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

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

%B Nat Genet %V 45 %P 690-6 %8 2013 Jun %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/23583978?dopt=Abstract %R 10.1038/ng.2608 %0 Journal Article %J 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 N Engl J Med %D 2014 %T Loss-of-function mutations in APOC3, triglycerides, and coronary disease. %A Crosby, Jacy %A Peloso, Gina M %A Auer, Paul L %A Crosslin, David R %A Stitziel, Nathan O %A Lange, Leslie A %A Lu, Yingchang %A Tang, Zheng-Zheng %A Zhang, He %A Hindy, George %A Masca, Nicholas %A Stirrups, Kathleen %A Kanoni, Stavroula %A Do, Ron %A Jun, Goo %A Hu, Youna %A Kang, Hyun Min %A Xue, Chenyi %A Goel, Anuj %A Farrall, Martin %A Duga, Stefano %A Merlini, Pier Angelica %A Asselta, Rosanna %A Girelli, Domenico %A Olivieri, Oliviero %A Martinelli, Nicola %A Yin, Wu %A Reilly, Dermot %A Speliotes, Elizabeth %A Fox, Caroline S %A Hveem, Kristian %A Holmen, Oddgeir L %A Nikpay, Majid %A Farlow, Deborah N %A Assimes, Themistocles L %A Franceschini, Nora %A Robinson, Jennifer %A North, Kari E %A Martin, Lisa W %A DePristo, Mark %A Gupta, Namrata %A Escher, Stefan A %A Jansson, Jan-Håkan %A Van Zuydam, Natalie %A Palmer, Colin N A %A Wareham, Nicholas %A Koch, Werner %A Meitinger, Thomas %A Peters, Annette %A Lieb, Wolfgang %A Erbel, Raimund %A König, Inke R %A Kruppa, Jochen %A Degenhardt, Franziska %A Gottesman, Omri %A Bottinger, Erwin P %A O'Donnell, Christopher J %A Psaty, Bruce M %A Ballantyne, Christie M %A Abecasis, Goncalo %A Ordovas, Jose M %A Melander, Olle %A Watkins, Hugh %A Orho-Melander, Marju %A Ardissino, Diego %A Loos, Ruth J F %A McPherson, Ruth %A Willer, Cristen J %A Erdmann, Jeanette %A Hall, Alistair S %A Samani, Nilesh J %A Deloukas, Panos %A Schunkert, Heribert %A Wilson, James G %A Kooperberg, Charles %A Rich, Stephen S %A Tracy, Russell P %A Lin, Dan-Yu %A Altshuler, David %A Gabriel, Stacey %A Nickerson, Deborah A %A Jarvik, Gail P %A Cupples, L Adrienne %A Reiner, Alex P %A Boerwinkle, Eric %A Kathiresan, Sekar %K African Continental Ancestry Group %K Apolipoprotein C-III %K Coronary Disease %K European Continental Ancestry Group %K Exome %K Genotype %K Heterozygote %K Humans %K Liver %K Mutation %K Risk Factors %K Sequence Analysis, DNA %K Triglycerides %X

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

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

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

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

%B N Engl J Med %V 371 %P 22-31 %8 2014 Jul 3 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/24941081?dopt=Abstract %R 10.1056/NEJMoa1307095 %0 Journal Article %J PLoS Genet %D 2014 %T Meta-analysis of genome-wide association studies in African Americans provides insights into the genetic architecture of type 2 diabetes. %A Ng, Maggie C Y %A Shriner, Daniel %A Chen, Brian H %A Li, Jiang %A Chen, Wei-Min %A Guo, Xiuqing %A Liu, Jiankang %A Bielinski, Suzette J %A Yanek, Lisa R %A Nalls, Michael A %A Comeau, Mary E %A Rasmussen-Torvik, Laura J %A Jensen, Richard A %A Evans, Daniel S %A Sun, Yan V %A An, Ping %A Patel, Sanjay R %A Lu, Yingchang %A Long, Jirong %A Armstrong, Loren L %A Wagenknecht, Lynne %A Yang, Lingyao %A Snively, Beverly M %A Palmer, Nicholette D %A Mudgal, Poorva %A Langefeld, Carl D %A Keene, Keith L %A Freedman, Barry I %A Mychaleckyj, Josyf C %A Nayak, Uma %A Raffel, Leslie J %A Goodarzi, Mark O %A Chen, Y-D Ida %A Taylor, Herman A %A Correa, Adolfo %A Sims, Mario %A Couper, David %A Pankow, James S %A Boerwinkle, Eric %A Adeyemo, Adebowale %A Doumatey, Ayo %A Chen, Guanjie %A Mathias, Rasika A %A Vaidya, Dhananjay %A Singleton, Andrew B %A Zonderman, Alan B %A Igo, Robert P %A Sedor, John R %A Kabagambe, Edmond K %A Siscovick, David S %A McKnight, Barbara %A Rice, Kenneth %A Liu, Yongmei %A Hsueh, Wen-Chi %A Zhao, Wei %A Bielak, Lawrence F %A Kraja, Aldi %A Province, Michael A %A Bottinger, Erwin P %A Gottesman, Omri %A Cai, Qiuyin %A Zheng, Wei %A Blot, William J %A Lowe, William L %A Pacheco, Jennifer A %A Crawford, Dana C %A Grundberg, Elin %A Rich, Stephen S %A Hayes, M Geoffrey %A Shu, Xiao-Ou %A Loos, Ruth J F %A Borecki, Ingrid B %A Peyser, Patricia A %A Cummings, Steven R %A Psaty, Bruce M %A Fornage, Myriam %A Iyengar, Sudha K %A Evans, Michele K %A Becker, Diane M %A Kao, W H Linda %A Wilson, James G %A Rotter, Jerome I %A Sale, Michèle M %A Liu, Simin %A Rotimi, Charles N %A Bowden, Donald W %K African Americans %K Diabetes Mellitus, Type 2 %K Genome-Wide Association Study %K HLA-B27 Antigen %K HMGA2 Protein %K Humans %K KCNQ1 Potassium Channel %K Mutant Chimeric Proteins %K Polymorphism, Single Nucleotide %K Transcription Factor 7-Like 2 Protein %X

Type 2 diabetes (T2D) is more prevalent in African Americans than in Europeans. However, little is known about the genetic risk in African Americans despite the recent identification of more than 70 T2D loci primarily by genome-wide association studies (GWAS) in individuals of European ancestry. In order to investigate the genetic architecture of T2D in African Americans, the MEta-analysis of type 2 DIabetes in African Americans (MEDIA) Consortium examined 17 GWAS on T2D comprising 8,284 cases and 15,543 controls in African Americans in stage 1 analysis. Single nucleotide polymorphisms (SNPs) association analysis was conducted in each study under the additive model after adjustment for age, sex, study site, and principal components. Meta-analysis of approximately 2.6 million genotyped and imputed SNPs in all studies was conducted using an inverse variance-weighted fixed effect model. Replications were performed to follow up 21 loci in up to 6,061 cases and 5,483 controls in African Americans, and 8,130 cases and 38,987 controls of European ancestry. We identified three known loci (TCF7L2, HMGA2 and KCNQ1) and two novel loci (HLA-B and INS-IGF2) at genome-wide significance (4.15 × 10(-94) %B PLoS Genet %V 10 %P e1004517 %8 2014 Aug %G eng %N 8 %1 http://www.ncbi.nlm.nih.gov/pubmed/25102180?dopt=Abstract %R 10.1371/journal.pgen.1004517 %0 Journal Article %J 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 Nat Commun %D 2015 %T Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility. %A Wessel, Jennifer %A Chu, Audrey Y %A Willems, Sara M %A Wang, Shuai %A Yaghootkar, Hanieh %A Brody, Jennifer A %A Dauriz, Marco %A Hivert, Marie-France %A Raghavan, Sridharan %A Lipovich, Leonard %A Hidalgo, Bertha %A Fox, Keolu %A Huffman, Jennifer E %A An, Ping %A Lu, Yingchang %A Rasmussen-Torvik, Laura J %A Grarup, Niels %A Ehm, Margaret G %A Li, Li %A Baldridge, Abigail S %A Stančáková, Alena %A Abrol, Ravinder %A Besse, Céline %A Boland, Anne %A Bork-Jensen, Jette %A Fornage, Myriam %A Freitag, Daniel F %A Garcia, Melissa E %A Guo, Xiuqing %A Hara, Kazuo %A Isaacs, Aaron %A Jakobsdottir, Johanna %A Lange, Leslie A %A Layton, Jill C %A Li, Man %A Hua Zhao, Jing %A Meidtner, Karina %A Morrison, Alanna C %A Nalls, Mike A %A Peters, Marjolein J %A Sabater-Lleal, Maria %A Schurmann, Claudia %A Silveira, Angela %A Smith, Albert V %A Southam, Lorraine %A Stoiber, Marcus H %A Strawbridge, Rona J %A Taylor, Kent D %A Varga, Tibor V %A Allin, Kristine H %A Amin, Najaf %A Aponte, Jennifer L %A Aung, Tin %A Barbieri, Caterina %A Bihlmeyer, Nathan A %A Boehnke, Michael %A Bombieri, Cristina %A Bowden, Donald W %A Burns, Sean M %A Chen, Yuning %A Chen, Yii-DerI %A Cheng, Ching-Yu %A Correa, Adolfo %A Czajkowski, Jacek %A Dehghan, Abbas %A Ehret, Georg B %A Eiriksdottir, Gudny %A Escher, Stefan A %A Farmaki, Aliki-Eleni %A Frånberg, Mattias %A Gambaro, Giovanni %A Giulianini, Franco %A Goddard, William A %A Goel, Anuj %A Gottesman, Omri %A Grove, Megan L %A Gustafsson, Stefan %A Hai, Yang %A Hallmans, Göran %A Heo, Jiyoung %A Hoffmann, Per %A Ikram, Mohammad K %A Jensen, Richard A %A Jørgensen, Marit E %A Jørgensen, Torben %A Karaleftheri, Maria %A Khor, Chiea C %A Kirkpatrick, Andrea %A Kraja, Aldi T %A Kuusisto, Johanna %A Lange, Ethan M %A Lee, I T %A Lee, Wen-Jane %A Leong, Aaron %A Liao, Jiemin %A Liu, Chunyu %A Liu, Yongmei %A Lindgren, Cecilia M %A Linneberg, Allan %A Malerba, Giovanni %A Mamakou, Vasiliki %A Marouli, Eirini %A Maruthur, Nisa M %A Matchan, Angela %A McKean-Cowdin, Roberta %A McLeod, Olga %A Metcalf, Ginger A %A Mohlke, Karen L %A Muzny, Donna M %A Ntalla, Ioanna %A Palmer, Nicholette D %A Pasko, Dorota %A Peter, Andreas %A Rayner, Nigel W %A Renstrom, Frida %A Rice, Ken %A Sala, Cinzia F %A Sennblad, Bengt %A Serafetinidis, Ioannis %A Smith, Jennifer A %A Soranzo, Nicole %A Speliotes, Elizabeth K %A Stahl, Eli A %A Stirrups, Kathleen %A Tentolouris, Nikos %A Thanopoulou, Anastasia %A Torres, Mina %A Traglia, Michela %A Tsafantakis, Emmanouil %A Javad, Sundas %A Yanek, Lisa R %A Zengini, Eleni %A Becker, Diane M %A Bis, Joshua C %A Brown, James B %A Cupples, L Adrienne %A Hansen, Torben %A Ingelsson, Erik %A Karter, Andrew J %A Lorenzo, Carlos %A Mathias, Rasika A %A Norris, Jill M %A Peloso, Gina M %A Sheu, Wayne H-H %A Toniolo, Daniela %A Vaidya, Dhananjay %A Varma, Rohit %A Wagenknecht, Lynne E %A Boeing, Heiner %A Bottinger, Erwin P %A Dedoussis, George %A Deloukas, Panos %A Ferrannini, Ele %A Franco, Oscar H %A Franks, Paul W %A Gibbs, Richard A %A Gudnason, Vilmundur %A Hamsten, Anders %A Harris, Tamara B %A Hattersley, Andrew T %A Hayward, Caroline %A Hofman, Albert %A Jansson, Jan-Håkan %A Langenberg, Claudia %A Launer, Lenore J %A Levy, Daniel %A Oostra, Ben A %A O'Donnell, Christopher J %A O'Rahilly, Stephen %A Padmanabhan, Sandosh %A Pankow, James S %A Polasek, Ozren %A Province, Michael A %A Rich, Stephen S %A Ridker, Paul M %A Rudan, Igor %A Schulze, Matthias B %A Smith, Blair H %A Uitterlinden, André G %A Walker, Mark %A Watkins, Hugh %A Wong, Tien Y %A Zeggini, Eleftheria %A Laakso, Markku %A Borecki, Ingrid B %A Chasman, Daniel I %A Pedersen, Oluf %A Psaty, Bruce M %A Tai, E Shyong %A van Duijn, Cornelia M %A Wareham, Nicholas J %A Waterworth, Dawn M %A Boerwinkle, Eric %A Kao, W H Linda %A Florez, Jose C %A Loos, Ruth J F %A Wilson, James G %A Frayling, Timothy M %A Siscovick, David S %A Dupuis, Josée %A Rotter, Jerome I %A Meigs, James B %A Scott, Robert A %A Goodarzi, Mark O %K African Continental Ancestry Group %K Blood Glucose %K Diabetes Mellitus, Type 2 %K European Continental Ancestry Group %K Exome %K Fasting %K Genetic Association Studies %K Genetic Loci %K Genetic Predisposition to Disease %K Genetic Variation %K Glucagon-Like Peptide-1 Receptor %K Glucose-6-Phosphatase %K Humans %K Insulin %K Mutation Rate %K Oligonucleotide Array Sequence Analysis %K Polymorphism, Single Nucleotide %X

Fasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492; MAF=1.4%) with lower FG (β=-0.09±0.01 mmol l(-1), P=3.4 × 10(-12)), T2D risk (OR[95%CI]=0.86[0.76-0.96], P=0.010), early insulin secretion (β=-0.07±0.035 pmolinsulin mmolglucose(-1), P=0.048), but higher 2-h glucose (β=0.16±0.05 mmol l(-1), P=4.3 × 10(-4)). We identify a gene-based association with FG at G6PC2 (pSKAT=6.8 × 10(-6)) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF=20%) in the first intron of ABO at the putative promoter of an antisense lncRNA, associating with higher FG (β=0.02±0.004 mmol l(-1), P=1.3 × 10(-8)). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility.

%B Nat Commun %V 6 %P 5897 %8 2015 %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/25631608?dopt=Abstract %R 10.1038/ncomms6897 %0 Journal Article %J Genet Epidemiol %D 2016 %T An Empirical Comparison of Joint and Stratified Frameworks for Studying G × E Interactions: Systolic Blood Pressure and Smoking in the CHARGE Gene-Lifestyle Interactions Working Group. %A Sung, Yun Ju %A Winkler, Thomas W %A Manning, Alisa K %A Aschard, Hugues %A Gudnason, Vilmundur %A Harris, Tamara B %A Smith, Albert V %A Boerwinkle, Eric %A Brown, Michael R %A Morrison, Alanna C %A Fornage, Myriam %A Lin, Li-An %A Richard, Melissa %A Bartz, Traci M %A Psaty, Bruce M %A Hayward, Caroline %A Polasek, Ozren %A Marten, Jonathan %A Rudan, Igor %A Feitosa, Mary F %A Kraja, Aldi T %A Province, Michael A %A Deng, Xuan %A Fisher, Virginia A %A Zhou, Yanhua %A Bielak, Lawrence F %A Smith, Jennifer %A Huffman, Jennifer E %A Padmanabhan, Sandosh %A Smith, Blair H %A Ding, Jingzhong %A Liu, Yongmei %A Lohman, Kurt %A Bouchard, Claude %A Rankinen, Tuomo %A Rice, Treva K %A Arnett, Donna %A Schwander, Karen %A Guo, Xiuqing %A Palmas, Walter %A Rotter, Jerome I %A Alfred, Tamuno %A Bottinger, Erwin P %A Loos, Ruth J F %A Amin, Najaf %A Franco, Oscar H %A van Duijn, Cornelia M %A Vojinovic, Dina %A Chasman, Daniel I %A Ridker, Paul M %A Rose, Lynda M %A Kardia, Sharon %A Zhu, Xiaofeng %A Rice, Kenneth %A Borecki, Ingrid B %A Rao, Dabeeru C %A Gauderman, W James %A Cupples, L Adrienne %X

Studying gene-environment (G × E) interactions is important, as they extend our knowledge of the genetic architecture of complex traits and may help to identify novel variants not detected via analysis of main effects alone. The main statistical framework for studying G × E interactions uses a single regression model that includes both the genetic main and G × E interaction effects (the "joint" framework). The alternative "stratified" framework combines results from genetic main-effect analyses carried out separately within the exposed and unexposed groups. Although there have been several investigations using theory and simulation, an empirical comparison of the two frameworks is lacking. Here, we compare the two frameworks using results from genome-wide association studies of systolic blood pressure for 3.2 million low frequency and 6.5 million common variants across 20 cohorts of European ancestry, comprising 79,731 individuals. Our cohorts have sample sizes ranging from 456 to 22,983 and include both family-based and population-based samples. In cohort-specific analyses, the two frameworks provided similar inference for population-based cohorts. The agreement was reduced for family-based cohorts. In meta-analyses, agreement between the two frameworks was less than that observed in cohort-specific analyses, despite the increased sample size. In meta-analyses, agreement depended on (1) the minor allele frequency, (2) inclusion of family-based cohorts in meta-analysis, and (3) filtering scheme. The stratified framework appears to approximate the joint framework well only for common variants in population-based cohorts. We conclude that the joint framework is the preferred approach and should be used to control false positives when dealing with low-frequency variants and/or family-based cohorts.

%B Genet Epidemiol %V 40 %P 404-15 %8 2016 Jul %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/27230302?dopt=Abstract %R 10.1002/gepi.21978 %0 Journal Article %J Am J Hum Genet %D 2016 %T Exome Genotyping Identifies Pleiotropic Variants Associated with Red Blood Cell Traits. %A Chami, Nathalie %A Chen, Ming-Huei %A Slater, Andrew J %A Eicher, John D %A Evangelou, Evangelos %A Tajuddin, Salman M %A Love-Gregory, Latisha %A Kacprowski, Tim %A Schick, Ursula M %A Nomura, Akihiro %A Giri, Ayush %A Lessard, Samuel %A Brody, Jennifer A %A Schurmann, Claudia %A Pankratz, Nathan %A Yanek, Lisa R %A Manichaikul, Ani %A Pazoki, Raha %A Mihailov, Evelin %A Hill, W David %A Raffield, Laura M %A Burt, Amber %A Bartz, Traci M %A Becker, Diane M %A Becker, Lewis C %A Boerwinkle, Eric %A Bork-Jensen, Jette %A Bottinger, Erwin P %A O'Donoghue, Michelle L %A Crosslin, David R %A de Denus, Simon %A Dubé, Marie-Pierre %A Elliott, Paul %A Engström, Gunnar %A Evans, Michele K %A Floyd, James S %A Fornage, Myriam %A Gao, He %A Greinacher, Andreas %A Gudnason, Vilmundur %A Hansen, Torben %A Harris, Tamara B %A Hayward, Caroline %A Hernesniemi, Jussi %A Highland, Heather M %A Hirschhorn, Joel N %A Hofman, Albert %A Irvin, Marguerite R %A Kähönen, Mika %A Lange, Ethan %A Launer, Lenore J %A Lehtimäki, Terho %A Li, Jin %A Liewald, David C M %A Linneberg, Allan %A Liu, Yongmei %A Lu, Yingchang %A Lyytikäinen, Leo-Pekka %A Mägi, Reedik %A Mathias, Rasika A %A Melander, Olle %A Metspalu, Andres %A Mononen, Nina %A Nalls, Mike A %A Nickerson, Deborah A %A Nikus, Kjell %A O'Donnell, Chris J %A Orho-Melander, Marju %A Pedersen, Oluf %A Petersmann, Astrid %A Polfus, Linda %A Psaty, Bruce M %A Raitakari, Olli T %A Raitoharju, Emma %A Richard, Melissa %A Rice, Kenneth M %A Rivadeneira, Fernando %A Rotter, Jerome I %A Schmidt, Frank %A Smith, Albert Vernon %A Starr, John M %A Taylor, Kent D %A Teumer, Alexander %A Thuesen, Betina H %A Torstenson, Eric S %A Tracy, Russell P %A Tzoulaki, Ioanna %A Zakai, Neil A %A Vacchi-Suzzi, Caterina %A van Duijn, Cornelia M %A van Rooij, Frank J A %A Cushman, Mary %A Deary, Ian J %A Velez Edwards, Digna R %A Vergnaud, Anne-Claire %A Wallentin, Lars %A Waterworth, Dawn M %A White, Harvey D %A Wilson, James G %A Zonderman, Alan B %A Kathiresan, Sekar %A Grarup, Niels %A Esko, Tõnu %A Loos, Ruth J F %A Lange, Leslie A %A Faraday, Nauder %A Abumrad, Nada A %A Edwards, Todd L %A Ganesh, Santhi K %A Auer, Paul L %A Johnson, Andrew D %A Reiner, Alexander P %A Lettre, Guillaume %X

Red blood cell (RBC) traits are important heritable clinical biomarkers and modifiers of disease severity. To identify coding genetic variants associated with these traits, we conducted meta-analyses of seven RBC phenotypes in 130,273 multi-ethnic individuals from studies genotyped on an exome array. After conditional analyses and replication in 27,480 independent individuals, we identified 16 new RBC variants. We found low-frequency missense variants in MAP1A (rs55707100, minor allele frequency [MAF] = 3.3%, p = 2 × 10(-10) for hemoglobin [HGB]) and HNF4A (rs1800961, MAF = 2.4%, p < 3 × 10(-8) for hematocrit [HCT] and HGB). In African Americans, we identified a nonsense variant in CD36 associated with higher RBC distribution width (rs3211938, MAF = 8.7%, p = 7 × 10(-11)) and showed that it is associated with lower CD36 expression and strong allelic imbalance in ex vivo differentiated human erythroblasts. We also identified a rare missense variant in ALAS2 (rs201062903, MAF = 0.2%) associated with lower mean corpuscular volume and mean corpuscular hemoglobin (p < 8 × 10(-9)). Mendelian mutations in ALAS2 are a cause of sideroblastic anemia and erythropoietic protoporphyria. Gene-based testing highlighted three rare missense variants in PKLR, a gene mutated in Mendelian non-spherocytic hemolytic anemia, associated with HGB and HCT (SKAT p < 8 × 10(-7)). These rare, low-frequency, and common RBC variants showed pleiotropy, being also associated with platelet, white blood cell, and lipid traits. Our association results and functional annotation suggest the involvement of new genes in human erythropoiesis. We also confirm that rare and low-frequency variants play a role in the architecture of complex human traits, although their phenotypic effect is generally smaller than originally anticipated.

