TY - JOUR T1 - Genome-Wide Association Study Meta-Analysis of Long-Term Average Blood Pressure in East Asians. JF - Circ Cardiovasc Genet Y1 - 2017 A1 - Li, Changwei A1 - Kim, Yun Kyoung A1 - Dorajoo, Rajkumar A1 - Li, Huaixing A1 - Lee, I-Te A1 - Cheng, Ching-Yu A1 - He, Meian A1 - Sheu, Wayne H-H A1 - Guo, Xiuqing A1 - Ganesh, Santhi K A1 - He, Jiang A1 - Lee, Juyoung A1 - Liu, Jianjun A1 - Hu, Yao A1 - Rao, Dabeeru C A1 - Tsai, Fuu-Jen A1 - Koh, Jia Yu A1 - Hu, Hua A1 - Liang, Kae-Woei A1 - Palmas, Walter A1 - Hixson, James E A1 - Han, Sohee A1 - Teo, Yik-Ying A1 - Wang, Yiqin A1 - Chen, Jing A1 - Lu, Chieh Hsiang A1 - Zheng, Yingfeng A1 - Gui, Lixuan A1 - Lee, Wen-Jane A1 - Yao, Jie A1 - Gu, Dongfeng A1 - Han, Bok-Ghee A1 - Sim, Xueling A1 - Sun, Liang A1 - Zhao, Jinying A1 - Chen, Chien-Hsiun A1 - Kumari, Neelam A1 - He, Yunfeng A1 - Taylor, Kent D A1 - Raffel, Leslie J A1 - Moon, Sanghoon A1 - Rotter, Jerome I A1 - Ida Chen, Yii-Der A1 - Wu, Tangchun A1 - Wong, Tien Yin A1 - Wu, Jer-Yuarn A1 - Lin, Xu A1 - Tai, E-Shyong A1 - Kim, Bong-Jo A1 - Kelly, Tanika N KW - Asian Continental Ancestry Group KW - Blood Pressure KW - Far East KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Humans KW - Male KW - Phenotype KW - Polymorphism, Single Nucleotide AB -

BACKGROUND: Genome-wide single marker and gene-based meta-analyses of long-term average (LTA) blood pressure (BP) phenotypes may reveal novel findings for BP.

METHODS AND RESULTS: We conducted genome-wide analysis among 18 422 East Asian participants (stage 1) followed by replication study of ≤46 629 participants of European ancestry (stage 2). Significant single-nucleotide polymorphisms and genes were determined by a P<5.0×10-8 and 2.5×10-6, respectively, in joint analyses of stage-1 and stage-2 data. We identified 1 novel ARL3 variant, rs4919669 at 10q24.32, influencing LTA systolic BP (stage-1 P=5.03×10-8, stage-2 P=8.64×10-3, joint P=2.63×10-8) and mean arterial pressure (stage-1 P=3.59×10-9, stage-2 P=2.35×10-2, joint P=2.64×10-8). Three previously reported BP loci (WBP1L, NT5C2, and ATP2B1) were also identified for all BP phenotypes. Gene-based analysis provided the first robust evidence for association of KCNJ11 with LTA systolic BP (stage-1 P=8.55×10-6, stage-2 P=1.62×10-5, joint P=3.28×10-9) and mean arterial pressure (stage-1 P=9.19×10-7, stage-2 P=9.69×10-5, joint P=2.15×10-9) phenotypes. Fourteen genes (TMEM180, ACTR1A, SUFU, ARL3, SFXN2, WBP1L, CYP17A1, C10orf32, C10orf32-ASMT, AS3MT, CNNM2, and NT5C2 at 10q24.32; ATP2B1 at 12q21.33; and NCR3LG1 at 11p15.1) implicated by previous genome-wide association study meta-analyses were also identified. Among the loci identified by the previous genome-wide association study meta-analysis of LTA BP, we transethnically replicated associations of the KCNK3 marker rs1275988 at 2p23.3 with LTA systolic BP and mean arterial pressure phenotypes (P=1.27×10-4 and 3.30×10-4, respectively).

CONCLUSIONS: We identified 1 novel variant and 1 novel gene and present the first direct evidence of relevance of the KCNK3 locus for LTA BP among East Asians.

