%0 Journal Article %J Circ Cardiovasc Genet %D 2012 %T Impact of ancestry and common genetic variants on QT interval in African Americans. %A Smith, J Gustav %A Avery, Christy L %A Evans, Daniel S %A Nalls, Michael A %A Meng, Yan A %A Smith, Erin N %A Palmer, Cameron %A Tanaka, Toshiko %A Mehra, Reena %A Butler, Anne M %A Young, Taylor %A Buxbaum, Sarah G %A Kerr, Kathleen F %A Berenson, Gerald S %A Schnabel, Renate B %A Li, Guo %A Ellinor, Patrick T %A Magnani, Jared W %A Chen, Wei %A Bis, Joshua C %A Curb, J David %A Hsueh, Wen-Chi %A Rotter, Jerome I %A Liu, Yongmei %A Newman, Anne B %A Limacher, Marian C %A North, Kari E %A Reiner, Alexander P %A Quibrera, P Miguel %A Schork, Nicholas J %A Singleton, Andrew B %A Psaty, Bruce M %A Soliman, Elsayed Z %A Solomon, Allen J %A Srinivasan, Sathanur R %A Alonso, Alvaro %A Wallace, Robert %A Redline, Susan %A Zhang, Zhu-Ming %A Post, Wendy S %A Zonderman, Alan B %A Taylor, Herman A %A Murray, Sarah S %A Ferrucci, Luigi %A Arking, Dan E %A Evans, Michele K %A Fox, Ervin R %A Sotoodehnia, Nona %A Heckbert, Susan R %A Whitsel, Eric A %A Newton-Cheh, Christopher %K Adult %K African Americans %K Aged %K Electrocardiography %K European Continental Ancestry Group %K Female %K Genealogy and Heraldry %K Genetic Variation %K Genome, Human %K Genome-Wide Association Study %K Humans %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %X

BACKGROUND: Ethnic differences in cardiac arrhythmia incidence have been reported, with a particularly high incidence of sudden cardiac death and low incidence of atrial fibrillation in individuals of African ancestry. We tested the hypotheses that African ancestry and common genetic variants are associated with prolonged duration of cardiac repolarization, a central pathophysiological determinant of arrhythmia, as measured by the electrocardiographic QT interval.

METHODS AND RESULTS: First, individual estimates of African and European ancestry were inferred from genome-wide single-nucleotide polymorphism (SNP) data in 7 population-based cohorts of African Americans (n=12,097) and regressed on measured QT interval from ECGs. Second, imputation was performed for 2.8 million SNPs, and a genome-wide association study of QT interval was performed in 10 cohorts (n=13,105). There was no evidence of association between genetic ancestry and QT interval (P=0.94). Genome-wide significant associations (P<2.5 × 10(-8)) were identified with SNPs at 2 loci, upstream of the genes NOS1AP (rs12143842, P=2 × 10(-15)) and ATP1B1 (rs1320976, P=2 × 10(-10)). The most significant SNP in NOS1AP was the same as the strongest SNP previously associated with QT interval in individuals of European ancestry. Low probability values (P<10(-5)) were observed for SNPs at several other loci previously identified in genome-wide association studies in individuals of European ancestry, including KCNQ1, KCNH2, LITAF, and PLN.

CONCLUSIONS: We observed no difference in duration of cardiac repolarization with global genetic indices of African American ancestry. In addition, our genome-wide association study extends the association of polymorphisms at several loci associated with repolarization in individuals of European ancestry to include individuals of African ancestry.

%B Circ Cardiovasc Genet %V 5 %P 647-55 %8 2012 Dec %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/23166209?dopt=Abstract %R 10.1161/CIRCGENETICS.112.962787 %0 Journal Article %J Circ Cardiovasc Genet %D 2012 %T Novel loci associated with PR interval in a genome-wide association study of 10 African American cohorts. %A Butler, Anne M %A Yin, Xiaoyan %A Evans, Daniel S %A Nalls, Michael A %A Smith, Erin N %A Tanaka, Toshiko %A Li, Guo %A Buxbaum, Sarah G %A Whitsel, Eric A %A Alonso, Alvaro %A Arking, Dan E %A Benjamin, Emelia J %A Berenson, Gerald S %A Bis, Josh C %A Chen, Wei %A Deo, Rajat %A Ellinor, Patrick T %A Heckbert, Susan R %A Heiss, Gerardo %A Hsueh, Wen-Chi %A Keating, Brendan J %A Kerr, Kathleen F %A Li, Yun %A Limacher, Marian C %A Liu, Yongmei %A Lubitz, Steven A %A Marciante, Kristin D %A Mehra, Reena %A Meng, Yan A %A Newman, Anne B %A Newton-Cheh, Christopher %A North, Kari E %A Palmer, Cameron D %A Psaty, Bruce M %A Quibrera, P Miguel %A Redline, Susan %A Reiner, Alex P %A Rotter, Jerome I %A Schnabel, Renate B %A Schork, Nicholas J %A Singleton, Andrew B %A Smith, J Gustav %A Soliman, Elsayed Z %A Srinivasan, Sathanur R %A Zhang, Zhu-Ming %A Zonderman, Alan B %A Ferrucci, Luigi %A Murray, Sarah S %A Evans, Michele K %A Sotoodehnia, Nona %A Magnani, Jared W %A Avery, Christy L %K Adult %K African Americans %K Cohort Studies %K Electrocardiography %K Female %K Genetic Loci %K Genome-Wide Association Study %K Humans %K Male %K Meta-Analysis as Topic %K Middle Aged %K Polymorphism, Single Nucleotide %X

BACKGROUND: The PR interval, as measured by the resting, standard 12-lead ECG, reflects the duration of atrial/atrioventricular nodal depolarization. Substantial evidence exists for a genetic contribution to PR, including genome-wide association studies that have identified common genetic variants at 9 loci influencing PR in populations of European and Asian descent. However, few studies have examined loci associated with PR in African Americans.

METHODS AND RESULTS: We present results from the largest genome-wide association study to date of PR in 13 415 adults of African descent from 10 cohorts. We tested for association between PR (ms) and ≈2.8 million genotyped and imputed single-nucleotide polymorphisms. Imputation was performed using HapMap 2 YRI and CEU panels. Study-specific results, adjusted for global ancestry and clinical correlates of PR, were meta-analyzed using the inverse variance method. Variation in genome-wide test statistic distributions was noted within studies (λ range: 0.9-1.1), although not after genomic control correction was applied to the overall meta-analysis (λ: 1.008). In addition to generalizing previously reported associations with MEIS1, SCN5A, ARHGAP24, CAV1, and TBX5 to African American populations at the genome-wide significance level (P<5.0 × 10(-8)), we also identified a novel locus: ITGA9, located in a region previously implicated in SCN5A expression. The 3p21 region harboring SCN5A also contained 2 additional independent secondary signals influencing PR (P<5.0 × 10(-8)).

CONCLUSIONS: This study demonstrates the ability to map novel loci in African Americans as well as the generalizability of loci associated with PR across populations of African, European, and Asian descent.

%B Circ Cardiovasc Genet %V 5 %P 639-46 %8 2012 Dec %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/23139255?dopt=Abstract %R 10.1161/CIRCGENETICS.112.963991 %0 Journal Article %J Nat Genet %D 2014 %T Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization. %A Arking, Dan E %A Pulit, Sara L %A Crotti, Lia %A van der Harst, Pim %A Munroe, Patricia B %A Koopmann, Tamara T %A Sotoodehnia, Nona %A Rossin, Elizabeth J %A Morley, Michael %A Wang, Xinchen %A Johnson, Andrew D %A Lundby, Alicia %A Gudbjartsson, Daniel F %A Noseworthy, Peter A %A Eijgelsheim, Mark %A Bradford, Yuki %A Tarasov, Kirill V %A Dörr, Marcus %A Müller-Nurasyid, Martina %A Lahtinen, Annukka M %A Nolte, Ilja M %A Smith, Albert Vernon %A Bis, Joshua C %A Isaacs, Aaron %A Newhouse, Stephen J %A Evans, Daniel S %A Post, Wendy S %A Waggott, Daryl %A Lyytikäinen, Leo-Pekka %A Hicks, Andrew A %A Eisele, Lewin %A Ellinghaus, David %A Hayward, Caroline %A Navarro, Pau %A Ulivi, Sheila %A Tanaka, Toshiko %A Tester, David J %A Chatel, Stéphanie %A Gustafsson, Stefan %A Kumari, Meena %A Morris, Richard W %A Naluai, Åsa T %A Padmanabhan, Sandosh %A Kluttig, Alexander %A Strohmer, Bernhard %A Panayiotou, Andrie G %A Torres, Maria %A Knoflach, Michael %A Hubacek, Jaroslav A %A Slowikowski, Kamil %A Raychaudhuri, Soumya %A Kumar, Runjun D %A Harris, Tamara B %A Launer, Lenore J %A Shuldiner, Alan R %A Alonso, Alvaro %A Bader, Joel S %A Ehret, Georg %A Huang, Hailiang %A Kao, W H Linda %A Strait, James B %A Macfarlane, Peter W %A Brown, Morris %A Caulfield, Mark J %A Samani, Nilesh J %A Kronenberg, Florian %A Willeit, Johann %A Smith, J Gustav %A Greiser, Karin H %A Meyer Zu Schwabedissen, Henriette %A Werdan, Karl %A Carella, Massimo %A Zelante, Leopoldo %A Heckbert, Susan R %A Psaty, Bruce M %A Rotter, Jerome I %A Kolcic, Ivana %A Polasek, Ozren %A Wright, Alan F %A Griffin, Maura %A Daly, Mark J %A Arnar, David O %A Holm, Hilma %A Thorsteinsdottir, Unnur %A Denny, Joshua C %A Roden, Dan M %A Zuvich, Rebecca L %A Emilsson, Valur %A Plump, Andrew S %A Larson, Martin G %A O'Donnell, Christopher J %A Yin, Xiaoyan %A Bobbo, Marco %A D'Adamo, Adamo P %A Iorio, Annamaria %A Sinagra, Gianfranco %A Carracedo, Angel %A Cummings, Steven R %A Nalls, Michael A %A Jula, Antti %A Kontula, Kimmo K %A Marjamaa, Annukka %A Oikarinen, Lasse %A Perola, Markus %A Porthan, Kimmo %A Erbel, Raimund %A Hoffmann, Per %A Jöckel, Karl-Heinz %A Kälsch, Hagen %A Nöthen, Markus M %A den Hoed, Marcel %A Loos, Ruth J F %A Thelle, Dag S %A Gieger, Christian %A Meitinger, Thomas %A Perz, Siegfried %A Peters, Annette %A Prucha, Hanna %A Sinner, Moritz F %A Waldenberger, Melanie %A de Boer, Rudolf A %A Franke, Lude %A van der Vleuten, Pieter A %A Beckmann, Britt Maria %A Martens, Eimo %A Bardai, Abdennasser %A Hofman, Nynke %A Wilde, Arthur A M %A Behr, Elijah R %A Dalageorgou, Chrysoula %A Giudicessi, John R %A Medeiros-Domingo, Argelia %A Barc, Julien %A Kyndt, Florence %A Probst, Vincent %A Ghidoni, Alice %A Insolia, Roberto %A Hamilton, Robert M %A Scherer, Stephen W %A Brandimarto, Jeffrey %A Margulies, Kenneth %A Moravec, Christine E %A del Greco M, Fabiola %A Fuchsberger, Christian %A O'Connell, Jeffrey R %A Lee, Wai K %A Watt, Graham C M %A Campbell, Harry %A Wild, Sarah H %A El Mokhtari, Nour E %A Frey, Norbert %A Asselbergs, Folkert W %A Mateo Leach, Irene %A Navis, Gerjan %A van den Berg, Maarten P %A van Veldhuisen, Dirk J %A Kellis, Manolis %A Krijthe, Bouwe P %A Franco, Oscar H %A Hofman, Albert %A Kors, Jan A %A Uitterlinden, André G %A Witteman, Jacqueline C M %A Kedenko, Lyudmyla %A Lamina, Claudia %A Oostra, Ben A %A Abecasis, Goncalo R %A Lakatta, Edward G %A Mulas, Antonella %A Orrù, Marco %A Schlessinger, David %A Uda, Manuela %A Markus, Marcello R P %A Völker, Uwe %A Snieder, Harold %A Spector, Timothy D %A Arnlöv, Johan %A Lind, Lars %A Sundström, Johan %A Syvänen, Ann-Christine %A Kivimaki, Mika %A Kähönen, Mika %A Mononen, Nina %A Raitakari, Olli T %A Viikari, Jorma S %A Adamkova, Vera %A Kiechl, Stefan %A Brion, Maria %A Nicolaides, Andrew N %A Paulweber, Bernhard %A Haerting, Johannes %A Dominiczak, Anna F %A Nyberg, Fredrik %A Whincup, Peter H %A Hingorani, Aroon D %A Schott, Jean-Jacques %A Bezzina, Connie R %A Ingelsson, Erik %A Ferrucci, Luigi %A Gasparini, Paolo %A Wilson, James F %A Rudan, Igor %A Franke, Andre %A Mühleisen, Thomas W %A Pramstaller, Peter P %A Lehtimäki, Terho J %A Paterson, Andrew D %A Parsa, Afshin %A Liu, Yongmei %A van Duijn, Cornelia M %A Siscovick, David S %A Gudnason, Vilmundur %A Jamshidi, Yalda %A Salomaa, Veikko %A Felix, Stephan B %A Sanna, Serena %A Ritchie, Marylyn D %A Stricker, Bruno H %A Stefansson, Kari %A Boyer, Laurie A %A Cappola, Thomas P %A Olsen, Jesper V %A Lage, Kasper %A Schwartz, Peter J %A Kääb, Stefan %A Chakravarti, Aravinda %A Ackerman, Michael J %A Pfeufer, Arne %A de Bakker, Paul I W %A Newton-Cheh, Christopher %K Adult %K Aged %K Arrhythmias, Cardiac %K Calcium Signaling %K Death, Sudden, Cardiac %K Electrocardiography %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genotype %K Heart Ventricles %K Humans %K Long QT Syndrome %K Male %K Middle Aged %K Myocardium %K Polymorphism, Single Nucleotide %X

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.