%B Am J Hum Genet %V 99 %P 8-21 %8 2016 Jul 7 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27346685?dopt=Abstract %R 10.1016/j.ajhg.2016.05.007 %0 Journal Article %J Am J Hum Genet %D 2016 %T Large-Scale Exome-wide Association Analysis Identifies Loci for White Blood Cell Traits and Pleiotropy with Immune-Mediated Diseases. %A Tajuddin, Salman M %A Schick, Ursula M %A Eicher, John D %A Chami, Nathalie %A Giri, Ayush %A Brody, Jennifer A %A Hill, W David %A Kacprowski, Tim %A Li, Jin %A Lyytikäinen, Leo-Pekka %A Manichaikul, Ani %A Mihailov, Evelin %A O'Donoghue, Michelle L %A Pankratz, Nathan %A Pazoki, Raha %A Polfus, Linda M %A Smith, Albert Vernon %A Schurmann, Claudia %A Vacchi-Suzzi, Caterina %A Waterworth, Dawn M %A Evangelou, Evangelos %A Yanek, Lisa R %A Burt, Amber %A Chen, Ming-Huei %A van Rooij, Frank J A %A Floyd, James S %A Greinacher, Andreas %A Harris, Tamara B %A Highland, Heather M %A Lange, Leslie A %A Liu, Yongmei %A Mägi, Reedik %A Nalls, Mike A %A Mathias, Rasika A %A Nickerson, Deborah A %A Nikus, Kjell %A Starr, John M %A Tardif, Jean-Claude %A Tzoulaki, Ioanna %A Velez Edwards, Digna R %A Wallentin, Lars %A Bartz, Traci M %A Becker, Lewis C %A Denny, Joshua C %A Raffield, Laura M %A Rioux, John D %A Friedrich, Nele %A Fornage, Myriam %A Gao, He %A Hirschhorn, Joel N %A Liewald, David C M %A Rich, Stephen S %A Uitterlinden, Andre %A Bastarache, Lisa %A Becker, Diane M %A Boerwinkle, Eric %A de Denus, Simon %A Bottinger, Erwin P %A Hayward, Caroline %A Hofman, Albert %A Homuth, Georg %A Lange, Ethan %A Launer, Lenore J %A Lehtimäki, Terho %A Lu, Yingchang %A Metspalu, Andres %A O'Donnell, Chris J %A Quarells, Rakale C %A Richard, Melissa %A Torstenson, Eric S %A Taylor, Kent D %A Vergnaud, Anne-Claire %A Zonderman, Alan B %A Crosslin, David R %A Deary, Ian J %A Dörr, Marcus %A Elliott, Paul %A Evans, Michele K %A Gudnason, Vilmundur %A Kähönen, Mika %A Psaty, Bruce M %A Rotter, Jerome I %A Slater, Andrew J %A Dehghan, Abbas %A White, Harvey D %A Ganesh, Santhi K %A Loos, Ruth J F %A Esko, Tõnu %A Faraday, Nauder %A Wilson, James G %A Cushman, Mary %A Johnson, Andrew D %A Edwards, Todd L %A Zakai, Neil A %A Lettre, Guillaume %A Reiner, Alex P %A Auer, Paul L %X

White blood cells play diverse roles in innate and adaptive immunity. Genetic association analyses of phenotypic variation in circulating white blood cell (WBC) counts from large samples of otherwise healthy individuals can provide insights into genes and biologic pathways involved in production, differentiation, or clearance of particular WBC lineages (myeloid, lymphoid) and also potentially inform the genetic basis of autoimmune, allergic, and blood diseases. We performed an exome array-based meta-analysis of total WBC and subtype counts (neutrophils, monocytes, lymphocytes, basophils, and eosinophils) in a multi-ancestry discovery and replication sample of ∼157,622 individuals from 25 studies. We identified 16 common variants (8 of which were coding variants) associated with one or more WBC traits, the majority of which are pleiotropically associated with autoimmune diseases. Based on functional annotation, these loci included genes encoding surface markers of myeloid, lymphoid, or hematopoietic stem cell differentiation (CD69, CD33, CD87), transcription factors regulating lineage specification during hematopoiesis (ASXL1, IRF8, IKZF1, JMJD1C, ETS2-PSMG1), and molecules involved in neutrophil clearance/apoptosis (C10orf54, LTA), adhesion (TNXB), or centrosome and microtubule structure/function (KIF9, TUBD1). Together with recent reports of somatic ASXL1 mutations among individuals with idiopathic cytopenias or clonal hematopoiesis of undetermined significance, the identification of a common regulatory 3' UTR variant of ASXL1 suggests that both germline and somatic ASXL1 mutations contribute to lower blood counts in otherwise asymptomatic individuals. These association results shed light on genetic mechanisms that regulate circulating WBC counts and suggest a prominent shared genetic architecture with inflammatory and autoimmune diseases.

%B Am J Hum Genet %V 99 %P 22-39 %8 2016 Jul 7 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27346689?dopt=Abstract %R 10.1016/j.ajhg.2016.05.003 %0 Journal Article %J Nat Genet %D 2016 %T Meta-analysis identifies common and rare variants influencing blood pressure and overlapping with metabolic trait loci. %A Liu, Chunyu %A Kraja, Aldi T %A Smith, Jennifer A %A Brody, Jennifer A %A Franceschini, Nora %A Bis, Joshua C %A Rice, Kenneth %A Morrison, Alanna C %A Lu, Yingchang %A Weiss, Stefan %A Guo, Xiuqing %A Palmas, Walter %A Martin, Lisa W %A Chen, Yii-Der Ida %A Surendran, Praveen %A Drenos, Fotios %A Cook, James P %A Auer, Paul L %A Chu, Audrey Y %A Giri, Ayush %A Zhao, Wei %A Jakobsdottir, Johanna %A Lin, Li-An %A Stafford, Jeanette M %A Amin, Najaf %A Mei, Hao %A Yao, Jie %A Voorman, Arend %A Larson, Martin G %A Grove, Megan L %A Smith, Albert V %A Hwang, Shih-Jen %A Chen, Han %A Huan, Tianxiao %A Kosova, Gulum %A Stitziel, Nathan O %A Kathiresan, Sekar %A Samani, Nilesh %A Schunkert, Heribert %A Deloukas, Panos %A Li, Man %A Fuchsberger, Christian %A Pattaro, Cristian %A Gorski, Mathias %A Kooperberg, Charles %A Papanicolaou, George J %A Rossouw, Jacques E %A Faul, Jessica D %A Kardia, Sharon L R %A Bouchard, Claude %A Raffel, Leslie J %A Uitterlinden, André G %A Franco, Oscar H %A Vasan, Ramachandran S %A O'Donnell, Christopher J %A Taylor, Kent D %A Liu, Kiang %A Bottinger, Erwin P %A Gottesman, Omri %A Daw, E Warwick %A Giulianini, Franco %A Ganesh, Santhi %A Salfati, Elias %A Harris, Tamara B %A Launer, Lenore J %A Dörr, Marcus %A Felix, Stephan B %A Rettig, Rainer %A Völzke, Henry %A Kim, Eric %A Lee, Wen-Jane %A Lee, I-Te %A Sheu, Wayne H-H %A Tsosie, Krystal S %A Edwards, Digna R Velez %A Liu, Yongmei %A Correa, Adolfo %A Weir, David R %A Völker, Uwe %A Ridker, Paul M %A Boerwinkle, Eric %A Gudnason, Vilmundur %A Reiner, Alexander P %A van Duijn, Cornelia M %A Borecki, Ingrid B %A Edwards, Todd L %A Chakravarti, Aravinda %A Rotter, Jerome I %A Psaty, Bruce M %A Loos, Ruth J F %A Fornage, Myriam %A Ehret, Georg B %A Newton-Cheh, Christopher %A Levy, Daniel %A Chasman, Daniel I %X

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

%B Nat Genet %V 48 %P 1162-70 %8 2016 Oct %G eng %N 10 %R 10.1038/ng.3660 %0 Journal Article %J Am J Hum Genet %D 2016 %T Platelet-Related Variants Identified by Exomechip Meta-analysis in 157,293 Individuals. %A Eicher, John D %A Chami, Nathalie %A Kacprowski, Tim %A Nomura, Akihiro %A Chen, Ming-Huei %A Yanek, Lisa R %A Tajuddin, Salman M %A Schick, Ursula M %A Slater, Andrew J %A Pankratz, Nathan %A Polfus, Linda %A Schurmann, Claudia %A Giri, Ayush %A Brody, Jennifer A %A Lange, Leslie A %A Manichaikul, Ani %A Hill, W David %A Pazoki, Raha %A Elliot, Paul %A Evangelou, Evangelos %A Tzoulaki, Ioanna %A Gao, He %A Vergnaud, Anne-Claire %A Mathias, Rasika A %A Becker, Diane M %A Becker, Lewis C %A Burt, Amber %A Crosslin, David R %A Lyytikäinen, Leo-Pekka %A Nikus, Kjell %A Hernesniemi, Jussi %A Kähönen, Mika %A Raitoharju, Emma %A Mononen, Nina %A Raitakari, Olli T %A Lehtimäki, Terho %A Cushman, Mary %A Zakai, Neil A %A Nickerson, Deborah A %A Raffield, Laura M %A Quarells, Rakale %A Willer, Cristen J %A Peloso, Gina M %A Abecasis, Goncalo R %A Liu, Dajiang J %A Deloukas, Panos %A Samani, Nilesh J %A Schunkert, Heribert %A Erdmann, Jeanette %A Fornage, Myriam %A Richard, Melissa %A Tardif, Jean-Claude %A Rioux, John D %A Dubé, Marie-Pierre %A de Denus, Simon %A Lu, Yingchang %A Bottinger, Erwin P %A Loos, Ruth J F %A Smith, Albert Vernon %A Harris, Tamara B %A Launer, Lenore J %A Gudnason, Vilmundur %A Velez Edwards, Digna R %A Torstenson, Eric S %A Liu, Yongmei %A Tracy, Russell P %A Rotter, Jerome I %A Rich, Stephen S %A Highland, Heather M %A Boerwinkle, Eric %A Li, Jin %A Lange, Ethan %A Wilson, James G %A Mihailov, Evelin %A Mägi, Reedik %A Hirschhorn, Joel %A Metspalu, Andres %A Esko, Tõnu %A Vacchi-Suzzi, Caterina %A Nalls, Mike A %A Zonderman, Alan B %A Evans, Michele K %A Engström, Gunnar %A Orho-Melander, Marju %A Melander, Olle %A O'Donoghue, Michelle L %A Waterworth, Dawn M %A Wallentin, Lars %A White, Harvey D %A Floyd, James S %A Bartz, Traci M %A Rice, Kenneth M %A Psaty, Bruce M %A Starr, J M %A Liewald, David C M %A Hayward, Caroline %A Deary, Ian J %A Greinacher, Andreas %A Völker, Uwe %A Thiele, Thomas %A Völzke, Henry %A van Rooij, Frank J A %A Uitterlinden, André G %A Franco, Oscar H %A Dehghan, Abbas %A Edwards, Todd L %A Ganesh, Santhi K %A Kathiresan, Sekar %A Faraday, Nauder %A Auer, Paul L %A Reiner, Alex P %A Lettre, Guillaume %A Johnson, Andrew D %X

Platelet production, maintenance, and clearance are tightly controlled processes indicative of platelets' important roles in hemostasis and thrombosis. Platelets are common targets for primary and secondary prevention of several conditions. They are monitored clinically by complete blood counts, specifically with measurements of platelet count (PLT) and mean platelet volume (MPV). Identifying genetic effects on PLT and MPV can provide mechanistic insights into platelet biology and their role in disease. Therefore, we formed the Blood Cell Consortium (BCX) to perform a large-scale meta-analysis of Exomechip association results for PLT and MPV in 157,293 and 57,617 individuals, respectively. Using the low-frequency/rare coding variant-enriched Exomechip genotyping array, we sought to identify genetic variants associated with PLT and MPV. In addition to confirming 47 known PLT and 20 known MPV associations, we identified 32 PLT and 18 MPV associations not previously observed in the literature across the allele frequency spectrum, including rare large effect (FCER1A), low-frequency (IQGAP2, MAP1A, LY75), and common (ZMIZ2, SMG6, PEAR1, ARFGAP3/PACSIN2) variants. Several variants associated with PLT/MPV (PEAR1, MRVI1, PTGES3) were also associated with platelet reactivity. In concurrent BCX analyses, there was overlap of platelet-associated variants with red (MAP1A, TMPRSS6, ZMIZ2) and white (PEAR1, ZMIZ2, LY75) blood cell traits, suggesting common regulatory pathways with shared genetic architecture among these hematopoietic lineages. Our large-scale Exomechip analyses identified previously undocumented associations with platelet traits and further indicate that several complex quantitative hematological, lipid, and cardiovascular traits share genetic factors.

%B Am J Hum Genet %V 99 %P 40-55 %8 2016 Jul 7 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27346686?dopt=Abstract %R 10.1016/j.ajhg.2016.05.005 %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 Am J Hum Genet %D 2016 %T Trans-ethnic Meta-analysis and Functional Annotation Illuminates the Genetic Architecture of Fasting Glucose and Insulin. %A Liu, Ching-Ti %A Raghavan, Sridharan %A Maruthur, Nisa %A Kabagambe, Edmond Kato %A Hong, Jaeyoung %A Ng, Maggie C Y %A Hivert, Marie-France %A Lu, Yingchang %A An, Ping %A Bentley, Amy R %A Drolet, Anne M %A Gaulton, Kyle J %A Guo, Xiuqing %A Armstrong, Loren L %A Irvin, Marguerite R %A Li, Man %A Lipovich, Leonard %A Rybin, Denis V %A Taylor, Kent D %A Agyemang, Charles %A Palmer, Nicholette D %A Cade, Brian E %A Chen, Wei-Min %A Dauriz, Marco %A Delaney, Joseph A C %A Edwards, Todd L %A Evans, Daniel S %A Evans, Michele K %A Lange, Leslie A %A Leong, Aaron %A Liu, Jingmin %A Liu, Yongmei %A Nayak, Uma %A Patel, Sanjay R %A Porneala, Bianca C %A Rasmussen-Torvik, Laura J %A Snijder, Marieke B %A Stallings, Sarah C %A Tanaka, Toshiko %A Yanek, Lisa R %A Zhao, Wei %A Becker, Diane M %A Bielak, Lawrence F %A Biggs, Mary L %A Bottinger, Erwin P %A Bowden, Donald W %A Chen, Guanjie %A Correa, Adolfo %A Couper, David J %A Crawford, Dana C %A Cushman, Mary %A Eicher, John D %A Fornage, Myriam %A Franceschini, Nora %A Fu, Yi-Ping %A Goodarzi, Mark O %A Gottesman, Omri %A Hara, Kazuo %A Harris, Tamara B %A Jensen, Richard A %A Johnson, Andrew D %A Jhun, Min A %A Karter, Andrew J %A Keller, Margaux F %A Kho, Abel N %A Kizer, Jorge R %A Krauss, Ronald M %A Langefeld, Carl D %A Li, Xiaohui %A Liang, Jingling %A Liu, Simin %A Lowe, William L %A Mosley, Thomas H %A North, Kari E %A Pacheco, Jennifer A %A Peyser, Patricia A %A Patrick, Alan L %A Rice, Kenneth M %A Selvin, Elizabeth %A Sims, Mario %A Smith, Jennifer A %A Tajuddin, Salman M %A Vaidya, Dhananjay %A Wren, Mary P %A Yao, Jie %A Zhu, Xiaofeng %A Ziegler, Julie T %A Zmuda, Joseph M %A Zonderman, Alan B %A Zwinderman, Aeilko H %A Adeyemo, Adebowale %A Boerwinkle, Eric %A Ferrucci, Luigi %A Hayes, M Geoffrey %A Kardia, Sharon L R %A Miljkovic, Iva %A Pankow, James S %A Rotimi, Charles N %A Sale, Michèle M %A Wagenknecht, Lynne E %A Arnett, Donna K %A Chen, Yii-Der Ida %A Nalls, Michael A %A Province, Michael A %A Kao, W H Linda %A Siscovick, David S %A Psaty, Bruce M %A Wilson, James G %A Loos, Ruth J F %A Dupuis, Josée %A Rich, Stephen S %A Florez, Jose C %A Rotter, Jerome I %A Morris, Andrew P %A Meigs, James B %X

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

%B Am J Hum Genet %V 99 %P 56-75 %8 2016 Jul 7 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27321945?dopt=Abstract %R 10.1016/j.ajhg.2016.05.006 %0 Journal Article %J PLoS Genet %D 2017 %T Discovery and fine-mapping of adiposity loci using high density imputation of genome-wide association studies in individuals of African ancestry: African ancestry anthropometry genetics consortium. %A Ng, Maggie C Y %A Graff, Mariaelisa %A Lu, Yingchang %A Justice, Anne E %A Mudgal, Poorva %A Liu, Ching-Ti %A Young, Kristin %A Yanek, Lisa R %A Feitosa, Mary F %A Wojczynski, Mary K %A Rand, Kristin %A Brody, Jennifer A %A Cade, Brian E %A Dimitrov, Latchezar %A Duan, Qing %A Guo, Xiuqing %A Lange, Leslie A %A Nalls, Michael A %A Okut, Hayrettin %A Tajuddin, Salman M %A Tayo, Bamidele O %A Vedantam, Sailaja %A Bradfield, Jonathan P %A Chen, Guanjie %A Chen, Wei-Min %A Chesi, Alessandra %A Irvin, Marguerite R %A Padhukasahasram, Badri %A Smith, Jennifer A %A Zheng, Wei %A Allison, Matthew A %A Ambrosone, Christine B %A Bandera, Elisa V %A Bartz, Traci M %A Berndt, Sonja I %A Bernstein, Leslie %A Blot, William J %A Bottinger, Erwin P %A Carpten, John %A Chanock, Stephen J %A Chen, Yii-Der Ida %A Conti, David V %A Cooper, Richard S %A Fornage, Myriam %A Freedman, Barry I %A Garcia, Melissa %A Goodman, Phyllis J %A Hsu, Yu-Han H %A Hu, Jennifer %A Huff, Chad D %A Ingles, Sue A %A John, Esther M %A Kittles, Rick %A Klein, Eric %A Li, Jin %A McKnight, Barbara %A Nayak, Uma %A Nemesure, Barbara %A Ogunniyi, Adesola %A Olshan, Andrew %A Press, Michael F %A Rohde, Rebecca %A Rybicki, Benjamin A %A Salako, Babatunde %A Sanderson, Maureen %A Shao, Yaming %A Siscovick, David S %A Stanford, Janet L %A Stevens, Victoria L %A Stram, Alex %A Strom, Sara S %A Vaidya, Dhananjay %A Witte, John S %A Yao, Jie %A Zhu, Xiaofeng %A Ziegler, Regina G %A Zonderman, Alan B %A Adeyemo, Adebowale %A Ambs, Stefan %A Cushman, Mary %A Faul, Jessica D %A Hakonarson, Hakon %A Levin, Albert M %A Nathanson, Katherine L %A Ware, Erin B %A Weir, David R %A Zhao, Wei %A Zhi, Degui %A Arnett, Donna K %A Grant, Struan F A %A Kardia, Sharon L R %A Oloapde, Olufunmilayo I %A Rao, D C %A Rotimi, Charles N %A Sale, Michèle M %A Williams, L Keoki %A Zemel, Babette S %A Becker, Diane M %A Borecki, Ingrid B %A Evans, Michele K %A Harris, Tamara B %A Hirschhorn, Joel N %A Li, Yun %A Patel, Sanjay R %A Psaty, Bruce M %A Rotter, Jerome I %A Wilson, James G %A Bowden, Donald W %A Cupples, L Adrienne %A Haiman, Christopher A %A Loos, Ruth J F %A North, Kari E %X

Genome-wide association studies (GWAS) have identified >300 loci associated with measures of adiposity including body mass index (BMI) and waist-to-hip ratio (adjusted for BMI, WHRadjBMI), but few have been identified through screening of the African ancestry genomes. We performed large scale meta-analyses and replications in up to 52,895 individuals for BMI and up to 23,095 individuals for WHRadjBMI from the African Ancestry Anthropometry Genetics Consortium (AAAGC) using 1000 Genomes phase 1 imputed GWAS to improve coverage of both common and low frequency variants in the low linkage disequilibrium African ancestry genomes. In the sex-combined analyses, we identified one novel locus (TCF7L2/HABP2) for WHRadjBMI and eight previously established loci at P < 5×10-8: seven for BMI, and one for WHRadjBMI in African ancestry individuals. An additional novel locus (SPRYD7/DLEU2) was identified for WHRadjBMI when combined with European GWAS. In the sex-stratified analyses, we identified three novel loci for BMI (INTS10/LPL and MLC1 in men, IRX4/IRX2 in women) and four for WHRadjBMI (SSX2IP, CASC8, PDE3B and ZDHHC1/HSD11B2 in women) in individuals of African ancestry or both African and European ancestry. For four of the novel variants, the minor allele frequency was low (<5%). In the trans-ethnic fine mapping of 47 BMI loci and 27 WHRadjBMI loci that were locus-wide significant (P < 0.05 adjusted for effective number of variants per locus) from the African ancestry sex-combined and sex-stratified analyses, 26 BMI loci and 17 WHRadjBMI loci contained ≤ 20 variants in the credible sets that jointly account for 99% posterior probability of driving the associations. The lead variants in 13 of these loci had a high probability of being causal. As compared to our previous HapMap imputed GWAS for BMI and WHRadjBMI including up to 71,412 and 27,350 African ancestry individuals, respectively, our results suggest that 1000 Genomes imputation showed modest improvement in identifying GWAS loci including low frequency variants. Trans-ethnic meta-analyses further improved fine mapping of putative causal variants in loci shared between the African and European ancestry populations.

%B PLoS Genet %V 13 %P e1006719 %8 2017 Apr 21 %G eng %N 4 %R 10.1371/journal.pgen.1006719 %0 Journal Article %J Nat Genet %D 2017 %T Exome-wide association study of plasma lipids in >300,000 individuals. %A Liu, Dajiang J %A Peloso, Gina M %A Yu, Haojie %A Butterworth, Adam S %A Wang, Xiao %A Mahajan, Anubha %A Saleheen, Danish %A Emdin, Connor %A Alam, Dewan %A Alves, Alexessander Couto %A Amouyel, Philippe %A Di Angelantonio, Emanuele %A Arveiler, Dominique %A Assimes, Themistocles L %A Auer, Paul L %A Baber, Usman %A Ballantyne, Christie M %A Bang, Lia E %A Benn, Marianne %A Bis, Joshua C %A Boehnke, Michael %A Boerwinkle, Eric %A Bork-Jensen, Jette %A Bottinger, Erwin P %A Brandslund, Ivan %A Brown, Morris %A Busonero, Fabio %A Caulfield, Mark J %A Chambers, John C %A Chasman, Daniel I %A Chen, Y Eugene %A Chen, Yii-Der Ida %A Chowdhury, Rajiv %A Christensen, Cramer %A Chu, Audrey Y %A Connell, John M %A Cucca, Francesco %A Cupples, L Adrienne %A Damrauer, Scott M %A Davies, Gail %A Deary, Ian J %A Dedoussis, George %A Denny, Joshua C %A Dominiczak, Anna %A Dubé, Marie-Pierre %A Ebeling, Tapani %A Eiriksdottir, Gudny %A Esko, Tõnu %A Farmaki, Aliki-Eleni %A Feitosa, Mary F %A Ferrario, Marco %A Ferrieres, Jean %A Ford, Ian %A Fornage, Myriam %A Franks, Paul W %A Frayling, Timothy M %A Frikke-Schmidt, Ruth %A Fritsche, Lars G %A Frossard, Philippe %A Fuster, Valentin %A Ganesh, Santhi K %A Gao, Wei %A Garcia, Melissa E %A Gieger, Christian %A Giulianini, Franco %A Goodarzi, Mark O %A Grallert, Harald %A Grarup, Niels %A Groop, Leif %A Grove, Megan L %A Gudnason, Vilmundur %A Hansen, Torben %A Harris, Tamara B %A Hayward, Caroline %A Hirschhorn, Joel N %A Holmen, Oddgeir L %A Huffman, Jennifer %A Huo, Yong %A Hveem, Kristian %A Jabeen, Sehrish %A Jackson, Anne U %A Jakobsdottir, Johanna %A Jarvelin, Marjo-Riitta %A Jensen, Gorm B %A Jørgensen, Marit E %A Jukema, J Wouter %A Justesen, Johanne M %A Kamstrup, Pia R %A Kanoni, Stavroula %A Karpe, Fredrik %A Kee, Frank %A Khera, Amit V %A Klarin, Derek %A Koistinen, Heikki A %A Kooner, Jaspal S %A Kooperberg, Charles %A Kuulasmaa, Kari %A Kuusisto, Johanna %A Laakso, Markku %A Lakka, Timo %A Langenberg, Claudia %A Langsted, Anne %A Launer, Lenore J %A Lauritzen, Torsten %A Liewald, David C M %A Lin, Li An %A Linneberg, Allan %A Loos, Ruth J F %A Lu, Yingchang %A Lu, Xiangfeng %A Mägi, Reedik %A Mälarstig, Anders %A Manichaikul, Ani %A Manning, Alisa K %A Mäntyselkä, Pekka %A Marouli, Eirini %A Masca, Nicholas G D %A Maschio, Andrea %A Meigs, James B %A Melander, Olle %A Metspalu, Andres %A Morris, Andrew P %A Morrison, Alanna C %A Mulas, Antonella %A Müller-Nurasyid, Martina %A Munroe, Patricia B %A Neville, Matt J %A Nielsen, Jonas B %A Nielsen, Sune F %A Nordestgaard, Børge G %A Ordovas, Jose M %A Mehran, Roxana %A O'Donnell, Christoper J %A Orho-Melander, Marju %A Molony, Cliona M %A Muntendam, Pieter %A Padmanabhan, Sandosh %A Palmer, Colin N A %A Pasko, Dorota %A Patel, Aniruddh P %A Pedersen, Oluf %A Perola, Markus %A Peters, Annette %A Pisinger, Charlotta %A Pistis, Giorgio %A Polasek, Ozren %A Poulter, Neil %A Psaty, Bruce M %A Rader, Daniel J %A Rasheed, Asif %A Rauramaa, Rainer %A Reilly, Dermot F %A Reiner, Alex P %A Renstrom, Frida %A Rich, Stephen S %A Ridker, Paul M %A Rioux, John D %A Robertson, Neil R %A Roden, Dan M %A Rotter, Jerome I %A Rudan, Igor %A Salomaa, Veikko %A Samani, Nilesh J %A Sanna, Serena %A Sattar, Naveed %A Schmidt, Ellen M %A Scott, Robert A %A Sever, Peter %A Sevilla, Raquel S %A Shaffer, Christian M %A Sim, Xueling %A Sivapalaratnam, Suthesh %A Small, Kerrin S %A Smith, Albert V %A Smith, Blair H %A Somayajula, Sangeetha %A Southam, Lorraine %A Spector, Timothy D %A Speliotes, Elizabeth K %A Starr, John M %A Stirrups, Kathleen E %A Stitziel, Nathan %A Strauch, Konstantin %A Stringham, Heather M %A Surendran, Praveen %A Tada, Hayato %A Tall, Alan R %A Tang, Hua %A Tardif, Jean-Claude %A Taylor, Kent D %A Trompet, Stella %A Tsao, Philip S %A Tuomilehto, Jaakko %A Tybjaerg-Hansen, Anne %A van Zuydam, Natalie R %A Varbo, Anette %A Varga, Tibor V %A Virtamo, Jarmo %A Waldenberger, Melanie %A Wang, Nan %A Wareham, Nick J %A Warren, Helen R %A Weeke, Peter E %A Weinstock, Joshua %A Wessel, Jennifer %A Wilson, James G %A Wilson, Peter W F %A Xu, Ming %A Yaghootkar, Hanieh %A Young, Robin %A Zeggini, Eleftheria %A Zhang, He %A Zheng, Neil S %A Zhang, Weihua %A Zhang, Yan %A Zhou, Wei %A Zhou, Yanhua %A Zoledziewska, Magdalena %A Howson, Joanna M M %A Danesh, John %A McCarthy, Mark I %A Cowan, Chad A %A Abecasis, Goncalo %A Deloukas, Panos %A Musunuru, Kiran %A Willer, Cristen J %A Kathiresan, Sekar %K Coronary Artery Disease %K Diabetes Mellitus, Type 2 %K Exome %K Genetic Association Studies %K Genetic Predisposition to Disease %K Genetic Variation %K Genotype %K Humans %K Lipids %K Macular Degeneration %K Phenotype %K Risk Factors %X

