulinna, Aki S %A Jula, Antti %A Sääksjärvi, Katri %A Salomaa, Veikko %A Guo, Xiuqing %A Heckbert, Susan R %A Lin, Henry J %A Rotter, Jerome I %A Taylor, Kent D %A Yao, Jie %A de Mutsert, Renée %A Maan, Arie C %A Mook-Kanamori, Dennis O %A Noordam, Raymond %A Cucca, Francesco %A Ding, Jun %A Lakatta, Edward G %A Qian, Yong %A Tarasov, Kirill V %A Levy, Daniel %A Lin, Honghuang %A Newton-Cheh, Christopher H %A Lunetta, Kathryn L %A Murray, Alison D %A Porteous, David J %A Smith, Blair H %A Stricker, Bruno H %A Uitterlinden, Andre %A van den Berg, Marten E %A Haessler, Jeffrey %A Jackson, Rebecca D %A Kooperberg, Charles %A Peters, Ulrike %A Reiner, Alexander P %A Whitsel, Eric A %A Alonso, Alvaro %A Arking, Dan E %A Boerwinkle, Eric %A Ehret, Georg B %A Soliman, Elsayed Z %A Avery, Christy L %A Gogarten, Stephanie M %A Kerr, Kathleen F %A Laurie, Cathy C %A Seyerle, Amanda A %A Stilp, Adrienne %A Assa, Solmaz %A Abdullah Said, M %A Yldau van der Ende, M %A Lambiase, Pier D %A Orini, Michele %A Ramirez, Julia %A Van Duijvenboden, Stefan %A Arnar, David O %A Gudbjartsson, Daniel F %A Holm, Hilma %A Sulem, Patrick %A Thorleifsson, Gudmar %A Thorolfsdottir, Rosa B %A Thorsteinsdottir, Unnur %A Benjamin, Emelia J %A Tinker, Andrew %A Stefansson, Kari %A Ellinor, Patrick T %A Jamshidi, Yalda %A Lubitz, Steven A %A Munroe, Patricia B %X

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.