%B Nat Genet %V 46 %P 826-36 %8 2014 Aug %G eng %N 8 %1 http://www.ncbi.nlm.nih.gov/pubmed/24952745?dopt=Abstract %R 10.1038/ng.3014 %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 Nat Commun %D 2014 %T Pharmacogenetic meta-analysis of genome-wide association studies of LDL cholesterol response to statins. %A Postmus, Iris %A Trompet, Stella %A Deshmukh, Harshal A %A Barnes, Michael R %A Li, Xiaohui %A Warren, Helen R %A Chasman, Daniel I %A Zhou, Kaixin %A Arsenault, Benoit J %A Donnelly, Louise A %A Wiggins, Kerri L %A Avery, Christy L %A Griffin, Paula %A Feng, QiPing %A Taylor, Kent D %A Li, Guo %A Evans, Daniel S %A Smith, Albert V %A de Keyser, Catherine E %A Johnson, Andrew D %A de Craen, Anton J M %A Stott, David J %A Buckley, Brendan M %A Ford, Ian %A Westendorp, Rudi G J %A Slagboom, P Eline %A Sattar, Naveed %A Munroe, Patricia B %A Sever, Peter %A Poulter, Neil %A Stanton, Alice %A Shields, Denis C %A O'Brien, Eoin %A Shaw-Hawkins, Sue %A Chen, Y-D Ida %A Nickerson, Deborah A %A Smith, Joshua D %A Dubé, Marie Pierre %A Boekholdt, S Matthijs %A Hovingh, G Kees %A Kastelein, John J P %A McKeigue, Paul M %A Betteridge, John %A Neil, Andrew %A Durrington, Paul N %A Doney, Alex %A Carr, Fiona %A Morris, Andrew %A McCarthy, Mark I %A Groop, Leif %A Ahlqvist, Emma %A Bis, Joshua C %A Rice, Kenneth %A Smith, Nicholas L %A Lumley, Thomas %A Whitsel, Eric A %A Stürmer, Til %A Boerwinkle, Eric %A Ngwa, Julius S %A O'Donnell, Christopher J %A Vasan, Ramachandran S %A Wei, Wei-Qi %A Wilke, Russell A %A Liu, Ching-Ti %A Sun, Fangui %A Guo, Xiuqing %A Heckbert, Susan R %A Post, Wendy %A Sotoodehnia, Nona %A Arnold, Alice M %A Stafford, Jeanette M %A Ding, Jingzhong %A Herrington, David M %A Kritchevsky, Stephen B %A Eiriksdottir, Gudny %A Launer, Leonore J %A Harris, Tamara B %A Chu, Audrey Y %A Giulianini, Franco %A MacFadyen, Jean G %A Barratt, Bryan J %A Nyberg, Fredrik %A Stricker, Bruno H %A Uitterlinden, André G %A Hofman, Albert %A Rivadeneira, Fernando %A Emilsson, Valur %A Franco, Oscar H %A Ridker, Paul M %A Gudnason, Vilmundur %A Liu, Yongmei %A Denny, Joshua C %A Ballantyne, Christie M %A Rotter, Jerome I %A Adrienne Cupples, L %A Psaty, Bruce M %A Palmer, Colin N A %A Tardif, Jean-Claude %A Colhoun, Helen M %A Hitman, Graham %A Krauss, Ronald M %A Wouter Jukema, J %A Caulfield, Mark J %K Cholesterol, LDL %K Genome-Wide Association Study %K Humans %K Hydroxymethylglutaryl-CoA Reductase Inhibitors %K Pharmacogenetics %K Polymorphism, Single Nucleotide %X

Statins effectively lower LDL cholesterol levels in large studies and the observed interindividual response variability may be partially explained by genetic variation. Here we perform a pharmacogenetic meta-analysis of genome-wide association studies (GWAS) in studies addressing the LDL cholesterol response to statins, including up to 18,596 statin-treated subjects. We validate the most promising signals in a further 22,318 statin recipients and identify two loci, SORT1/CELSR2/PSRC1 and SLCO1B1, not previously identified in GWAS. Moreover, we confirm the previously described associations with APOE and LPA. Our findings advance the understanding of the pharmacogenetic architecture of statin response.

%B Nat Commun %V 5 %P 5068 %8 2014 Oct 28 %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/25350695?dopt=Abstract %R 10.1038/ncomms6068 %0 Journal Article %J PLoS One %D 2015 %T Drug-Gene Interactions of Antihypertensive Medications and Risk of Incident Cardiovascular Disease: A Pharmacogenomics Study from the CHARGE Consortium. %A Bis, Joshua C %A Sitlani, Colleen %A Irvin, Ryan %A Avery, Christy L %A Smith, Albert Vernon %A Sun, Fangui %A Evans, Daniel S %A Musani, Solomon K %A Li, Xiaohui %A Trompet, Stella %A Krijthe, Bouwe P %A Harris, Tamara B %A Quibrera, P Miguel %A Brody, Jennifer A %A Demissie, Serkalem %A Davis, Barry R %A Wiggins, Kerri L %A Tranah, Gregory J %A Lange, Leslie A %A Sotoodehnia, Nona %A Stott, David J %A Franco, Oscar H %A Launer, Lenore J %A Stürmer, Til %A Taylor, Kent D %A Cupples, L Adrienne %A Eckfeldt, John H %A Smith, Nicholas L %A Liu, Yongmei %A Wilson, James G %A Heckbert, Susan R %A Buckley, Brendan M %A Ikram, M Arfan %A Boerwinkle, Eric %A Chen, Yii-Der Ida %A de Craen, Anton J M %A Uitterlinden, André G %A Rotter, Jerome I %A Ford, Ian %A Hofman, Albert %A Sattar, Naveed %A Slagboom, P Eline %A Westendorp, Rudi G J %A Gudnason, Vilmundur %A Vasan, Ramachandran S %A Lumley, Thomas %A Cummings, Steven R %A Taylor, Herman A %A Post, Wendy %A Jukema, J Wouter %A Stricker, Bruno H %A Whitsel, Eric A %A Psaty, Bruce M %A Arnett, Donna %K African Americans %K Aged %K Antihypertensive Agents %K Cardiovascular Diseases %K European Continental Ancestry Group %K Female %K Genome-Wide Association Study %K Humans %K Hypertension %K Incidence %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Treatment Outcome %X

BACKGROUND: Hypertension is a major risk factor for a spectrum of cardiovascular diseases (CVD), including myocardial infarction, sudden death, and stroke. In the US, over 65 million people have high blood pressure and a large proportion of these individuals are prescribed antihypertensive medications. Although large long-term clinical trials conducted in the last several decades have identified a number of effective antihypertensive treatments that reduce the risk of future clinical complications, responses to therapy and protection from cardiovascular events vary among individuals.

METHODS: Using a genome-wide association study among 21,267 participants with pharmaceutically treated hypertension, we explored the hypothesis that genetic variants might influence or modify the effectiveness of common antihypertensive therapies on the risk of major cardiovascular outcomes. The classes of drug treatments included angiotensin-converting enzyme inhibitors, beta-blockers, calcium channel blockers, and diuretics. In the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, each study performed array-based genome-wide genotyping, imputed to HapMap Phase II reference panels, and used additive genetic models in proportional hazards or logistic regression models to evaluate drug-gene interactions for each of four therapeutic drug classes. We used meta-analysis to combine study-specific interaction estimates for approximately 2 million single nucleotide polymorphisms (SNPs) in a discovery analysis among 15,375 European Ancestry participants (3,527 CVD cases) with targeted follow-up in a case-only study of 1,751 European Ancestry GenHAT participants as well as among 4,141 African-Americans (1,267 CVD cases).

RESULTS: Although drug-SNP interactions were biologically plausible, exposures and outcomes were well measured, and power was sufficient to detect modest interactions, we did not identify any statistically significant interactions from the four antihypertensive therapy meta-analyses (Pinteraction > 5.0×10-8). Similarly, findings were null for meta-analyses restricted to 66 SNPs with significant main effects on coronary artery disease or blood pressure from large published genome-wide association studies (Pinteraction ≥ 0.01). Our results suggest that there are no major pharmacogenetic influences of common SNPs on the relationship between blood pressure medications and the risk of incident CVD.

%B PLoS One %V 10 %P e0140496 %8 2015 %G eng %N 10 %1 http://www.ncbi.nlm.nih.gov/pubmed/26516778?dopt=Abstract %R 10.1371/journal.pone.0140496 %0 Journal Article %J J Gerontol A Biol Sci Med Sci %D 2015 %T GWAS of longevity in CHARGE consortium confirms APOE and FOXO3 candidacy. %A Broer, Linda %A Buchman, Aron S %A Deelen, Joris %A Evans, Daniel S %A Faul, Jessica D %A Lunetta, Kathryn L %A Sebastiani, Paola %A Smith, Jennifer A %A Smith, Albert V %A Tanaka, Toshiko %A Yu, Lei %A Arnold, Alice M %A Aspelund, Thor %A Benjamin, Emelia J %A De Jager, Philip L %A Eirkisdottir, Gudny %A Evans, Denis A %A Garcia, Melissa E %A Hofman, Albert %A Kaplan, Robert C %A Kardia, Sharon L R %A Kiel, Douglas P %A Oostra, Ben A %A Orwoll, Eric S %A Parimi, Neeta %A Psaty, Bruce M %A Rivadeneira, Fernando %A Rotter, Jerome I %A Seshadri, Sudha %A Singleton, Andrew %A Tiemeier, Henning %A Uitterlinden, André G %A Zhao, Wei %A Bandinelli, Stefania %A Bennett, David A %A Ferrucci, Luigi %A Gudnason, Vilmundur %A Harris, Tamara B %A Karasik, David %A Launer, Lenore J %A Perls, Thomas T %A Slagboom, P Eline %A Tranah, Gregory J %A Weir, David R %A Newman, Anne B %A van Duijn, Cornelia M %A Murabito, Joanne M %K Aged %K Aged, 80 and over %K Apolipoproteins E %K Cell Adhesion Molecules %K Cohort Studies %K Female %K Forkhead Box Protein O3 %K Forkhead Transcription Factors %K Genome-Wide Association Study %K Humans %K Longevity %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Receptors, Kainic Acid %X

BACKGROUND: The genetic contribution to longevity in humans has been estimated to range from 15% to 25%. Only two genes, APOE and FOXO3, have shown association with longevity in multiple independent studies.

METHODS: We conducted a meta-analysis of genome-wide association studies including 6,036 longevity cases, age ≥90 years, and 3,757 controls that died between ages 55 and 80 years. We additionally attempted to replicate earlier identified single nucleotide polymorphism (SNP) associations with longevity.

RESULTS: In our meta-analysis, we found suggestive evidence for the association of SNPs near CADM2 (odds ratio [OR] = 0.81; p value = 9.66 × 10(-7)) and GRIK2 (odds ratio = 1.24; p value = 5.09 × 10(-8)) with longevity. When attempting to replicate findings earlier identified in genome-wide association studies, only the APOE locus consistently replicated. In an additional look-up of the candidate gene FOXO3, we found that an earlier identified variant shows a highly significant association with longevity when including published data with our meta-analysis (odds ratio = 1.17; p value = 1.85×10(-10)).

CONCLUSIONS: We did not identify new genome-wide significant associations with longevity and did not replicate earlier findings except for APOE and FOXO3. Our inability to find new associations with survival to ages ≥90 years because longevity represents multiple complex traits with heterogeneous genetic underpinnings, or alternatively, that longevity may be regulated by rare variants that are not captured by standard genome-wide genotyping and imputation of common variants.

%B J Gerontol A Biol Sci Med Sci %V 70 %P 110-8 %8 2015 Jan %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/25199915?dopt=Abstract %R 10.1093/gerona/glu166 %0 Journal Article %J Hum Mol Genet %D 2016 %T Common variants in DRD2 are associated with sleep duration: the CARe consortium. %A Cade, Brian E %A Gottlieb, Daniel J %A Lauderdale, Diane S %A Bennett, David A %A Buchman, Aron S %A Buxbaum, Sarah G %A De Jager, Philip L %A Evans, Daniel S %A Fulop, Tibor %A Gharib, Sina A %A Johnson, W Craig %A Kim, Hyun %A Larkin, Emma K %A Lee, Seung Ku %A Lim, Andrew S %A Punjabi, Naresh M %A Shin, Chol %A Stone, Katie L %A Tranah, Gregory J %A Weng, Jia %A Yaffe, Kristine %A Zee, Phyllis C %A Patel, Sanjay R %A Zhu, Xiaofeng %A Redline, Susan %A Saxena, Richa %K Cohort Studies %K Ethnic Groups %K Humans %K Polymorphism, Single Nucleotide %K Polysomnography %K Receptors, Dopamine D2 %K Sleep %K Time Factors %X

Sleep duration is implicated in the etiologies of chronic diseases and premature mortality. However, the genetic basis for sleep duration is poorly defined. We sought to identify novel genetic components influencing sleep duration in a multi-ethnic sample. Meta-analyses were conducted of genetic associations with self-reported, habitual sleep duration from seven Candidate Gene Association Resource (CARe) cohorts of over 25 000 individuals of African, Asian, European and Hispanic American ancestry. All individuals were genotyped for ∼50 000 SNPs from 2000 candidate heart, lung, blood and sleep genes. African-Americans had additional genome-wide genotypes. Four cohorts provided replication. A SNP (rs17601612) in the dopamine D2 receptor gene (DRD2) was significantly associated with sleep duration (P = 9.8 × 10(-7)). Conditional analysis identified a second DRD2 signal with opposite effects on sleep duration. In exploratory analysis, suggestive association was observed for rs17601612 with polysomnographically determined sleep latency (P = 0.002). The lead DRD2 signal was recently identified in a schizophrenia GWAS, and a genetic risk score of 11 additional schizophrenia GWAS loci genotyped on the IBC array was also associated with longer sleep duration (P = 0.03). These findings support a role for DRD2 in influencing sleep duration. Our work motivates future pharmocogenetics research on alerting agents such as caffeine and modafinil that interact with the dopaminergic pathway and further investigation of genetic overlap between sleep and neuro-psychiatric traits.