We screened variants on an exome-focused genotyping array in >300,000 participants (replication in >280,000 participants) and identified 444 independent variants in 250 loci significantly associated with total cholesterol (TC), high-density-lipoprotein cholesterol (HDL-C), low-density-lipoprotein cholesterol (LDL-C), and/or triglycerides (TG). At two loci (JAK2 and A1CF), experimental analysis in mice showed lipid changes consistent with the human data. We also found that: (i) beta-thalassemia trait carriers displayed lower TC and were protected from coronary artery disease (CAD); (ii) excluding the CETP locus, there was not a predictable relationship between plasma HDL-C and risk for age-related macular degeneration; (iii) only some mechanisms of lowering LDL-C appeared to increase risk for type 2 diabetes (T2D); and (iv) TG-lowering alleles involved in hepatic production of TG-rich lipoproteins (TM6SF2 and PNPLA3) tracked with higher liver fat, higher risk for T2D, and lower risk for CAD, whereas TG-lowering alleles involved in peripheral lipolysis (LPL and ANGPTL4) had no effect on liver fat but decreased risks for both T2D and CAD.

%B Nat Genet %V 49 %P 1758-1766 %8 2017 Dec %G eng %N 12 %R 10.1038/ng.3977 %0 Journal Article %J PLoS Med %D 2017 %T Impact of common genetic determinants of Hemoglobin A1c on type 2 diabetes risk and diagnosis in ancestrally diverse populations: A transethnic genome-wide meta-analysis. %A Wheeler, Eleanor %A Leong, Aaron %A Liu, Ching-Ti %A Hivert, Marie-France %A Strawbridge, Rona J %A Podmore, Clara %A Li, Man %A Yao, Jie %A Sim, Xueling %A Hong, Jaeyoung %A Chu, Audrey Y %A Zhang, Weihua %A Wang, Xu %A Chen, Peng %A Maruthur, Nisa M %A Porneala, Bianca C %A Sharp, Stephen J %A Jia, Yucheng %A Kabagambe, Edmond K %A Chang, Li-Ching %A Chen, Wei-Min %A Elks, Cathy E %A Evans, Daniel S %A Fan, Qiao %A Giulianini, Franco %A Go, Min Jin %A Hottenga, Jouke-Jan %A Hu, Yao %A Jackson, Anne U %A Kanoni, Stavroula %A Kim, Young Jin %A Kleber, Marcus E %A Ladenvall, Claes %A Lecoeur, Cécile %A Lim, Sing-Hui %A Lu, Yingchang %A Mahajan, Anubha %A Marzi, Carola %A Nalls, Mike A %A Navarro, Pau %A Nolte, Ilja M %A Rose, Lynda M %A Rybin, Denis V %A Sanna, Serena %A Shi, Yuan %A Stram, Daniel O %A Takeuchi, Fumihiko %A Tan, Shu Pei %A van der Most, Peter J %A van Vliet-Ostaptchouk, Jana V %A Wong, Andrew %A Yengo, Loic %A Zhao, Wanting %A Goel, Anuj %A Martinez Larrad, Maria Teresa %A Radke, Dörte %A Salo, Perttu %A Tanaka, Toshiko %A van Iperen, Erik P A %A Abecasis, Goncalo %A Afaq, Saima %A Alizadeh, Behrooz Z %A Bertoni, Alain G %A Bonnefond, Amélie %A Böttcher, Yvonne %A Bottinger, Erwin P %A Campbell, Harry %A Carlson, Olga D %A Chen, Chien-Hsiun %A Cho, Yoon Shin %A Garvey, W Timothy %A Gieger, Christian %A Goodarzi, Mark O %A Grallert, Harald %A Hamsten, Anders %A Hartman, Catharina A %A Herder, Christian %A Hsiung, Chao Agnes %A Huang, Jie %A Igase, Michiya %A Isono, Masato %A Katsuya, Tomohiro %A Khor, Chiea-Chuen %A Kiess, Wieland %A Kohara, Katsuhiko %A Kovacs, Peter %A Lee, Juyoung %A Lee, Wen-Jane %A Lehne, Benjamin %A Li, Huaixing %A Liu, Jianjun %A Lobbens, Stephane %A Luan, Jian'an %A Lyssenko, Valeriya %A Meitinger, Thomas %A Miki, Tetsuro %A Miljkovic, Iva %A Moon, Sanghoon %A Mulas, Antonella %A Müller, Gabriele %A Müller-Nurasyid, Martina %A Nagaraja, Ramaiah %A Nauck, Matthias %A Pankow, James S %A Polasek, Ozren %A Prokopenko, Inga %A Ramos, Paula S %A Rasmussen-Torvik, Laura %A Rathmann, Wolfgang %A Rich, Stephen S %A Robertson, Neil R %A Roden, Michael %A Roussel, Ronan %A Rudan, Igor %A Scott, Robert A %A Scott, William R %A Sennblad, Bengt %A Siscovick, David S %A Strauch, Konstantin %A Sun, Liang %A Swertz, Morris %A Tajuddin, Salman M %A Taylor, Kent D %A Teo, Yik-Ying %A Tham, Yih Chung %A Tönjes, Anke %A Wareham, Nicholas J %A Willemsen, Gonneke %A Wilsgaard, Tom %A Hingorani, Aroon D %A Egan, Josephine %A Ferrucci, Luigi %A Hovingh, G Kees %A Jula, Antti %A Kivimaki, Mika %A Kumari, Meena %A Njølstad, Inger %A Palmer, Colin N A %A Serrano Ríos, Manuel %A Stumvoll, Michael %A Watkins, Hugh %A Aung, Tin %A Blüher, Matthias %A Boehnke, Michael %A Boomsma, Dorret I %A Bornstein, Stefan R %A Chambers, John C %A Chasman, Daniel I %A Chen, Yii-Der Ida %A Chen, Yduan-Tsong %A Cheng, Ching-Yu %A Cucca, Francesco %A de Geus, Eco J C %A Deloukas, Panos %A Evans, Michele K %A Fornage, Myriam %A Friedlander, Yechiel %A Froguel, Philippe %A Groop, Leif %A Gross, Myron D %A Harris, Tamara B %A Hayward, Caroline %A Heng, Chew-Kiat %A Ingelsson, Erik %A Kato, Norihiro %A Kim, Bong-Jo %A Koh, Woon-Puay %A Kooner, Jaspal S %A Körner, Antje %A Kuh, Diana %A Kuusisto, Johanna %A Laakso, Markku %A Lin, Xu %A Liu, Yongmei %A Loos, Ruth J F %A Magnusson, Patrik K E %A März, Winfried %A McCarthy, Mark I %A Oldehinkel, Albertine J %A Ong, Ken K %A Pedersen, Nancy L %A Pereira, Mark A %A Peters, Annette %A Ridker, Paul M %A Sabanayagam, Charumathi %A Sale, Michele %A Saleheen, Danish %A Saltevo, Juha %A Schwarz, Peter Eh %A Sheu, Wayne H H %A Snieder, Harold %A Spector, Timothy D %A Tabara, Yasuharu %A Tuomilehto, Jaakko %A van Dam, Rob M %A Wilson, James G %A Wilson, James F %A Wolffenbuttel, Bruce H R %A Wong, Tien Yin %A Wu, Jer-Yuarn %A Yuan, Jian-Min %A Zonderman, Alan B %A Soranzo, Nicole %A Guo, Xiuqing %A Roberts, David J %A Florez, Jose C %A Sladek, Robert %A Dupuis, Josée %A Morris, Andrew P %A Tai, E-Shyong %A Selvin, Elizabeth %A Rotter, Jerome I %A Langenberg, Claudia %A Barroso, Inês %A Meigs, James B %K Diabetes Mellitus, Type 2 %K Genetic Variation %K Genome-Wide Association Study %K Glycated Hemoglobin A %K Humans %K Phenotype %K Risk %X

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

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

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

%B PLoS Med %V 14 %P e1002383 %8 2017 Sep %G eng %N 9 %R 10.1371/journal.pmed.1002383 %0 Journal Article %J Hypertension %D 2017 %T Novel Blood Pressure Locus and Gene Discovery Using Genome-Wide Association Study and Expression Data Sets From Blood and the Kidney. %A Wain, Louise V %A Vaez, Ahmad %A Jansen, Rick %A Joehanes, Roby %A van der Most, Peter J %A Erzurumluoglu, A Mesut %A O'Reilly, Paul F %A Cabrera, Claudia P %A Warren, Helen R %A Rose, Lynda M %A Verwoert, Germaine C %A Hottenga, Jouke-Jan %A Strawbridge, Rona J %A Esko, Tõnu %A Arking, Dan E %A Hwang, Shih-Jen %A Guo, Xiuqing %A Kutalik, Zoltán %A Trompet, Stella %A Shrine, Nick %A Teumer, Alexander %A Ried, Janina S %A Bis, Joshua C %A Smith, Albert V %A Amin, Najaf %A Nolte, Ilja M %A Lyytikäinen, Leo-Pekka %A Mahajan, Anubha %A Wareham, Nicholas J %A Hofer, Edith %A Joshi, Peter K %A Kristiansson, Kati %A Traglia, Michela %A Havulinna, Aki S %A Goel, Anuj %A Nalls, Mike A %A Sõber, Siim %A Vuckovic, Dragana %A Luan, Jian'an %A del Greco M, Fabiola %A Ayers, Kristin L %A Marrugat, Jaume %A Ruggiero, Daniela %A Lopez, Lorna M %A Niiranen, Teemu %A Enroth, Stefan %A Jackson, Anne U %A Nelson, Christopher P %A Huffman, Jennifer E %A Zhang, Weihua %A Marten, Jonathan %A Gandin, Ilaria %A Harris, Sarah E %A Zemunik, Tatijana %A Lu, Yingchang %A Evangelou, Evangelos %A Shah, Nabi %A de Borst, Martin H %A Mangino, Massimo %A Prins, Bram P %A Campbell, Archie %A Li-Gao, Ruifang %A Chauhan, Ganesh %A Oldmeadow, Christopher %A Abecasis, Goncalo %A Abedi, Maryam %A Barbieri, Caterina M %A Barnes, Michael R %A Batini, Chiara %A Beilby, John %A Blake, Tineka %A Boehnke, Michael %A Bottinger, Erwin P %A Braund, Peter S %A Brown, Morris %A Brumat, Marco %A Campbell, Harry %A Chambers, John C %A Cocca, Massimiliano %A Collins, Francis %A Connell, John %A Cordell, Heather J %A Damman, Jeffrey J %A Davies, Gail %A de Geus, Eco J %A de Mutsert, Renée %A Deelen, Joris %A Demirkale, Yusuf %A Doney, Alex S F %A Dörr, Marcus %A Farrall, Martin %A Ferreira, Teresa %A Frånberg, Mattias %A Gao, He %A Giedraitis, Vilmantas %A Gieger, Christian %A Giulianini, Franco %A Gow, Alan J %A Hamsten, Anders %A Harris, Tamara B %A Hofman, Albert %A Holliday, Elizabeth G %A Hui, Jennie %A Jarvelin, Marjo-Riitta %A Johansson, Asa %A Johnson, Andrew D %A Jousilahti, Pekka %A Jula, Antti %A Kähönen, Mika %A Kathiresan, Sekar %A Khaw, Kay-Tee %A Kolcic, Ivana %A Koskinen, Seppo %A Langenberg, Claudia %A Larson, Marty %A Launer, Lenore J %A Lehne, Benjamin %A Liewald, David C M %A Lin, Li %A Lind, Lars %A Mach, François %A Mamasoula, Chrysovalanto %A Menni, Cristina %A Mifsud, Borbala %A Milaneschi, Yuri %A Morgan, Anna %A Morris, Andrew D %A Morrison, Alanna C %A Munson, Peter J %A Nandakumar, Priyanka %A Nguyen, Quang Tri %A Nutile, Teresa %A Oldehinkel, Albertine J %A Oostra, Ben A %A Org, Elin %A Padmanabhan, Sandosh %A Palotie, Aarno %A Paré, Guillaume %A Pattie, Alison %A Penninx, Brenda W J H %A Poulter, Neil %A Pramstaller, Peter P %A Raitakari, Olli T %A Ren, Meixia %A Rice, Kenneth %A Ridker, Paul M %A Riese, Harriëtte %A Ripatti, Samuli %A Robino, Antonietta %A Rotter, Jerome I %A Rudan, Igor %A Saba, Yasaman %A Saint Pierre, Aude %A Sala, Cinzia F %A Sarin, Antti-Pekka %A Schmidt, Reinhold %A Scott, Rodney %A Seelen, Marc A %A Shields, Denis C %A Siscovick, David %A Sorice, Rossella %A Stanton, Alice %A Stott, David J %A Sundström, Johan %A Swertz, Morris %A Taylor, Kent D %A Thom, Simon %A Tzoulaki, Ioanna %A Tzourio, Christophe %A Uitterlinden, André G %A Völker, Uwe %A Vollenweider, Peter %A Wild, Sarah %A Willemsen, Gonneke %A Wright, Alan F %A Yao, Jie %A Thériault, Sébastien %A Conen, David %A Attia, John %A Sever, Peter %A Debette, Stephanie %A Mook-Kanamori, Dennis O %A Zeggini, Eleftheria %A Spector, Tim D %A van der Harst, Pim %A Palmer, Colin N A %A Vergnaud, Anne-Claire %A Loos, Ruth J F %A Polasek, Ozren %A Starr, John M %A Girotto, Giorgia %A Hayward, Caroline %A Kooner, Jaspal S %A Lindgren, Cecila M %A Vitart, Veronique %A Samani, Nilesh J %A Tuomilehto, Jaakko %A Gyllensten, Ulf %A Knekt, Paul %A Deary, Ian J %A Ciullo, Marina %A Elosua, Roberto %A Keavney, Bernard D %A Hicks, Andrew A %A Scott, Robert A %A Gasparini, Paolo %A Laan, Maris %A Liu, Yongmei %A Watkins, Hugh %A Hartman, Catharina A %A Salomaa, Veikko %A Toniolo, Daniela %A Perola, Markus %A Wilson, James F %A Schmidt, Helena %A Zhao, Jing Hua %A Lehtimäki, Terho %A van Duijn, Cornelia M %A Gudnason, Vilmundur %A Psaty, Bruce M %A Peters, Annette %A Rettig, Rainer %A James, Alan %A Jukema, J Wouter %A Strachan, David P %A Palmas, Walter %A Metspalu, Andres %A Ingelsson, Erik %A Boomsma, Dorret I %A Franco, Oscar H %A Bochud, Murielle %A Newton-Cheh, Christopher %A Munroe, Patricia B %A Elliott, Paul %A Chasman, Daniel I %A Chakravarti, Aravinda %A Knight, Joanne %A Morris, Andrew P %A Levy, Daniel %A Tobin, Martin D %A Snieder, Harold %A Caulfield, Mark J %A Ehret, Georg B %X

Elevated blood pressure is a major risk factor for cardiovascular disease and has a substantial genetic contribution. Genetic variation influencing blood pressure has the potential to identify new pharmacological targets for the treatment of hypertension. To discover additional novel blood pressure loci, we used 1000 Genomes Project-based imputation in 150 134 European ancestry individuals and sought significant evidence for independent replication in a further 228 245 individuals. We report 6 new signals of association in or near HSPB7, TNXB, LRP12, LOC283335, SEPT9, and AKT2, and provide new replication evidence for a further 2 signals in EBF2 and NFKBIA Combining large whole-blood gene expression resources totaling 12 607 individuals, we investigated all novel and previously reported signals and identified 48 genes with evidence for involvement in blood pressure regulation that are significant in multiple resources. Three novel kidney-specific signals were also detected. These robustly implicated genes may provide new leads for therapeutic innovation.

%B Hypertension %8 2017 Jul 24 %G eng %R 10.1161/HYPERTENSIONAHA.117.09438 %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 Hum Genet %D 2017 %T Trans-ethnic fine-mapping of genetic loci for body mass index in the diverse ancestral populations of the Population Architecture using Genomics and Epidemiology (PAGE) Study reveals evidence for multiple signals at established loci. %A Fernandez-Rhodes, Lindsay %A Gong, Jian %A Haessler, Jeffrey %A Franceschini, Nora %A Graff, Mariaelisa %A Nishimura, Katherine K %A Wang, Yujie %A Highland, Heather M %A Yoneyama, Sachiko %A Bush, William S %A Goodloe, Robert %A Ritchie, Marylyn D %A Crawford, Dana %A Gross, Myron %A Fornage, Myriam %A Bůzková, Petra %A Tao, Ran %A Isasi, Carmen %A Avilés-Santa, Larissa %A Daviglus, Martha %A Mackey, Rachel H %A Houston, Denise %A Gu, C Charles %A Ehret, Georg %A Nguyen, Khanh-Dung H %A Lewis, Cora E %A Leppert, Mark %A Irvin, Marguerite R %A Lim, Unhee %A Haiman, Christopher A %A Le Marchand, Loïc %A Schumacher, Fredrick %A Wilkens, Lynne %A Lu, Yingchang %A Bottinger, Erwin P %A Loos, Ruth J L %A Sheu, Wayne H-H %A Guo, Xiuqing %A Lee, Wen-Jane %A Hai, Yang %A Hung, Yi-Jen %A Absher, Devin %A Wu, I-Chien %A Taylor, Kent D %A Lee, I-Te %A Liu, Yeheng %A Wang, Tzung-Dau %A Quertermous, Thomas %A Juang, Jyh-Ming J %A Rotter, Jerome I %A Assimes, Themistocles %A Hsiung, Chao A %A Chen, Yii-Der Ida %A Prentice, Ross %A Kuller, Lewis H %A Manson, JoAnn E %A Kooperberg, Charles %A Smokowski, Paul %A Robinson, Whitney R %A Gordon-Larsen, Penny %A Li, Rongling %A Hindorff, Lucia %A Buyske, Steven %A Matise, Tara C %A Peters, Ulrike %A North, Kari E %K Body Mass Index %K Ethnic Groups %K Genetics, Population %K Humans %K Obesity %X