VL - 10 IS - 2 ER - TY - JOUR T1 - A Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure. JF - Am J Hum Genet Y1 - 2018 A1 - Sung, Yun J A1 - Winkler, Thomas W A1 - de Las Fuentes, Lisa A1 - Bentley, Amy R A1 - Brown, Michael R A1 - Kraja, Aldi T A1 - Schwander, Karen A1 - Ntalla, Ioanna A1 - Guo, Xiuqing A1 - Franceschini, Nora A1 - Lu, Yingchang A1 - Cheng, Ching-Yu A1 - Sim, Xueling A1 - Vojinovic, Dina A1 - Marten, Jonathan A1 - Musani, Solomon K A1 - Li, Changwei A1 - Feitosa, Mary F A1 - Kilpeläinen, Tuomas O A1 - Richard, Melissa A A1 - Noordam, Raymond A1 - Aslibekyan, Stella A1 - Aschard, Hugues A1 - Bartz, Traci M A1 - Dorajoo, Rajkumar A1 - Liu, Yongmei A1 - Manning, Alisa K A1 - Rankinen, Tuomo A1 - Smith, Albert Vernon A1 - Tajuddin, Salman M A1 - Tayo, Bamidele O A1 - Warren, Helen R A1 - Zhao, Wei A1 - Zhou, Yanhua A1 - Matoba, Nana A1 - Sofer, Tamar A1 - Alver, Maris A1 - Amini, Marzyeh A1 - Boissel, Mathilde A1 - Chai, Jin Fang A1 - Chen, Xu A1 - Divers, Jasmin A1 - Gandin, Ilaria A1 - Gao, Chuan A1 - Giulianini, Franco A1 - Goel, Anuj A1 - Harris, Sarah E A1 - Hartwig, Fernando Pires A1 - Horimoto, Andrea R V R A1 - Hsu, Fang-Chi A1 - Jackson, Anne U A1 - Kähönen, Mika A1 - Kasturiratne, Anuradhani A1 - Kuhnel, Brigitte A1 - Leander, Karin A1 - Lee, Wen-Jane A1 - Lin, Keng-Hung A1 - 'an Luan, Jian A1 - McKenzie, Colin A A1 - Meian, He A1 - Nelson, Christopher P A1 - Rauramaa, Rainer A1 - Schupf, Nicole A1 - Scott, Robert A A1 - Sheu, Wayne H H A1 - Stančáková, Alena A1 - Takeuchi, Fumihiko A1 - van der Most, Peter J A1 - Varga, Tibor V A1 - Wang, Heming A1 - Wang, Yajuan A1 - Ware, Erin B A1 - Weiss, Stefan A1 - Wen, Wanqing A1 - Yanek, Lisa R A1 - Zhang, Weihua A1 - Zhao, Jing Hua A1 - Afaq, Saima A1 - Alfred, Tamuno A1 - Amin, Najaf A1 - Arking, Dan A1 - Aung, Tin A1 - Barr, R Graham A1 - Bielak, Lawrence F A1 - Boerwinkle, Eric A1 - Bottinger, Erwin P A1 - Braund, Peter S A1 - Brody, Jennifer A A1 - Broeckel, Ulrich A1 - Cabrera, Claudia P A1 - Cade, Brian A1 - Caizheng, Yu A1 - Campbell, Archie A1 - Canouil, Mickaël A1 - Chakravarti, Aravinda A1 - Chauhan, Ganesh A1 - Christensen, Kaare A1 - Cocca, Massimiliano A1 - Collins, Francis S A1 - Connell, John M A1 - de Mutsert, Renée A1 - de Silva, H Janaka A1 - Debette, Stephanie A1 - Dörr, Marcus A1 - Duan, Qing A1 - Eaton, Charles B A1 - Ehret, Georg A1 - Evangelou, Evangelos A1 - Faul, Jessica D A1 - Fisher, Virginia A A1 - Forouhi, Nita G A1 - Franco, Oscar H A1 - Friedlander, Yechiel A1 - Gao, He A1 - Gigante, Bruna A1 - Graff, Misa A1 - Gu, C Charles A1 - Gu, Dongfeng A1 - Gupta, Preeti A1 - Hagenaars, Saskia P A1 - Harris, Tamara B