%B Hum Mol Genet %V 25 %P 167-79 %8 2016 Jan 1 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26464489?dopt=Abstract %R 10.1093/hmg/ddv434 %0 Journal Article %J Hum Mol Genet %D 2016 %T Fine-mapping, novel loci identification, and SNP association transferability in a genome-wide association study of QRS duration in African Americans. %A Evans, Daniel S %A Avery, Christy L %A Nalls, Mike A %A Li, Guo %A Barnard, John %A Smith, Erin N %A Tanaka, Toshiko %A Butler, Anne M %A Buxbaum, Sarah G %A Alonso, Alvaro %A Arking, Dan E %A Berenson, Gerald S %A Bis, Joshua C %A Buyske, Steven %A Carty, Cara L %A Chen, Wei %A Chung, Mina K %A Cummings, Steven R %A Deo, Rajat %A Eaton, Charles B %A Fox, Ervin R %A Heckbert, Susan R %A Heiss, Gerardo %A Hindorff, Lucia A %A Hsueh, Wen-Chi %A Isaacs, Aaron %A Jamshidi, Yalda %A Kerr, Kathleen F %A Liu, Felix %A Liu, Yongmei %A Lohman, Kurt K %A Magnani, Jared W %A Maher, Joseph F %A Mehra, Reena %A Meng, Yan A %A Musani, Solomon K %A Newton-Cheh, Christopher %A North, Kari E %A Psaty, Bruce M %A Redline, Susan %A Rotter, Jerome I %A Schnabel, Renate B %A Schork, Nicholas J %A Shohet, Ralph V %A Singleton, Andrew B %A Smith, Jonathan D %A Soliman, Elsayed Z %A Srinivasan, Sathanur R %A Taylor, Herman A %A Van Wagoner, David R %A Wilson, James G %A Young, Taylor %A Zhang, Zhu-Ming %A Zonderman, Alan B %A Evans, Michele K %A Ferrucci, Luigi %A Murray, Sarah S %A Tranah, Gregory J %A Whitsel, Eric A %A Reiner, Alex P %A Sotoodehnia, Nona %X

The electrocardiographic QRS duration, a measure of ventricular depolarization and conduction, is associated with cardiovascular mortality. While single nucleotide polymorphisms (SNPs) associated with QRS duration have been identified at 22 loci in populations of European descent, the genetic architecture of QRS duration in non-European populations is largely unknown. We therefore performed a genome-wide association study (GWAS) meta-analysis of QRS duration in 13,031 African Americans from ten cohorts and a transethnic GWAS meta-analysis with additional results from populations of European descent. In the African American GWAS, a single genome-wide significant SNP association was identified (rs3922844, P = 4 × 10(-14)) in intron 16 of SCN5A, a voltage-gated cardiac sodium channel gene. The QRS-prolonging rs3922844 C allele was also associated with decreased SCN5A RNA expression in human atrial tissue (P = 1.1 × 10(-4)). High density genotyping revealed that the SCN5A association region in African Americans was confined to intron 16. Transethnic GWAS meta-analysis identified novel SNP associations on chromosome 18 in MYL12A (rs1662342, P = 4.9 × 10(-8)) and chromosome 1 near CD1E and SPTA1 (rs7547997, P = 7.9 × 10(-9)). The 22 QRS loci previously identified in populations of European descent were enriched for significant SNP associations with QRS duration in African Americans (P = 9.9 × 10(-7)), and index SNP associations in or near SCN5A, SCN10A, CDKN1A, NFIA, HAND1, TBX5 and SETBP1 replicated in African Americans. In summary, rs3922844 was associated with QRS duration and SCN5A expression, two novel QRS loci were identified using transethnic meta-analysis, and a significant proportion of QRS-SNP associations discovered in populations of European descent were transferable to African Americans when adequate power was achieved.

%B Hum Mol Genet %8 2016 Aug 29 %G eng %R 10.1093/hmg/ddw284 %0 Journal Article %J Eur J Hum Genet %D 2016 %T Genetic variants in RBFOX3 are associated with sleep latency. %A Amin, Najaf %A Allebrandt, Karla V %A van der Spek, Ashley %A Müller-Myhsok, Bertram %A Hek, Karin %A Teder-Laving, Maris %A Hayward, Caroline %A Esko, Tõnu %A van Mill, Josine G %A Mbarek, Hamdi %A Watson, Nathaniel F %A Melville, Scott A %A Del Greco, Fabiola M %A Byrne, Enda M %A Oole, Edwin %A Kolcic, Ivana %A Chen, Ting-Hsu %A Evans, Daniel S %A Coresh, Josef %A Vogelzangs, Nicole %A Karjalainen, Juha %A Willemsen, Gonneke %A Gharib, Sina A %A Zgaga, Lina %A Mihailov, Evelin %A Stone, Katie L %A Campbell, Harry %A Brouwer, Rutger Ww %A Demirkan, Ayse %A Isaacs, Aaron %A Dogas, Zoran %A Marciante, Kristin D %A Campbell, Susan %A Borovecki, Fran %A Luik, Annemarie I %A Li, Man %A Hottenga, Jouke Jan %A Huffman, Jennifer E %A van den Hout, Mirjam Cgn %A Cummings, Steven R %A Aulchenko, Yurii S %A Gehrman, Philip R %A Uitterlinden, André G %A Wichmann, Heinz-Erich %A Müller-Nurasyid, Martina %A Fehrmann, Rudolf Sn %A Montgomery, Grant W %A Hofman, Albert %A Kao, Wen Hong Linda %A Oostra, Ben A %A Wright, Alan F %A Vink, Jacqueline M %A Wilson, James F %A Pramstaller, Peter P %A Hicks, Andrew A %A Polasek, Ozren %A Punjabi, Naresh M %A Redline, Susan %A Psaty, Bruce M %A Heath, Andrew C %A Merrow, Martha %A Tranah, Gregory J %A Gottlieb, Daniel J %A Boomsma, Dorret I %A Martin, Nicholas G %A Rudan, Igor %A Tiemeier, Henning %A van IJcken, Wilfred Fj %A Penninx, Brenda W %A Metspalu, Andres %A Meitinger, Thomas %A Franke, Lude %A Roenneberg, Till %A van Duijn, Cornelia M %X

Time to fall asleep (sleep latency) is a major determinant of sleep quality. Chronic, long sleep latency is a major characteristic of sleep-onset insomnia and/or delayed sleep phase syndrome. In this study we aimed to discover common polymorphisms that contribute to the genetics of sleep latency. We performed a meta-analysis of genome-wide association studies (GWAS) including 2 572 737 single nucleotide polymorphisms (SNPs) established in seven European cohorts including 4242 individuals. We found a cluster of three highly correlated variants (rs9900428, rs9907432 and rs7211029) in the RNA-binding protein fox-1 homolog 3 gene (RBFOX3) associated with sleep latency (P-values=5.77 × 10(-08), 6.59 × 10(-)(08) and 9.17 × 10(-)(08)). These SNPs were replicated in up to 12 independent populations including 30 377 individuals (P-values=1.5 × 10(-)(02), 7.0 × 10(-)(03) and 2.5 × 10(-)(03); combined meta-analysis P-values=5.5 × 10(-07), 5.4 × 10(-07) and 1.0 × 10(-07)). A functional prediction of RBFOX3 based on co-expression with other genes shows that this gene is predominantly expressed in brain (P-value=1.4 × 10(-316)) and the central nervous system (P-value=7.5 × 10(-)(321)). The predicted function of RBFOX3 based on co-expression analysis with other genes shows that this gene is significantly involved in the release cycle of neurotransmitters including gamma-aminobutyric acid and various monoamines (P-values<2.9 × 10(-11)) that are crucial in triggering the onset of sleep. To conclude, in this first large-scale GWAS of sleep latency we report a novel association of variants in RBFOX3 gene. Further, a functional prediction of RBFOX3 supports the involvement of RBFOX3 with sleep latency.

%B Eur J Hum Genet %V 24 %P 1488-95 %8 2016 Oct %G eng %N 10 %1 http://www.ncbi.nlm.nih.gov/pubmed/27142678?dopt=Abstract %R 10.1038/ejhg.2016.31 %0 Journal Article %J Bone Rep %D 2016 %T A genome-wide association study meta-analysis of clinical fracture in 10,012 African American women. %A Taylor, Kira C %A Evans, Daniel S %A Edwards, Digna R Velez %A Edwards, Todd L %A Sofer, Tamar %A Li, Guo %A Liu, Youfang %A Franceschini, Nora %A Jackson, Rebecca D %A Giri, Ayush %A Donneyong, Macarius %A Psaty, Bruce %A Rotter, Jerome I %A LaCroix, Andrea Z %A Jordan, Joanne M %A Robbins, John A %A Lewis, Beth %A Stefanick, Marcia L %A Liu, Yongmei %A Garcia, Melissa %A Harris, Tamara %A Cauley, Jane A %A North, Kari E %X

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

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

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

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

%B Bone Rep %V 5 %P 233-242 %8 2016 Dec %G eng %R 10.1016/j.bonr.2016.08.005 %0 Journal Article %J Aging Cell %D 2016 %T GWAS analysis of handgrip and lower body strength in older adults in the CHARGE consortium. %A Matteini, Amy M %A Tanaka, Toshiko %A Karasik, David %A Atzmon, Gil %A Chou, Wen-Chi %A Eicher, John D %A Johnson, Andrew D %A Arnold, Alice M %A Callisaya, Michele L %A Davies, Gail %A Evans, Daniel S %A Holtfreter, Birte %A Lohman, Kurt %A Lunetta, Kathryn L %A Mangino, Massimo %A Smith, Albert V %A Smith, Jennifer A %A Teumer, Alexander %A Yu, Lei %A Arking, Dan E %A Buchman, Aron S %A Chibinik, Lori B %A De Jager, Philip L %A Evans, Denis A %A Faul, Jessica D %A Garcia, Melissa E %A Gillham-Nasenya, Irina %A Gudnason, Vilmundur %A Hofman, Albert %A Hsu, Yi-Hsiang %A Ittermann, Till %A Lahousse, Lies %A Liewald, David C %A Liu, Yongmei %A Lopez, Lorna %A Rivadeneira, Fernando %A Rotter, Jerome I %A Siggeirsdottir, Kristin %A Starr, John M %A Thomson, Russell %A Tranah, Gregory J %A Uitterlinden, André G %A Völker, Uwe %A Völzke, Henry %A Weir, David R %A Yaffe, Kristine %A Zhao, Wei %A Zhuang, Wei Vivian %A Zmuda, Joseph M %A Bennett, David A %A Cummings, Steven R %A Deary, Ian J %A Ferrucci, Luigi %A Harris, Tamara B %A Kardia, Sharon L R %A Kocher, Thomas %A Kritchevsky, Stephen B %A Psaty, Bruce M %A Seshadri, Sudha %A Spector, Timothy D %A Srikanth, Velandai K %A Windham, B Gwen %A Zillikens, M Carola %A Newman, Anne B %A Walston, Jeremy D %A Kiel, Douglas P %A Murabito, Joanne M %X

Decline in muscle strength with aging is an important predictor of health trajectory in the elderly. Several factors, including genetics, are proposed contributors to variability in muscle strength. To identify genetic contributors to muscle strength, a meta-analysis of genomewide association studies of handgrip was conducted. Grip strength was measured using a handheld dynamometer in 27 581 individuals of European descent over 65 years of age from 14 cohort studies. Genomewide association analysis was conducted on ~2.7 million imputed and genotyped variants (SNPs). Replication of the most significant findings was conducted using data from 6393 individuals from three cohorts. GWAS of lower body strength was also characterized in a subset of cohorts. Two genomewide significant (P-value< 5 × 10(-8) ) and 39 suggestive (P-value< 5 × 10(-5) ) associations were observed from meta-analysis of the discovery cohorts. After meta-analysis with replication cohorts, genomewide significant association was observed for rs752045 on chromosome 8 (β = 0.47, SE = 0.08, P-value = 5.20 × 10(-10) ). This SNP is mapped to an intergenic region and is located within an accessible chromatin region (DNase hypersensitivity site) in skeletal muscle myotubes differentiated from the human skeletal muscle myoblasts cell line. This locus alters a binding motif of the CCAAT/enhancer-binding protein-β (CEBPB) that is implicated in muscle repair mechanisms. GWAS of lower body strength did not yield significant results. A common genetic variant in a chromosomal region that regulates myotube differentiation and muscle repair may contribute to variability in grip strength in the elderly. Further studies are needed to uncover the mechanisms that link this genetic variant with muscle strength.