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

%B Hum Genet %V 136 %P 771-800 %8 2017 Jun %G eng %N 6 %R 10.1007/s00439-017-1787-6 %0 Journal Article %J Nat Genet %D 2018 %T Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits. %A Evangelou, Evangelos %A Warren, Helen R %A Mosen-Ansorena, David %A Mifsud, Borbala %A Pazoki, Raha %A Gao, He %A Ntritsos, Georgios %A Dimou, Niki %A Cabrera, Claudia P %A Karaman, Ibrahim %A Ng, Fu Liang %A Evangelou, Marina %A Witkowska, Katarzyna %A Tzanis, Evan %A Hellwege, Jacklyn N %A Giri, Ayush %A Velez Edwards, Digna R %A Sun, Yan V %A Cho, Kelly %A Gaziano, J Michael %A Wilson, Peter W F %A Tsao, Philip S %A Kovesdy, Csaba P %A Esko, Tõnu %A Mägi, Reedik %A Milani, Lili %A Almgren, Peter %A Boutin, Thibaud %A Debette, Stephanie %A Ding, Jun %A Giulianini, Franco %A Holliday, Elizabeth G %A Jackson, Anne U %A Li-Gao, Ruifang %A Lin, Wei-Yu %A Luan, Jian'an %A Mangino, Massimo %A Oldmeadow, Christopher %A Prins, Bram Peter %A Qian, Yong %A Sargurupremraj, Muralidharan %A Shah, Nabi %A Surendran, Praveen %A Thériault, Sébastien %A Verweij, Niek %A Willems, Sara M %A Zhao, Jing-Hua %A Amouyel, Philippe %A Connell, John %A de Mutsert, Renée %A Doney, Alex S F %A Farrall, Martin %A Menni, Cristina %A Morris, Andrew D %A Noordam, Raymond %A Paré, Guillaume %A Poulter, Neil R %A Shields, Denis C %A Stanton, Alice %A Thom, Simon %A Abecasis, Goncalo %A Amin, Najaf %A Arking, Dan E %A Ayers, Kristin L %A Barbieri, Caterina M %A Batini, Chiara %A Bis, Joshua C %A Blake, Tineka %A Bochud, Murielle %A Boehnke, Michael %A Boerwinkle, Eric %A Boomsma, Dorret I %A Bottinger, Erwin P %A Braund, Peter S %A Brumat, Marco %A Campbell, Archie %A Campbell, Harry %A Chakravarti, Aravinda %A Chambers, John C %A Chauhan, Ganesh %A Ciullo, Marina %A Cocca, Massimiliano %A Collins, Francis %A Cordell, Heather J %A Davies, Gail %A Borst, Martin H de %A Geus, Eco J de %A Deary, Ian J %A Deelen, Joris %A del Greco M, Fabiola %A Demirkale, Cumhur Yusuf %A Dörr, Marcus %A Ehret, Georg B %A Elosua, Roberto %A Enroth, Stefan %A Erzurumluoglu, A Mesut %A Ferreira, Teresa %A Frånberg, Mattias %A Franco, Oscar H %A Gandin, Ilaria %A Gasparini, Paolo %A Giedraitis, Vilmantas %A Gieger, Christian %A Girotto, Giorgia %A Goel, Anuj %A Gow, Alan J %A Gudnason, Vilmundur %A Guo, Xiuqing %A Gyllensten, Ulf %A Hamsten, Anders %A Harris, Tamara B %A Harris, Sarah E %A Hartman, Catharina A %A Havulinna, Aki S %A Hicks, Andrew A %A Hofer, Edith %A Hofman, Albert %A Hottenga, Jouke-Jan %A Huffman, Jennifer E %A Hwang, Shih-Jen %A Ingelsson, Erik %A James, Alan %A Jansen, Rick %A Jarvelin, Marjo-Riitta %A Joehanes, Roby %A Johansson, Asa %A Johnson, Andrew D %A Joshi, Peter K %A Jousilahti, Pekka %A Jukema, J Wouter %A Jula, Antti %A Kähönen, Mika %A Kathiresan, Sekar %A Keavney, Bernard D %A Khaw, Kay-Tee %A Knekt, Paul %A Knight, Joanne %A Kolcic, Ivana %A Kooner, Jaspal S %A Koskinen, Seppo %A Kristiansson, Kati %A Kutalik, Zoltán %A Laan, Maris %A Larson, Marty %A Launer, Lenore J %A Lehne, Benjamin %A Lehtimäki, Terho %A Liewald, David C M %A Lin, Li %A Lind, Lars %A Lindgren, Cecilia M %A Liu, Yongmei %A Loos, Ruth J F %A Lopez, Lorna M %A Lu, Yingchang %A Lyytikäinen, Leo-Pekka %A Mahajan, Anubha %A Mamasoula, Chrysovalanto %A Marrugat, Jaume %A Marten, Jonathan %A Milaneschi, Yuri %A Morgan, Anna %A Morris, Andrew P %A Morrison, Alanna C %A Munson, Peter J %A Nalls, Mike A %A Nandakumar, Priyanka %A Nelson, Christopher P %A Niiranen, Teemu %A Nolte, Ilja M %A Nutile, Teresa %A Oldehinkel, Albertine J %A Oostra, Ben A %A O'Reilly, Paul F %A Org, Elin %A Padmanabhan, Sandosh %A Palmas, Walter %A Palotie, Aarno %A Pattie, Alison %A Penninx, Brenda W J H %A Perola, Markus %A Peters, Annette %A Polasek, Ozren %A Pramstaller, Peter P %A Nguyen, Quang Tri %A Raitakari, Olli T %A Ren, Meixia %A Rettig, Rainer %A Rice, Kenneth %A Ridker, Paul M %A Ried, Janina S %A Riese, Harriëtte %A Ripatti, Samuli %A Robino, Antonietta %A Rose, Lynda M %A Rotter, Jerome I %A Rudan, Igor %A Ruggiero, Daniela %A Saba, Yasaman %A Sala, Cinzia F %A Salomaa, Veikko %A Samani, Nilesh J %A Sarin, Antti-Pekka %A Schmidt, Reinhold %A Schmidt, Helena %A Shrine, Nick %A Siscovick, David %A Smith, Albert V %A Snieder, Harold %A Sõber, Siim %A Sorice, Rossella %A Starr, John M %A Stott, David J %A Strachan, David P %A Strawbridge, Rona J %A Sundström, Johan %A Swertz, Morris A %A Taylor, Kent D %A Teumer, Alexander %A Tobin, Martin D %A Tomaszewski, Maciej %A Toniolo, Daniela %A Traglia, Michela %A Trompet, Stella %A Tuomilehto, Jaakko %A Tzourio, Christophe %A Uitterlinden, André G %A Vaez, Ahmad %A van der Most, Peter J %A van Duijn, Cornelia M %A Vergnaud, Anne-Claire %A Verwoert, Germaine C %A Vitart, Veronique %A Völker, Uwe %A Vollenweider, Peter %A Vuckovic, Dragana %A Watkins, Hugh %A Wild, Sarah H %A Willemsen, Gonneke %A Wilson, James F %A Wright, Alan F %A Yao, Jie %A Zemunik, Tatijana %A Zhang, Weihua %A Attia, John R %A Butterworth, Adam S %A Chasman, Daniel I %A Conen, David %A Cucca, Francesco %A Danesh, John %A Hayward, Caroline %A Howson, Joanna M M %A Laakso, Markku %A Lakatta, Edward G %A Langenberg, Claudia %A Melander, Olle %A Mook-Kanamori, Dennis O %A Palmer, Colin N A %A Risch, Lorenz %A Scott, Robert A %A Scott, Rodney J %A Sever, Peter %A Spector, Tim D %A van der Harst, Pim %A Wareham, Nicholas J %A Zeggini, Eleftheria %A Levy, Daniel %A Munroe, Patricia B %A Newton-Cheh, Christopher %A Brown, Morris J %A Metspalu, Andres %A Hung, Adriana M %A O'Donnell, Christopher J %A Edwards, Todd L %A Psaty, Bruce M %A Tzoulaki, Ioanna %A Barnes, Michael R %A Wain, Louise V %A Elliott, Paul %A Caulfield, Mark J %X

High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.

%B Nat Genet %V 50 %P 1412-1425 %8 2018 Oct %G eng %N 10 %R 10.1038/s41588-018-0205-x %0 Journal Article %J Am J Hum Genet %D 2018 %T Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders. %A Ligthart, Symen %A Vaez, Ahmad %A Võsa, Urmo %A Stathopoulou, Maria G %A de Vries, Paul S %A Prins, Bram P %A van der Most, Peter J %A Tanaka, Toshiko %A Naderi, Elnaz %A Rose, Lynda M %A Wu, Ying %A Karlsson, Robert %A Barbalic, Maja %A Lin, Honghuang %A Pool, Rene %A Zhu, Gu %A Mace, Aurelien %A Sidore, Carlo %A Trompet, Stella %A Mangino, Massimo %A Sabater-Lleal, Maria %A Kemp, John P %A Abbasi, Ali %A Kacprowski, Tim %A Verweij, Niek %A Smith, Albert V %A Huang, Tao %A Marzi, Carola %A Feitosa, Mary F %A Lohman, Kurt K %A Kleber, Marcus E %A Milaneschi, Yuri %A Mueller, Christian %A Huq, Mahmudul %A Vlachopoulou, Efthymia %A Lyytikäinen, Leo-Pekka %A Oldmeadow, Christopher %A Deelen, Joris %A Perola, Markus %A Zhao, Jing Hua %A Feenstra, Bjarke %A Amini, Marzyeh %A Lahti, Jari %A Schraut, Katharina E %A Fornage, Myriam %A Suktitipat, Bhoom %A Chen, Wei-Min %A Li, Xiaohui %A Nutile, Teresa %A Malerba, Giovanni %A Luan, Jian'an %A Bak, Tom %A Schork, Nicholas %A del Greco M, Fabiola %A Thiering, Elisabeth %A Mahajan, Anubha %A Marioni, Riccardo E %A Mihailov, Evelin %A Eriksson, Joel %A Ozel, Ayse Bilge %A Zhang, Weihua %A Nethander, Maria %A Cheng, Yu-Ching %A Aslibekyan, Stella %A Ang, Wei %A Gandin, Ilaria %A Yengo, Loic %A Portas, Laura %A Kooperberg, Charles %A Hofer, Edith %A Rajan, Kumar B %A Schurmann, Claudia %A den Hollander, Wouter %A Ahluwalia, Tarunveer S %A Zhao, Jing %A Draisma, Harmen H M %A Ford, Ian %A Timpson, Nicholas %A Teumer, Alexander %A Huang, Hongyan %A Wahl, Simone %A Liu, Yongmei %A Huang, Jie %A Uh, Hae-Won %A Geller, Frank %A Joshi, Peter K %A Yanek, Lisa R %A Trabetti, Elisabetta %A Lehne, Benjamin %A Vozzi, Diego %A Verbanck, Marie %A Biino, Ginevra %A Saba, Yasaman %A Meulenbelt, Ingrid %A O'Connell, Jeff R %A Laakso, Markku %A Giulianini, Franco %A Magnusson, Patrik K E %A Ballantyne, Christie M %A Hottenga, Jouke Jan %A Montgomery, Grant W %A Rivadineira, Fernando %A Rueedi, Rico %A Steri, Maristella %A Herzig, Karl-Heinz %A Stott, David J %A Menni, Cristina %A Frånberg, Mattias %A St Pourcain, Beate %A Felix, Stephan B %A Pers, Tune H %A Bakker, Stephan J L %A Kraft, Peter %A Peters, Annette %A Vaidya, Dhananjay %A Delgado, Graciela %A Smit, Johannes H %A Großmann, Vera %A Sinisalo, Juha %A Seppälä, Ilkka %A Williams, Stephen R %A Holliday, Elizabeth G %A Moed, Matthijs %A Langenberg, Claudia %A Räikkönen, Katri %A Ding, Jingzhong %A Campbell, Harry %A Sale, Michèle M %A Chen, Yii-der I %A James, Alan L %A Ruggiero, Daniela %A Soranzo, Nicole %A Hartman, Catharina A %A Smith, Erin N %A Berenson, Gerald S %A Fuchsberger, Christian %A Hernandez, Dena %A Tiesler, Carla M T %A Giedraitis, Vilmantas %A Liewald, David %A Fischer, Krista %A Mellström, Dan %A Larsson, Anders %A Wang, Yunmei %A Scott, William R %A Lorentzon, Matthias %A Beilby, John %A Ryan, Kathleen A %A Pennell, Craig E %A Vuckovic, Dragana %A Balkau, Beverly %A Concas, Maria Pina %A Schmidt, Reinhold %A Mendes de Leon, Carlos F %A Bottinger, Erwin P %A Kloppenburg, Margreet %A Paternoster, Lavinia %A Boehnke, Michael %A Musk, A W %A Willemsen, Gonneke %A Evans, David M %A Madden, Pamela A F %A Kähönen, Mika %A Kutalik, Zoltán %A Zoledziewska, Magdalena %A Karhunen, Ville %A Kritchevsky, Stephen B %A Sattar, Naveed %A Lachance, Genevieve %A Clarke, Robert %A Harris, Tamara B %A Raitakari, Olli T %A Attia, John R %A van Heemst, Diana %A Kajantie, Eero %A Sorice, Rossella %A Gambaro, Giovanni %A Scott, Robert A %A Hicks, Andrew A %A Ferrucci, Luigi %A Standl, Marie %A Lindgren, Cecilia M %A Starr, John M %A Karlsson, Magnus %A Lind, Lars %A Li, Jun Z %A Chambers, John C %A Mori, Trevor A %A de Geus, Eco J C N %A Heath, Andrew C %A Martin, Nicholas G %A Auvinen, Juha %A Buckley, Brendan M %A de Craen, Anton J M %A Waldenberger, Melanie %A Strauch, Konstantin %A Meitinger, Thomas %A Scott, Rodney J %A McEvoy, Mark %A Beekman, Marian %A Bombieri, Cristina %A Ridker, Paul M %A Mohlke, Karen L %A Pedersen, Nancy L %A Morrison, Alanna C %A Boomsma, Dorret I %A Whitfield, John B %A Strachan, David P %A Hofman, Albert %A Vollenweider, Peter %A Cucca, Francesco %A Jarvelin, Marjo-Riitta %A Jukema, J Wouter %A Spector, Tim D %A Hamsten, Anders %A Zeller, Tanja %A Uitterlinden, André G %A Nauck, Matthias %A Gudnason, Vilmundur %A Qi, Lu %A Grallert, Harald %A Borecki, Ingrid B %A Rotter, Jerome I %A März, Winfried %A Wild, Philipp S %A Lokki, Marja-Liisa %A Boyle, Michael %A Salomaa, Veikko %A Melbye, Mads %A Eriksson, Johan G %A Wilson, James F %A Penninx, Brenda W J H %A Becker, Diane M %A Worrall, Bradford B %A Gibson, Greg %A Krauss, Ronald M %A Ciullo, Marina %A Zaza, Gianluigi %A Wareham, Nicholas J %A Oldehinkel, Albertine J %A Palmer, Lyle J %A Murray, Sarah S %A Pramstaller, Peter P %A Bandinelli, Stefania %A Heinrich, Joachim %A Ingelsson, Erik %A Deary, Ian J %A Mägi, Reedik %A Vandenput, Liesbeth %A van der Harst, Pim %A Desch, Karl C %A Kooner, Jaspal S %A Ohlsson, Claes %A Hayward, Caroline %A Lehtimäki, Terho %A Shuldiner, Alan R %A Arnett, Donna K %A Beilin, Lawrence J %A Robino, Antonietta %A Froguel, Philippe %A Pirastu, Mario %A Jess, Tine %A Koenig, Wolfgang %A Loos, Ruth J F %A Evans, Denis A %A Schmidt, Helena %A Smith, George Davey %A Slagboom, P Eline %A Eiriksdottir, Gudny %A Morris, Andrew P %A Psaty, Bruce M %A Tracy, Russell P %A Nolte, Ilja M %A Boerwinkle, Eric %A Visvikis-Siest, Sophie %A Reiner, Alex P %A Gross, Myron %A Bis, Joshua C %A Franke, Lude %A Franco, Oscar H %A Benjamin, Emelia J %A Chasman, Daniel I %A Dupuis, Josée %A Snieder, Harold %A Dehghan, Abbas %A Alizadeh, Behrooz Z %X

C-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p < 5 × 10). After adjustment for body mass index in the regression analysis, the associations at all except three loci remained. The lead variants at the distinct loci explained up to 7.0% of the variance in circulating amounts of CRP. We identified 66 gene sets that were organized in two substantially correlated clusters, one mainly composed of immune pathways and the other characterized by metabolic pathways in the liver. Mendelian randomization analyses revealed a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder. Our findings provide further insights into the biology of inflammation and could lead to interventions for treating inflammation and its clinical consequences.

%B Am J Hum Genet %V 103 %P 691-706 %8 2018 Nov 01 %G eng %N 5 %R 10.1016/j.ajhg.2018.09.009 %0 Journal Article %J Am J Hum Genet %D 2018 %T A Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure. %A Sung, Yun J %A Winkler, Thomas W %A de Las Fuentes, Lisa %A Bentley, Amy R %A Brown, Michael R %A Kraja, Aldi T %A Schwander, Karen %A Ntalla, Ioanna %A Guo, Xiuqing %A Franceschini, Nora %A Lu, Yingchang %A Cheng, Ching-Yu %A Sim, Xueling %A Vojinovic, Dina %A Marten, Jonathan %A Musani, Solomon K %A Li, Changwei %A Feitosa, Mary F %A Kilpeläinen, Tuomas O %A Richard, Melissa A %A Noordam, Raymond %A Aslibekyan, Stella %A Aschard, Hugues %A Bartz, Traci M %A Dorajoo, Rajkumar %A Liu, Yongmei %A Manning, Alisa K %A Rankinen, Tuomo %A Smith, Albert Vernon %A Tajuddin, Salman M %A Tayo, Bamidele O %A Warren, Helen R %A Zhao, Wei %A Zhou, Yanhua %A Matoba, Nana %A Sofer, Tamar %A Alver, Maris %A Amini, Marzyeh %A Boissel, Mathilde %A Chai, Jin Fang %A Chen, Xu %A Divers, Jasmin %A Gandin, Ilaria %A Gao, Chuan %A Giulianini, Franco %A Goel, Anuj %A Harris, Sarah E %A Hartwig, Fernando Pires %A Horimoto, Andrea R V R %A Hsu, Fang-Chi %A Jackson, Anne U %A Kähönen, Mika %A Kasturiratne, Anuradhani %A Kuhnel, Brigitte %A Leander, Karin %A Lee, Wen-Jane %A Lin, Keng-Hung %A 'an Luan, Jian %A McKenzie, Colin A %A Meian, He %A Nelson, Christopher P %A Rauramaa, Rainer %A Schupf, Nicole %A Scott, Robert A %A Sheu, Wayne H H %A Stančáková, Alena %A Takeuchi, Fumihiko %A van der Most, Peter J %A Varga, Tibor V %A Wang, Heming %A Wang, Yajuan %A Ware, Erin B %A Weiss, Stefan %A Wen, Wanqing %A Yanek, Lisa R %A Zhang, Weihua %A Zhao, Jing Hua %A Afaq, Saima %A Alfred, Tamuno %A Amin, Najaf %A Arking, Dan %A Aung, Tin %A Barr, R Graham %A Bielak, Lawrence F %A Boerwinkle, Eric %A Bottinger, Erwin P %A Braund, Peter S %A Brody, Jennifer A %A Broeckel, Ulrich %A Cabrera, Claudia P %A Cade, Brian %A Caizheng, Yu %A Campbell, Archie %A Canouil, Mickaël %A Chakravarti, Aravinda %A Chauhan, Ganesh %A Christensen, Kaare %A Cocca, Massimiliano %A Collins, Francis S %A Connell, John M %A de Mutsert, Renée %A de Silva, H Janaka %A Debette, Stephanie %A Dörr, Marcus %A Duan, Qing %A Eaton, Charles B %A Ehret, Georg %A Evangelou, Evangelos %A Faul, Jessica D %A Fisher, Virginia A %A Forouhi, Nita G %A Franco, Oscar H %A Friedlander, Yechiel %A Gao, He %A Gigante, Bruna %A Graff, Misa %A Gu, C Charles %A Gu, Dongfeng %A Gupta, Preeti %A Hagenaars, Saskia P %A Harris, Tamara B %A He, Jiang %A Heikkinen, Sami %A Heng, Chew-Kiat %A Hirata, Makoto %A Hofman, Albert %A Howard, Barbara V %A Hunt, Steven %A Irvin, Marguerite R %A Jia, Yucheng %A Joehanes, Roby %A Justice, Anne E %A Katsuya, Tomohiro %A Kaufman, Joel %A Kerrison, Nicola D %A Khor, Chiea Chuen %A Koh, Woon-Puay %A Koistinen, Heikki A %A Komulainen, Pirjo %A Kooperberg, Charles %A Krieger, Jose E %A Kubo, Michiaki %A Kuusisto, Johanna %A Langefeld, Carl D %A Langenberg, Claudia %A Launer, Lenore J %A Lehne, Benjamin %A Lewis, Cora E %A Li, Yize %A Lim, Sing Hui %A Lin, Shiow %A Liu, Ching-Ti %A Liu, Jianjun %A Liu, Jingmin %A Liu, Kiang %A Liu, Yeheng %A Loh, Marie %A Lohman, Kurt K %A Long, Jirong %A Louie, Tin %A Mägi, Reedik %A Mahajan, Anubha %A Meitinger, Thomas %A Metspalu, Andres %A Milani, Lili %A Momozawa, Yukihide %A Morris, Andrew P %A Mosley, Thomas H %A Munson, Peter %A Murray, Alison D %A Nalls, Mike A %A Nasri, Ubaydah %A Norris, Jill M %A North, Kari %A Ogunniyi, Adesola %A Padmanabhan, Sandosh %A Palmas, Walter R %A Palmer, Nicholette D %A Pankow, James S %A Pedersen, Nancy L %A Peters, Annette %A Peyser, Patricia A %A Polasek, Ozren %A Raitakari, Olli T %A Renstrom, Frida %A Rice, Treva K %A Ridker, Paul M %A Robino, Antonietta %A Robinson, Jennifer G %A Rose, Lynda M %A Rudan, Igor %A Sabanayagam, Charumathi %A Salako, Babatunde L %A Sandow, Kevin %A Schmidt, Carsten O %A Schreiner, Pamela J %A Scott, William R %A Seshadri, Sudha %A Sever, Peter %A Sitlani, Colleen M %A Smith, Jennifer A %A Snieder, Harold %A Starr, John M %A Strauch, Konstantin %A Tang, Hua %A Taylor, Kent D %A Teo, Yik Ying %A Tham, Yih Chung %A Uitterlinden, André G %A Waldenberger, Melanie %A Wang, Lihua %A Wang, Ya X %A Wei, Wen Bin %A Williams, Christine %A Wilson, Gregory %A Wojczynski, Mary K %A Yao, Jie %A Yuan, Jian-Min %A Zonderman, Alan B %A Becker, Diane M %A Boehnke, Michael %A Bowden, Donald W %A Chambers, John C %A Chen, Yii-Der Ida %A de Faire, Ulf %A Deary, Ian J %A Esko, Tõnu %A Farrall, Martin %A Forrester, Terrence %A Franks, Paul W %A Freedman, Barry I %A Froguel, Philippe %A Gasparini, Paolo %A Gieger, Christian %A Horta, Bernardo Lessa %A Hung, Yi-Jen %A Jonas, Jost B %A Kato, Norihiro %A Kooner, Jaspal S %A Laakso, Markku %A Lehtimäki, Terho %A Liang, Kae-Woei %A Magnusson, Patrik K E %A Newman, Anne B %A Oldehinkel, Albertine J %A Pereira, Alexandre C %A Redline, Susan %A Rettig, Rainer %A Samani, Nilesh J %A Scott, James %A Shu, Xiao-Ou %A van der Harst, Pim %A Wagenknecht, Lynne E %A Wareham, Nicholas J %A Watkins, Hugh %A Weir, David R %A Wickremasinghe, Ananda R %A Wu, Tangchun %A Zheng, Wei %A Kamatani, Yoichiro %A Laurie, Cathy C %A Bouchard, Claude %A Cooper, Richard S %A Evans, Michele K %A Gudnason, Vilmundur %A Kardia, Sharon L R %A Kritchevsky, Stephen B %A Levy, Daniel %A O'Connell, Jeff R %A Psaty, Bruce M %A van Dam, Rob M %A Sims, Mario %A Arnett, Donna K %A Mook-Kanamori, Dennis O %A Kelly, Tanika N %A Fox, Ervin R %A Hayward, Caroline %A Fornage, Myriam %A Rotimi, Charles N %A Province, Michael A %A van Duijn, Cornelia M %A Tai, E Shyong %A Wong, Tien Yin %A Loos, Ruth J F %A Reiner, Alex P %A Rotter, Jerome I %A Zhu, Xiaofeng %A Bierut, Laura J %A Gauderman, W James %A Caulfield, Mark J %A Elliott, Paul %A Rice, Kenneth %A Munroe, Patricia B %A Morrison, Alanna C %A Cupples, L Adrienne %A Rao, Dabeeru C %A Chasman, Daniel I %X