A1 - He, Jiang A1 - Heikkinen, Sami A1 - Heng, Chew-Kiat A1 - Hirata, Makoto A1 - Hofman, Albert A1 - Howard, Barbara V A1 - Hunt, Steven A1 - Irvin, Marguerite R A1 - Jia, Yucheng A1 - Joehanes, Roby A1 - Justice, Anne E A1 - Katsuya, Tomohiro A1 - Kaufman, Joel A1 - Kerrison, Nicola D A1 - Khor, Chiea Chuen A1 - Koh, Woon-Puay A1 - Koistinen, Heikki A A1 - Komulainen, Pirjo A1 - Kooperberg, Charles A1 - Krieger, Jose E A1 - Kubo, Michiaki A1 - Kuusisto, Johanna A1 - Langefeld, Carl D A1 - Langenberg, Claudia A1 - Launer, Lenore J A1 - Lehne, Benjamin A1 - Lewis, Cora E A1 - Li, Yize A1 - Lim, Sing Hui A1 - Lin, Shiow A1 - Liu, Ching-Ti A1 - Liu, Jianjun A1 - Liu, Jingmin A1 - Liu, Kiang A1 - Liu, Yeheng A1 - Loh, Marie A1 - Lohman, Kurt K A1 - Long, Jirong A1 - Louie, Tin A1 - Mägi, Reedik A1 - Mahajan, Anubha A1 - Meitinger, Thomas A1 - Metspalu, Andres A1 - Milani, Lili A1 - Momozawa, Yukihide A1 - Morris, Andrew P A1 - Mosley, Thomas H A1 - Munson, Peter A1 - Murray, Alison D A1 - Nalls, Mike A A1 - Nasri, Ubaydah A1 - Norris, Jill M A1 - North, Kari A1 - Ogunniyi, Adesola A1 - Padmanabhan, Sandosh A1 - Palmas, Walter R A1 - Palmer, Nicholette D A1 - Pankow, James S A1 - Pedersen, Nancy L A1 - Peters, Annette A1 - Peyser, Patricia A A1 - Polasek, Ozren A1 - Raitakari, Olli T A1 - Renstrom, Frida A1 - Rice, Treva K A1 - Ridker, Paul M A1 - Robino, Antonietta A1 - Robinson, Jennifer G A1 - Rose, Lynda M A1 - Rudan, Igor A1 - Sabanayagam, Charumathi A1 - Salako, Babatunde L A1 - Sandow, Kevin A1 - Schmidt, Carsten O A1 - Schreiner, Pamela J A1 - Scott, William R A1 - Seshadri, Sudha A1 - Sever, Peter A1 - Sitlani, Colleen M A1 - Smith, Jennifer A A1 - Snieder, Harold A1 - Starr, John M A1 - Strauch, Konstantin A1 - Tang, Hua A1 - Taylor, Kent D A1 - Teo, Yik Ying A1 - Tham, Yih Chung A1 - Uitterlinden, André G A1 - Waldenberger, Melanie A1 - Wang, Lihua A1 - Wang, Ya X A1 - Wei, Wen Bin A1 - Williams, Christine A1 - Wilson, Gregory A1 - Wojczynski, Mary K A1 - Yao, Jie A1 - Yuan, Jian-Min A1 - Zonderman, Alan B A1 - Becker, Diane M A1 - Boehnke, Michael A1 - Bowden, Donald W A1 - Chambers, John C A1 - Chen, Yii-Der Ida A1 - de Faire, Ulf A1 - Deary, Ian J A1 - Esko, Tõnu A1 - Farrall, Martin A1 - Forrester, Terrence A1 - Franks, Paul W A1 - Freedman, Barry I A1 - Froguel, Philippe A1 - Gasparini, Paolo A1 - Gieger, Christian A1 - Horta, Bernardo Lessa A1 - Hung, Yi-Jen A1 - Jonas, Jost B A1 - Kato, Norihiro A1 - Kooner, Jaspal S A1 - Laakso, Markku A1 - Lehtimäki, Terho A1 - Liang, Kae-Woei A1 - Magnusson, Patrik K E A1 - Newman, Anne B A1 - Oldehinkel, Albertine J A1 - Pereira, Alexandre C A1 - Redline, Susan