%B Aging Cell %V 15 %P 792-800 %8 2016 Oct %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/27325353?dopt=Abstract %R 10.1111/acel.12468 %0 Journal Article %J J Med Genet %D 2016 %T Meta-analysis of genome-wide association studies of HDL cholesterol response to statins. %A Postmus, Iris %A Warren, Helen R %A Trompet, Stella %A Arsenault, Benoit J %A Avery, Christy L %A Bis, Joshua C %A Chasman, Daniel I %A de Keyser, Catherine E %A Deshmukh, Harshal A %A Evans, Daniel S %A Feng, QiPing %A Li, Xiaohui %A Smit, Roelof A J %A Smith, Albert V %A Sun, Fangui %A Taylor, Kent D %A Arnold, Alice M %A Barnes, Michael R %A Barratt, Bryan J %A Betteridge, John %A Boekholdt, S Matthijs %A Boerwinkle, Eric %A Buckley, Brendan M %A Chen, Y-D Ida %A de Craen, Anton J M %A Cummings, Steven R %A Denny, Joshua C %A Dubé, Marie Pierre %A Durrington, Paul N %A Eiriksdottir, Gudny %A Ford, Ian %A Guo, Xiuqing %A Harris, Tamara B %A Heckbert, Susan R %A Hofman, Albert %A Hovingh, G Kees %A Kastelein, John J P %A Launer, Leonore J %A Liu, Ching-Ti %A Liu, Yongmei %A Lumley, Thomas %A McKeigue, Paul M %A Munroe, Patricia B %A Neil, Andrew %A Nickerson, Deborah A %A Nyberg, Fredrik %A O'Brien, Eoin %A O'Donnell, Christopher J %A Post, Wendy %A Poulter, Neil %A Vasan, Ramachandran S %A Rice, Kenneth %A Rich, Stephen S %A Rivadeneira, Fernando %A Sattar, Naveed %A Sever, Peter %A Shaw-Hawkins, Sue %A Shields, Denis C %A Slagboom, P Eline %A Smith, Nicholas L %A Smith, Joshua D %A Sotoodehnia, Nona %A Stanton, Alice %A Stott, David J %A Stricker, Bruno H %A Stürmer, Til %A Uitterlinden, André G %A Wei, Wei-Qi %A Westendorp, Rudi G J %A Whitsel, Eric A %A Wiggins, Kerri L %A Wilke, Russell A %A Ballantyne, Christie M %A Colhoun, Helen M %A Cupples, L Adrienne %A Franco, Oscar H %A Gudnason, Vilmundur %A Hitman, Graham %A Palmer, Colin N A %A Psaty, Bruce M %A Ridker, Paul M %A Stafford, Jeanette M %A Stein, Charles M %A Tardif, Jean-Claude %A Caulfield, Mark J %A Jukema, J Wouter %A Rotter, Jerome I %A Krauss, Ronald M %X

BACKGROUND: In addition to lowering low density lipoprotein cholesterol (LDL-C), statin therapy also raises high density lipoprotein cholesterol (HDL-C) levels. Inter-individual variation in HDL-C response to statins may be partially explained by genetic variation.

METHODS AND RESULTS: We performed a meta-analysis of genome-wide association studies (GWAS) to identify variants with an effect on statin-induced high density lipoprotein cholesterol (HDL-C) changes. The 123 most promising signals with p<1×10(-4) from the 16 769 statin-treated participants in the first analysis stage were followed up in an independent group of 10 951 statin-treated individuals, providing a total sample size of 27 720 individuals. The only associations of genome-wide significance (p<5×10(-8)) were between minor alleles at the CETP locus and greater HDL-C response to statin treatment.

CONCLUSIONS: Based on results from this study that included a relatively large sample size, we suggest that CETP may be the only detectable locus with common genetic variants that influence HDL-C response to statins substantially in individuals of European descent. Although CETP is known to be associated with HDL-C, we provide evidence that this pharmacogenetic effect is independent of its association with baseline HDL-C levels.

%B J Med Genet %V 53 %P 835-845 %8 2016 Dec %G eng %N 12 %R 10.1136/jmedgenet-2016-103966 %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 Aging (Albany NY) %D 2017 %T The complex genetics of gait speed: genome-wide meta-analysis approach. %A Ben-Avraham, Dan %A Karasik, David %A Verghese, Joe %A Lunetta, Kathryn L %A Smith, Jennifer A %A Eicher, John D %A Vered, Rotem %A Deelen, Joris %A Arnold, Alice M %A Buchman, Aron S %A Tanaka, Toshiko %A Faul, Jessica D %A Nethander, Maria %A Fornage, Myriam %A Adams, Hieab H %A Matteini, Amy M %A Callisaya, Michele L %A Smith, Albert V %A Yu, Lei %A De Jager, Philip L %A Evans, Denis A %A Gudnason, Vilmundur %A Hofman, Albert %A Pattie, Alison %A Corley, Janie %A Launer, Lenore J %A Knopman, Davis S %A Parimi, Neeta %A Turner, Stephen T %A Bandinelli, Stefania %A Beekman, Marian %A Gutman, Danielle %A Sharvit, Lital %A Mooijaart, Simon P %A Liewald, David C %A Houwing-Duistermaat, Jeanine J %A Ohlsson, Claes %A Moed, Matthijs %A Verlinden, Vincent J %A Mellström, Dan %A van der Geest, Jos N %A Karlsson, Magnus %A Hernandez, Dena %A McWhirter, Rebekah %A Liu, Yongmei %A Thomson, Russell %A Tranah, Gregory J %A Uitterlinden, André G %A Weir, David R %A Zhao, Wei %A Starr, John M %A Johnson, Andrew D %A Ikram, M Arfan %A Bennett, David A %A Cummings, Steven R %A Deary, Ian J %A Harris, Tamara B %A Kardia, Sharon L R %A Mosley, Thomas H %A Srikanth, Velandai K %A Windham, Beverly G %A Newman, Ann B %A Walston, Jeremy D %A Davies, Gail %A Evans, Daniel S %A Slagboom, Eline P %A Ferrucci, Luigi %A Kiel, Douglas P %A Murabito, Joanne M %A Atzmon, Gil %X

Emerging evidence suggests that the basis for variation in late-life mobility is attributable, in part, to genetic factors, which may become increasingly important with age. Our objective was to systematically assess the contribution of genetic variation to gait speed in older individuals. We conducted a meta-analysis of gait speed GWASs in 31,478 older adults from 17 cohorts of the CHARGE consortium, and validated our results in 2,588 older adults from 4 independent studies. We followed our initial discoveries with network and eQTL analysis of candidate signals in tissues. The meta-analysis resulted in a list of 536 suggestive genome wide significant SNPs in or near 69 genes. Further interrogation with Pathway Analysis placed gait speed as a polygenic complex trait in five major networks. Subsequent eQTL analysis revealed several SNPs significantly associated with the expression of PRSS16, WDSUB1 and PTPRT, which in addition to the meta-analysis and pathway suggested that genetic effects on gait speed may occur through synaptic function and neuronal development pathways. No genome-wide significant signals for gait speed were identified from this moderately large sample of older adults, suggesting that more refined physical function phenotypes will be needed to identify the genetic basis of gait speed in aging.

%B Aging (Albany NY) %V 9 %P 209-246 %8 2017 Jan 10 %G eng %N 1 %R 10.18632/aging.101151 %0 Journal Article %J J Med Genet %D 2017 %T A genome-wide interaction analysis of tricyclic/tetracyclic antidepressants and RR and QT intervals: a pharmacogenomics study from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium. %A Noordam, Raymond %A Sitlani, Colleen M %A Avery, Christy L %A Stewart, James D %A Gogarten, Stephanie M %A Wiggins, Kerri L %A Trompet, Stella %A Warren, Helen R %A Sun, Fangui %A Evans, Daniel S %A Li, Xiaohui %A Li, Jin %A Smith, Albert V %A Bis, Joshua C %A Brody, Jennifer A %A Busch, Evan L %A Caulfield, Mark J %A Chen, Yii-der I %A Cummings, Steven R %A Cupples, L Adrienne %A Duan, Qing %A Franco, Oscar H %A Méndez-Giráldez, Rául %A Harris, Tamara B %A Heckbert, Susan R %A van Heemst, Diana %A Hofman, Albert %A Floyd, James S %A Kors, Jan A %A Launer, Lenore J %A Li, Yun %A Li-Gao, Ruifang %A Lange, Leslie A %A Lin, Henry J %A de Mutsert, Renée %A Napier, Melanie D %A Newton-Cheh, Christopher %A Poulter, Neil %A Reiner, Alexander P %A Rice, Kenneth M %A Roach, Jeffrey %A Rodriguez, Carlos J %A Rosendaal, Frits R %A Sattar, Naveed %A Sever, Peter %A Seyerle, Amanda A %A Slagboom, P Eline %A Soliman, Elsayed Z %A Sotoodehnia, Nona %A Stott, David J %A Stürmer, Til %A Taylor, Kent D %A Thornton, Timothy A %A Uitterlinden, André G %A Wilhelmsen, Kirk C %A Wilson, James G %A Gudnason, Vilmundur %A Jukema, J Wouter %A Laurie, Cathy C %A Liu, Yongmei %A Mook-Kanamori, Dennis O %A Munroe, Patricia B %A Rotter, Jerome I %A Vasan, Ramachandran S %A Psaty, Bruce M %A Stricker, Bruno H %A Whitsel, Eric A %X

BACKGROUND: Increased heart rate and a prolonged QT interval are important risk factors for cardiovascular morbidity and mortality, and can be influenced by the use of various medications, including tricyclic/tetracyclic antidepressants (TCAs). We aim to identify genetic loci that modify the association between TCA use and RR and QT intervals.

METHODS AND RESULTS: We conducted race/ethnic-specific genome-wide interaction analyses (with HapMap phase II imputed reference panel imputation) of TCAs and resting RR and QT intervals in cohorts of European (n=45 706; n=1417 TCA users), African (n=10 235; n=296 TCA users) and Hispanic/Latino (n=13 808; n=147 TCA users) ancestry, adjusted for clinical covariates. Among the populations of European ancestry, two genome-wide significant loci were identified for RR interval: rs6737205 in BRE (β=56.3, pinteraction=3.9e(-9)) and rs9830388 in UBE2E2 (β=25.2, pinteraction=1.7e(-8)). In Hispanic/Latino cohorts, rs2291477 in TGFBR3 significantly modified the association between TCAs and QT intervals (β=9.3, pinteraction=2.55e(-8)). In the meta-analyses of the other ethnicities, these loci either were excluded from the meta-analyses (as part of quality control), or their effects did not reach the level of nominal statistical significance (pinteraction>0.05). No new variants were identified in these ethnicities. No additional loci were identified after inverse-variance-weighted meta-analysis of the three ancestries.

CONCLUSIONS: Among Europeans, TCA interactions with variants in BRE and UBE2E2 were identified in relation to RR intervals. Among Hispanic/Latinos, variants in TGFBR3 modified the relation between TCAs and QT intervals. Future studies are required to confirm our results.

%B J Med Genet %V 54 %P 313-323 %8 2017 May %G eng %N 5 %R 10.1136/jmedgenet-2016-104112 %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 Nat Commun %D 2017 %T Large meta-analysis of genome-wide association studies identifies five loci for lean body mass. %A Zillikens, M Carola %A Demissie, Serkalem %A Hsu, Yi-Hsiang %A Yerges-Armstrong, Laura M %A Chou, Wen-Chi %A Stolk, Lisette %A Livshits, Gregory %A Broer, Linda %A Johnson, Toby %A Koller, Daniel L %A Kutalik, Zoltán %A Luan, Jian'an %A Malkin, Ida %A Ried, Janina S %A Smith, Albert V %A Thorleifsson, Gudmar %A Vandenput, Liesbeth %A Hua Zhao, Jing %A Zhang, Weihua %A Aghdassi, Ali %A Åkesson, Kristina %A Amin, Najaf %A Baier, Leslie J %A Barroso, Inês %A Bennett, David A %A Bertram, Lars %A Biffar, Rainer %A Bochud, Murielle %A Boehnke, Michael %A Borecki, Ingrid B %A Buchman, Aron S %A Byberg, Liisa %A Campbell, Harry %A Campos Obanda, Natalia %A Cauley, Jane A %A Cawthon, Peggy M %A Cederberg, Henna %A Chen, Zhao %A Cho, Nam H %A Jin Choi, Hyung %A Claussnitzer, Melina %A Collins, Francis %A Cummings, Steven R %A De Jager, Philip L %A Demuth, Ilja %A Dhonukshe-Rutten, Rosalie A M %A Diatchenko, Luda %A Eiriksdottir, Gudny %A Enneman, Anke W %A Erdos, Mike %A Eriksson, Johan G %A Eriksson, Joel %A Estrada, Karol %A Evans, Daniel S %A Feitosa, Mary F %A Fu, Mao %A Garcia, Melissa %A Gieger, Christian %A Girke, Thomas %A Glazer, Nicole L %A Grallert, Harald %A Grewal, Jagvir %A Han, Bok-Ghee %A Hanson, Robert L %A Hayward, Caroline %A Hofman, Albert %A Hoffman, Eric P %A Homuth, Georg %A Hsueh, Wen-Chi %A Hubal, Monica J %A Hubbard, Alan %A Huffman, Kim M %A Husted, Lise B %A Illig, Thomas %A Ingelsson, Erik %A Ittermann, Till %A Jansson, John-Olov %A Jordan, Joanne M %A Jula, Antti %A Karlsson, Magnus %A Khaw, Kay-Tee %A Kilpeläinen, Tuomas O %A Klopp, Norman %A Kloth, Jacqueline S L %A Koistinen, Heikki A %A Kraus, William E %A Kritchevsky, Stephen %A Kuulasmaa, Teemu %A Kuusisto, Johanna %A Laakso, Markku %A Lahti, Jari %A Lang, Thomas %A Langdahl, Bente L %A Launer, Lenore J %A Lee, Jong-Young %A Lerch, Markus M %A Lewis, Joshua R %A Lind, Lars %A Lindgren, Cecilia %A Liu, Yongmei %A Liu, Tian %A Liu, Youfang %A Ljunggren, Osten %A Lorentzon, Mattias %A Luben, Robert N %A Maixner, William %A McGuigan, Fiona E %A Medina-Gómez, Carolina %A Meitinger, Thomas %A Melhus, Håkan %A Mellström, Dan %A Melov, Simon %A Michaëlsson, Karl %A Mitchell, Braxton D %A Morris, Andrew P %A Mosekilde, Leif %A Newman, Anne %A Nielson, Carrie M %A O'Connell, Jeffrey R %A Oostra, Ben A %A Orwoll, Eric S %A Palotie, Aarno %A Parker, Stephen C J %A Peacock, Munro %A Perola, Markus %A Peters, Annette %A Polasek, Ozren %A Prince, Richard L %A Räikkönen, Katri %A Ralston, Stuart H %A Ripatti, Samuli %A Robbins, John A %A Rotter, Jerome I %A Rudan, Igor %A Salomaa, Veikko %A Satterfield, Suzanne %A Schadt, Eric E %A Schipf, Sabine %A Scott, Laura %A Sehmi, Joban %A Shen, Jian %A Soo Shin, Chan %A Sigurdsson, Gunnar %A Smith, Shad %A Soranzo, Nicole %A Stančáková, Alena %A Steinhagen-Thiessen, Elisabeth %A Streeten, Elizabeth A %A Styrkarsdottir, Unnur %A Swart, Karin M A %A Tan, Sian-Tsung %A Tarnopolsky, Mark A %A Thompson, Patricia %A Thomson, Cynthia A %A Thorsteinsdottir, Unnur %A Tikkanen, Emmi %A Tranah, Gregory J %A Tuomilehto, Jaakko %A van Schoor, Natasja M %A Verma, Arjun %A Vollenweider, Peter %A Völzke, Henry %A Wactawski-Wende, Jean %A Walker, Mark %A Weedon, Michael N %A Welch, Ryan %A Wichmann, H-Erich %A Widen, Elisabeth %A Williams, Frances M K %A Wilson, James F %A Wright, Nicole C %A Xie, Weijia %A Yu, Lei %A Zhou, Yanhua %A Chambers, John C %A Döring, Angela %A van Duijn, Cornelia M %A Econs, Michael J %A Gudnason, Vilmundur %A Kooner, Jaspal S %A Psaty, Bruce M %A Spector, Timothy D %A Stefansson, Kari %A Rivadeneira, Fernando %A Uitterlinden, André G %A Wareham, Nicholas J %A Ossowski, Vicky %A Waterworth, Dawn %A Loos, Ruth J F %A Karasik, David %A Harris, Tamara B %A Ohlsson, Claes %A Kiel, Douglas P %X