%B Nat Commun %V 11 %P 2542 %8 2020 May 21 %G eng %N 1 %R 10.1038/s41467-020-15706-x %0 Journal Article %J Nature %D 2021 %T Genetic insights into biological mechanisms governing human ovarian ageing. %A Ruth, Katherine S %A Day, Felix R %A Hussain, Jazib %A Martínez-Marchal, Ana %A Aiken, Catherine E %A Azad, Ajuna %A Thompson, Deborah J %A Knoblochova, Lucie %A Abe, Hironori %A Tarry-Adkins, Jane L %A Gonzalez, Javier Martin %A Fontanillas, Pierre %A Claringbould, Annique %A Bakker, Olivier B %A Sulem, Patrick %A Walters, Robin G %A Terao, Chikashi %A Turon, Sandra %A Horikoshi, Momoko %A Lin, Kuang %A Onland-Moret, N Charlotte %A Sankar, Aditya %A Hertz, Emil Peter Thrane %A Timshel, Pascal N %A Shukla, Vallari %A Borup, Rehannah %A Olsen, Kristina W %A Aguilera, Paula %A Ferrer-Roda, Mònica %A Huang, Yan %A Stankovic, Stasa %A Timmers, Paul R H J %A Ahearn, Thomas U %A Alizadeh, Behrooz Z %A Naderi, Elnaz %A Andrulis, Irene L %A Arnold, Alice M %A Aronson, Kristan J %A Augustinsson, Annelie %A Bandinelli, Stefania %A Barbieri, Caterina M %A Beaumont, Robin N %A Becher, Heiko %A Beckmann, Matthias W %A Benonisdottir, Stefania %A Bergmann, Sven %A Bochud, Murielle %A Boerwinkle, Eric %A Bojesen, Stig E %A Bolla, Manjeet K %A Boomsma, Dorret I %A Bowker, Nicholas %A Brody, Jennifer A %A Broer, Linda %A Buring, Julie E %A Campbell, Archie %A Campbell, Harry %A Castelao, Jose E %A Catamo, Eulalia %A Chanock, Stephen J %A Chenevix-Trench, Georgia %A Ciullo, Marina %A Corre, Tanguy %A Couch, Fergus J %A Cox, Angela %A Crisponi, Laura %A Cross, Simon S %A Cucca, Francesco %A Czene, Kamila %A Smith, George Davey %A de Geus, Eco J C N %A de Mutsert, Renée %A De Vivo, Immaculata %A Demerath, Ellen W %A Dennis, Joe %A Dunning, Alison M %A Dwek, Miriam %A Eriksson, Mikael %A Esko, Tõnu %A Fasching, Peter A %A Faul, Jessica D %A Ferrucci, Luigi %A Franceschini, Nora %A Frayling, Timothy M %A Gago-Dominguez, Manuela %A Mezzavilla, Massimo %A García-Closas, Montserrat %A Gieger, Christian %A Giles, Graham G %A Grallert, Harald %A Gudbjartsson, Daniel F %A Gudnason, Vilmundur %A Guénel, Pascal %A Haiman, Christopher A %A Håkansson, Niclas %A Hall, Per %A Hayward, Caroline %A He, Chunyan %A He, Wei %A Heiss, Gerardo %A Høffding, Miya K %A Hopper, John L %A Hottenga, Jouke J %A Hu, Frank %A Hunter, David %A Ikram, Mohammad A %A Jackson, Rebecca D %A Joaquim, Micaella D R %A John, Esther M %A Joshi, Peter K %A Karasik, David %A Kardia, Sharon L R %A Kartsonaki, Christiana %A Karlsson, Robert %A Kitahara, Cari M %A Kolcic, Ivana %A Kooperberg, Charles %A Kraft, Peter %A Kurian, Allison W %A Kutalik, Zoltán %A La Bianca, Martina %A Lachance, Genevieve %A Langenberg, Claudia %A Launer, Lenore J %A Laven, Joop S E %A Lawlor, Deborah A %A Le Marchand, Loïc %A Li, Jingmei %A Lindblom, Annika %A Lindström, Sara %A Lindstrom, Tricia %A Linet, Martha %A Liu, Yongmei %A Liu, Simin %A Luan, Jian'an %A Mägi, Reedik %A Magnusson, Patrik K E %A Mangino, Massimo %A Mannermaa, Arto %A Marco, Brumat %A Marten, Jonathan %A Martin, Nicholas G %A Mbarek, Hamdi %A McKnight, Barbara %A Medland, Sarah E %A Meisinger, Christa %A Meitinger, Thomas %A Menni, Cristina %A Metspalu, Andres %A Milani, Lili %A Milne, Roger L %A Montgomery, Grant W %A Mook-Kanamori, Dennis O %A Mulas, Antonella %A Mulligan, Anna M %A Murray, Alison %A Nalls, Mike A %A Newman, Anne %A Noordam, Raymond %A Nutile, Teresa %A Nyholt, Dale R %A Olshan, Andrew F %A Olsson, Håkan %A Painter, Jodie N %A Patel, Alpa V %A Pedersen, Nancy L %A Perjakova, Natalia %A Peters, Annette %A Peters, Ulrike %A Pharoah, Paul D P %A Polasek, Ozren %A Porcu, Eleonora %A Psaty, Bruce M %A Rahman, Iffat %A Rennert, Gad %A Rennert, Hedy S %A Ridker, Paul M %A Ring, Susan M %A Robino, Antonietta %A Rose, Lynda M %A Rosendaal, Frits R %A Rossouw, Jacques %A Rudan, Igor %A Rueedi, Rico %A Ruggiero, Daniela %A Sala, Cinzia F %A Saloustros, Emmanouil %A Sandler, Dale P %A Sanna, Serena %A Sawyer, Elinor J %A Sarnowski, Chloe %A Schlessinger, David %A Schmidt, Marjanka K %A Schoemaker, Minouk J %A Schraut, Katharina E %A Scott, Christopher %A Shekari, Saleh %A Shrikhande, Amruta %A Smith, Albert V %A Smith, Blair H %A Smith, Jennifer A %A Sorice, Rossella %A Southey, Melissa C %A Spector, Tim D %A Spinelli, John J %A Stampfer, Meir %A Stöckl, Doris %A van Meurs, Joyce B J %A Strauch, Konstantin %A Styrkarsdottir, Unnur %A Swerdlow, Anthony J %A Tanaka, Toshiko %A Teras, Lauren R %A Teumer, Alexander %A Þorsteinsdottir, Unnur %A Timpson, Nicholas J %A Toniolo, Daniela %A Traglia, Michela %A Troester, Melissa A %A Truong, Thérèse %A Tyrrell, Jessica %A Uitterlinden, André G %A Ulivi, Sheila %A Vachon, Celine M %A Vitart, Veronique %A Völker, Uwe %A Vollenweider, Peter %A Völzke, Henry %A Wang, Qin %A Wareham, Nicholas J %A Weinberg, Clarice R %A Weir, David R %A Wilcox, Amber N %A van Dijk, Ko Willems %A Willemsen, Gonneke %A Wilson, James F %A Wolffenbuttel, Bruce H R %A Wolk, Alicja %A Wood, Andrew R %A Zhao, Wei %A Zygmunt, Marek %A Chen, Zhengming %A Li, Liming %A Franke, Lude %A Burgess, Stephen %A Deelen, Patrick %A Pers, Tune H %A Grøndahl, Marie Louise %A Andersen, Claus Yding %A Pujol, Anna %A Lopez-Contreras, Andres J %A Daniel, Jeremy A %A Stefansson, Kari %A Chang-Claude, Jenny %A van der Schouw, Yvonne T %A Lunetta, Kathryn L %A Chasman, Daniel I %A Easton, Douglas F %A Visser, Jenny A %A Ozanne, Susan E %A Namekawa, Satoshi H %A Solc, Petr %A Murabito, Joanne M %A Ong, Ken K %A Hoffmann, Eva R %A Murray, Anna %A Roig, Ignasi %A Perry, John R B %X