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

%B Am J Hum Genet %V 102 %P 375-400 %8 2018 Mar 01 %G eng %N 3 %R 10.1016/j.ajhg.2018.01.015 %0 Journal Article %J Nat Genet %D 2018 %T Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes. %A Mahajan, Anubha %A Wessel, Jennifer %A Willems, Sara M %A Zhao, Wei %A Robertson, Neil R %A Chu, Audrey Y %A Gan, Wei %A Kitajima, Hidetoshi %A Taliun, Daniel %A Rayner, N William %A Guo, Xiuqing %A Lu, Yingchang %A Li, Man %A Jensen, Richard A %A Hu, Yao %A Huo, Shaofeng %A Lohman, Kurt K %A Zhang, Weihua %A Cook, James P %A Prins, Bram Peter %A Flannick, Jason %A Grarup, Niels %A Trubetskoy, Vassily Vladimirovich %A Kravic, Jasmina %A Kim, Young Jin %A Rybin, Denis V %A Yaghootkar, Hanieh %A Müller-Nurasyid, Martina %A Meidtner, Karina %A Li-Gao, Ruifang %A Varga, Tibor V %A Marten, Jonathan %A Li, Jin %A Smith, Albert Vernon %A An, Ping %A Ligthart, Symen %A Gustafsson, Stefan %A Malerba, Giovanni %A Demirkan, Ayse %A Tajes, Juan Fernandez %A Steinthorsdottir, Valgerdur %A Wuttke, Matthias %A Lecoeur, Cécile %A Preuss, Michael %A Bielak, Lawrence F %A Graff, Marielisa %A Highland, Heather M %A Justice, Anne E %A Liu, Dajiang J %A Marouli, Eirini %A Peloso, Gina Marie %A Warren, Helen R %A Afaq, Saima %A Afzal, Shoaib %A Ahlqvist, Emma %A Almgren, Peter %A Amin, Najaf %A Bang, Lia B %A Bertoni, Alain G %A Bombieri, Cristina %A Bork-Jensen, Jette %A Brandslund, Ivan %A Brody, Jennifer A %A Burtt, Noel P %A Canouil, Mickaël %A Chen, Yii-Der Ida %A Cho, Yoon Shin %A Christensen, Cramer %A Eastwood, Sophie V %A Eckardt, Kai-Uwe %A Fischer, Krista %A Gambaro, Giovanni %A Giedraitis, Vilmantas %A Grove, Megan L %A de Haan, Hugoline G %A Hackinger, Sophie %A Hai, Yang %A Han, Sohee %A Tybjærg-Hansen, Anne %A Hivert, Marie-France %A Isomaa, Bo %A Jäger, Susanne %A Jørgensen, Marit E %A Jørgensen, Torben %A Käräjämäki, AnneMari %A Kim, Bong-Jo %A Kim, Sung Soo %A Koistinen, Heikki A %A Kovacs, Peter %A Kriebel, Jennifer %A Kronenberg, Florian %A Läll, Kristi %A Lange, Leslie A %A Lee, Jung-Jin %A Lehne, Benjamin %A Li, Huaixing %A Lin, Keng-Hung %A Linneberg, Allan %A Liu, Ching-Ti %A Liu, Jun %A Loh, Marie %A Mägi, Reedik %A Mamakou, Vasiliki %A McKean-Cowdin, Roberta %A Nadkarni, Girish %A Neville, Matt %A Nielsen, Sune F %A Ntalla, Ioanna %A Peyser, Patricia A %A Rathmann, Wolfgang %A Rice, Kenneth %A Rich, Stephen S %A Rode, Line %A Rolandsson, Olov %A Schönherr, Sebastian %A Selvin, Elizabeth %A Small, Kerrin S %A Stančáková, Alena %A Surendran, Praveen %A Taylor, Kent D %A Teslovich, Tanya M %A Thorand, Barbara %A Thorleifsson, Gudmar %A Tin, Adrienne %A Tönjes, Anke %A Varbo, Anette %A Witte, Daniel R %A Wood, Andrew R %A Yajnik, Pranav %A Yao, Jie %A Yengo, Loic %A Young, Robin %A Amouyel, Philippe %A Boeing, Heiner %A Boerwinkle, Eric %A Bottinger, Erwin P %A Chowdhury, Rajiv %A Collins, Francis S %A Dedoussis, George %A Dehghan, Abbas %A Deloukas, Panos %A Ferrario, Marco M %A Ferrieres, Jean %A Florez, Jose C %A Frossard, Philippe %A Gudnason, Vilmundur %A Harris, Tamara B %A Heckbert, Susan R %A Howson, Joanna M M %A Ingelsson, Martin %A Kathiresan, Sekar %A Kee, Frank %A Kuusisto, Johanna %A Langenberg, Claudia %A Launer, Lenore J %A Lindgren, Cecilia M %A Männistö, Satu %A Meitinger, Thomas %A Melander, Olle %A Mohlke, Karen L %A Moitry, Marie %A Morris, Andrew D %A Murray, Alison D %A de Mutsert, Renée %A Orho-Melander, Marju %A Owen, Katharine R %A Perola, Markus %A Peters, Annette %A Province, Michael A %A Rasheed, Asif %A Ridker, Paul M %A Rivadineira, Fernando %A Rosendaal, Frits R %A Rosengren, Anders H %A Salomaa, Veikko %A Sheu, Wayne H-H %A Sladek, Rob %A Smith, Blair H %A Strauch, Konstantin %A Uitterlinden, André G %A Varma, Rohit %A Willer, Cristen J %A Blüher, Matthias %A Butterworth, Adam S %A Chambers, John Campbell %A Chasman, Daniel I %A Danesh, John %A van Duijn, Cornelia %A Dupuis, Josée %A Franco, Oscar H %A Franks, Paul W %A Froguel, Philippe %A Grallert, Harald %A Groop, Leif %A Han, Bok-Ghee %A Hansen, Torben %A Hattersley, Andrew T %A Hayward, Caroline %A Ingelsson, Erik %A Kardia, Sharon L R %A Karpe, Fredrik %A Kooner, Jaspal Singh %A Köttgen, Anna %A Kuulasmaa, Kari %A Laakso, Markku %A Lin, Xu %A Lind, Lars %A Liu, Yongmei %A Loos, Ruth J F %A Marchini, Jonathan %A Metspalu, Andres %A Mook-Kanamori, Dennis %A Nordestgaard, Børge G %A Palmer, Colin N A %A Pankow, James S %A Pedersen, Oluf %A Psaty, Bruce M %A Rauramaa, Rainer %A Sattar, Naveed %A Schulze, Matthias B %A Soranzo, Nicole %A Spector, Timothy D %A Stefansson, Kari %A Stumvoll, Michael %A Thorsteinsdottir, Unnur %A Tuomi, Tiinamaija %A Tuomilehto, Jaakko %A Wareham, Nicholas J %A Wilson, James G %A Zeggini, Eleftheria %A Scott, Robert A %A Barroso, Inês %A Frayling, Timothy M %A Goodarzi, Mark O %A Meigs, James B %A Boehnke, Michael %A Saleheen, Danish %A Morris, Andrew P %A Rotter, Jerome I %A McCarthy, Mark I %X

We aggregated coding variant data for 81,412 type 2 diabetes cases and 370,832 controls of diverse ancestry, identifying 40 coding variant association signals (P < 2.2 × 10); of these, 16 map outside known risk-associated loci. We make two important observations. First, only five of these signals are driven by low-frequency variants: even for these, effect sizes are modest (odds ratio ≤1.29). Second, when we used large-scale genome-wide association data to fine-map the associated variants in their regional context, accounting for the global enrichment of complex trait associations in coding sequence, compelling evidence for coding variant causality was obtained for only 16 signals. At 13 others, the associated coding variants clearly represent 'false leads' with potential to generate erroneous mechanistic inference. Coding variant associations offer a direct route to biological insight for complex diseases and identification of validated therapeutic targets; however, appropriate mechanistic inference requires careful specification of their causal contribution to disease predisposition.

%B Nat Genet %V 50 %P 559-571 %8 2018 Apr %G eng %N 4 %R 10.1038/s41588-018-0084-1 %0 Journal Article %J J Clin Endocrinol Metab %D 2018 %T Trans-ethnic Evaluation Identifies Novel Low Frequency Loci Associated with 25-Hydroxyvitamin D Concentrations. %A Hong, Jaeyoung %A Hatchell, Kathryn E %A Bradfield, Jonathan P %A Andrew, Bjonnes %A Alessandra, Chesi %A Chao-Qiang, Lai %A Langefeld, Carl D %A Lu, Lingyi %A Lu, Yingchang %A Lutsey, Pamela L %A Musani, Solomon K %A Nalls, Mike A %A Robinson-Cohen, Cassianne %A Roizen, Jeffery D %A Saxena, Richa %A Tucker, Katherine L %A Ziegler, Julie T %A Arking, Dan E %A Bis, Joshua C %A Boerwinkle, Eric %A Bottinger, Erwin P %A Bowden, Donald W %A Gilsanz, Vincente %A Houston, Denise K %A Kalkwarf, Heidi J %A Kelly, Andrea %A Lappe, Joan M %A Liu, Yongmei %A Michos, Erin D %A Oberfield, Sharon E %A Palmer, Nicholette D %A Rotter, Jerome I %A Sapkota, Bishwa %A Shepherd, John A %A Wilson, James G %A Basu, Saonli %A de Boer, Ian H %A Divers, Jasmin %A Freedman, Barry I %A Grant, Struan F A %A Hakanarson, Hakon %A Harris, Tamara B %A Kestenbaum, Bryan R %A Kritchevsky, Stephen B %A Loos, Ruth J F %A Norris, Jill M %A Norwood, Arnita F %A Ordovas, Jose M %A Pankow, James S %A Psaty, Bruce M %A Sanhgera, Dharambir K %A Wagenknecht, Lynne E %A Zemel, Babette S %A Meigs, James %A Dupuis, Josée %A Florez, Jose C %A Wang, Thomas %A Liu, Ching-Ti %A Engelman, Corinne D %A Billings, Liana K %X

Context: Vitamin D inadequacy is common in the adult population of the United States. While the genetic determinants underlying vitamin D inadequacy have been studied in people of European ancestry, less is known in Hispanic or African ancestry populations.

Objective: The TRANSCEN-D (TRANS-ethniC Evaluation of vitamiN D GWAS) consortium was assembled to replicate genetic associations with 25-hydroxyvitamin D (25(OH)D) concentrations from the meta-analyses of European ancestry (SUNLIGHT) and to identify novel genetic variants related to vitamin D concentrations in African and Hispanic ancestries.

Design: Ancestry-specific (Hispanic and African) and trans-ethnic (Hispanic, African and European) meta-analyses were performed using the METAL software.

Patients or Other Participants: In total, 8,541 African-American and 3,485 Hispanic-American (from North America) participants from twelve cohorts, and 16,124 European participants from SUNLIGHT were included in the study.

Main Outcome Measure(s): Blood concentrations of 25(OH)D were measured for all participants.

Results: Ancestry-specific analyses in African and Hispanic Americans replicated SNPs in GC (2 and 4 SNPs, respectively). A potentially novel SNP (rs79666294) near the KIF4B gene was identified in the African-American cohort. Trans-ethnic evaluation replicated GC and DHCR7 region SNPs. Additionally, the trans-ethnic analyses revealed novel SNPs rs719700 and rs1410656 near the ANO6/ARID2 and HTR2A genes, respectively.

Conclusions: Ancestry-specific and trans-ethnic GWAS of 25(OH)D confirmed findings in GC and DHCR7 for African and Hispanic American samples and revealed novel findings near KIF4B, ANO6/ARID2, and HTR2A. The biological mechanisms that link these regions with 25(OH)D metabolism require further investigation.

%B J Clin Endocrinol Metab %8 2018 Jan 09 %G eng %R 10.1210/jc.2017-01802 %0 Journal Article %J Nat Commun %D 2019 %T Associations of autozygosity with a broad range of human phenotypes. %A Clark, David W %A Okada, Yukinori %A Moore, Kristjan H S %A Mason, Dan %A Pirastu, Nicola %A Gandin, Ilaria %A Mattsson, Hannele %A Barnes, Catriona L K %A Lin, Kuang %A Zhao, Jing Hua %A Deelen, Patrick %A Rohde, Rebecca %A Schurmann, Claudia %A Guo, Xiuqing %A Giulianini, Franco %A Zhang, Weihua %A Medina-Gómez, Carolina %A Karlsson, Robert %A Bao, Yanchun %A Bartz, Traci M %A Baumbach, Clemens %A Biino, Ginevra %A Bixley, Matthew J %A Brumat, Marco %A Chai, Jin-Fang %A Corre, Tanguy %A Cousminer, Diana L %A Dekker, Annelot M %A Eccles, David A %A van Eijk, Kristel R %A Fuchsberger, Christian %A Gao, He %A Germain, Marine %A Gordon, Scott D %A de Haan, Hugoline G %A Harris, Sarah E %A Hofer, Edith %A Huerta-Chagoya, Alicia %A Igartua, Catherine %A Jansen, Iris E %A Jia, Yucheng %A Kacprowski, Tim %A Karlsson, Torgny %A Kleber, Marcus E %A Li, Shengchao Alfred %A Li-Gao, Ruifang %A Mahajan, Anubha %A Matsuda, Koichi %A Meidtner, Karina %A Meng, Weihua %A Montasser, May E %A van der Most, Peter J %A Munz, Matthias %A Nutile, Teresa %A Palviainen, Teemu %A Prasad, Gauri %A Prasad, Rashmi B %A Priyanka, Tallapragada Divya Sri %A Rizzi, Federica %A Salvi, Erika %A Sapkota, Bishwa R %A Shriner, Daniel %A Skotte, Line %A Smart, Melissa C %A Smith, Albert Vernon %A van der Spek, Ashley %A Spracklen, Cassandra N %A Strawbridge, Rona J %A Tajuddin, Salman M %A Trompet, Stella %A Turman, Constance %A Verweij, Niek %A Viberti, Clara %A Wang, Lihua %A Warren, Helen R %A Wootton, Robyn E %A Yanek, Lisa R %A Yao, Jie %A Yousri, Noha A %A Zhao, Wei %A Adeyemo, Adebowale A %A Afaq, Saima %A Aguilar-Salinas, Carlos Alberto %A Akiyama, Masato %A Albert, Matthew L %A Allison, Matthew A %A Alver, Maris %A Aung, Tin %A Azizi, Fereidoun %A Bentley, Amy R %A Boeing, Heiner %A Boerwinkle, Eric %A Borja, Judith B %A de Borst, Gert J %A Bottinger, Erwin P %A Broer, Linda %A Campbell, Harry %A Chanock, Stephen %A Chee, Miao-Li %A Chen, Guanjie %A Chen, Yii-der I %A Chen, Zhengming %A Chiu, Yen-Feng %A Cocca, Massimiliano %A Collins, Francis S %A Concas, Maria Pina %A Corley, Janie %A Cugliari, Giovanni %A van Dam, Rob M %A Damulina, Anna %A Daneshpour, Maryam S %A Day, Felix R %A Delgado, Graciela E %A Dhana, Klodian %A Doney, Alexander S F %A Dörr, Marcus %A Doumatey, Ayo P %A Dzimiri, Nduna %A Ebenesersdóttir, S Sunna %A Elliott, Joshua %A Elliott, Paul %A Ewert, Ralf %A Felix, Janine F %A Fischer, Krista %A Freedman, Barry I %A Girotto, Giorgia %A Goel, Anuj %A Gögele, Martin %A Goodarzi, Mark O %A Graff, Mariaelisa %A Granot-Hershkovitz, Einat %A Grodstein, Francine %A Guarrera, Simonetta %A Gudbjartsson, Daniel F %A Guity, Kamran %A Gunnarsson, Bjarni %A Guo, Yu %A Hagenaars, Saskia P %A Haiman, Christopher A %A Halevy, Avner %A Harris, Tamara B %A Hedayati, Mehdi %A van Heel, David A %A Hirata, Makoto %A Höfer, Imo %A Hsiung, Chao Agnes %A Huang, Jinyan %A Hung, Yi-Jen %A Ikram, M Arfan %A Jagadeesan, Anuradha %A Jousilahti, Pekka %A Kamatani, Yoichiro %A Kanai, Masahiro %A Kerrison, Nicola D %A Kessler, Thorsten %A Khaw, Kay-Tee %A Khor, Chiea Chuen %A de Kleijn, Dominique P V %A Koh, Woon-Puay %A Kolcic, Ivana %A Kraft, Peter %A Krämer, Bernhard K %A Kutalik, Zoltán %A Kuusisto, Johanna %A Langenberg, Claudia %A Launer, Lenore J %A Lawlor, Deborah A %A Lee, I-Te %A Lee, Wen-Jane %A Lerch, Markus M %A Li, Liming %A Liu, Jianjun %A Loh, Marie %A London, Stephanie J %A Loomis, Stephanie %A Lu, Yingchang %A Luan, Jian'an %A Mägi, Reedik %A Manichaikul, Ani W %A Manunta, Paolo %A Másson, Gísli %A Matoba, Nana %A Mei, Xue W %A Meisinger, Christa %A Meitinger, Thomas %A Mezzavilla, Massimo %A Milani, Lili %A Millwood, Iona Y %A Momozawa, Yukihide %A Moore, Amy %A Morange, Pierre-Emmanuel %A Moreno-Macias, Hortensia %A Mori, Trevor A %A Morrison, Alanna C %A Muka, Taulant %A Murakami, Yoshinori %A Murray, Alison D %A de Mutsert, Renée %A Mychaleckyj, Josyf C %A Nalls, Mike A %A Nauck, Matthias %A Neville, Matt J %A Nolte, Ilja M %A Ong, Ken K %A Orozco, Lorena %A Padmanabhan, Sandosh %A Pálsson, Gunnar %A Pankow, James S %A Pattaro, Cristian %A Pattie, Alison %A Polasek, Ozren %A Poulter, Neil %A Pramstaller, Peter P %A Quintana-Murci, Lluis %A Räikkönen, Katri %A Ralhan, Sarju %A Rao, Dabeeru C %A van Rheenen, Wouter %A Rich, Stephen S %A Ridker, Paul M %A Rietveld, Cornelius A %A Robino, Antonietta %A van Rooij, Frank J A %A Ruggiero, Daniela %A Saba, Yasaman %A Sabanayagam, Charumathi %A Sabater-Lleal, Maria %A Sala, Cinzia Felicita %A Salomaa, Veikko %A Sandow, Kevin %A Schmidt, Helena %A Scott, Laura J %A Scott, William R %A Sedaghati-Khayat, Bahareh %A Sennblad, Bengt %A van Setten, Jessica %A Sever, Peter J %A Sheu, Wayne H-H %A Shi, Yuan %A Shrestha, Smeeta %A Shukla, Sharvari Rahul %A Sigurdsson, Jon K %A Sikka, Timo Tonis %A Singh, Jai Rup %A Smith, Blair H %A Stančáková, Alena %A Stanton, Alice %A Starr, John M %A Stefansdottir, Lilja %A Straker, Leon %A Sulem, Patrick %A Sveinbjornsson, Gardar %A Swertz, Morris A %A Taylor, Adele M %A Taylor, Kent D %A Terzikhan, Natalie %A Tham, Yih-Chung %A Thorleifsson, Gudmar %A Thorsteinsdottir, Unnur %A Tillander, Annika %A Tracy, Russell P %A Tusié-Luna, Teresa %A Tzoulaki, Ioanna %A Vaccargiu, Simona %A Vangipurapu, Jagadish %A Veldink, Jan H %A Vitart, Veronique %A Völker, Uwe %A Vuoksimaa, Eero %A Wakil, Salma M %A Waldenberger, Melanie %A Wander, Gurpreet S %A Wang, Ya Xing %A Wareham, Nicholas J %A Wild, Sarah %A Yajnik, Chittaranjan S %A Yuan, Jian-Min %A Zeng, Lingyao %A Zhang, Liang %A Zhou, Jie %A Amin, Najaf %A Asselbergs, Folkert W %A Bakker, Stephan J L %A Becker, Diane M %A Lehne, Benjamin %A Bennett, David A %A van den Berg, Leonard H %A Berndt, Sonja I %A Bharadwaj, Dwaipayan %A Bielak, Lawrence F %A Bochud, Murielle %A Boehnke, Mike %A Bouchard, Claude %A Bradfield, Jonathan P %A Brody, Jennifer A %A Campbell, Archie %A Carmi, Shai %A Caulfield, Mark J %A Cesarini, David %A Chambers, John C %A Chandak, Giriraj Ratan %A Cheng, Ching-Yu %A Ciullo, Marina %A Cornelis, Marilyn %A Cusi, Daniele %A Smith, George Davey %A Deary, Ian J %A Dorajoo, Rajkumar %A van Duijn, Cornelia M %A Ellinghaus, David %A Erdmann, Jeanette %A Eriksson, Johan G %A Evangelou, Evangelos %A Evans, Michele K %A Faul, Jessica D %A Feenstra, Bjarke %A Feitosa, Mary %A Foisy, Sylvain %A Franke, Andre %A Friedlander, Yechiel %A Gasparini, Paolo %A Gieger, Christian %A Gonzalez, Clicerio %A Goyette, Philippe %A Grant, Struan F A %A Griffiths, Lyn R %A Groop, Leif %A Gudnason, Vilmundur %A Gyllensten, Ulf %A Hakonarson, Hakon %A Hamsten, Anders %A van der Harst, Pim %A Heng, Chew-Kiat %A Hicks, Andrew A %A Hochner, Hagit %A Huikuri, Heikki %A Hunt, Steven C %A Jaddoe, Vincent W V %A De Jager, Philip L %A Johannesson, Magnus %A Johansson, Asa %A Jonas, Jost B %A Jukema, J Wouter %A Junttila, Juhani %A Kaprio, Jaakko %A Kardia, Sharon L R %A Karpe, Fredrik %A Kumari, Meena %A Laakso, Markku %A van der Laan, Sander W %A Lahti, Jari %A Laudes, Matthias %A Lea, Rodney A %A Lieb, Wolfgang %A Lumley, Thomas %A Martin, Nicholas G %A März, Winfried %A Matullo, Giuseppe %A McCarthy, Mark I %A Medland, Sarah E %A Merriman, Tony R %A Metspalu, Andres %A Meyer, Brian F %A Mohlke, Karen L %A Montgomery, Grant W %A Mook-Kanamori, Dennis %A Munroe, Patricia B %A North, Kari E %A Nyholt, Dale R %A O'Connell, Jeffery R %A Ober, Carole %A Oldehinkel, Albertine J %A Palmas, Walter %A Palmer, Colin %A Pasterkamp, Gerard G %A Patin, Etienne %A Pennell, Craig E %A Perusse, Louis %A Peyser, Patricia A %A Pirastu, Mario %A Polderman, Tinca J C %A Porteous, David J %A Posthuma, Danielle %A Psaty, Bruce M %A Rioux, John D %A Rivadeneira, Fernando %A Rotimi, Charles %A Rotter, Jerome I %A Rudan, Igor %A den Ruijter, Hester M %A Sanghera, Dharambir K %A Sattar, Naveed %A Schmidt, Reinhold %A Schulze, Matthias B %A Schunkert, Heribert %A Scott, Robert A %A Shuldiner, Alan R %A Sim, Xueling %A Small, Neil %A Smith, Jennifer A %A Sotoodehnia, Nona %A Tai, E-Shyong %A Teumer, Alexander %A Timpson, Nicholas J %A Toniolo, Daniela %A Trégouët, David-Alexandre %A Tuomi, Tiinamaija %A Vollenweider, Peter %A Wang, Carol A %A Weir, David R %A Whitfield, John B %A Wijmenga, Cisca %A Wong, Tien-Yin %A Wright, John %A Yang, Jingyun %A Yu, Lei %A Zemel, Babette S %A Zonderman, Alan B %A Perola, Markus %A Magnusson, Patrik K E %A Uitterlinden, André G %A Kooner, Jaspal S %A Chasman, Daniel I %A Loos, Ruth J F %A Franceschini, Nora %A Franke, Lude %A Haley, Chris S %A Hayward, Caroline %A Walters, Robin G %A Perry, John R B %A Esko, Tõnu %A Helgason, Agnar %A Stefansson, Kari %A Joshi, Peter K %A Kubo, Michiaki %A Wilson, James F %X