Lean body mass, consisting mostly of skeletal muscle, is important for healthy aging. We performed a genome-wide association study for whole body (20 cohorts of European ancestry with n = 38,292) and appendicular (arms and legs) lean body mass (n = 28,330) measured using dual energy X-ray absorptiometry or bioelectrical impedance analysis, adjusted for sex, age, height, and fat mass. Twenty-one single-nucleotide polymorphisms were significantly associated with lean body mass either genome wide (p < 5 × 10-8) or suggestively genome wide (p < 2.3 × 10-6). Replication in 63,475 (47,227 of European ancestry) individuals from 33 cohorts for whole body lean body mass and in 45,090 (42,360 of European ancestry) subjects from 25 cohorts for appendicular lean body mass was successful for five single-nucleotide polymorphisms in/near HSD17B11, VCAN, ADAMTSL3, IRS1, and FTO for total lean body mass and for three single-nucleotide polymorphisms in/near VCAN, ADAMTSL3, and IRS1 for appendicular lean body mass. Our findings provide new insight into the genetics of lean body mass.Lean body mass is a highly heritable trait and is associated with various health conditions. Here, Kiel and colleagues perform a meta-analysis of genome-wide association studies for whole body lean body mass and find five novel genetic loci to be significantly associated.

%B Nat Commun %V 8 %P 80 %8 2017 Jul 19 %G eng %N 1 %R 10.1038/s41467-017-00031-7 %0 Journal Article %J Circ Cardiovasc Genet %D 2017 %T PCSK9 Loss-of-Function Variants, Low-Density Lipoprotein Cholesterol, and Risk of Coronary Heart Disease and Stroke: Data From 9 Studies of Blacks and Whites. %A Kent, Shia T %A Rosenson, Robert S %A Avery, Christy L %A Chen, Yii-der I %A Correa, Adolfo %A Cummings, Steven R %A Cupples, L Adrienne %A Cushman, Mary %A Evans, Daniel S %A Gudnason, Vilmundur %A Harris, Tamara B %A Howard, George %A Irvin, Marguerite R %A Judd, Suzanne E %A Jukema, J Wouter %A Lange, Leslie %A Levitan, Emily B %A Li, Xiaohui %A Liu, Yongmei %A Post, Wendy S %A Postmus, Iris %A Psaty, Bruce M %A Rotter, Jerome I %A Safford, Monika M %A Sitlani, Colleen M %A Smith, Albert V %A Stewart, James D %A Trompet, Stella %A Sun, Fangui %A Vasan, Ramachandran S %A Woolley, J Michael %A Whitsel, Eric A %A Wiggins, Kerri L %A Wilson, James G %A Muntner, Paul %X

BACKGROUND: PCSK9 loss-of-function (LOF) variants allow for the examination of the effects of lifetime reduced low-density lipoprotein cholesterol (LDL-C) on cardiovascular events. We examined the association of PCSK9 LOF variants with LDL-C and incident coronary heart disease and stroke through a meta-analysis of data from 8 observational cohorts and 1 randomized trial of statin therapy.

METHODS AND RESULTS: These 9 studies together included 17 459 blacks with 403 (2.3%) having at least 1 Y142X or C679X variant and 31 306 whites with 955 (3.1%) having at least 1 R46L variant. Unadjusted odds ratios for associations between PCSK9 LOF variants and incident coronary heart disease (851 events in blacks and 2662 events in whites) and stroke (523 events in blacks and 1660 events in whites) were calculated using pooled Mantel-Haenszel estimates with continuity correction factors. Pooling results across studies using fixed-effects inverse-variance-weighted models, PCSK9 LOF variants were associated with 35 mg/dL (95% confidence interval [CI], 32-39) lower LDL-C in blacks and 13 mg/dL (95% CI, 11-16) lower LDL-C in whites. PCSK9 LOF variants were associated with a pooled odds ratio for coronary heart disease of 0.51 (95% CI, 0.28-0.92) in blacks and 0.82 (95% CI, 0.63-1.06) in whites. PCSK9 LOF variants were not associated with incident stroke (odds ratio, 0.84; 95% CI, 0.48-1.47 in blacks and odds ratio, 1.06; 95% CI, 0.80-1.41 in whites).

CONCLUSIONS: PCSK9 LOF variants were associated with lower LDL-C and coronary heart disease incidence. PCSK9 LOF variants were not associated with stroke risk.

%B Circ Cardiovasc Genet %V 10 %P e001632 %8 2017 Aug %G eng %N 4 %R 10.1161/CIRCGENETICS.116.001632 %0 Journal Article %J PLoS Genet %D 2018 %T Genome-wide meta-analysis of 158,000 individuals of European ancestry identifies three loci associated with chronic back pain. %A Suri, Pradeep %A Palmer, Melody R %A Tsepilov, Yakov A %A Freidin, Maxim B %A Boer, Cindy G %A Yau, Michelle S %A Evans, Daniel S %A Gelemanovic, Andrea %A Bartz, Traci M %A Nethander, Maria %A Arbeeva, Liubov %A Karssen, Lennart %A Neogi, Tuhina %A Campbell, Archie %A Mellström, Dan %A Ohlsson, Claes %A Marshall, Lynn M %A Orwoll, Eric %A Uitterlinden, Andre %A Rotter, Jerome I %A Lauc, Gordan %A Psaty, Bruce M %A Karlsson, Magnus K %A Lane, Nancy E %A Jarvik, Gail P %A Polasek, Ozren %A Hochberg, Marc %A Jordan, Joanne M %A van Meurs, Joyce B J %A Jackson, Rebecca %A Nielson, Carrie M %A Mitchell, Braxton D %A Smith, Blair H %A Hayward, Caroline %A Smith, Nicholas L %A Aulchenko, Yurii S %A Williams, Frances M K %X

Back pain is the #1 cause of years lived with disability worldwide, yet surprisingly little is known regarding the biology underlying this symptom. We conducted a genome-wide association study (GWAS) meta-analysis of chronic back pain (CBP). Adults of European ancestry were included from 15 cohorts in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and from the UK Biobank interim data release. CBP cases were defined as those reporting back pain present for ≥3-6 months; non-cases were included as comparisons ("controls"). Each cohort conducted genotyping using commercially available arrays followed by imputation. GWAS used logistic regression models with additive genetic effects, adjusting for age, sex, study-specific covariates, and population substructure. The threshold for genome-wide significance in the fixed-effect inverse-variance weighted meta-analysis was p<5×10-8. Suggestive (p<5×10-7) and genome-wide significant (p<5×10-8) variants were carried forward for replication or further investigation in the remaining UK Biobank participants not included in the discovery sample. The discovery sample comprised 158,025 individuals, including 29,531 CBP cases. A genome-wide significant association was found for the intronic variant rs12310519 in SOX5 (OR 1.08, p = 7.2×10-10). This was subsequently replicated in 283,752 UK Biobank participants not included in the discovery sample, including 50,915 cases (OR 1.06, p = 5.3×10-11), and exceeded genome-wide significance in joint meta-analysis (OR 1.07, p = 4.5×10-19). We found suggestive associations at three other loci in the discovery sample, two of which exceeded genome-wide significance in joint meta-analysis: an intergenic variant, rs7833174, located between CCDC26 and GSDMC (OR 1.05, p = 4.4×10-13), and an intronic variant, rs4384683, in DCC (OR 0.97, p = 2.4×10-10). In this first reported meta-analysis of GWAS for CBP, we identified and replicated a genetic locus associated with CBP (SOX5). We also identified 2 other loci that reached genome-wide significance in a 2-stage joint meta-analysis (CCDC26/GSDMC and DCC).

%B PLoS Genet %V 14 %P e1007601 %8 2018 Sep %G eng %N 9 %R 10.1371/journal.pgen.1007601 %0 Journal Article %J Am J Respir Cell Mol Biol %D 2018 %T Multiethnic Meta-Analysis Identifies RAI1 as a Possible Obstructive Sleep Apnea-related Quantitative Trait Locus in Men. %A Chen, Han %A Cade, Brian E %A Gleason, Kevin J %A Bjonnes, Andrew C %A Stilp, Adrienne M %A Sofer, Tamar %A Conomos, Matthew P %A Ancoli-Israel, Sonia %A Arens, Raanan %A Azarbarzin, Ali %A Bell, Graeme I %A Below, Jennifer E %A Chun, Sung %A Evans, Daniel S %A Ewert, Ralf %A Frazier-Wood, Alexis C %A Gharib, Sina A %A Haba-Rubio, José %A Hagen, Erika W %A Heinzer, Raphael %A Hillman, David R %A Johnson, W Craig %A Kutalik, Zoltán %A Lane, Jacqueline M %A Larkin, Emma K %A Lee, Seung Ku %A Liang, Jingjing %A Loredo, Jose S %A Mukherjee, Sutapa %A Palmer, Lyle J %A Papanicolaou, George J %A Penzel, Thomas %A Peppard, Paul E %A Post, Wendy S %A Ramos, Alberto R %A Rice, Ken %A Rotter, Jerome I %A Sands, Scott A %A Shah, Neomi A %A Shin, Chol %A Stone, Katie L %A Stubbe, Beate %A Sul, Jae Hoon %A Tafti, Mehdi %A Taylor, Kent D %A Teumer, Alexander %A Thornton, Timothy A %A Tranah, Gregory J %A Wang, Chaolong %A Wang, Heming %A Warby, Simon C %A Wellman, D Andrew %A Zee, Phyllis C %A Hanis, Craig L %A Laurie, Cathy C %A Gottlieb, Daniel J %A Patel, Sanjay R %A Zhu, Xiaofeng %A Sunyaev, Shamil R %A Saxena, Richa %A Lin, Xihong %A Redline, Susan %X

Obstructive sleep apnea (OSA) is a common heritable disorder displaying marked sexual dimorphism in disease prevalence and progression. Previous genetic association studies have identified a few genetic loci associated with OSA and related quantitative traits, but they have only focused on single ethnic groups, and a large proportion of the heritability remains unexplained. The apnea-hypopnea index (AHI) is a commonly used quantitative measure characterizing OSA severity. Because OSA differs by sex, and the pathophysiology of obstructive events differ in rapid eye movement (REM) and non-REM (NREM) sleep, we hypothesized that additional genetic association signals would be identified by analyzing the NREM/REM-specific AHI and by conducting sex-specific analyses in multiethnic samples. We performed genome-wide association tests for up to 19,733 participants of African, Asian, European, and Hispanic/Latino American ancestry in 7 studies. We identified rs12936587 on chromosome 17 as a possible quantitative trait locus for NREM AHI in men (N = 6,737; P = 1.7 × 10) but not in women (P = 0.77). The association with NREM AHI was replicated in a physiological research study (N = 67; P = 0.047). This locus overlapping the RAI1 gene and encompassing genes PEMT1, SREBF1, and RASD1 was previously reported to be associated with coronary artery disease, lipid metabolism, and implicated in Potocki-Lupski syndrome and Smith-Magenis syndrome, which are characterized by abnormal sleep phenotypes. We also identified gene-by-sex interactions in suggestive association regions, suggesting that genetic variants for AHI appear to vary by sex, consistent with the clinical observations of strong sexual dimorphism.