A1 - Rettig, Rainer A1 - Samani, Nilesh J A1 - Scott, James A1 - Shu, Xiao-Ou A1 - van der Harst, Pim A1 - Wagenknecht, Lynne E A1 - Wareham, Nicholas J A1 - Watkins, Hugh A1 - Weir, David R A1 - Wickremasinghe, Ananda R A1 - Wu, Tangchun A1 - Zheng, Wei A1 - Kamatani, Yoichiro A1 - Laurie, Cathy C A1 - Bouchard, Claude A1 - Cooper, Richard S A1 - Evans, Michele K A1 - Gudnason, Vilmundur A1 - Kardia, Sharon L R A1 - Kritchevsky, Stephen B A1 - Levy, Daniel A1 - O'Connell, Jeff R A1 - Psaty, Bruce M A1 - van Dam, Rob M A1 - Sims, Mario A1 - Arnett, Donna K A1 - Mook-Kanamori, Dennis O A1 - Kelly, Tanika N A1 - Fox, Ervin R A1 - Hayward, Caroline A1 - Fornage, Myriam A1 - Rotimi, Charles N A1 - Province, Michael A A1 - van Duijn, Cornelia M A1 - Tai, E Shyong A1 - Wong, Tien Yin A1 - Loos, Ruth J F A1 - Reiner, Alex P A1 - Rotter, Jerome I A1 - Zhu, Xiaofeng A1 - Bierut, Laura J A1 - Gauderman, W James A1 - Caulfield, Mark J A1 - Elliott, Paul A1 - Rice, Kenneth A1 - Munroe, Patricia B A1 - Morrison, Alanna C A1 - Cupples, L Adrienne A1 - Rao, Dabeeru C A1 - Chasman, Daniel I AB -

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

VL - 102 IS - 3 ER - TY - JOUR T1 - Novel genetic associations for blood pressure identified via gene-alcohol interaction in up to 570K individuals across multiple ancestries. JF - PLoS One Y1 - 2018 A1 - Feitosa, Mary F A1 - Kraja, Aldi T A1 - Chasman, Daniel I A1 - Sung, Yun J A1 - Winkler, Thomas W A1 - Ntalla, Ioanna A1 - Guo, Xiuqing A1 - Franceschini, Nora A1 - Cheng, Ching-Yu A1 - Sim, Xueling A1 - Vojinovic, Dina A1 - Marten, Jonathan A1 - Musani, Solomon K A1 - Li, Changwei A1 - Bentley, Amy R A1 - Brown, Michael R A1 - Schwander, Karen A1 - Richard, Melissa A A1 - Noordam, Raymond A1 - Aschard, Hugues A1 - Bartz, Traci M A1 - Bielak, Lawrence F A1 - Dorajoo, Rajkumar A1 - Fisher, Virginia A1 - Hartwig, Fernando P A1 - Horimoto, Andrea R V R A1 - Lohman, Kurt K A1 - Manning, Alisa K A1 - Rankinen, Tuomo A1 - Smith, Albert V A1 - Tajuddin, Salman M A1 - Wojczynski, Mary K A1 - Alver, Maris A1 - Boissel, Mathilde A1 - Cai, Qiuyin A1 - Campbell, Archie A1 - Chai, Jin Fang A1 - Chen, Xu A1 - Divers, Jasmin A1 - Gao, Chuan A1 - Goel, Anuj A1 - Hagemeijer, Yanick A1 - Harris, Sarah E A1 - He, Meian A1 - Hsu, Fang-Chi A1 - Jackson, Anne U A1 - Kähönen, Mika A1 - Kasturiratne, Anuradhani A1 - Komulainen, Pirjo A1 - Kuhnel, Brigitte A1 - Laguzzi, Federica A1 - Luan, Jian'an A1 - Matoba, Nana A1 - Nolte, Ilja M A1 - Padmanabhan, Sandosh A1 - Riaz, Muhammad A1 - Rueedi, Rico A1 - Robino, Antonietta A1 - Said, M Abdullah A1 - Scott, Robert A A1 - Sofer, Tamar A1 - Stančáková, Alena