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.

%B Nature %V 596 %P 393-397 %8 2021 Aug %G eng %N 7872 %R 10.1038/s41586-021-03779-7 %0 Journal Article %J Am J Epidemiol %D 2021 %T A System for Phenotype Harmonization in the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program. %A Stilp, Adrienne M %A Emery, Leslie S %A Broome, Jai G %A Buth, Erin J %A Khan, Alyna T %A Laurie, Cecelia A %A Wang, Fei Fei %A Wong, Quenna %A Chen, Dongquan %A D'Augustine, Catherine M %A Heard-Costa, Nancy L %A Hohensee, Chancellor R %A Johnson, William Craig %A Juarez, Lucia D %A Liu, Jingmin %A Mutalik, Karen M %A Raffield, Laura M %A Wiggins, Kerri L %A de Vries, Paul S %A Kelly, Tanika N %A Kooperberg, Charles %A Natarajan, Pradeep %A Peloso, Gina M %A Peyser, Patricia A %A Reiner, Alex P %A Arnett, Donna K %A Aslibekyan, Stella %A Barnes, Kathleen C %A Bielak, Lawrence F %A Bis, Joshua C %A Cade, Brian E %A Chen, Ming-Huei %A Correa, Adolfo %A Cupples, L Adrienne %A de Andrade, Mariza %A Ellinor, Patrick T %A Fornage, Myriam %A Franceschini, Nora %A Gan, Weiniu %A Ganesh, Santhi K %A Graffelman, Jan %A Grove, Megan L %A Guo, Xiuqing %A Hawley, Nicola L %A Hsu, Wan-Ling %A Jackson, Rebecca D %A Jaquish, Cashell E %A Johnson, Andrew D %A Kardia, Sharon L R %A Kelly, Shannon %A Lee, Jiwon %A Mathias, Rasika A %A McGarvey, Stephen T %A Mitchell, Braxton D %A Montasser, May E %A Morrison, Alanna C %A North, Kari E %A Nouraie, Seyed Mehdi %A Oelsner, Elizabeth C %A Pankratz, Nathan %A Rich, Stephen S %A Rotter, Jerome I %A Smith, Jennifer A %A Taylor, Kent D %A Vasan, Ramachandran S %A Weeks, Daniel E %A Weiss, Scott T %A Wilson, Carla G %A Yanek, Lisa R %A Psaty, Bruce M %A Heckbert, Susan R %A Laurie, Cathy C %X

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.