%B Am J Respir Cell Mol Biol %V 58 %P 391-401 %8 2018 Mar %G eng %N 3 %R 10.1165/rcmb.2017-0237OC %0 Journal Article %J Nat Commun %D 2018 %T PR interval genome-wide association meta-analysis identifies 50 loci associated with atrial and atrioventricular electrical activity. %A van Setten, Jessica %A Brody, Jennifer A %A Jamshidi, Yalda %A Swenson, Brenton R %A Butler, Anne M %A Campbell, Harry %A Del Greco, Fabiola M %A Evans, Daniel S %A Gibson, Quince %A Gudbjartsson, Daniel F %A Kerr, Kathleen F %A Krijthe, Bouwe P %A Lyytikäinen, Leo-Pekka %A Müller, Christian %A Müller-Nurasyid, Martina %A Nolte, Ilja M %A Padmanabhan, Sandosh %A Ritchie, Marylyn D %A Robino, Antonietta %A Smith, Albert V %A Steri, Maristella %A Tanaka, Toshiko %A Teumer, Alexander %A Trompet, Stella %A Ulivi, Sheila %A Verweij, Niek %A Yin, Xiaoyan %A Arnar, David O %A Asselbergs, Folkert W %A Bader, Joel S %A Barnard, John %A Bis, Josh %A Blankenberg, Stefan %A Boerwinkle, Eric %A Bradford, Yuki %A Buckley, Brendan M %A Chung, Mina K %A Crawford, Dana %A den Hoed, Marcel %A Denny, Josh C %A Dominiczak, Anna F %A Ehret, Georg B %A Eijgelsheim, Mark %A Ellinor, Patrick T %A Felix, Stephan B %A Franco, Oscar H %A Franke, Lude %A Harris, Tamara B %A Holm, Hilma %A Ilaria, Gandin %A Iorio, Annamaria %A Kähönen, Mika %A Kolcic, Ivana %A Kors, Jan A %A Lakatta, Edward G %A Launer, Lenore J %A Lin, Honghuang %A Lin, Henry J %A Loos, Ruth J F %A Lubitz, Steven A %A Macfarlane, Peter W %A Magnani, Jared W %A Leach, Irene Mateo %A Meitinger, Thomas %A Mitchell, Braxton D %A Münzel, Thomas %A Papanicolaou, George J %A Peters, Annette %A Pfeufer, Arne %A Pramstaller, Peter P %A Raitakari, Olli T %A Rotter, Jerome I %A Rudan, Igor %A Samani, Nilesh J %A Schlessinger, David %A Silva Aldana, Claudia T %A Sinner, Moritz F %A Smith, Jonathan D %A Snieder, Harold %A Soliman, Elsayed Z %A Spector, Timothy D %A Stott, David J %A Strauch, Konstantin %A Tarasov, Kirill V %A Thorsteinsdottir, Unnur %A Uitterlinden, André G %A Van Wagoner, David R %A Völker, Uwe %A Völzke, Henry %A Waldenberger, Melanie %A Jan Westra, Harm %A Wild, Philipp S %A Zeller, Tanja %A Alonso, Alvaro %A Avery, Christy L %A Bandinelli, Stefania %A Benjamin, Emelia J %A Cucca, Francesco %A Dörr, Marcus %A Ferrucci, Luigi %A Gasparini, Paolo %A Gudnason, Vilmundur %A Hayward, Caroline %A Heckbert, Susan R %A Hicks, Andrew A %A Jukema, J Wouter %A Kääb, Stefan %A Lehtimäki, Terho %A Liu, Yongmei %A Munroe, Patricia B %A Parsa, Afshin %A Polasek, Ozren %A Psaty, Bruce M %A Roden, Dan M %A Schnabel, Renate B %A Sinagra, Gianfranco %A Stefansson, Kari %A Stricker, Bruno H %A van der Harst, Pim %A van Duijn, Cornelia M %A Wilson, James F %A Gharib, Sina A %A de Bakker, Paul I W %A Isaacs, Aaron %A Arking, Dan E %A Sotoodehnia, Nona %X

Electrocardiographic PR interval measures atrio-ventricular depolarization and conduction, and abnormal PR interval is a risk factor for atrial fibrillation and heart block. Our genome-wide association study of over 92,000 European-descent individuals identifies 44 PR interval loci (34 novel). Examination of these loci reveals known and previously not-yet-reported biological processes involved in cardiac atrial electrical activity. Genes in these loci are over-represented in cardiac disease processes including heart block and atrial fibrillation. Variants in over half of the 44 loci were associated with atrial or blood transcript expression levels, or were in high linkage disequilibrium with missense variants. Six additional loci were identified either by meta-analysis of ~105,000 African and European-descent individuals and/or by pleiotropic analyses combining PR interval with heart rate, QRS interval, and atrial fibrillation. These findings implicate developmental pathways, and identify transcription factors, ion-channel genes, and cell-junction/cell-signaling proteins in atrio-ventricular conduction, identifying potential targets for drug development.

%B Nat Commun %V 9 %P 2904 %8 2018 Jul 25 %G eng %N 1 %R 10.1038/s41467-018-04766-9 %0 Journal Article %J Hum Mol Genet %D 2019 %T Admixture mapping identifies novel loci for obstructive sleep apnea in Hispanic/Latino Americans. %A Wang, Heming %A Cade, Brian E %A Sofer, Tamar %A Sands, Scott A %A Chen, Han %A Browning, Sharon R %A Stilp, Adrienne M %A Louie, Tin L %A Thornton, Timothy A %A Johnson, W Craig %A Below, Jennifer E %A Conomos, Matthew P %A Evans, Daniel S %A Gharib, Sina A %A Guo, Xiuqing %A Wood, Alexis C %A Mei, Hao %A Yaffe, Kristine %A Loredo, Jose S %A Ramos, Alberto R %A Barrett-Connor, Elizabeth %A Ancoli-Israel, Sonia %A Zee, Phyllis C %A Arens, Raanan %A Shah, Neomi A %A Taylor, Kent D %A Tranah, Gregory J %A Stone, Katie L %A Hanis, Craig L %A Wilson, James G %A Gottlieb, Daniel J %A Patel, Sanjay R %A Rice, Ken %A Post, Wendy S %A Rotter, Jerome I %A Sunyaev, Shamil R %A Cai, Jianwen %A Lin, Xihong %A Purcell, Shaun M %A Laurie, Cathy C %A Saxena, Richa %A Redline, Susan %A Zhu, Xiaofeng %X

Obstructive sleep apnea (OSA) is a common disorder associated with increased risk of cardiovascular disease and mortality. Its prevalence and severity vary across ancestral background. Although OSA traits are heritable, few genetic associations have been identified. To identify genetic regions associated with OSA and improve statistical power, we applied admixture mapping on three primary OSA traits [the apnea hypopnea index (AHI), overnight average oxyhemoglobin saturation (SaO2) and percentage time SaO2 < 90%] and a secondary trait (respiratory event duration) in a Hispanic/Latino American population study of 11 575 individuals with significant variation in ancestral background. Linear mixed models were performed using previously inferred African, European and Amerindian local genetic ancestry markers. Global African ancestry was associated with a lower AHI, higher SaO2 and shorter event duration. Admixture mapping analysis of the primary OSA traits identified local African ancestry at the chromosomal region 2q37 as genome-wide significantly associated with AHI (P < 5.7 × 10-5), and European and Amerindian ancestries at 18q21 suggestively associated with both AHI and percentage time SaO2 < 90% (P < 10-3). Follow-up joint ancestry-SNP association analyses identified novel variants in ferrochelatase (FECH), significantly associated with AHI and percentage time SaO2 < 90% after adjusting for multiple tests (P < 8 × 10-6). These signals contributed to the admixture mapping associations and were replicated in independent cohorts. In this first admixture mapping study of OSA, novel associations with variants in the iron/heme metabolism pathway suggest a role for iron in influencing respiratory traits underlying OSA.

%B Hum Mol Genet %V 28 %P 675-687 %8 2019 02 15 %G eng %N 4 %R 10.1093/hmg/ddy387 %0 Journal Article %J PLoS Genet %D 2019 %T Associations of variants In the hexokinase 1 and interleukin 18 receptor regions with oxyhemoglobin saturation during sleep. %A Cade, Brian E %A Chen, Han %A Stilp, Adrienne M %A Louie, Tin %A Ancoli-Israel, Sonia %A Arens, Raanan %A Barfield, Richard %A Below, Jennifer E %A Cai, Jianwen %A Conomos, Matthew P %A Evans, Daniel S %A Frazier-Wood, Alexis C %A Gharib, Sina A %A Gleason, Kevin J %A Gottlieb, Daniel J %A Hillman, David R %A Johnson, W Craig %A Lederer, David J %A Lee, Jiwon %A Loredo, Jose S %A Mei, Hao %A Mukherjee, Sutapa %A Patel, Sanjay R %A Post, Wendy S %A Purcell, Shaun M %A Ramos, Alberto R %A Reid, Kathryn J %A Rice, Ken %A Shah, Neomi A %A Sofer, Tamar %A Taylor, Kent D %A Thornton, Timothy A %A Wang, Heming %A Yaffe, Kristine %A Zee, Phyllis C %A Hanis, Craig L %A Palmer, Lyle J %A Rotter, Jerome I %A Stone, Katie L %A Tranah, Gregory J %A Wilson, James G %A Sunyaev, Shamil R %A Laurie, Cathy C %A Zhu, Xiaofeng %A Saxena, Richa %A Lin, Xihong %A Redline, Susan %K Adolescent %K Adult %K Aged %K Aged, 80 and over %K Cell Adhesion Molecules, Neuronal %K Computational Biology %K Extracellular Matrix Proteins %K Female %K Gene Regulatory Networks %K Genetic Variation %K Genome-Wide Association Study %K Hexokinase %K Humans %K Hypoxia %K Interleukin-18 Receptor alpha Subunit %K Male %K Middle Aged %K Nerve Tissue Proteins %K NLR Family, Pyrin Domain-Containing 3 Protein %K Oxygen %K Oxyhemoglobins %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %K Serine Endopeptidases %K Sleep %K Sleep Apnea Syndromes %K Young Adult %X

Sleep disordered breathing (SDB)-related overnight hypoxemia is associated with cardiometabolic disease and other comorbidities. Understanding the genetic bases for variations in nocturnal hypoxemia may help understand mechanisms influencing oxygenation and SDB-related mortality. We conducted genome-wide association tests across 10 cohorts and 4 populations to identify genetic variants associated with three correlated measures of overnight oxyhemoglobin saturation: average and minimum oxyhemoglobin saturation during sleep and the percent of sleep with oxyhemoglobin saturation under 90%. The discovery sample consisted of 8,326 individuals. Variants with p < 1 × 10(-6) were analyzed in a replication group of 14,410 individuals. We identified 3 significantly associated regions, including 2 regions in multi-ethnic analyses (2q12, 10q22). SNPs in the 2q12 region associated with minimum SpO2 (rs78136548 p = 2.70 × 10(-10)). SNPs at 10q22 were associated with all three traits including average SpO2 (rs72805692 p = 4.58 × 10(-8)). SNPs in both regions were associated in over 20,000 individuals and are supported by prior associations or functional evidence. Four additional significant regions were detected in secondary sex-stratified and combined discovery and replication analyses, including a region overlapping Reelin, a known marker of respiratory complex neurons.These are the first genome-wide significant findings reported for oxyhemoglobin saturation during sleep, a phenotype of high clinical interest. Our replicated associations with HK1 and IL18R1 suggest that variants in inflammatory pathways, such as the biologically-plausible NLRP3 inflammasome, may contribute to nocturnal hypoxemia.

%B PLoS Genet %V 15 %P e1007739 %8 2019 04 %G eng %N 4 %R 10.1371/journal.pgen.1007739 %0 Journal Article %J Am J Clin Nutr %D 2019 %T Disentangling the genetics of lean mass. %A Karasik, David %A Zillikens, M Carola %A Hsu, Yi-Hsiang %A Aghdassi, Ali %A Åkesson, Kristina %A Amin, Najaf %A Barroso, Inês %A Bennett, David A %A Bertram, Lars %A Bochud, Murielle %A Borecki, Ingrid B %A Broer, Linda %A Buchman, Aron S %A Byberg, Liisa %A Campbell, Harry %A Campos-Obando, Natalia %A Cauley, Jane A %A Cawthon, Peggy M %A Chambers, John C %A Chen, Zhao %A Cho, Nam H %A Choi, Hyung Jin %A Chou, Wen-Chi %A Cummings, Steven R %A de Groot, Lisette C P G M %A De Jager, Phillip L %A Demuth, Ilja %A Diatchenko, Luda %A Econs, Michael J %A Eiriksdottir, Gudny %A Enneman, Anke W %A Eriksson, Joel %A Eriksson, Johan G %A Estrada, Karol %A Evans, Daniel S %A Feitosa, Mary F %A Fu, Mao %A Gieger, Christian %A Grallert, Harald %A Gudnason, Vilmundur %A Lenore, Launer J %A Hayward, Caroline %A Hofman, Albert %A Homuth, Georg %A Huffman, Kim M %A Husted, Lise B %A Illig, Thomas %A Ingelsson, Erik %A Ittermann, Till %A Jansson, John-Olov %A Johnson, Toby %A Biffar, Reiner %A Jordan, Joanne M %A Jula, Antti %A Karlsson, Magnus %A Khaw, Kay-Tee %A Kilpeläinen, Tuomas O %A Klopp, Norman %A Kloth, Jacqueline S L %A Koller, Daniel L %A Kooner, Jaspal S %A Kraus, William E %A Kritchevsky, Stephen %A Kutalik, Zoltán %A Kuulasmaa, Teemu %A Kuusisto, Johanna %A Laakso, Markku %A Lahti, Jari %A Lang, Thomas %A Langdahl, Bente L %A Lerch, Markus M %A Lewis, Joshua R %A Lill, Christina %A Lind, Lars %A Lindgren, Cecilia %A Liu, Yongmei %A Livshits, Gregory %A Ljunggren, Osten %A Loos, Ruth J F %A Lorentzon, Mattias %A Luan, Jian'an %A Luben, Robert N %A Malkin, Ida %A McGuigan, Fiona E %A Medina-Gómez, Carolina %A Meitinger, Thomas %A Melhus, Håkan %A Mellström, Dan %A Michaëlsson, Karl %A Mitchell, Braxton D %A Morris, Andrew P %A Mosekilde, Leif %A Nethander, Maria %A Newman, Anne B %A O'Connell, Jeffery R %A Oostra, Ben A %A Orwoll, Eric S %A Palotie, Aarno %A Peacock, Munro %A Perola, Markus %A Peters, Annette %A Prince, Richard L %A Psaty, Bruce M %A Räikkönen, Katri %A Ralston, Stuart H %A Ripatti, Samuli %A Rivadeneira, Fernando %A Robbins, John A %A Rotter, Jerome I %A Rudan, Igor %A Salomaa, Veikko %A Satterfield, Suzanne %A Schipf, Sabine %A Shin, Chan Soo %A Smith, Albert V %A Smith, Shad B %A Soranzo, Nicole %A Spector, Timothy D %A Stančáková, Alena %A Stefansson, Kari %A Steinhagen-Thiessen, Elisabeth %A Stolk, Lisette %A Streeten, Elizabeth A %A Styrkarsdottir, Unnur %A Swart, Karin M A %A Thompson, Patricia %A Thomson, Cynthia A %A Thorleifsson, Gudmar %A Thorsteinsdottir, Unnur %A Tikkanen, Emmi %A Tranah, Gregory J %A Uitterlinden, André G %A van Duijn, Cornelia M %A van Schoor, Natasja M %A Vandenput, Liesbeth %A Vollenweider, Peter %A Völzke, Henry %A Wactawski-Wende, Jean %A Walker, Mark %A J Wareham, Nicholas %A Waterworth, Dawn %A Weedon, Michael N %A Wichmann, H-Erich %A Widen, Elisabeth %A Williams, Frances M K %A Wilson, James F %A Wright, Nicole C %A Yerges-Armstrong, Laura M %A Yu, Lei %A Zhang, Weihua %A Zhao, Jing Hua %A Zhou, Yanhua %A Nielson, Carrie M %A Harris, Tamara B %A Demissie, Serkalem %A Kiel, Douglas P %A Ohlsson, Claes %X

Background: Lean body mass (LM) plays an important role in mobility and metabolic function. We previously identified five loci associated with LM adjusted for fat mass in kilograms. Such an adjustment may reduce the power to identify genetic signals having an association with both lean mass and fat mass.