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

%B Nat Commun %V 10 %P 4957 %8 2019 Oct 31 %G eng %N 1 %R 10.1038/s41467-019-12283-6 %0 Journal Article %J Nat Genet %D 2019 %T A catalog of genetic loci associated with kidney function from analyses of a million individuals. %A Wuttke, Matthias %A Li, Yong %A Li, Man %A Sieber, Karsten B %A Feitosa, Mary F %A Gorski, Mathias %A Tin, Adrienne %A Wang, Lihua %A Chu, Audrey Y %A Hoppmann, Anselm %A Kirsten, Holger %A Giri, Ayush %A Chai, Jin-Fang %A Sveinbjornsson, Gardar %A Tayo, Bamidele O %A Nutile, Teresa %A Fuchsberger, Christian %A Marten, Jonathan %A Cocca, Massimiliano %A Ghasemi, Sahar %A Xu, Yizhe %A Horn, Katrin %A Noce, Damia %A van der Most, Peter J %A Sedaghat, Sanaz %A Yu, Zhi %A Akiyama, Masato %A Afaq, Saima %A Ahluwalia, Tarunveer S %A Almgren, Peter %A Amin, Najaf %A Arnlöv, Johan %A Bakker, Stephan J L %A Bansal, Nisha %A Baptista, Daniela %A Bergmann, Sven %A Biggs, Mary L %A Biino, Ginevra %A Boehnke, Michael %A Boerwinkle, Eric %A Boissel, Mathilde %A Bottinger, Erwin P %A Boutin, Thibaud S %A Brenner, Hermann %A Brumat, Marco %A Burkhardt, Ralph %A Butterworth, Adam S %A Campana, Eric %A Campbell, Archie %A Campbell, Harry %A Canouil, Mickaël %A Carroll, Robert J %A Catamo, Eulalia %A Chambers, John C %A Chee, Miao-Ling %A Chee, Miao-Li %A Chen, Xu %A Cheng, Ching-Yu %A Cheng, Yurong %A Christensen, Kaare %A Cifkova, Renata %A Ciullo, Marina %A Concas, Maria Pina %A Cook, James P %A Coresh, Josef %A Corre, Tanguy %A Sala, Cinzia Felicita %A Cusi, Daniele %A Danesh, John %A Daw, E Warwick %A de Borst, Martin H %A De Grandi, Alessandro %A de Mutsert, Renée %A de Vries, Aiko P J %A Degenhardt, Frauke %A Delgado, Graciela %A Demirkan, Ayse %A Di Angelantonio, Emanuele %A Dittrich, Katalin %A Divers, Jasmin %A Dorajoo, Rajkumar %A Eckardt, Kai-Uwe %A Ehret, Georg %A Elliott, Paul %A Endlich, Karlhans %A Evans, Michele K %A Felix, Janine F %A Foo, Valencia Hui Xian %A Franco, Oscar H %A Franke, Andre %A Freedman, Barry I %A Freitag-Wolf, Sandra %A Friedlander, Yechiel %A Froguel, Philippe %A Gansevoort, Ron T %A Gao, He %A Gasparini, Paolo %A Gaziano, J Michael %A Giedraitis, Vilmantas %A Gieger, Christian %A Girotto, Giorgia %A Giulianini, Franco %A Gögele, Martin %A Gordon, Scott D %A Gudbjartsson, Daniel F %A Gudnason, Vilmundur %A Haller, Toomas %A Hamet, Pavel %A Harris, Tamara B %A Hartman, Catharina A %A Hayward, Caroline %A Hellwege, Jacklyn N %A Heng, Chew-Kiat %A Hicks, Andrew A %A Hofer, Edith %A Huang, Wei %A Hutri-Kähönen, Nina %A Hwang, Shih-Jen %A Ikram, M Arfan %A Indridason, Olafur S %A Ingelsson, Erik %A Ising, Marcus %A Jaddoe, Vincent W V %A Jakobsdottir, Johanna %A Jonas, Jost B %A Joshi, Peter K %A Josyula, Navya Shilpa %A Jung, Bettina %A Kähönen, Mika %A Kamatani, Yoichiro %A Kammerer, Candace M %A Kanai, Masahiro %A Kastarinen, Mika %A Kerr, Shona M %A Khor, Chiea-Chuen %A Kiess, Wieland %A Kleber, Marcus E %A Koenig, Wolfgang %A Kooner, Jaspal S %A Körner, Antje %A Kovacs, Peter %A Kraja, Aldi T %A Krajcoviechova, Alena %A Kramer, Holly %A Krämer, Bernhard K %A Kronenberg, Florian %A Kubo, Michiaki %A Kuhnel, Brigitte %A Kuokkanen, Mikko %A Kuusisto, Johanna %A La Bianca, Martina %A Laakso, Markku %A Lange, Leslie A %A Langefeld, Carl D %A Lee, Jeannette Jen-Mai %A Lehne, Benjamin %A Lehtimäki, Terho %A Lieb, Wolfgang %A Lim, Su-Chi %A Lind, Lars %A Lindgren, Cecilia M %A Liu, Jun %A Liu, Jianjun %A Loeffler, Markus %A Loos, Ruth J F %A Lucae, Susanne %A Lukas, Mary Ann %A Lyytikäinen, Leo-Pekka %A Mägi, Reedik %A Magnusson, Patrik K E %A Mahajan, Anubha %A Martin, Nicholas G %A Martins, Jade %A März, Winfried %A Mascalzoni, Deborah %A Matsuda, Koichi %A Meisinger, Christa %A Meitinger, Thomas %A Melander, Olle %A Metspalu, Andres %A Mikaelsdottir, Evgenia K %A Milaneschi, Yuri %A Miliku, Kozeta %A Mishra, Pashupati P %A Mohlke, Karen L %A Mononen, Nina %A Montgomery, Grant W %A Mook-Kanamori, Dennis O %A Mychaleckyj, Josyf C %A Nadkarni, Girish N %A Nalls, Mike A %A Nauck, Matthias %A Nikus, Kjell %A Ning, Boting %A Nolte, Ilja M %A Noordam, Raymond %A O'Connell, Jeffrey %A O'Donoghue, Michelle L %A Olafsson, Isleifur %A Oldehinkel, Albertine J %A Orho-Melander, Marju %A Ouwehand, Willem H %A Padmanabhan, Sandosh %A Palmer, Nicholette D %A Palsson, Runolfur %A Penninx, Brenda W J H %A Perls, Thomas %A Perola, Markus %A Pirastu, Mario %A Pirastu, Nicola %A Pistis, Giorgio %A Podgornaia, Anna I %A Polasek, Ozren %A Ponte, Belen %A Porteous, David J %A Poulain, Tanja %A Pramstaller, Peter P %A Preuss, Michael H %A Prins, Bram P %A Province, Michael A %A Rabelink, Ton J %A Raffield, Laura M %A Raitakari, Olli T %A Reilly, Dermot F %A Rettig, Rainer %A Rheinberger, Myriam %A Rice, Kenneth M %A Ridker, Paul M %A Rivadeneira, Fernando %A Rizzi, Federica %A Roberts, David J %A Robino, Antonietta %A Rossing, Peter %A Rudan, Igor %A Rueedi, Rico %A Ruggiero, Daniela %A Ryan, Kathleen A %A Saba, Yasaman %A Sabanayagam, Charumathi %A Salomaa, Veikko %A Salvi, Erika %A Saum, Kai-Uwe %A Schmidt, Helena %A Schmidt, Reinhold %A Schöttker, Ben %A Schulz, Christina-Alexandra %A Schupf, Nicole %A Shaffer, Christian M %A Shi, Yuan %A Smith, Albert V %A Smith, Blair H %A Soranzo, Nicole %A Spracklen, Cassandra N %A Strauch, Konstantin %A Stringham, Heather M %A Stumvoll, Michael %A Svensson, Per O %A Szymczak, Silke %A Tai, E-Shyong %A Tajuddin, Salman M %A Tan, Nicholas Y Q %A Taylor, Kent D %A Teren, Andrej %A Tham, Yih-Chung %A Thiery, Joachim %A Thio, Chris H L %A Thomsen, Hauke %A Thorleifsson, Gudmar %A Toniolo, Daniela %A Tönjes, Anke %A Tremblay, Johanne %A Tzoulaki, Ioanna %A Uitterlinden, André G %A Vaccargiu, Simona %A van Dam, Rob M %A van der Harst, Pim %A van Duijn, Cornelia M %A Velez Edward, Digna R %A Verweij, Niek %A Vogelezang, Suzanne %A Völker, Uwe %A Vollenweider, Peter %A Waeber, Gérard %A Waldenberger, Melanie %A Wallentin, Lars %A Wang, Ya Xing %A Wang, Chaolong %A Waterworth, Dawn M %A Bin Wei, Wen %A White, Harvey %A Whitfield, John B %A Wild, Sarah H %A Wilson, James F %A Wojczynski, Mary K %A Wong, Charlene %A Wong, Tien-Yin %A Xu, Liang %A Yang, Qiong %A Yasuda, Masayuki %A Yerges-Armstrong, Laura M %A Zhang, Weihua %A Zonderman, Alan B %A Rotter, Jerome I %A Bochud, Murielle %A Psaty, Bruce M %A Vitart, Veronique %A Wilson, James G %A Dehghan, Abbas %A Parsa, Afshin %A Chasman, Daniel I %A Ho, Kevin %A Morris, Andrew P %A Devuyst, Olivier %A Akilesh, Shreeram %A Pendergrass, Sarah A %A Sim, Xueling %A Böger, Carsten A %A Okada, Yukinori %A Edwards, Todd L %A Snieder, Harold %A Stefansson, Kari %A Hung, Adriana M %A Heid, Iris M %A Scholz, Markus %A Teumer, Alexander %A Köttgen, Anna %A Pattaro, Cristian %K Chromosome Mapping %K European Continental Ancestry Group %K Genetic Association Studies %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Glomerular Filtration Rate %K Humans %K Inheritance Patterns %K Kidney Function Tests %K Phenotype %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %K Quantitative Trait, Heritable %K Renal Insufficiency, Chronic %K Uromodulin %X

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

%B Nat Genet %V 51 %P 957-972 %8 2019 06 %G eng %N 6 %R 10.1038/s41588-019-0407-x %0 Journal Article %J Nat Genet %D 2019 %T Multi-ancestry genome-wide gene-smoking interaction study of 387,272 individuals identifies new loci associated with serum lipids. %A Bentley, Amy R %A Sung, Yun J %A Brown, Michael R %A Winkler, Thomas W %A Kraja, Aldi T %A Ntalla, Ioanna %A Schwander, Karen %A Chasman, Daniel I %A Lim, Elise %A Deng, Xuan %A Guo, Xiuqing %A Liu, Jingmin %A Lu, Yingchang %A Cheng, Ching-Yu %A Sim, Xueling %A Vojinovic, Dina %A Huffman, Jennifer E %A Musani, Solomon K %A Li, Changwei %A Feitosa, Mary F %A Richard, Melissa A %A Noordam, Raymond %A Baker, Jenna %A Chen, Guanjie %A Aschard, Hugues %A Bartz, Traci M %A Ding, Jingzhong %A Dorajoo, Rajkumar %A Manning, Alisa K %A Rankinen, Tuomo %A Smith, Albert V %A Tajuddin, Salman M %A Zhao, Wei %A Graff, Mariaelisa %A Alver, Maris %A Boissel, Mathilde %A Chai, Jin Fang %A Chen, Xu %A Divers, Jasmin %A Evangelou, Evangelos %A Gao, Chuan %A Goel, Anuj %A Hagemeijer, Yanick %A Harris, Sarah E %A Hartwig, Fernando P %A He, Meian %A Horimoto, Andrea R V R %A Hsu, Fang-Chi %A Hung, Yi-Jen %A Jackson, Anne U %A Kasturiratne, Anuradhani %A Komulainen, Pirjo %A Kuhnel, Brigitte %A Leander, Karin %A Lin, Keng-Hung %A Luan, Jian'an %A Lyytikäinen, Leo-Pekka %A Matoba, Nana %A Nolte, Ilja M %A Pietzner, Maik %A Prins, Bram %A Riaz, Muhammad %A Robino, Antonietta %A Said, M Abdullah %A Schupf, Nicole %A Scott, Robert A %A Sofer, Tamar %A Stančáková, Alena %A Takeuchi, Fumihiko %A Tayo, Bamidele O %A van der Most, Peter J %A Varga, Tibor V %A Wang, Tzung-Dau %A Wang, Yajuan %A Ware, Erin B %A Wen, Wanqing %A Xiang, Yong-Bing %A Yanek, Lisa R %A Zhang, Weihua %A Zhao, Jing Hua %A Adeyemo, Adebowale %A Afaq, Saima %A Amin, Najaf %A Amini, Marzyeh %A Arking, Dan E %A Arzumanyan, Zorayr %A Aung, Tin %A Ballantyne, Christie %A Barr, R Graham %A Bielak, Lawrence F %A Boerwinkle, Eric %A Bottinger, Erwin P %A Broeckel, Ulrich %A Brown, Morris %A Cade, Brian E %A Campbell, Archie %A Canouil, Mickaël %A Charumathi, Sabanayagam %A Chen, Yii-Der Ida %A Christensen, Kaare %A Concas, Maria Pina %A Connell, John M %A de Las Fuentes, Lisa %A de Silva, H Janaka %A de Vries, Paul S %A Doumatey, Ayo %A Duan, Qing %A Eaton, Charles B %A Eppinga, Ruben N %A Faul, Jessica D %A Floyd, James S %A Forouhi, Nita G %A Forrester, Terrence %A Friedlander, Yechiel %A Gandin, Ilaria %A Gao, He %A Ghanbari, Mohsen %A Gharib, Sina A %A Gigante, Bruna %A Giulianini, Franco %A Grabe, Hans J %A Gu, C Charles %A Harris, Tamara B %A Heikkinen, Sami %A Heng, Chew-Kiat %A Hirata, Makoto %A Hixson, James E %A Ikram, M Arfan %A Jia, Yucheng %A Joehanes, Roby %A Johnson, Craig %A Jonas, Jost Bruno %A Justice, Anne E %A Katsuya, Tomohiro %A Khor, Chiea Chuen %A Kilpeläinen, Tuomas O %A Koh, Woon-Puay %A Kolcic, Ivana %A Kooperberg, Charles %A Krieger, Jose E %A Kritchevsky, Stephen B %A Kubo, Michiaki %A Kuusisto, Johanna %A Lakka, Timo A %A Langefeld, Carl D %A Langenberg, Claudia %A Launer, Lenore J %A Lehne, Benjamin %A Lewis, Cora E %A Li, Yize %A Liang, Jingjing %A Lin, Shiow %A Liu, Ching-Ti %A Liu, Jianjun %A Liu, Kiang %A Loh, Marie %A Lohman, Kurt K %A Louie, Tin %A Luzzi, Anna %A Mägi, Reedik %A Mahajan, Anubha %A Manichaikul, Ani W %A McKenzie, Colin A %A Meitinger, Thomas %A Metspalu, Andres %A Milaneschi, Yuri %A Milani, Lili %A Mohlke, Karen L %A Momozawa, Yukihide %A Morris, Andrew P %A Murray, Alison D %A Nalls, Mike A %A Nauck, Matthias %A Nelson, Christopher P %A North, Kari E %A O'Connell, Jeffrey R %A Palmer, Nicholette D %A Papanicolau, George J %A Pedersen, Nancy L %A Peters, Annette %A Peyser, Patricia A %A Polasek, Ozren %A Poulter, Neil %A Raitakari, Olli T %A Reiner, Alex P %A Renstrom, Frida %A Rice, Treva K %A Rich, Stephen S %A Robinson, Jennifer G %A Rose, Lynda M %A Rosendaal, Frits R %A Rudan, Igor %A Schmidt, Carsten O %A Schreiner, Pamela J %A Scott, William R %A Sever, Peter %A Shi, Yuan %A Sidney, Stephen %A Sims, Mario %A Smith, Jennifer A %A Snieder, Harold %A Starr, John M %A Strauch, Konstantin %A Stringham, Heather M %A Tan, Nicholas Y Q %A Tang, Hua %A Taylor, Kent D %A Teo, Yik Ying %A Tham, Yih Chung %A Tiemeier, Henning %A Turner, Stephen T %A Uitterlinden, André G %A van Heemst, Diana %A Waldenberger, Melanie %A Wang, Heming %A Wang, Lan %A Wang, Lihua %A Wei, Wen Bin %A Williams, Christine A %A Wilson, Gregory %A Wojczynski, Mary K %A Yao, Jie %A Young, Kristin %A Yu, Caizheng %A Yuan, Jian-Min %A Zhou, Jie %A Zonderman, Alan B %A Becker, Diane M %A Boehnke, Michael %A Bowden, Donald W %A Chambers, John C %A Cooper, Richard S %A de Faire, Ulf %A Deary, Ian J %A Elliott, Paul %A Esko, Tõnu %A Farrall, Martin %A Franks, Paul W %A Freedman, Barry I %A Froguel, Philippe %A Gasparini, Paolo %A Gieger, Christian %A Horta, Bernardo L %A Juang, Jyh-Ming Jimmy %A Kamatani, Yoichiro %A Kammerer, Candace M %A Kato, Norihiro %A Kooner, Jaspal S %A Laakso, Markku %A Laurie, Cathy C %A Lee, I-Te %A Lehtimäki, Terho %A Magnusson, Patrik K E %A Oldehinkel, Albertine J %A Penninx, Brenda W J H %A Pereira, Alexandre C %A Rauramaa, Rainer %A Redline, Susan %A Samani, Nilesh J %A Scott, James %A Shu, Xiao-Ou %A van der Harst, Pim %A Wagenknecht, Lynne E %A Wang, Jun-Sing %A Wang, Ya Xing %A Wareham, Nicholas J %A Watkins, Hugh %A Weir, David R %A Wickremasinghe, Ananda R %A Wu, Tangchun %A Zeggini, Eleftheria %A Zheng, Wei %A Bouchard, Claude %A Evans, Michele K %A Gudnason, Vilmundur %A Kardia, Sharon L R %A Liu, Yongmei %A Psaty, Bruce M %A Ridker, Paul M %A van Dam, Rob M %A Mook-Kanamori, Dennis O %A Fornage, Myriam %A Province, Michael A %A Kelly, Tanika N %A Fox, Ervin R %A Hayward, Caroline %A van Duijn, Cornelia M %A Tai, E Shyong %A Wong, Tien Yin %A Loos, Ruth J F %A Franceschini, Nora %A Rotter, Jerome I %A Zhu, Xiaofeng %A Bierut, Laura J %A Gauderman, W James %A Rice, Kenneth %A Munroe, Patricia B %A Morrison, Alanna C %A Rao, Dabeeru C %A Rotimi, Charles N %A Cupples, L Adrienne %X

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

%B Nat Genet %V 51 %P 636-648 %8 2019 Apr %G eng %N 4 %R 10.1038/s41588-019-0378-y %0 Journal Article %J Nat Genet %D 2019 %T Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels. %A Tin, Adrienne %A Marten, Jonathan %A Halperin Kuhns, Victoria L %A Li, Yong %A Wuttke, Matthias %A Kirsten, Holger %A Sieber, Karsten B %A Qiu, Chengxiang %A Gorski, Mathias %A Yu, Zhi %A Giri, Ayush %A Sveinbjornsson, Gardar %A Li, Man %A Chu, Audrey Y %A Hoppmann, Anselm %A O'Connor, Luke J %A Prins, Bram %A Nutile, Teresa %A Noce, Damia %A Akiyama, Masato %A Cocca, Massimiliano %A Ghasemi, Sahar %A van der Most, Peter J %A Horn, Katrin %A Xu, Yizhe %A Fuchsberger, Christian %A Sedaghat, Sanaz %A Afaq, Saima %A Amin, Najaf %A Arnlöv, Johan %A Bakker, Stephan J L %A Bansal, Nisha %A Baptista, Daniela %A Bergmann, Sven %A Biggs, Mary L %A Biino, Ginevra %A Boerwinkle, Eric %A Bottinger, Erwin P %A Boutin, Thibaud S %A Brumat, Marco %A Burkhardt, Ralph %A Campana, Eric %A Campbell, Archie %A Campbell, Harry %A Carroll, Robert J %A Catamo, Eulalia %A Chambers, John C %A Ciullo, Marina %A Concas, Maria Pina %A Coresh, Josef %A Corre, Tanguy %A Cusi, Daniele %A Felicita, Sala Cinzia %A de Borst, Martin H %A De Grandi, Alessandro %A de Mutsert, Renée %A de Vries, Aiko P J %A Delgado, Graciela %A Demirkan, Ayse %A Devuyst, Olivier %A Dittrich, Katalin %A Eckardt, Kai-Uwe %A Ehret, Georg %A Endlich, Karlhans %A Evans, Michele K %A Gansevoort, Ron T %A Gasparini, Paolo %A Giedraitis, Vilmantas %A Gieger, Christian %A Girotto, Giorgia %A Gögele, Martin %A Gordon, Scott D %A Gudbjartsson, Daniel F %A Gudnason, Vilmundur %A Haller, Toomas %A Hamet, Pavel %A Harris, Tamara B %A Hayward, Caroline %A Hicks, Andrew A %A Hofer, Edith %A Holm, Hilma %A Huang, Wei %A Hutri-Kähönen, Nina %A Hwang, Shih-Jen %A Ikram, M Arfan %A Lewis, Raychel M %A Ingelsson, Erik %A Jakobsdottir, Johanna %A Jonsdottir, Ingileif %A Jonsson, Helgi %A Joshi, Peter K %A Josyula, Navya Shilpa %A Jung, Bettina %A Kähönen, Mika %A Kamatani, Yoichiro %A Kanai, Masahiro %A Kerr, Shona M %A Kiess, Wieland %A Kleber, Marcus E %A Koenig, Wolfgang %A Kooner, Jaspal S %A Körner, Antje %A Kovacs, Peter %A Krämer, Bernhard K %A Kronenberg, Florian %A Kubo, Michiaki %A Kuhnel, Brigitte %A La Bianca, Martina %A Lange, Leslie A %A Lehne, Benjamin %A Lehtimäki, Terho %A Liu, Jun %A Loeffler, Markus %A Loos, Ruth J F %A Lyytikäinen, Leo-Pekka %A Mägi, Reedik %A Mahajan, Anubha %A Martin, Nicholas G %A März, Winfried %A Mascalzoni, Deborah %A Matsuda, Koichi %A Meisinger, Christa %A Meitinger, Thomas %A Metspalu, Andres %A Milaneschi, Yuri %A O'Donnell, Christopher J %A Wilson, Otis D %A Gaziano, J Michael %A Mishra, Pashupati P %A Mohlke, Karen L %A Mononen, Nina %A Montgomery, Grant W %A Mook-Kanamori, Dennis O %A Müller-Nurasyid, Martina %A Nadkarni, Girish N %A Nalls, Mike A %A Nauck, Matthias %A Nikus, Kjell %A Ning, Boting %A Nolte, Ilja M %A Noordam, Raymond %A O'Connell, Jeffrey R %A Olafsson, Isleifur %A Padmanabhan, Sandosh %A Penninx, Brenda W J H %A Perls, Thomas %A Peters, Annette %A Pirastu, Mario %A Pirastu, Nicola %A Pistis, Giorgio %A Polasek, Ozren %A Ponte, Belen %A Porteous, David J %A Poulain, Tanja %A Preuss, Michael H %A Rabelink, Ton J %A Raffield, Laura M %A Raitakari, Olli T %A Rettig, Rainer %A Rheinberger, Myriam %A Rice, Kenneth M %A Rizzi, Federica %A Robino, Antonietta %A Rudan, Igor %A Krajcoviechova, Alena %A Cifkova, Renata %A Rueedi, Rico %A Ruggiero, Daniela %A Ryan, Kathleen A %A Saba, Yasaman %A Salvi, Erika %A Schmidt, Helena %A Schmidt, Reinhold %A Shaffer, Christian M %A Smith, Albert V %A Smith, Blair H %A Spracklen, Cassandra N %A Strauch, Konstantin %A Stumvoll, Michael %A Sulem, Patrick %A Tajuddin, Salman M %A Teren, Andrej %A Thiery, Joachim %A Thio, Chris H L %A Thorsteinsdottir, Unnur %A Toniolo, Daniela %A Tönjes, Anke %A Tremblay, Johanne %A Uitterlinden, André G %A Vaccargiu, Simona %A van der Harst, Pim %A van Duijn, Cornelia M %A Verweij, Niek %A Völker, Uwe %A Vollenweider, Peter %A Waeber, Gérard %A Waldenberger, Melanie %A Whitfield, John B %A Wild, Sarah H %A Wilson, James F %A Yang, Qiong %A Zhang, Weihua %A Zonderman, Alan B %A Bochud, Murielle %A Wilson, James G %A Pendergrass, Sarah A %A Ho, Kevin %A Parsa, Afshin %A Pramstaller, Peter P %A Psaty, Bruce M %A Böger, Carsten A %A Snieder, Harold %A Butterworth, Adam S %A Okada, Yukinori %A Edwards, Todd L %A Stefansson, Kari %A Susztak, Katalin %A Scholz, Markus %A Heid, Iris M %A Hung, Adriana M %A Teumer, Alexander %A Pattaro, Cristian %A Woodward, Owen M %A Vitart, Veronique %A Köttgen, Anna %X