%B Am J Epidemiol %8 2021 Apr 16 %G eng %R 10.1093/aje/kwab115 %0 Journal Article %J Circulation %D 2022 %T Cross-Ancestry Investigation of Venous Thromboembolism Genomic Predictors. %A Thibord, Florian %A Klarin, Derek %A Brody, Jennifer A %A Chen, Ming-Huei %A Levin, Michael G %A Chasman, Daniel I %A Goode, Ellen L %A Hveem, Kristian %A Teder-Laving, Maris %A Martinez-Perez, Angel %A Aïssi, Dylan %A Daian-Bacq, Delphine %A Ito, Kaoru %A Natarajan, Pradeep %A Lutsey, Pamela L %A Nadkarni, Girish N %A de Vries, Paul S %A Cuellar-Partida, Gabriel %A Wolford, Brooke N %A Pattee, Jack W %A Kooperberg, Charles %A Braekkan, Sigrid K %A Li-Gao, Ruifang %A Saut, Noémie %A Sept, Corriene %A Germain, Marine %A Judy, Renae L %A Wiggins, Kerri L %A Ko, Darae %A O'Donnell, Christopher J %A Taylor, Kent D %A Giulianini, Franco %A de Andrade, Mariza %A Nøst, Therese H %A Boland, Anne %A Empana, Jean-Philippe %A Koyama, Satoshi %A Gilliland, Thomas %A Do, Ron %A Huffman, Jennifer E %A Wang, Xin %A Zhou, Wei %A Manuel Soria, Jose %A Carlos Souto, Juan %A Pankratz, Nathan %A Haessler, Jeffery %A Hindberg, Kristian %A Rosendaal, Frits R %A Turman, Constance %A Olaso, Robert %A Kember, Rachel L %A Bartz, Traci M %A Lynch, Julie A %A Heckbert, Susan R %A Armasu, Sebastian M %A Brumpton, Ben %A Smadja, David M %A Jouven, Xavier %A Komuro, Issei %A Clapham, Katharine R %A Loos, Ruth J F %A Willer, Cristen J %A Sabater-Lleal, Maria %A Pankow, James S %A Reiner, Alexander P %A Morelli, Vania M %A Ridker, Paul M %A Vlieg, Astrid van Hylckama %A Deleuze, Jean-Francois %A Kraft, Peter %A Rader, Daniel J %A Min Lee, Kyung %A Psaty, Bruce M %A Heidi Skogholt, Anne %A Emmerich, Joseph %A Suchon, Pierre %A Rich, Stephen S %A Vy, Ha My T %A Tang, Weihong %A Jackson, Rebecca D %A Hansen, John-Bjarne %A Morange, Pierre-Emmanuel %A Kabrhel, Christopher %A Trégouët, David-Alexandre %A Damrauer, Scott M %A Johnson, Andrew D %A Smith, Nicholas L %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genomics %K Humans %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %K Thrombosis %K Venous Thromboembolism %X