Objectives: To determine the impact of different fat mass adjustments on genetic architecture of LM and identify additional LM loci.

Methods: We performed genome-wide association analyses for whole-body LM (20 cohorts of European ancestry with n = 38,292) measured using dual-energy X-ray absorptiometry) or bioelectrical impedance analysis, adjusted for sex, age, age2, and height with or without fat mass adjustments (Model 1 no fat adjustment; Model 2 adjustment for fat mass as a percentage of body mass; Model 3 adjustment for fat mass in kilograms).

Results: Seven single-nucleotide polymorphisms (SNPs) in separate loci, including one novel LM locus (TNRC6B), were successfully replicated in an additional 47,227 individuals from 29 cohorts. Based on the strengths of the associations in Model 1 vs Model 3, we divided the LM loci into those with an effect on both lean mass and fat mass in the same direction and refer to those as "sumo wrestler" loci (FTO and MC4R). In contrast, loci with an impact specifically on LM were termed "body builder" loci (VCAN and ADAMTSL3). Using existing available genome-wide association study databases, LM increasing alleles of SNPs in sumo wrestler loci were associated with an adverse metabolic profile, whereas LM increasing alleles of SNPs in "body builder" loci were associated with metabolic protection.

Conclusions: In conclusion, we identified one novel LM locus (TNRC6B). Our results suggest that a genetically determined increase in lean mass might exert either harmful or protective effects on metabolic traits, depending on its relation to fat mass.

%B Am J Clin Nutr %V 109 %P 276-287 %8 2019 Feb 01 %G eng %N 2 %R 10.1093/ajcn/nqy272 %0 Journal Article %J Am J Hum Genet %D 2019 %T Sequencing Analysis at 8p23 Identifies Multiple Rare Variants in DLC1 Associated with Sleep-Related Oxyhemoglobin Saturation Level. %A Liang, Jingjing %A Cade, Brian E %A He, Karen Y %A Wang, Heming %A Lee, Jiwon %A Sofer, Tamar %A Williams, Stephanie %A Li, Ruitong %A Chen, Han %A Gottlieb, Daniel J %A Evans, Daniel S %A Guo, Xiuqing %A Gharib, Sina A %A Hale, Lauren %A Hillman, David R %A Lutsey, Pamela L %A Mukherjee, Sutapa %A Ochs-Balcom, Heather M %A Palmer, Lyle J %A Rhodes, Jessica %A Purcell, Shaun %A Patel, Sanjay R %A Saxena, Richa %A Stone, Katie L %A Tang, Weihong %A Tranah, Gregory J %A Boerwinkle, Eric %A Lin, Xihong %A Liu, Yongmei %A Psaty, Bruce M %A Vasan, Ramachandran S %A Cho, Michael H %A Manichaikul, Ani %A Silverman, Edwin K %A Barr, R Graham %A Rich, Stephen S %A Rotter, Jerome I %A Wilson, James G %A Redline, Susan %A Zhu, Xiaofeng %X

Average arterial oxyhemoglobin saturation during sleep (AvSpOS) is a clinically relevant measure of physiological stress associated with sleep-disordered breathing, and this measure predicts incident cardiovascular disease and mortality. Using high-depth whole-genome sequencing data from the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) project and focusing on genes with linkage evidence on chromosome 8p23, we observed that six coding and 51 noncoding variants in a gene that encodes the GTPase-activating protein (DLC1) are significantly associated with AvSpOS and replicated in independent subjects. The combined DLC1 association evidence of discovery and replication cohorts reaches genome-wide significance in European Americans (p = 7.9 × 10). A risk score for these variants, built on an independent dataset, explains 0.97% of the AvSpOS variation and contributes to the linkage evidence. The 51 noncoding variants are enriched in regulatory features in a human lung fibroblast cell line and contribute to DLC1 expression variation. Mendelian randomization analysis using these variants indicates a significant causal effect of DLC1 expression in fibroblasts on AvSpOS. Multiple sources of information, including genetic variants, gene expression, and methylation, consistently suggest that DLC1 is a gene associated with AvSpOS.

%B Am J Hum Genet %V 105 %P 1057-1068 %8 2019 Nov 07 %G eng %N 5 %R 10.1016/j.ajhg.2019.10.002 %0 Journal Article %J Genome Med %D 2021 %T Whole-genome association analyses of sleep-disordered breathing phenotypes in the NHLBI TOPMed program. %A Cade, Brian E %A Lee, Jiwon %A Sofer, Tamar %A Wang, Heming %A Zhang, Man %A Chen, Han %A Gharib, Sina A %A Gottlieb, Daniel J %A Guo, Xiuqing %A Lane, Jacqueline M %A Liang, Jingjing %A Lin, Xihong %A Mei, Hao %A Patel, Sanjay R %A Purcell, Shaun M %A Saxena, Richa %A Shah, Neomi A %A Evans, Daniel S %A Hanis, Craig L %A Hillman, David R %A Mukherjee, Sutapa %A Palmer, Lyle J %A Stone, Katie L %A Tranah, Gregory J %A Abecasis, Goncalo R %A Boerwinkle, Eric A %A Correa, Adolfo %A Cupples, L Adrienne %A Kaplan, Robert C %A Nickerson, Deborah A %A North, Kari E %A Psaty, Bruce M %A Rotter, Jerome I %A Rich, Stephen S %A Tracy, Russell P %A Vasan, Ramachandran S %A Wilson, James G %A Zhu, Xiaofeng %A Redline, Susan %X

BACKGROUND: Sleep-disordered breathing is a common disorder associated with significant morbidity. The genetic architecture of sleep-disordered breathing remains poorly understood. Through the NHLBI Trans-Omics for Precision Medicine (TOPMed) program, we performed the first whole-genome sequence analysis of sleep-disordered breathing.

METHODS: The study sample was comprised of 7988 individuals of diverse ancestry. Common-variant and pathway analyses included an additional 13,257 individuals. We examined five complementary traits describing different aspects of sleep-disordered breathing: the apnea-hypopnea index, average oxyhemoglobin desaturation per event, average and minimum oxyhemoglobin saturation across the sleep episode, and the percentage of sleep with oxyhemoglobin saturation < 90%. We adjusted for age, sex, BMI, study, and family structure using MMSKAT and EMMAX mixed linear model approaches. Additional bioinformatics analyses were performed with MetaXcan, GIGSEA, and ReMap.

RESULTS: We identified a multi-ethnic set-based rare-variant association (p = 3.48 × 10) on chromosome X with ARMCX3. Additional rare-variant associations include ARMCX3-AS1, MRPS33, and C16orf90. Novel common-variant loci were identified in the NRG1 and SLC45A2 regions, and previously associated loci in the IL18RAP and ATP2B4 regions were associated with novel phenotypes. Transcription factor binding site enrichment identified associations with genes implicated with respiratory and craniofacial traits. Additional analyses identified significantly associated pathways.

CONCLUSIONS: We have identified the first gene-based rare-variant associations with objectively measured sleep-disordered breathing traits. Our results increase the understanding of the genetic architecture of sleep-disordered breathing and highlight associations in genes that modulate lung development, inflammation, respiratory rhythmogenesis, and HIF1A-mediated hypoxic response.

%B Genome Med %V 13 %P 136 %8 2021 08 26 %G eng %N 1 %R 10.1186/s13073-021-00917-8 %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 %0 Journal Article %J Am J Respir Crit Care Med %D 2022 %T Targeted Genome Sequencing Identifies Multiple Rare Variants in Caveolin-1 Associated with Obstructive Sleep Apnea. %A Liang, Jingjing %A Wang, Heming %A Cade, Brian E %A Kurniansyah, Nuzulul %A He, Karen Y %A Lee, Jiwon %A Sands, Scott A %A Brody, Jennifer %A Chen, Han %A Gottlieb, Daniel J %A Evans, Daniel S %A Guo, Xiuqing %A Gharib, Sina A %A Hale, Lauren %A Hillman, David R %A Lutsey, Pamela L %A Mukherjee, Sutapa %A Ochs-Balcom, Heather M %A Palmer, Lyle J %A Purcell, Shaun %A Saxena, Richa %A Patel, Sanjay R %A Stone, Katie L %A Tranah, Gregory J %A Boerwinkle, Eric %A Lin, Xihong %A Liu, Yongmei %A Psaty, Bruce M %A Vasan, Ramachandran S %A Manichaikul, Ani %A Rich, Stephen S %A Rotter, Jerome I %A Sofer, Tamar %A Redline, Susan %A Zhu, Xiaofeng %X

INTRODUCTION: Obstructive sleep apnea (OSA) is a common disorder associated with increased risk for cardiovascular disease, diabetes, and premature mortality. There is strong clinical and epi-demiologic evidence supporting the importance of genetic factors influencing OSA, but limited data implicating specific genes.

METHODS: Leveraging high depth genomic sequencing data from the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) program and imputed genotype data from multiple population-based studies, we performed linkage analysis in the Cleve-land Family Study (CFS) followed by multi-stage gene-based association analyses in independent cohorts to search for rare variants contributing to OSA severity as assessed by the apnea-hypopnea index (AHI) in a total of 7,708 individuals of European ancestry.

RESULTS: Linkage analysis in CFS identified a suggestive linkage peak on chromosome 7q31 (LOD=2.31). Gene-based analysis identified 21 non-coding rare variants in Caveolin-1 (CAV1) associated with lower AHI after accounting for multiple comparisons (p=7.4×10-8). These non-coding variants together significantly contributed to the linkage evidence (p<10-3). Follow-up anal-ysis revealed significant associations between these variants and increased CAV1 expression, and increased CAV1 expression in peripheral monocytes was associated with lower AHI (p=0.024) and higher minimum overnight oxygen saturation (p=0.007).

CONCLUSION: Rare variants in CAV1, a membrane scaffolding protein essential in multiple cellular and metabolic functions, are associated with higher CAV1 gene expression and lower OSA severity, suggesting a novel target for modulating OSA severity.