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

%B Nat Genet %V 51 %P 1459-1474 %8 2019 Oct %G eng %N 10 %R 10.1038/s41588-019-0504-x %0 Journal Article %J Kidney Int %D 2020 %T Meta-analysis uncovers genome-wide significant variants for rapid kidney function decline. %A Gorski, Mathias %A Jung, Bettina %A Li, Yong %A Matias-Garcia, Pamela R %A Wuttke, Matthias %A Coassin, Stefan %A Thio, Chris H L %A Kleber, Marcus E %A Winkler, Thomas W %A Wanner, Veronika %A Chai, Jin-Fang %A Chu, Audrey Y %A Cocca, Massimiliano %A Feitosa, Mary F %A Ghasemi, Sahar %A Hoppmann, Anselm %A Horn, Katrin %A Li, Man %A Nutile, Teresa %A Scholz, Markus %A Sieber, Karsten B %A Teumer, Alexander %A Tin, Adrienne %A Wang, Judy %A Tayo, Bamidele O %A Ahluwalia, Tarunveer S %A Almgren, Peter %A Bakker, Stephan J L %A Banas, Bernhard %A Bansal, Nisha %A Biggs, Mary L %A Boerwinkle, Eric %A Bottinger, Erwin P %A Brenner, Hermann %A Carroll, Robert J %A Chalmers, John %A Chee, Miao-Li %A Chee, Miao-Ling %A Cheng, Ching-Yu %A Coresh, Josef %A de Borst, Martin H %A Degenhardt, Frauke %A Eckardt, Kai-Uwe %A Endlich, Karlhans %A Franke, Andre %A Freitag-Wolf, Sandra %A Gampawar, Piyush %A Gansevoort, Ron T %A Ghanbari, Mohsen %A Gieger, Christian %A Hamet, Pavel %A Ho, Kevin %A Hofer, Edith %A Holleczek, Bernd %A Xian Foo, Valencia Hui %A Hutri-Kähönen, Nina %A Hwang, Shih-Jen %A Ikram, M Arfan %A Josyula, Navya Shilpa %A Kähönen, Mika %A Khor, Chiea-Chuen %A Koenig, Wolfgang %A Kramer, Holly %A Krämer, Bernhard K %A Kuhnel, Brigitte %A Lange, Leslie A %A Lehtimäki, Terho %A Lieb, Wolfgang %A Loos, Ruth J F %A Lukas, Mary Ann %A Lyytikäinen, Leo-Pekka %A Meisinger, Christa %A Meitinger, Thomas %A Melander, Olle %A Milaneschi, Yuri %A Mishra, Pashupati P %A Mononen, Nina %A Mychaleckyj, Josyf C %A Nadkarni, Girish N %A Nauck, Matthias %A Nikus, Kjell %A Ning, Boting %A Nolte, Ilja M %A O'Donoghue, Michelle L %A Orho-Melander, Marju %A Pendergrass, Sarah A %A Penninx, Brenda W J H %A Preuss, Michael H %A Psaty, Bruce M %A Raffield, Laura M %A Raitakari, Olli T %A Rettig, Rainer %A Rheinberger, Myriam %A Rice, Kenneth M %A Rosenkranz, Alexander R %A Rossing, Peter %A Rotter, Jerome I %A Sabanayagam, Charumathi %A Schmidt, Helena %A Schmidt, Reinhold %A Schöttker, Ben %A Schulz, Christina-Alexandra %A Sedaghat, Sanaz %A Shaffer, Christian M %A Strauch, Konstantin %A Szymczak, Silke %A Taylor, Kent D %A Tremblay, Johanne %A Chaker, Layal %A van der Harst, Pim %A van der Most, Peter J %A Verweij, Niek %A Völker, Uwe %A Waldenberger, Melanie %A Wallentin, Lars %A Waterworth, Dawn M %A White, Harvey D %A Wilson, James G %A Wong, Tien-Yin %A Woodward, Mark %A Yang, Qiong %A Yasuda, Masayuki %A Yerges-Armstrong, Laura M %A Zhang, Yan %A Snieder, Harold %A Wanner, Christoph %A Böger, Carsten A %A Köttgen, Anna %A Kronenberg, Florian %A Pattaro, Cristian %A Heid, Iris M %X

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

%B Kidney Int %8 2020 Oct 30 %G eng %R 10.1016/j.kint.2020.09.030 %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 Cell %D 2020 %T The Polygenic and Monogenic Basis of Blood Traits and Diseases. %A Vuckovic, Dragana %A Bao, Erik L %A Akbari, Parsa %A Lareau, Caleb A %A Mousas, Abdou %A Jiang, Tao %A Chen, Ming-Huei %A Raffield, Laura M %A Tardaguila, Manuel %A Huffman, Jennifer E %A Ritchie, Scott C %A Megy, Karyn %A Ponstingl, Hannes %A Penkett, Christopher J %A Albers, Patrick K %A Wigdor, Emilie M %A Sakaue, Saori %A Moscati, Arden %A Manansala, Regina %A Lo, Ken Sin %A Qian, Huijun %A Akiyama, Masato %A Bartz, Traci M %A Ben-Shlomo, Yoav %A Beswick, Andrew %A Bork-Jensen, Jette %A Bottinger, Erwin P %A Brody, Jennifer A %A van Rooij, Frank J A %A Chitrala, Kumaraswamy N %A Wilson, Peter W F %A Choquet, Helene %A Danesh, John %A Di Angelantonio, Emanuele %A Dimou, Niki %A Ding, Jingzhong %A Elliott, Paul %A Esko, Tõnu %A Evans, Michele K %A Felix, Stephan B %A Floyd, James S %A Broer, Linda %A Grarup, Niels %A Guo, Michael H %A Guo, Qi %A Greinacher, Andreas %A Haessler, Jeff %A Hansen, Torben %A Howson, Joanna M M %A Huang, Wei %A Jorgenson, Eric %A Kacprowski, Tim %A Kähönen, Mika %A Kamatani, Yoichiro %A Kanai, Masahiro %A Karthikeyan, Savita %A Koskeridis, Fotios %A Lange, Leslie A %A Lehtimäki, Terho %A Linneberg, Allan %A Liu, Yongmei %A Lyytikäinen, Leo-Pekka %A Manichaikul, Ani %A Matsuda, Koichi %A Mohlke, Karen L %A Mononen, Nina %A Murakami, Yoshinori %A Nadkarni, Girish N %A Nikus, Kjell %A Pankratz, Nathan %A Pedersen, Oluf %A Preuss, Michael %A Psaty, Bruce M %A Raitakari, Olli T %A Rich, Stephen S %A Rodriguez, Benjamin A T %A Rosen, Jonathan D %A Rotter, Jerome I %A Schubert, Petra %A Spracklen, Cassandra N %A Surendran, Praveen %A Tang, Hua %A Tardif, Jean-Claude %A Ghanbari, Mohsen %A Völker, Uwe %A Völzke, Henry %A Watkins, Nicholas A %A Weiss, Stefan %A Cai, Na %A Kundu, Kousik %A Watt, Stephen B %A Walter, Klaudia %A Zonderman, Alan B %A Cho, Kelly %A Li, Yun %A Loos, Ruth J F %A Knight, Julian C %A Georges, Michel %A Stegle, Oliver %A Evangelou, Evangelos %A Okada, Yukinori %A Roberts, David J %A Inouye, Michael %A Johnson, Andrew D %A Auer, Paul L %A Astle, William J %A Reiner, Alexander P %A Butterworth, Adam S %A Ouwehand, Willem H %A Lettre, Guillaume %A Sankaran, Vijay G %A Soranzo, Nicole %X

Blood cells play essential roles in human health, underpinning physiological processes such as immunity, oxygen transport, and clotting, which when perturbed cause a significant global health burden. Here we integrate data from UK Biobank and a large-scale international collaborative effort, including data for 563,085 European ancestry participants, and discover 5,106 new genetic variants independently associated with 29 blood cell phenotypes covering a range of variation impacting hematopoiesis. We holistically characterize the genetic architecture of hematopoiesis, assess the relevance of the omnigenic model to blood cell phenotypes, delineate relevant hematopoietic cell states influenced by regulatory genetic variants and gene networks, identify novel splice-altering variants mediating the associations, and assess the polygenic prediction potential for blood traits and clinical disorders at the interface of complex and Mendelian genetics. These results show the power of large-scale blood cell trait GWAS to interrogate clinically meaningful variants across a wide allelic spectrum of human variation.

%B Cell %V 182 %P 1214-1231.e11 %8 2020 Sep 03 %G eng %N 5 %R 10.1016/j.cell.2020.08.008 %0 Journal Article %J Cell %D 2020 %T Trans-ethnic and Ancestry-Specific Blood-Cell Genetics in 746,667 Individuals from 5 Global Populations. %A Chen, Ming-Huei %A Raffield, Laura M %A Mousas, Abdou %A Sakaue, Saori %A Huffman, Jennifer E %A Moscati, Arden %A Trivedi, Bhavi %A Jiang, Tao %A Akbari, Parsa %A Vuckovic, Dragana %A Bao, Erik L %A Zhong, Xue %A Manansala, Regina %A Laplante, Véronique %A Chen, Minhui %A Lo, Ken Sin %A Qian, Huijun %A Lareau, Caleb A %A Beaudoin, Mélissa %A Hunt, Karen A %A Akiyama, Masato %A Bartz, Traci M %A Ben-Shlomo, Yoav %A Beswick, Andrew %A Bork-Jensen, Jette %A Bottinger, Erwin P %A Brody, Jennifer A %A van Rooij, Frank J A %A Chitrala, Kumaraswamynaidu %A Cho, Kelly %A Choquet, Helene %A Correa, Adolfo %A Danesh, John %A Di Angelantonio, Emanuele %A Dimou, Niki %A Ding, Jingzhong %A Elliott, Paul %A Esko, Tõnu %A Evans, Michele K %A Floyd, James S %A Broer, Linda %A Grarup, Niels %A Guo, Michael H %A Greinacher, Andreas %A Haessler, Jeff %A Hansen, Torben %A Howson, Joanna M M %A Huang, Qin Qin %A Huang, Wei %A Jorgenson, Eric %A Kacprowski, Tim %A Kähönen, Mika %A Kamatani, Yoichiro %A Kanai, Masahiro %A Karthikeyan, Savita %A Koskeridis, Fotis %A Lange, Leslie A %A Lehtimäki, Terho %A Lerch, Markus M %A Linneberg, Allan %A Liu, Yongmei %A Lyytikäinen, Leo-Pekka %A Manichaikul, Ani %A Martin, Hilary C %A Matsuda, Koichi %A Mohlke, Karen L %A Mononen, Nina %A Murakami, Yoshinori %A Nadkarni, Girish N %A Nauck, Matthias %A Nikus, Kjell %A Ouwehand, Willem H %A Pankratz, Nathan %A Pedersen, Oluf %A Preuss, Michael %A Psaty, Bruce M %A Raitakari, Olli T %A Roberts, David J %A Rich, Stephen S %A Rodriguez, Benjamin A T %A Rosen, Jonathan D %A Rotter, Jerome I %A Schubert, Petra %A Spracklen, Cassandra N %A Surendran, Praveen %A Tang, Hua %A Tardif, Jean-Claude %A Trembath, Richard C %A Ghanbari, Mohsen %A Völker, Uwe %A Völzke, Henry %A Watkins, Nicholas A %A Zonderman, Alan B %A Wilson, Peter W F %A Li, Yun %A Butterworth, Adam S %A Gauchat, Jean-François %A Chiang, Charleston W K %A Li, Bingshan %A Loos, Ruth J F %A Astle, William J %A Evangelou, Evangelos %A van Heel, David A %A Sankaran, Vijay G %A Okada, Yukinori %A Soranzo, Nicole %A Johnson, Andrew D %A Reiner, Alexander P %A Auer, Paul L %A Lettre, Guillaume %X

Most loci identified by GWASs have been found in populations of European ancestry (EUR). In trans-ethnic meta-analyses for 15 hematological traits in 746,667 participants, including 184,535 non-EUR individuals, we identified 5,552 trait-variant associations at p < 5 × 10, including 71 novel associations not found in EUR populations. We also identified 28 additional novel variants in ancestry-specific, non-EUR meta-analyses, including an IL7 missense variant in South Asians associated with lymphocyte count in vivo and IL-7 secretion levels in vitro. Fine-mapping prioritized variants annotated as functional and generated 95% credible sets that were 30% smaller when using the trans-ethnic as opposed to the EUR-only results. We explored the clinical significance and predictive value of trans-ethnic variants in multiple populations and compared genetic architecture and the effect of natural selection on these blood phenotypes between populations. Altogether, our results for hematological traits highlight the value of a more global representation of populations in genetic studies.

%B Cell %V 182 %P 1198-1213.e14 %8 2020 Sep 03 %G eng %N 5 %R 10.1016/j.cell.2020.06.045 %0 Journal Article %J Am J Hum Genet %D 2021 %T Discovery and fine-mapping of height loci via high-density imputation of GWASs in individuals of African ancestry. %A Graff, Mariaelisa %A Justice, Anne E %A Young, Kristin L %A Marouli, Eirini %A Zhang, Xinruo %A Fine, Rebecca S %A Lim, Elise %A Buchanan, Victoria %A Rand, Kristin %A Feitosa, Mary F %A Wojczynski, Mary K %A Yanek, Lisa R %A Shao, Yaming %A Rohde, Rebecca %A Adeyemo, Adebowale A %A Aldrich, Melinda C %A Allison, Matthew A %A Ambrosone, Christine B %A Ambs, Stefan %A Amos, Christopher %A Arnett, Donna K %A Atwood, Larry %A Bandera, Elisa V %A Bartz, Traci %A Becker, Diane M %A Berndt, Sonja I %A Bernstein, Leslie %A Bielak, Lawrence F %A Blot, William J %A Bottinger, Erwin P %A Bowden, Donald W %A Bradfield, Jonathan P %A Brody, Jennifer A %A Broeckel, Ulrich %A Burke, Gregory %A Cade, Brian E %A Cai, Qiuyin %A Caporaso, Neil %A Carlson, Chris %A Carpten, John %A Casey, Graham %A Chanock, Stephen J %A Chen, Guanjie %A Chen, Minhui %A Chen, Yii-der I %A Chen, Wei-Min %A Chesi, Alessandra %A Chiang, Charleston W K %A Chu, Lisa %A Coetzee, Gerry A %A Conti, David V %A Cooper, Richard S %A Cushman, Mary %A Demerath, Ellen %A Deming, Sandra L %A Dimitrov, Latchezar %A Ding, Jingzhong %A Diver, W Ryan %A Duan, Qing %A Evans, Michele K %A Falusi, Adeyinka G %A Faul, Jessica D %A Fornage, Myriam %A Fox, Caroline %A Freedman, Barry I %A Garcia, Melissa %A Gillanders, Elizabeth M %A Goodman, Phyllis %A Gottesman, Omri %A Grant, Struan F A %A Guo, Xiuqing %A Hakonarson, Hakon %A Haritunians, Talin %A Harris, Tamara B %A Harris, Curtis C %A Henderson, Brian E %A Hennis, Anselm %A Hernandez, Dena G %A Hirschhorn, Joel N %A McNeill, Lorna Haughton %A Howard, Timothy D %A Howard, Barbara %A Hsing, Ann W %A Hsu, Yu-Han H %A Hu, Jennifer J %A Huff, Chad D %A Huo, Dezheng %A Ingles, Sue A %A Irvin, Marguerite R %A John, Esther M %A Johnson, Karen C %A Jordan, Joanne M %A Kabagambe, Edmond K %A Kang, Sun J %A Kardia, Sharon L %A Keating, Brendan J %A Kittles, Rick A %A Klein, Eric A %A Kolb, Suzanne %A Kolonel, Laurence N %A Kooperberg, Charles %A Kuller, Lewis %A Kutlar, Abdullah %A Lange, Leslie %A Langefeld, Carl D %A Le Marchand, Loïc %A Leonard, Hampton %A Lettre, Guillaume %A Levin, Albert M %A Li, Yun %A Li, Jin %A Liu, Yongmei %A Liu, Youfang %A Liu, Simin %A Lohman, Kurt %A Lotay, Vaneet %A Lu, Yingchang %A Maixner, William %A Manson, JoAnn E %A McKnight, Barbara %A Meng, Yan %A Monda, Keri L %A Monroe, Kris %A Moore, Jason H %A Mosley, Thomas H %A Mudgal, Poorva %A Murphy, Adam B %A Nadukuru, Rajiv %A Nalls, Mike A %A Nathanson, Katherine L %A Nayak, Uma %A N'diaye, Amidou %A Nemesure, Barbara %A Neslund-Dudas, Christine %A Neuhouser, Marian L %A Nyante, Sarah %A Ochs-Balcom, Heather %A Ogundiran, Temidayo O %A Ogunniyi, Adesola %A Ojengbede, Oladosu %A Okut, Hayrettin %A Olopade, Olufunmilayo I %A Olshan, Andrew %A Padhukasahasram, Badri %A Palmer, Julie %A Palmer, Cameron D %A Palmer, Nicholette D %A Papanicolaou, George %A Patel, Sanjay R %A Pettaway, Curtis A %A Peyser, Patricia A %A Press, Michael F %A Rao, D C %A Rasmussen-Torvik, Laura J %A Redline, Susan %A Reiner, Alex P %A Rhie, Suhn K %A Rodriguez-Gil, Jorge L %A Rotimi, Charles N %A Rotter, Jerome I %A Ruiz-Narvaez, Edward A %A Rybicki, Benjamin A %A Salako, Babatunde %A Sale, Michèle M %A Sanderson, Maureen %A Schadt, Eric %A Schreiner, Pamela J %A Schurmann, Claudia %A Schwartz, Ann G %A Shriner, Daniel A %A Signorello, Lisa B %A Singleton, Andrew B %A Siscovick, David S %A Smith, Jennifer A %A Smith, Shad %A Speliotes, Elizabeth %A Spitz, Margaret %A Stanford, Janet L %A Stevens, Victoria L %A Stram, Alex %A Strom, Sara S %A Sucheston, Lara %A Sun, Yan V %A Tajuddin, Salman M %A Taylor, Herman %A Taylor, Kira %A Tayo, Bamidele O %A Thun, Michael J %A Tucker, Margaret A %A Vaidya, Dhananjay %A Van Den Berg, David J %A Vedantam, Sailaja %A Vitolins, Mara %A Wang, Zhaoming %A Ware, Erin B %A Wassertheil-Smoller, Sylvia %A Weir, David R %A Wiencke, John K %A Williams, Scott M %A Williams, L Keoki %A Wilson, James G %A Witte, John S %A Wrensch, Margaret %A Wu, Xifeng %A Yao, Jie %A Zakai, Neil %A Zanetti, Krista %A Zemel, Babette S %A Zhao, Wei %A Zhao, Jing Hua %A Zheng, Wei %A Zhi, Degui %A Zhou, Jie %A Zhu, Xiaofeng %A Ziegler, Regina G %A Zmuda, Joe %A Zonderman, Alan B %A Psaty, Bruce M %A Borecki, Ingrid B %A Cupples, L Adrienne %A Liu, Ching-Ti %A Haiman, Christopher A %A Loos, Ruth %A Ng, Maggie C Y %A North, Kari E %X

Although many loci have been associated with height in European ancestry populations, very few have been identified in African ancestry individuals. Furthermore, many of the known loci have yet to be generalized to and fine-mapped within a large-scale African ancestry sample. We performed sex-combined and sex-stratified meta-analyses in up to 52,764 individuals with height and genome-wide genotyping data from the African Ancestry Anthropometry Genetics Consortium (AAAGC). We additionally combined our African ancestry meta-analysis results with published European genome-wide association study (GWAS) data. In the African ancestry analyses, we identified three novel loci (SLC4A3, NCOA2, ECD/FAM149B1) in sex-combined results and two loci (CRB1, KLF6) in women only. In the African plus European sex-combined GWAS, we identified an additional three novel loci (RCCD1, G6PC3, CEP95) which were equally driven by AAAGC and European results. Among 39 genome-wide significant signals at known loci, conditioning index SNPs from European studies identified 20 secondary signals. Two of the 20 new secondary signals and none of the 8 novel loci had minor allele frequencies (MAF) < 5%. Of 802 known European height signals, 643 displayed directionally consistent associations with height, of which 205 were nominally significant (p < 0.05) in the African ancestry sex-combined sample. Furthermore, 148 of 241 loci contained ≤20 variants in the credible sets that jointly account for 99% of the posterior probability of driving the associations. In summary, trans-ethnic meta-analyses revealed novel signals and further improved fine-mapping of putative causal variants in loci shared between African and European ancestry populations.