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

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

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

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

%B Circulation %V 146 %P 1225-1242 %8 2022 Oct 18 %G eng %N 16 %R 10.1161/CIRCULATIONAHA.122.059675 %0 Journal Article %J Front Endocrinol (Lausanne) %D 2022 %T The Value of Rare Genetic Variation in the Prediction of Common Obesity in European Ancestry Populations. %A Wang, Zhe %A Choi, Shing Wan %A Chami, Nathalie %A Boerwinkle, Eric %A Fornage, Myriam %A Redline, Susan %A Bis, Joshua C %A Brody, Jennifer A %A Psaty, Bruce M %A Kim, Wonji %A McDonald, Merry-Lynn N %A Regan, Elizabeth A %A Silverman, Edwin K %A Liu, Ching-Ti %A Vasan, Ramachandran S %A Kalyani, Rita R %A Mathias, Rasika A %A Yanek, Lisa R %A Arnett, Donna K %A Justice, Anne E %A North, Kari E %A Kaplan, Robert %A Heckbert, Susan R %A de Andrade, Mariza %A Guo, Xiuqing %A Lange, Leslie A %A Rich, Stephen S %A Rotter, Jerome I %A Ellinor, Patrick T %A Lubitz, Steven A %A Blangero, John %A Shoemaker, M Benjamin %A Darbar, Dawood %A Gladwin, Mark T %A Albert, Christine M %A Chasman, Daniel I %A Jackson, Rebecca D %A Kooperberg, Charles %A Reiner, Alexander P %A O'Reilly, Paul F %A Loos, Ruth J F %K Gene Frequency %K Genetic Variation %K Genome-Wide Association Study %K Humans %K Obesity %K Whole Genome Sequencing %X

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

%B Front Endocrinol (Lausanne) %V 13 %P 863893 %8 2022 %G eng %R 10.3389/fendo.2022.863893 %0 Journal Article %J Nat Commun %D 2023 %T Genetic architecture of spatial electrical biomarkers for cardiac arrhythmia and relationship with cardiovascular disease. %A Young, William J %A Haessler, Jeffrey %A Benjamins, Jan-Walter %A Repetto, Linda %A Yao, Jie %A Isaacs, Aaron %A Harper, Andrew R %A Ramirez, Julia %A Garnier, Sophie %A Van Duijvenboden, Stefan %A Baldassari, Antoine R %A Concas, Maria Pina %A Duong, ThuyVy %A Foco, Luisa %A Isaksen, Jonas L %A Mei, Hao %A Noordam, Raymond %A Nursyifa, Casia %A Richmond, Anne %A Santolalla, Meddly L %A Sitlani, Colleen M %A Soroush, Negin %A Thériault, Sébastien %A Trompet, Stella %A Aeschbacher, Stefanie %A Ahmadizar, Fariba %A Alonso, Alvaro %A Brody, Jennifer A %A Campbell, Archie %A Correa, Adolfo %A Darbar, Dawood %A De Luca, Antonio %A Deleuze, Jean-Francois %A Ellervik, Christina %A Fuchsberger, Christian %A Goel, Anuj %A Grace, Christopher %A Guo, Xiuqing %A Hansen, Torben %A Heckbert, Susan R %A Jackson, Rebecca D %A Kors, Jan A %A Lima-Costa, Maria Fernanda %A Linneberg, Allan %A Macfarlane, Peter W %A Morrison, Alanna C %A Navarro, Pau %A Porteous, David J %A Pramstaller, Peter P %A Reiner, Alexander P %A Risch, Lorenz %A Schotten, Ulrich %A Shen, Xia %A Sinagra, Gianfranco %A Soliman, Elsayed Z %A Stoll, Monika %A Tarazona-Santos, Eduardo %A Tinker, Andrew %A Trajanoska, Katerina %A Villard, Eric %A Warren, Helen R %A Whitsel, Eric A %A Wiggins, Kerri L %A Arking, Dan E %A Avery, Christy L %A Conen, David %A Girotto, Giorgia %A Grarup, Niels %A Hayward, Caroline %A Jukema, J Wouter %A Mook-Kanamori, Dennis O %A Olesen, Morten Salling %A Padmanabhan, Sandosh %A Psaty, Bruce M %A Pattaro, Cristian %A Ribeiro, Antonio Luiz P %A Rotter, Jerome I %A Stricker, Bruno H %A van der Harst, Pim %A van Duijn, Cornelia M %A Verweij, Niek %A Wilson, James G %A Orini, Michele %A Charron, Philippe %A Watkins, Hugh %A Kooperberg, Charles %A Lin, Henry J %A Wilson, James F %A Kanters, Jørgen K %A Sotoodehnia, Nona %A Mifsud, Borbala %A Lambiase, Pier D %A Tereshchenko, Larisa G %A Munroe, Patricia B %K Arrhythmias, Cardiac %K Atrioventricular Block %K Biomarkers %K Cardiovascular Diseases %K Electrocardiography %K Genome-Wide Association Study %K Humans %K Risk Factors %X