%B Am J Respir Crit Care Med %8 2022 Jul 13 %G eng %R 10.1164/rccm.202203-0618OC %0 Journal Article %J medRxiv %D 2023 %T Multi-ancestry genome-wide study in >2.5 million individuals reveals heterogeneity in mechanistic pathways of type 2 diabetes and complications. %A Suzuki, Ken %A Hatzikotoulas, Konstantinos %A Southam, Lorraine %A Taylor, Henry J %A Yin, Xianyong %A Lorenz, Kim M %A Mandla, Ravi %A Huerta-Chagoya, Alicia %A Rayner, Nigel W %A Bocher, Ozvan %A Ana Luiza de, S V Arruda %A Sonehara, Kyuto %A Namba, Shinichi %A Lee, Simon S K %A Preuss, Michael H %A Petty, Lauren E %A Schroeder, Philip %A Vanderwerff, Brett %A Kals, Mart %A Bragg, Fiona %A Lin, Kuang %A Guo, Xiuqing %A Zhang, Weihua %A Yao, Jie %A Kim, Young Jin %A Graff, Mariaelisa %A Takeuchi, Fumihiko %A Nano, Jana %A Lamri, Amel %A Nakatochi, Masahiro %A Moon, Sanghoon %A Scott, Robert A %A Cook, James P %A Lee, Jung-Jin %A Pan, Ian %A Taliun, Daniel %A Parra, Esteban J %A Chai, Jin-Fang %A Bielak, Lawrence F %A Tabara, Yasuharu %A Hai, Yang %A Thorleifsson, Gudmar %A Grarup, Niels %A Sofer, Tamar %A Wuttke, Matthias %A Sarnowski, Chloe %A Gieger, Christian %A Nousome, Darryl %A Trompet, Stella %A Kwak, Soo-Heon %A Long, Jirong %A Sun, Meng %A Tong, Lin %A Chen, Wei-Min %A Nongmaithem, Suraj S %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 Prins, Bram Peter %A Nicolas, Aude %A Yanek, Lisa R %A Chen, Guanjie %A Brody, Jennifer A %A Kabagambe, Edmond %A An, Ping %A Xiang, Anny H %A Choi, Hyeok Sun %A Cade, Brian E %A Tan, Jingyi %A Alaine Broadaway, K %A Williamson, Alice %A Kamali, Zoha %A Cui, Jinrui %A Adair, Linda S %A Adeyemo, Adebowale %A Aguilar-Salinas, Carlos A %A Ahluwalia, Tarunveer S %A Anand, Sonia S %A Bertoni, Alain %A Bork-Jensen, Jette %A Brandslund, Ivan %A Buchanan, Thomas A %A Burant, Charles F %A Butterworth, Adam S %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 Danesh, John %A Das, Swapan K %A Janaka de Silva, H %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 Franco, Oscar H %A Frayling, Timothy M %A Freedman, Barry I %A Genter, Pauline %A Gerstein, Hertzel C %A Giedraitis, Vilmantas %A González-Villalpando, Clicerio %A Gonzalez-Villalpando, Maria Elena %A Gordon-Larsen, Penny %A Gross, Myron %A Guare, Lindsay A %A Hackinger, Sophie %A Han, Sohee %A Hattersley, Andrew T %A Herder, Christian %A Horikoshi, Momoko %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, Torben %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 Kronenberg, Florian %A Kuusisto, Johanna %A Läll, Kristi %A Lange, Leslie A %A Lee, Kyung Min %A Lee, Myung-Shik %A Lee, Nanette R %A Leong, Aaron %A Li, Liming %A Li, Yun %A Li-Gao, Ruifang %A Lithgart, 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 Lynch, Julie A %A Lyssenko, Valeriya %A Maeda, Shiro %A Mamakou, Vasiliki %A Mansuri, Sohail Rafik %A Matsuda, Koichi %A Meitinger, Thomas %A Metspalu, Andres %A Mo, Huan %A Morris, Andrew D %A Nadler, Jerry L %A Nalls, Michael A %A Nayak, Uma %A Ntalla, Ioanna %A Okada, Yukinori %A Orozco, Lorena %A Patel, Sanjay R %A Patil, Snehal %A Pei, Pei %A Pereira, Mark A %A Peters, Annette %A Pirie, Fraser J %A Polikowsky, Hannah G %A Porneala, Bianca %A Prasad, Gauri %A Rasmussen-Torvik, Laura J %A Reiner, Alexander P %A Roden, Michael %A Rohde, Rebecca %A Roll, Katheryn %A Sabanayagam, Charumathi %A Sandow, Kevin %A Sankareswaran, Alagu %A Sattar, Naveed %A Schönherr, Sebastian %A Shahriar, Mohammad %A Shen, Botong %A Shi, Jinxiu %A Shin, Dong Mun %A Shojima, Nobuhiro %A Smith, Jennifer A %A So, Wing Yee %A Stančáková, Alena %A Steinthorsdottir, Valgerdur %A Stilp, Adrienne M %A Strauch, Konstantin %A Taylor, Kent D %A Thorand, Barbara %A Thorsteinsdottir, Unnur %A Tomlinson, Brian %A Tran, Tam C %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 Wacher-Rodarte, Niels %A Wheeler, Eleanor %A Wickremasinghe, Ananda R %A van Dijk, Ko Willems %A Witte, Daniel R %A Yajnik, Chittaranjan S %A Yamamoto, Ken %A Yamamoto, Kenichi %A Yoon, Kyungheon %A Yu, Canqing %A Yuan, Jian-Min %A Yusuf, Salim %A Zawistowski, Matthew %A Zhang, Liang %A Zheng, Wei %A Project, Biobank Japan %A BioBank, Penn Medicine %A Center, Regeneron Genetics %A Consortium, eMERGE %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 Fornage, Myriam %A Hanis, Craig L %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 Yokota, Mitsuhiro %A Kardia, Sharon L R %A Peyser, Patricia A %A Pankow, James S %A Engert, James C %A Bonnefond, Amélie %A Froguel, Philippe %A Wilson, James G %A Sheu, Wayne H H %A Wu, Jer-Yuarn %A Geoffrey Hayes, M %A Ma, Ronald C W %A Wong, Tien-Yin %A Mook-Kanamori, Dennis O %A Tuomi, Tiinamaija %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 Chen, Yii-Der Ida %A Rich, Stephen S %A McKean-Cowdin, Roberta %A Grallert, Harald %A Cheng, Ching-Yu %A Ghanbari, Mohsen %A Tai, E-Shyong %A Dupuis, Josée %A Kato, Norihiro %A Laakso, Markku %A Köttgen, Anna %A Koh, Woon-Puay %A Bowden, Donald W %A Palmer, Colin N A %A Kooner, Jaspal S %A Kooperberg, Charles %A Liu, Simin %A North, Kari E %A Saleheen, Danish %A Hansen, Torben %A Pedersen, Oluf %A Wareham, Nicholas J %A Lee, Juyoung %A Kim, Bong-Jo %A Millwood, Iona Y %A Walters, Robin G %A Stefansson, Kari %A Goodarzi, Mark O %A Mohlke, Karen L %A Langenberg, Claudia %A Haiman, Christopher A %A Loos, Ruth J F %A Florez, Jose C %A Rader, Daniel J %A Ritchie, Marylyn D %A Zöllner, Sebastian %A Mägi, Reedik %A Denny, Joshua C %A Yamauchi, Toshimasa %A Kadowaki, Takashi %A Chambers, John C %A Ng, Maggie C Y %A Sim, Xueling %A Below, Jennifer E %A Tsao, Philip S %A Chang, Kyong-Mi %A McCarthy, Mark I %A Meigs, James B %A Mahajan, Anubha %A Spracklen, Cassandra N %A Mercader, Josep M %A Boehnke, Michael %A Rotter, Jerome I %A Vujkovic, Marijana %A Voight, Benjamin F %A Morris, Andrew P %A Zeggini, Eleftheria %X

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes. To characterise the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study (GWAS) data from 2,535,601 individuals (39.7% non-European ancestry), including 428,452 T2D cases. We identify 1,289 independent association signals at genome-wide significance (P<5×10 ) that map to 611 loci, of which 145 loci are previously unreported. We define eight non-overlapping clusters of T2D signals characterised by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial, and enteroendocrine cells. We build cluster-specific partitioned genetic risk scores (GRS) in an additional 137,559 individuals of diverse ancestry, including 10,159 T2D cases, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned GRS are more strongly associated with coronary artery disease and end-stage diabetic nephropathy than an overall T2D GRS across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings demonstrate the value of integrating multi-ancestry GWAS with single-cell epigenomics to disentangle the aetiological heterogeneity driving the development and progression of T2D, which may offer a route to optimise global access to genetically-informed diabetes care.

%B medRxiv %8 2023 Mar 31 %G eng %R 10.1101/2023.03.31.23287839 %0 Journal Article %J Nature %D 2024 %T Genetic drivers of heterogeneity in type 2 diabetes pathophysiology. %A Suzuki, Ken %A Hatzikotoulas, Konstantinos %A Southam, Lorraine %A Taylor, Henry J %A Yin, Xianyong %A Lorenz, Kim M %A Mandla, Ravi %A Huerta-Chagoya, Alicia %A Melloni, Giorgio E M %A Kanoni, Stavroula %A Rayner, Nigel W %A Bocher, Ozvan %A Arruda, Ana Luiza %A Sonehara, Kyuto %A Namba, Shinichi %A Lee, Simon S K %A Preuss, Michael H %A Petty, Lauren E %A Schroeder, Philip %A Vanderwerff, Brett %A Kals, Mart %A Bragg, Fiona %A Lin, Kuang %A Guo, Xiuqing %A Zhang, Weihua %A Yao, Jie %A Kim, Young Jin %A Graff, Mariaelisa %A Takeuchi, Fumihiko %A Nano, Jana %A Lamri, Amel %A Nakatochi, Masahiro %A Moon, Sanghoon %A Scott, Robert A %A Cook, James P %A Lee, Jung-Jin %A Pan, Ian %A Taliun, Daniel %A Parra, Esteban J %A Chai, Jin-Fang %A Bielak, Lawrence F %A Tabara, Yasuharu %A Hai, Yang %A Thorleifsson, Gudmar %A Grarup, Niels %A Sofer, Tamar %A Wuttke, Matthias %A Sarnowski, Chloe %A Gieger, Christian %A Nousome, Darryl %A Trompet, Stella %A Kwak, Soo-Heon %A Long, Jirong %A Sun, Meng %A Tong, Lin %A Chen, Wei-Min %A Nongmaithem, Suraj S %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 Prins, Bram Peter %A Nicolas, Aude %A Yanek, Lisa R %A Chen, Guanjie %A Brody, Jennifer A %A Kabagambe, Edmond %A An, Ping %A Xiang, Anny H %A Choi, Hyeok Sun %A Cade, Brian E %A Tan, Jingyi %A Broadaway, K Alaine %A Williamson, Alice %A Kamali, Zoha %A Cui, Jinrui %A Thangam, Manonanthini %A Adair, Linda S %A Adeyemo, Adebowale %A Aguilar-Salinas, Carlos A %A Ahluwalia, Tarunveer S %A Anand, Sonia S %A Bertoni, Alain %A Bork-Jensen, Jette %A Brandslund, Ivan %A Buchanan, Thomas A %A Burant, Charles F %A Butterworth, Adam S %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 Danesh, John %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 Franco, Oscar H %A Frayling, Timothy M %A Freedman, Barry I %A Genter, Pauline %A Gerstein, Hertzel C %A Giedraitis, Vilmantas %A González-Villalpando, Clicerio %A Gonzalez-Villalpando, Maria Elena %A Gordon-Larsen, Penny %A Gross, Myron %A Guare, Lindsay A %A Hackinger, Sophie %A Hakaste, Liisa %A Han, Sohee %A Hattersley, Andrew T %A Herder, Christian %A Horikoshi, Momoko %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, Torben %A Kamanu, Frederick K %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 Kronenberg, Florian %A Kuusisto, Johanna %A Läll, Kristi %A Lange, Leslie A %A Lee, Kyung Min %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 Lynch, Julie A %A Lyssenko, Valeriya %A Maeda, Shiro %A Mamakou, Vasiliki %A Mansuri, Sohail Rafik %A Matsuda, Koichi %A Meitinger, Thomas %A Melander, Olle %A Metspalu, Andres %A Mo, Huan %A Morris, Andrew D %A Moura, Filipe A %A Nadler, Jerry L %A Nalls, Michael A %A Nayak, Uma %A Ntalla, Ioanna %A Okada, Yukinori %A Orozco, Lorena %A Patel, Sanjay R %A Patil, Snehal %A Pei, Pei %A Pereira, Mark A %A Peters, Annette %A Pirie, Fraser J %A Polikowsky, Hannah G %A Porneala, Bianca %A Prasad, Gauri %A Rasmussen-Torvik, Laura J %A Reiner, Alexander P %A Roden, Michael %A Rohde, Rebecca %A Roll, Katheryn %A Sabanayagam, Charumathi %A Sandow, Kevin %A Sankareswaran, Alagu %A Sattar, Naveed %A Schönherr, Sebastian %A Shahriar, Mohammad %A Shen, Botong %A Shi, Jinxiu %A Shin, Dong Mun %A Shojima, Nobuhiro %A Smith, Jennifer A %A So, Wing Yee %A Stančáková, Alena %A Steinthorsdottir, Valgerdur %A Stilp, Adrienne M %A Strauch, Konstantin %A Taylor, Kent D %A Thorand, Barbara %A Thorsteinsdottir, Unnur %A Tomlinson, Brian %A Tran, Tam C %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 Wacher-Rodarte, Niels %A Wheeler, Eleanor %A Wickremasinghe, Ananda R %A van Dijk, Ko Willems %A Witte, Daniel R %A Yajnik, Chittaranjan S %A Yamamoto, Ken %A Yamamoto, Kenichi %A Yoon, Kyungheon %A Yu, Canqing %A Yuan, Jian-Min %A Yusuf, Salim %A Zawistowski, Matthew %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 Fornage, Myriam %A Hanis, Craig L %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 Yokota, Mitsuhiro %A Kardia, Sharon L R %A Peyser, Patricia A %A Pankow, James S %A Engert, James C %A Bonnefond, Amélie %A Froguel, Philippe %A Wilson, James G %A Sheu, Wayne H H %A Wu, Jer-Yuarn %A Hayes, M Geoffrey %A Ma, Ronald C W %A Wong, Tien-Yin %A Mook-Kanamori, Dennis O %A Tuomi, Tiinamaija %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 Chen, Yii-Der Ida %A Rich, Stephen S %A McKean-Cowdin, Roberta %A Grallert, Harald %A Cheng, Ching-Yu %A Ghanbari, Mohsen %A Tai, E-Shyong %A Dupuis, Josée %A Kato, Norihiro %A Laakso, Markku %A Köttgen, Anna %A Koh, Woon-Puay %A Bowden, Donald W %A Palmer, Colin N A %A Kooner, Jaspal S %A Kooperberg, Charles %A Liu, Simin %A North, Kari E %A Saleheen, Danish %A Hansen, Torben %A Pedersen, Oluf %A Wareham, Nicholas J %A Lee, Juyoung %A Kim, Bong-Jo %A Millwood, Iona Y %A Walters, Robin G %A Stefansson, Kari %A Ahlqvist, Emma %A Goodarzi, Mark O %A Mohlke, Karen L %A Langenberg, Claudia %A Haiman, Christopher A %A Loos, Ruth J F %A Florez, Jose C %A Rader, Daniel J %A Ritchie, Marylyn D %A Zöllner, Sebastian %A Mägi, Reedik %A Marston, Nicholas A %A Ruff, Christian T %A van Heel, David A %A Finer, Sarah %A Denny, Joshua C %A Yamauchi, Toshimasa %A Kadowaki, Takashi %A Chambers, John C %A Ng, Maggie C Y %A Sim, Xueling %A Below, Jennifer E %A Tsao, Philip S %A Chang, Kyong-Mi %A McCarthy, Mark I %A Meigs, James B %A Mahajan, Anubha %A Spracklen, Cassandra N %A Mercader, Josep M %A Boehnke, Michael %A Rotter, Jerome I %A Vujkovic, Marijana %A Voight, Benjamin F %A Morris, Andrew P %A Zeggini, Eleftheria %X

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes and molecular mechanisms that are often specific to cell type. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P < 5 × 10) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care.

%B Nature %8 2024 Feb 19 %G eng %R 10.1038/s41586-024-07019-6