%B Am J Hum Genet %V 108 %P 564-582 %8 2021 Apr 01 %G eng %N 4 %R 10.1016/j.ajhg.2021.02.011 %0 Journal Article %J Commun Biol %D 2022 %T Differential and shared genetic effects on kidney function between diabetic and non-diabetic individuals. %A Winkler, Thomas W %A Rasheed, Humaira %A Teumer, Alexander %A Gorski, Mathias %A Rowan, Bryce X %A Stanzick, Kira J %A Thomas, Laurent F %A Tin, Adrienne %A Hoppmann, Anselm %A Chu, Audrey Y %A Tayo, Bamidele %A Thio, Chris H L %A Cusi, Daniele %A Chai, Jin-Fang %A Sieber, Karsten B %A Horn, Katrin %A Li, Man %A Scholz, Markus %A Cocca, Massimiliano %A Wuttke, Matthias %A van der Most, Peter J %A Yang, Qiong %A Ghasemi, Sahar %A Nutile, Teresa %A Li, Yong %A Pontali, Giulia %A Günther, Felix %A Dehghan, Abbas %A Correa, Adolfo %A Parsa, Afshin %A Feresin, Agnese %A de Vries, Aiko P J %A Zonderman, Alan B %A Smith, Albert V %A Oldehinkel, Albertine J %A De Grandi, Alessandro %A Rosenkranz, Alexander R %A Franke, Andre %A Teren, Andrej %A Metspalu, Andres %A Hicks, Andrew A %A Morris, Andrew P %A Tönjes, Anke %A Morgan, Anna %A Podgornaia, Anna I %A Peters, Annette %A Körner, Antje %A Mahajan, Anubha %A Campbell, Archie %A Freedman, Barry I %A Spedicati, Beatrice %A Ponte, Belen %A Schöttker, Ben %A Brumpton, Ben %A Banas, Bernhard %A Krämer, Bernhard K %A Jung, Bettina %A Åsvold, Bjørn Olav %A Smith, Blair H %A Ning, Boting %A Penninx, Brenda W J H %A Vanderwerff, Brett R %A Psaty, Bruce M %A Kammerer, Candace M %A Langefeld, Carl D %A Hayward, Caroline %A Spracklen, Cassandra N %A Robinson-Cohen, Cassianne %A Hartman, Catharina A %A Lindgren, Cecilia M %A Wang, Chaolong %A Sabanayagam, Charumathi %A Heng, Chew-Kiat %A Lanzani, Chiara %A Khor, Chiea-Chuen %A Cheng, Ching-Yu %A Fuchsberger, Christian %A Gieger, Christian %A Shaffer, Christian M %A Schulz, Christina-Alexandra %A Willer, Cristen J %A Chasman, Daniel I %A Gudbjartsson, Daniel F %A Ruggiero, Daniela %A Toniolo, Daniela %A Czamara, Darina %A Porteous, David J %A Waterworth, Dawn M %A Mascalzoni, Deborah %A Mook-Kanamori, Dennis O %A Reilly, Dermot F %A Daw, E Warwick %A Hofer, Edith %A Boerwinkle, Eric %A Salvi, Erika %A Bottinger, Erwin P %A Tai, E-Shyong %A Catamo, Eulalia %A Rizzi, Federica %A Guo, Feng %A Rivadeneira, Fernando %A Guilianini, Franco %A Sveinbjornsson, Gardar %A Ehret, Georg %A Waeber, Gérard %A Biino, Ginevra %A Girotto, Giorgia %A Pistis, Giorgio %A Nadkarni, Girish N %A Delgado, Graciela E %A Montgomery, Grant W %A Snieder, Harold %A Campbell, Harry %A White, Harvey D %A Gao, He %A Stringham, Heather M %A Schmidt, Helena %A Li, Hengtong %A Brenner, Hermann %A Holm, Hilma %A Kirsten, Holgen %A Kramer, Holly %A Rudan, Igor %A Nolte, Ilja M %A Tzoulaki, Ioanna %A Olafsson, Isleifur %A Martins, Jade %A Cook, James P %A Wilson, James F %A Halbritter, Jan %A Felix, Janine F %A Divers, Jasmin %A Kooner, Jaspal S %A Lee, Jeannette Jen-Mai %A O'Connell, Jeffrey %A Rotter, Jerome I %A Liu, Jianjun %A Xu, Jie %A Thiery, Joachim %A Arnlöv, Johan %A Kuusisto, Johanna %A Jakobsdottir, Johanna %A Tremblay, Johanne %A Chambers, John C %A Whitfield, John B %A Gaziano, John M %A Marten, Jonathan %A Coresh, Josef %A Jonas, Jost B %A Mychaleckyj, Josyf C %A Christensen, Kaare %A Eckardt, Kai-Uwe %A Mohlke, Karen L %A Endlich, Karlhans %A Dittrich, Katalin %A Ryan, Kathleen A %A Rice, Kenneth M %A Taylor, Kent D %A Ho, Kevin %A Nikus, Kjell %A Matsuda, Koichi %A Strauch, Konstantin %A Miliku, Kozeta %A Hveem, Kristian %A Lind, Lars %A Wallentin, Lars %A Yerges-Armstrong, Laura M %A Raffield, Laura M %A Phillips, Lawrence S %A Launer, Lenore J %A Lyytikäinen, Leo-Pekka %A Lange, Leslie A %A Citterio, Lorena %A Klaric, Lucija %A Ikram, M Arfan %A Ising, Marcus %A Kleber, Marcus E %A Francescatto, Margherita %A Concas, Maria Pina %A Ciullo, Marina %A Piratsu, Mario %A Orho-Melander, Marju %A Laakso, Markku %A Loeffler, Markus %A Perola, Markus %A de Borst, Martin H %A Gögele, Martin %A Bianca, Martina La %A Lukas, Mary Ann %A Feitosa, Mary F %A Biggs, Mary L %A Wojczynski, Mary K %A Kavousi, Maryam %A Kanai, Masahiro %A Akiyama, Masato %A Yasuda, Masayuki %A Nauck, Matthias %A Waldenberger, Melanie %A Chee, Miao-Li %A Chee, Miao-Ling %A Boehnke, Michael %A Preuss, Michael H %A Stumvoll, Michael %A Province, Michael A %A Evans, Michele K %A O'Donoghue, Michelle L %A Kubo, Michiaki %A Kähönen, Mika %A Kastarinen, Mika %A Nalls, Mike A %A Kuokkanen, Mikko %A Ghanbari, Mohsen %A Bochud, Murielle %A Josyula, Navya Shilpa %A Martin, Nicholas G %A Tan, Nicholas Y Q %A Palmer, Nicholette D %A Pirastu, Nicola %A Schupf, Nicole %A Verweij, Niek %A Hutri-Kähönen, Nina %A Mononen, Nina %A Bansal, Nisha %A Devuyst, Olivier %A Melander, Olle %A Raitakari, Olli T %A Polasek, Ozren %A Manunta, Paolo %A Gasparini, Paolo %A Mishra, Pashupati P %A Sulem, Patrick %A Magnusson, Patrik K E %A Elliott, Paul %A Ridker, Paul M %A Hamet, Pavel %A Svensson, Per O %A Joshi, Peter K %A Kovacs, Peter %A Pramstaller, Peter P %A Rossing, Peter %A Vollenweider, Peter %A van der Harst, Pim %A Dorajoo, Rajkumar %A Sim, Ralene Z H %A Burkhardt, Ralph %A Tao, Ran %A Noordam, Raymond %A Mägi, Reedik %A Schmidt, Reinhold %A de Mutsert, Renée %A Rueedi, Rico %A van Dam, Rob M %A Carroll, Robert J %A Gansevoort, Ron T %A Loos, Ruth J F %A Felicita, Sala Cinzia %A Sedaghat, Sanaz %A Padmanabhan, Sandosh %A Freitag-Wolf, Sandra %A Pendergrass, Sarah A %A Graham, Sarah E %A Gordon, Scott D %A Hwang, Shih-Jen %A Kerr, Shona M %A Vaccargiu, Simona %A Patil, Snehal B %A Hallan, Stein %A Bakker, Stephan J L %A Lim, Su-Chi %A Lucae, Susanne %A Vogelezang, Suzanne %A Bergmann, Sven %A Corre, Tanguy %A Ahluwalia, Tarunveer S %A Lehtimäki, Terho %A Boutin, Thibaud S %A Meitinger, Thomas %A Wong, Tien-Yin %A Bergler, Tobias %A Rabelink, Ton J %A Esko, Tõnu %A Haller, Toomas %A Thorsteinsdottir, Unnur %A Völker, Uwe %A Foo, Valencia Hui Xian %A Salomaa, Veikko %A Vitart, Veronique %A Giedraitis, Vilmantas %A Gudnason, Vilmundur %A Jaddoe, Vincent W V %A Huang, Wei %A Zhang, Weihua %A Wei, Wen Bin %A Kiess, Wieland %A März, Winfried %A Koenig, Wolfgang %A Lieb, Wolfgang %A Gào, Xīn %A Sim, Xueling %A Wang, Ya Xing %A Friedlander, Yechiel %A Tham, Yih-Chung %A Kamatani, Yoichiro %A Okada, Yukinori %A Milaneschi, Yuri %A Yu, Zhi %A Stark, Klaus J %A Stefansson, Kari %A Böger, Carsten A %A Hung, Adriana M %A Kronenberg, Florian %A Köttgen, Anna %A Pattaro, Cristian %A Heid, Iris M %K Creatinine %K Diabetes Mellitus %K Diabetic Nephropathies %K Genome-Wide Association Study %K Glomerular Filtration Rate %K Humans %K Kidney %X

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

%B Commun Biol %V 5 %P 580 %8 2022 Jun 13 %G eng %N 1 %R 10.1038/s42003-022-03448-z %0 Journal Article %J Kidney Int %D 2022 %T Genetic loci and prioritization of genes for kidney function decline derived from a meta-analysis of 62 longitudinal genome-wide association studies. %A Gorski, Mathias %A Rasheed, Humaira %A Teumer, Alexander %A Thomas, Laurent F %A Graham, Sarah E %A Sveinbjornsson, Gardar %A Winkler, Thomas W %A Günther, Felix %A Stark, Klaus J %A Chai, Jin-Fang %A Tayo, Bamidele O %A Wuttke, Matthias %A Li, Yong %A Tin, Adrienne %A Ahluwalia, Tarunveer S %A Arnlöv, Johan %A Åsvold, Bjørn Olav %A Bakker, Stephan J L %A Banas, Bernhard %A Bansal, Nisha %A Biggs, Mary L %A Biino, Ginevra %A Böhnke, Michael %A Boerwinkle, Eric %A Bottinger, Erwin P %A Brenner, Hermann %A Brumpton, Ben %A Carroll, Robert J %A Chaker, Layal %A Chalmers, John %A Chee, Miao-Li %A Chee, Miao-Ling %A Cheng, Ching-Yu %A Chu, Audrey Y %A Ciullo, Marina %A Cocca, Massimiliano %A Cook, James P %A Coresh, Josef %A Cusi, Daniele %A de Borst, Martin H %A Degenhardt, Frauke %A Eckardt, Kai-Uwe %A Endlich, Karlhans %A Evans, Michele K %A Feitosa, Mary F %A Franke, Andre %A Freitag-Wolf, Sandra %A Fuchsberger, Christian %A Gampawar, Piyush %A Gansevoort, Ron T %A Ghanbari, Mohsen %A Ghasemi, Sahar %A Giedraitis, Vilmantas %A Gieger, Christian %A Gudbjartsson, Daniel F %A Hallan, Stein %A Hamet, Pavel %A Hishida, Asahi %A Ho, Kevin %A Hofer, Edith %A Holleczek, Bernd %A Holm, Hilma %A Hoppmann, Anselm %A Horn, Katrin %A Hutri-Kähönen, Nina %A Hveem, Kristian %A Hwang, Shih-Jen %A Ikram, M Arfan %A Josyula, Navya Shilpa %A Jung, Bettina %A Kähönen, Mika %A Karabegović, Irma %A Khor, Chiea-Chuen %A Koenig, Wolfgang %A Kramer, Holly %A Krämer, Bernhard K %A Kuhnel, Brigitte %A Kuusisto, Johanna %A Laakso, Markku %A Lange, Leslie A %A Lehtimäki, Terho %A Li, Man %A Lieb, Wolfgang %A Lind, Lars %A Lindgren, Cecilia M %A Loos, Ruth J F %A Lukas, Mary Ann %A Lyytikäinen, Leo-Pekka %A Mahajan, Anubha %A Matias-Garcia, Pamela R %A Meisinger, Christa %A Meitinger, Thomas %A Melander, Olle %A Milaneschi, Yuri %A Mishra, Pashupati P %A Mononen, Nina %A Morris, Andrew P %A Mychaleckyj, Josyf C %A Nadkarni, Girish N %A Naito, Mariko %A Nakatochi, Masahiro %A Nalls, Mike A %A Nauck, Matthias %A Nikus, Kjell %A Ning, Boting %A Nolte, Ilja M %A Nutile, Teresa %A O'Donoghue, Michelle L %A O'Connell, Jeffrey %A Olafsson, Isleifur %A Orho-Melander, Marju %A Parsa, Afshin %A Pendergrass, Sarah A %A Penninx, Brenda W J H %A Pirastu, Mario %A Preuss, Michael H %A Psaty, Bruce M %A Raffield, Laura M %A Raitakari, Olli T %A Rheinberger, Myriam %A Rice, Kenneth M %A Rizzi, Federica %A Rosenkranz, Alexander R %A Rossing, Peter %A Rotter, Jerome I %A Ruggiero, Daniela %A Ryan, Kathleen A %A Sabanayagam, Charumathi %A Salvi, Erika %A Schmidt, Helena %A Schmidt, Reinhold %A Scholz, Markus %A Schöttker, Ben %A Schulz, Christina-Alexandra %A Sedaghat, Sanaz %A Shaffer, Christian M %A Sieber, Karsten B %A Sim, Xueling %A Sims, Mario %A Snieder, Harold %A Stanzick, Kira J %A Thorsteinsdottir, Unnur %A Stocker, Hannah %A Strauch, Konstantin %A Stringham, Heather M %A Sulem, Patrick %A Szymczak, Silke %A Taylor, Kent D %A Thio, Chris H L %A Tremblay, Johanne %A Vaccargiu, Simona %A van der Harst, Pim %A van der Most, Peter J %A Verweij, Niek %A Völker, Uwe %A Wakai, Kenji %A Waldenberger, Melanie %A Wallentin, Lars %A Wallner, Stefan %A Wang, Judy %A Waterworth, Dawn M %A White, Harvey D %A Willer, Cristen J %A Wong, Tien-Yin %A Woodward, Mark %A Yang, Qiong %A Yerges-Armstrong, Laura M %A Zimmermann, Martina %A Zonderman, Alan B %A Bergler, Tobias %A Stefansson, Kari %A Böger, Carsten A %A Pattaro, Cristian %A Köttgen, Anna %A Kronenberg, Florian %A Heid, Iris M %X

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

%B Kidney Int %8 2022 Jun 16 %G eng %R 10.1016/j.kint.2022.05.021 %0 Journal Article %J Hypertension %D 2022 %T Insights From a Large-Scale Whole-Genome Sequencing Study of Systolic Blood Pressure, Diastolic Blood Pressure, and Hypertension. %A Kelly, Tanika N %A Sun, Xiao %A He, Karen Y %A Brown, Michael R %A Taliun, Sarah A Gagliano %A Hellwege, Jacklyn N %A Irvin, Marguerite R %A Mi, Xuenan %A Brody, Jennifer A %A Franceschini, Nora %A Guo, Xiuqing %A Hwang, Shih-Jen %A de Vries, Paul S %A Gao, Yan %A Moscati, Arden %A Nadkarni, Girish N %A Yanek, Lisa R %A Elfassy, Tali %A Smith, Jennifer A %A Chung, Ren-Hua %A Beitelshees, Amber L %A Patki, Amit %A Aslibekyan, Stella %A Blobner, Brandon M %A Peralta, Juan M %A Assimes, Themistocles L %A Palmas, Walter R %A Liu, Chunyu %A Bress, Adam P %A Huang, Zhijie %A Becker, Lewis C %A Hwa, Chii-Min %A O'Connell, Jeffrey R %A Carlson, Jenna C %A Warren, Helen R %A Das, Sayantan %A Giri, Ayush %A Martin, Lisa W %A Craig Johnson, W %A Fox, Ervin R %A Bottinger, Erwin P %A Razavi, Alexander C %A Vaidya, Dhananjay %A Chuang, Lee-Ming %A Chang, Yen-Pei C %A Naseri, Take %A Jain, Deepti %A Kang, Hyun Min %A Hung, Adriana M %A Srinivasasainagendra, Vinodh %A Snively, Beverly M %A Gu, Dongfeng %A Montasser, May E %A Reupena, Muagututi'a Sefuiva %A Heavner, Benjamin D %A LeFaive, Jonathon %A Hixson, James E %A Rice, Kenneth M %A Wang, Fei Fei %A Nielsen, Jonas B %A Huang, Jianfeng %A Khan, Alyna T %A Zhou, Wei %A Nierenberg, Jovia L %A Laurie, Cathy C %A Armstrong, Nicole D %A Shi, Mengyao %A Pan, Yang %A Stilp, Adrienne M %A Emery, Leslie %A Wong, Quenna %A Hawley, Nicola L %A Minster, Ryan L %A Curran, Joanne E %A Munroe, Patricia B %A Weeks, Daniel E %A North, Kari E %A Tracy, Russell P %A Kenny, Eimear E %A Shimbo, Daichi %A Chakravarti, Aravinda %A Rich, Stephen S %A Reiner, Alex P %A Blangero, John %A Redline, Susan %A Mitchell, Braxton D %A Rao, Dabeeru C %A Ida Chen, Yii-Der %A Kardia, Sharon L R %A Kaplan, Robert C %A Mathias, Rasika A %A He, Jiang %A Psaty, Bruce M %A Fornage, Myriam %A Loos, Ruth J F %A Correa, Adolfo %A Boerwinkle, Eric %A Rotter, Jerome I %A Kooperberg, Charles %A Edwards, Todd L %A Abecasis, Goncalo R %A Zhu, Xiaofeng %A Levy, Daniel %A Arnett, Donna K %A Morrison, Alanna C %X

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

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

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

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

%B Hypertension %P 101161HYPERTENSIONAHA12219324 %8 2022 Jun 02 %G eng %R 10.1161/HYPERTENSIONAHA.122.19324 %0 Journal Article %J Nat Genet %D 2022 %T Multi-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation. %A Mahajan, Anubha %A Spracklen, Cassandra N %A Zhang, Weihua %A Ng, Maggie C Y %A Petty, Lauren E %A Kitajima, Hidetoshi %A Yu, Grace Z %A Rüeger, Sina %A Speidel, Leo %A Kim, Young Jin %A Horikoshi, Momoko %A Mercader, Josep M %A Taliun, Daniel %A Moon, Sanghoon %A Kwak, Soo-Heon %A Robertson, Neil R %A Rayner, Nigel W %A Loh, Marie %A Kim, Bong-Jo %A Chiou, Joshua %A Miguel-Escalada, Irene %A Della Briotta Parolo, Pietro %A Lin, Kuang %A Bragg, Fiona %A Preuss, Michael H %A Takeuchi, Fumihiko %A Nano, Jana %A Guo, Xiuqing %A Lamri, Amel %A Nakatochi, Masahiro %A Scott, Robert A %A Lee, Jung-Jin %A Huerta-Chagoya, Alicia %A Graff, Mariaelisa %A Chai, Jin-Fang %A Parra, Esteban J %A Yao, Jie %A Bielak, Lawrence F %A Tabara, Yasuharu %A Hai, Yang %A Steinthorsdottir, Valgerdur %A Cook, James P %A Kals, Mart %A Grarup, Niels %A Schmidt, Ellen M %A Pan, Ian %A Sofer, Tamar %A Wuttke, Matthias %A Sarnowski, Chloe %A Gieger, Christian %A Nousome, Darryl %A Trompet, Stella %A Long, Jirong %A Sun, Meng %A Tong, Lin %A Chen, Wei-Min %A Ahmad, Meraj %A Noordam, Raymond %A Lim, Victor J Y %A Tam, Claudia H T %A Joo, Yoonjung Yoonie %A Chen, Chien-Hsiun %A Raffield, Laura M %A Lecoeur, Cécile %A Prins, Bram Peter %A Nicolas, Aude %A Yanek, Lisa R %A Chen, Guanjie %A Jensen, Richard A %A Tajuddin, Salman %A Kabagambe, Edmond K %A An, Ping %A Xiang, Anny H %A Choi, Hyeok Sun %A Cade, Brian E %A Tan, Jingyi %A Flanagan, Jack %A Abaitua, Fernando %A Adair, Linda S %A Adeyemo, Adebowale %A Aguilar-Salinas, Carlos A %A Akiyama, Masato %A Anand, Sonia S %A Bertoni, Alain %A Bian, Zheng %A Bork-Jensen, Jette %A Brandslund, Ivan %A Brody, Jennifer A %A Brummett, Chad M %A Buchanan, Thomas A %A Canouil, Mickaël %A Chan, Juliana C N %A Chang, Li-Ching %A Chee, Miao-Li %A Chen, Ji %A Chen, Shyh-Huei %A Chen, Yuan-Tsong %A Chen, Zhengming %A Chuang, Lee-Ming %A Cushman, Mary %A Das, Swapan K %A de Silva, H Janaka %A Dedoussis, George %A Dimitrov, Latchezar %A Doumatey, Ayo P %A Du, Shufa %A Duan, Qing %A Eckardt, Kai-Uwe %A Emery, Leslie S %A Evans, Daniel S %A Evans, Michele K %A Fischer, Krista %A Floyd, James S %A Ford, Ian %A Fornage, Myriam %A Franco, Oscar H %A Frayling, Timothy M %A Freedman, Barry I %A Fuchsberger, Christian %A Genter, Pauline %A Gerstein, Hertzel C %A Giedraitis, Vilmantas %A González-Villalpando, Clicerio %A Gonzalez-Villalpando, Maria Elena %A Goodarzi, Mark O %A Gordon-Larsen, Penny %A Gorkin, David %A Gross, Myron %A Guo, Yu %A Hackinger, Sophie %A Han, Sohee %A Hattersley, Andrew T %A Herder, Christian %A Howard, Annie-Green %A Hsueh, Willa %A Huang, Mengna %A Huang, Wei %A Hung, Yi-Jen %A Hwang, Mi Yeong %A Hwu, Chii-Min %A Ichihara, Sahoko %A Ikram, Mohammad Arfan %A Ingelsson, Martin %A Islam, Md Tariqul %A Isono, Masato %A Jang, Hye-Mi %A Jasmine, Farzana %A Jiang, Guozhi %A Jonas, Jost B %A Jørgensen, Marit E %A Jørgensen, Torben %A Kamatani, Yoichiro %A Kandeel, Fouad R %A Kasturiratne, Anuradhani %A Katsuya, Tomohiro %A Kaur, Varinderpal %A Kawaguchi, Takahisa %A Keaton, Jacob M %A Kho, Abel N %A Khor, Chiea-Chuen %A Kibriya, Muhammad G %A Kim, Duk-Hwan %A Kohara, Katsuhiko %A Kriebel, Jennifer %A Kronenberg, Florian %A Kuusisto, Johanna %A Läll, Kristi %A Lange, Leslie A %A Lee, Myung-Shik %A Lee, Nanette R %A Leong, Aaron %A Li, Liming %A Li, Yun %A Li-Gao, Ruifang %A Ligthart, Symen %A Lindgren, Cecilia M %A Linneberg, Allan %A Liu, Ching-Ti %A Liu, Jianjun %A Locke, Adam E %A Louie, Tin %A Luan, Jian'an %A Luk, Andrea O %A Luo, Xi %A Lv, Jun %A Lyssenko, Valeriya %A Mamakou, Vasiliki %A Mani, K Radha %A Meitinger, Thomas %A Metspalu, Andres %A Morris, Andrew D %A Nadkarni, Girish N %A Nadler, Jerry L %A Nalls, Michael A %A Nayak, Uma %A Nongmaithem, Suraj S %A Ntalla, Ioanna %A Okada, Yukinori %A Orozco, Lorena %A Patel, Sanjay R %A Pereira, Mark A %A Peters, Annette %A Pirie, Fraser J %A Porneala, Bianca %A Prasad, Gauri %A Preissl, Sebastian %A Rasmussen-Torvik, Laura J %A Reiner, Alexander P %A Roden, Michael %A Rohde, Rebecca %A Roll, Kathryn %A Sabanayagam, Charumathi %A Sander, Maike %A Sandow, Kevin %A Sattar, Naveed %A Schönherr, Sebastian %A Schurmann, Claudia %A Shahriar, Mohammad %A Shi, Jinxiu %A Shin, Dong Mun %A Shriner, Daniel %A Smith, Jennifer A %A So, Wing Yee %A Stančáková, Alena %A Stilp, Adrienne M %A Strauch, Konstantin %A Suzuki, Ken %A Takahashi, Atsushi %A Taylor, Kent D %A Thorand, Barbara %A Thorleifsson, Gudmar %A Thorsteinsdottir, Unnur %A Tomlinson, Brian %A Torres, Jason M %A Tsai, Fuu-Jen %A Tuomilehto, Jaakko %A Tusié-Luna, Teresa %A Udler, Miriam S %A Valladares-Salgado, Adan %A van Dam, Rob M %A van Klinken, Jan B %A Varma, Rohit %A Vujkovic, Marijana %A Wacher-Rodarte, Niels %A Wheeler, Eleanor %A Whitsel, Eric A %A Wickremasinghe, Ananda R %A van Dijk, Ko Willems %A Witte, Daniel R %A Yajnik, Chittaranjan S %A Yamamoto, Ken %A Yamauchi, Toshimasa %A Yengo, Loic %A Yoon, Kyungheon %A Yu, Canqing %A Yuan, Jian-Min %A Yusuf, Salim %A Zhang, Liang %A Zheng, Wei %A Raffel, Leslie J %A Igase, Michiya %A Ipp, Eli %A Redline, Susan %A Cho, Yoon Shin %A Lind, Lars %A Province, Michael A %A Hanis, Craig L %A Peyser, Patricia A %A Ingelsson, Erik %A Zonderman, Alan B %A Psaty, Bruce M %A Wang, Ya-Xing %A Rotimi, Charles N %A Becker, Diane M %A Matsuda, Fumihiko %A Liu, Yongmei %A Zeggini, Eleftheria %A Yokota, Mitsuhiro %A Rich, Stephen S %A Kooperberg, Charles %A Pankow, James S %A Engert, James C %A Chen, Yii-Der Ida %A Froguel, Philippe %A Wilson, James G %A Sheu, Wayne H H %A Kardia, Sharon L R %A Wu, Jer-Yuarn %A Hayes, M Geoffrey %A Ma, Ronald C W %A Wong, Tien-Yin %A Groop, Leif %A Mook-Kanamori, Dennis O %A Chandak, Giriraj R %A Collins, Francis S %A Bharadwaj, Dwaipayan %A Paré, Guillaume %A Sale, Michèle M %A Ahsan, Habibul %A Motala, Ayesha A %A Shu, Xiao-Ou %A Park, Kyong-Soo %A Jukema, J Wouter %A Cruz, Miguel %A McKean-Cowdin, Roberta %A Grallert, Harald %A Cheng, Ching-Yu %A Bottinger, Erwin P %A Dehghan, Abbas %A Tai, E-Shyong %A Dupuis, Josée %A Kato, Norihiro %A Laakso, Markku %A Köttgen, Anna %A Koh, Woon-Puay %A Palmer, Colin N A %A Liu, Simin %A Abecasis, Goncalo %A Kooner, Jaspal S %A Loos, Ruth J F %A North, Kari E %A Haiman, Christopher A %A Florez, Jose C %A Saleheen, Danish %A Hansen, Torben %A Pedersen, Oluf %A Mägi, Reedik %A Langenberg, Claudia %A Wareham, Nicholas J %A Maeda, Shiro %A Kadowaki, Takashi %A Lee, Juyoung %A Millwood, Iona Y %A Walters, Robin G %A Stefansson, Kari %A Myers, Simon R %A Ferrer, Jorge %A Gaulton, Kyle J %A Meigs, James B %A Mohlke, Karen L %A Gloyn, Anna L %A Bowden, Donald W %A Below, Jennifer E %A Chambers, John C %A Sim, Xueling %A Boehnke, Michael %A Rotter, Jerome I %A McCarthy, Mark I %A Morris, Andrew P %K Diabetes Mellitus, Type 2 %K Ethnicity %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Polymorphism, Single Nucleotide %K Risk Factors %X

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

%B Nat Genet %V 54 %P 560-572 %8 2022 May %G eng %N 5 %R 10.1038/s41588-022-01058-3