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

%B Nat Commun %V 14 %P 1411 %8 2023 Mar 14 %G eng %N 1 %R 10.1038/s41467-023-36997-w %0 Journal Article %J medRxiv %D 2023 %T Time-to-Event Genome-Wide Association Study for Incident Cardiovascular Disease in People with Type 2 Diabetes Mellitus. %A Kwak, Soo Heon %A Hernandez-Cancela, Ryan B %A DiCorpo, Daniel A %A Condon, David E %A Merino, Jordi %A Wu, Peitao %A Brody, Jennifer A %A Yao, Jie %A Guo, Xiuqing %A Ahmadizar, Fariba %A Meyer, Mariah %A Sincan, Murat %A Mercader, Josep M %A Lee, Sujin %A Haessler, Jeffrey %A Vy, Ha My T %A Lin, Zhaotong %A Armstrong, Nicole D %A Gu, Shaopeng %A Tsao, Noah L %A Lange, Leslie A %A Wang, Ningyuan %A Wiggins, Kerri L %A Trompet, Stella %A Liu, Simin %A Loos, Ruth J F %A Judy, Renae %A Schroeder, Philip H %A Hasbani, Natalie R %A Bos, Maxime M %A Morrison, Alanna C %A Jackson, Rebecca D %A Reiner, Alexander P %A Manson, JoAnn E %A Chaudhary, Ninad S %A Carmichael, Lynn K %A Chen, Yii-Der Ida %A Taylor, Kent D %A Ghanbari, Mohsen %A van Meurs, Joyce %A Pitsillides, Achilleas N %A Psaty, Bruce M %A Noordam, Raymond %A Do, Ron %A Park, Kyong Soo %A Jukema, J Wouter %A Kavousi, Maryam %A Correa, Adolfo %A Rich, Stephen S %A Damrauer, Scott M %A Hajek, Catherine %A Cho, Nam H %A Irvin, Marguerite R %A Pankow, James S %A Nadkarni, Girish N %A Sladek, Robert %A Goodarzi, Mark O %A Florez, Jose C %A Chasman, Daniel I %A Heckbert, Susan R %A Kooperberg, Charles %A Dupuis, Josée %A Malhotra, Rajeev %A de Vries, Paul S %A Liu, Ching-Ti %A Rotter, Jerome I %A Meigs, James B %X

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.

%B medRxiv %8 2023 Jul 28 %G eng %R 10.1101/2023.07.25.23293180 %0 Journal Article %J Circ Genom Precis Med %D 2023 %T Whole Genome Analysis of Venous Thromboembolism: the Trans-Omics for Precision Medicine Program. %A Seyerle, Amanda A %A Laurie, Cecelia A %A Coombes, Brandon J %A Jain, Deepti %A Conomos, Matthew P %A Brody, Jennifer %A Chen, Ming-Huei %A Gogarten, Stephanie M %A Beutel, Kathleen M %A Gupta, Namrata %A Heckbert, Susan R %A Jackson, Rebecca D %A Johnson, Andrew D %A Ko, Darae %A Manson, JoAnn E %A McKnight, Barbara %A Metcalf, Ginger A %A Morrison, Alanna C %A Reiner, Alexander P %A Sofer, Tamar %A Tang, Weihong %A Wiggins, Kerri L %A Boerwinkle, Eric %A Andrade, Mariza de %A Gabriel, Stacey B %A Gibbs, Richard A %A Laurie, Cathy C %A Psaty, Bruce M %A Vasan, Ramachandran S %A Rice, Ken %A Kooperberg, Charles %A Pankow, James S %A Smith, Nicholas L %A Pankratz, Nathan %X

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.

%B Circ Genom Precis Med %P e003532 %8 2023 Mar 24 %G eng %R 10.1161/CIRCGEN.121.003532 %0 Journal Article %J medRxiv %D 2023 %T WHOLE GENOME SEQUENCING ANALYSIS OF BODY MASS INDEX IDENTIFIES NOVEL AFRICAN ANCESTRY-SPECIFIC RISK ALLELE. %A Zhang, Xinruo %A Brody, Jennifer A %A Graff, Mariaelisa %A Highland, Heather M %A Chami, Nathalie %A Xu, Hanfei %A Wang, Zhe %A Ferrier, Kendra %A Chittoor, Geetha %A Josyula, Navya S %A Li, Xihao %A Li, Zilin %A Allison, Matthew A %A Becker, Diane M %A Bielak, Lawrence F %A Bis, Joshua C %A Boorgula, Meher Preethi %A Bowden, Donald W %A Broome, Jai G %A Buth, Erin J %A Carlson, Christopher S %A Chang, Kyong-Mi %A Chavan, Sameer %A Chiu, Yen-Feng %A Chuang, Lee-Ming %A Conomos, Matthew P %A DeMeo, Dawn L %A Du, Margaret %A Duggirala, Ravindranath %A Eng, Celeste %A Fohner, Alison E %A Freedman, Barry I %A Garrett, Melanie E %A Guo, Xiuqing %A Haiman, Chris %A Heavner, Benjamin D %A Hidalgo, Bertha %A Hixson, James E %A Ho, Yuk-Lam %A Hobbs, Brian D %A Hu, Donglei %A Hui, Qin %A Hwu, Chii-Min %A Jackson, Rebecca D %A Jain, Deepti %A Kalyani, Rita R %A Kardia, Sharon L R %A Kelly, Tanika N %A Lange, Ethan M %A LeNoir, Michael %A Li, Changwei %A Marchand, Loic Le %A McDonald, Merry-Lynn N %A McHugh, Caitlin P %A Morrison, Alanna C %A Naseri, Take %A O'Connell, Jeffrey %A O'Donnell, Christopher J %A Palmer, Nicholette D %A Pankow, James S %A Perry, James A %A Peters, Ulrike %A Preuss, Michael H %A Rao, D C %A Regan, Elizabeth A %A Reupena, Sefuiva M %A Roden, Dan M %A Rodriguez-Santana, Jose %A Sitlani, Colleen M %A Smith, Jennifer A %A Tiwari, Hemant K %A Vasan, Ramachandran S %A Wang, Zeyuan %A Weeks, Daniel E %A Wessel, Jennifer %A Wiggins, Kerri L %A Wilkens, Lynne R %A Wilson, Peter W F %A Yanek, Lisa R %A Yoneda, Zachary T %A Zhao, Wei %A Zöllner, Sebastian %A Arnett, Donna K %A Ashley-Koch, Allison E %A Barnes, Kathleen C %A Blangero, John %A Boerwinkle, Eric %A Burchard, Esteban G %A Carson, April P %A Chasman, Daniel I %A Chen, Yii-Der Ida %A Curran, Joanne E %A Fornage, Myriam %A Gordeuk, Victor R %A He, Jiang %A Heckbert, Susan R %A Hou, Lifang %A Irvin, Marguerite R %A Kooperberg, Charles %A Minster, Ryan L %A Mitchell, Braxton D %A Nouraie, Mehdi %A Psaty, Bruce M %A Raffield, Laura M %A Reiner, Alexander P %A Rich, Stephen S %A Rotter, Jerome I %A Shoemaker, M Benjamin %A Smith, Nicholas L %A Taylor, Kent D %A Telen, Marilyn J %A Weiss, Scott T %A Zhang, Yingze %A Costa, Nancy Heard- %A Sun, Yan V %A Lin, Xihong %A Cupples, L Adrienne %A Lange, Leslie A %A Liu, Ching-Ti %A Loos, Ruth J F %A North, Kari E %A Justice, Anne E %X

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.

%B medRxiv %8 2023 Aug 22 %G eng %R 10.1101/2023.08.21.23293271