A1 - Takeuchi, Fumihiko A1 - Tayo, Bamidele O A1 - van der Most, Peter J A1 - Varga, Tibor V A1 - Vitart, Veronique A1 - Wang, Yajuan A1 - Ware, Erin B A1 - Warren, Helen R A1 - Weiss, Stefan A1 - Wen, Wanqing A1 - Yanek, Lisa R A1 - Zhang, Weihua A1 - Zhao, Jing Hua A1 - Afaq, Saima A1 - Amin, Najaf A1 - Amini, Marzyeh A1 - Arking, Dan E A1 - Aung, Tin A1 - Boerwinkle, Eric A1 - Borecki, Ingrid A1 - Broeckel, Ulrich A1 - Brown, Morris A1 - Brumat, Marco A1 - Burke, Gregory L A1 - Canouil, Mickaël A1 - Chakravarti, Aravinda A1 - Charumathi, Sabanayagam A1 - Ida Chen, Yii-Der A1 - Connell, John M A1 - Correa, Adolfo A1 - de Las Fuentes, Lisa A1 - de Mutsert, Renée A1 - de Silva, H Janaka A1 - Deng, Xuan A1 - Ding, Jingzhong A1 - Duan, Qing A1 - Eaton, Charles B A1 - Ehret, Georg A1 - Eppinga, Ruben N A1 - Evangelou, Evangelos A1 - Faul, Jessica D A1 - Felix, Stephan B A1 - Forouhi, Nita G A1 - Forrester, Terrence A1 - Franco, Oscar H A1 - Friedlander, Yechiel A1 - Gandin, Ilaria A1 - Gao, He A1 - Ghanbari, Mohsen A1 - Gigante, Bruna A1 - Gu, C Charles A1 - Gu, Dongfeng A1 - Hagenaars, Saskia P A1 - Hallmans, Göran A1 - Harris, Tamara B A1 - He, Jiang A1 - Heikkinen, Sami A1 - Heng, Chew-Kiat A1 - Hirata, Makoto A1 - Howard, Barbara V A1 - Ikram, M Arfan A1 - John, Ulrich A1 - Katsuya, Tomohiro A1 - Khor, Chiea Chuen A1 - Kilpeläinen, Tuomas O A1 - Koh, Woon-Puay A1 - Krieger, Jose E A1 - Kritchevsky, Stephen B A1 - Kubo, Michiaki A1 - Kuusisto, Johanna A1 - Lakka, Timo A A1 - Langefeld, Carl D A1 - Langenberg, Claudia A1 - Launer, Lenore J A1 - Lehne, Benjamin A1 - Lewis, Cora E A1 - Li, Yize A1 - Lin, Shiow A1 - Liu, Jianjun A1 - Liu, Jingmin A1 - Loh, Marie A1 - Louie, Tin A1 - Mägi, Reedik A1 - McKenzie, Colin A A1 - Meitinger, Thomas A1 - Metspalu, Andres A1 - Milaneschi, Yuri A1 - Milani, Lili A1 - Mohlke, Karen L A1 - Momozawa, Yukihide A1 - Nalls, Mike A A1 - Nelson, Christopher P A1 - Sotoodehnia, Nona A1 - Norris, Jill M A1 - O'Connell, Jeff R A1 - Palmer, Nicholette D A1 - Perls, Thomas A1 - Pedersen, Nancy L A1 - Peters, Annette A1 - Peyser, Patricia A A1 - Poulter, Neil A1 - Raffel, Leslie J A1 - Raitakari, Olli T A1 - Roll, Kathryn A1 - Rose, Lynda M A1 - Rosendaal, Frits R A1 - Rotter, Jerome I A1 - Schmidt, Carsten O A1 - Schreiner, Pamela J A1 - Schupf, Nicole A1 - Scott, William R A1 - Sever, Peter S A1 - Shi, Yuan A1 - Sidney, Stephen A1 - Sims, Mario A1 - Sitlani, Colleen M A1 - Smith, Jennifer A A1 - Snieder, Harold A1 - Starr, John M A1 - Strauch, Konstantin A1 - Stringham, Heather M A1 - Tan, Nicholas Y Q A1 - Tang, Hua A1 - Taylor, Kent D A1 - Teo, Yik Ying A1 - Tham, Yih Chung A1 - Turner, Stephen T A1 - Uitterlinden, André G A1 - Vollenweider, Peter A1 - Waldenberger, Melanie A1 - Wang, Lihua A1 - Wang, Ya Xing A1 - Wei, Wen Bin A1 - Williams, Christine A1 - Yao, Jie A1 - Yu, Caizheng A1 - Yuan, Jian-Min A1 - Zhao, Wei A1 - Zonderman, Alan B A1 - Becker, Diane M A1 - Boehnke, Michael A1 - Bowden, Donald W A1 - Chambers, John C A1 - Deary, Ian J A1 - Esko, Tõnu A1 - Farrall, Martin A1 - Franks, Paul W A1 - Freedman, Barry I A1 - Froguel, Philippe A1 - Gasparini, Paolo A1 - Gieger, Christian A1 - Jonas, Jost Bruno A1 - Kamatani, Yoichiro A1 - Kato, Norihiro A1 - Kooner, Jaspal S A1 - Kutalik, Zoltán A1 - Laakso, Markku A1 - Laurie, Cathy C A1 - Leander, Karin A1 - Lehtimäki, Terho A1 - Study, Lifelines Cohort A1 - Magnusson, Patrik K E A1 - Oldehinkel, Albertine J A1 - Penninx, Brenda W J H A1 - Polasek, Ozren A1 - Porteous, David J A1 - Rauramaa, Rainer A1 - Samani, Nilesh J A1 - Scott, James A1 - Shu, Xiao-Ou A1 - van der Harst, Pim A1 - Wagenknecht, Lynne E A1 - Wareham, Nicholas J A1 - Watkins, Hugh A1 - Weir, David R A1 - Wickremasinghe, Ananda R A1 - Wu, Tangchun A1 - Zheng, Wei A1 - Bouchard, Claude A1 - Christensen, Kaare A1 - Evans, Michele K A1 - Gudnason, Vilmundur A1 - Horta, Bernardo L A1 - Kardia, Sharon L R A1 - Liu, Yongmei A1 - Pereira, Alexandre C A1 - Psaty, Bruce M A1 - Ridker, Paul M A1 - van Dam, Rob M A1 - Gauderman, W James A1 - Zhu, Xiaofeng A1 - Mook-Kanamori, Dennis O A1 - Fornage, Myriam A1 - Rotimi, Charles N A1 - Cupples, L Adrienne A1 - Kelly, Tanika N A1 - Fox, Ervin R A1 - Hayward, Caroline A1 - van Duijn, Cornelia M A1 - Tai, E Shyong A1 - Wong, Tien Yin A1 - Kooperberg, Charles A1 - Palmas, Walter A1 - Rice, Kenneth A1 - Morrison, Alanna C A1 - Elliott, Paul A1 - Caulfield, Mark J A1 - Munroe, Patricia B A1 - Rao, Dabeeru C A1 - Province, Michael A A1 - Levy, Daniel AB -

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

VL - 13 IS - 6 ER - TY - JOUR T1 - Multi-Ancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions. JF - Am J Epidemiol Y1 - 2019 A1 - de Vries, Paul S A1 - Brown, Michael R A1 - Bentley, Amy R A1 - Sung, Yun J A1 - Winkler, Thomas W A1 - Ntalla, Ioanna A1 - Schwander, Karen A1 - Kraja, Aldi T A1 - Guo, Xiuqing A1 - Franceschini, Nora A1 - Cheng, Ching-Yu A1 - Sim, Xueling A1 - Vojinovic, Dina A1 - Huffman, Jennifer E A1 - Musani, Solomon K A1 - Li, Changwei A1 - Feitosa, Mary F A1 - Richard, Melissa A A1 - Noordam, Raymond A1 - Aschard, Hugues A1 - Bartz, Traci M A1 - Bielak, Lawrence F A1 - Deng, Xuan A1 - Dorajoo, Rajkumar A1 - Lohman, Kurt K A1 - Manning, Alisa K A1 - Rankinen, Tuomo A1 - Smith, Albert V A1 - Tajuddin, Salman M A1 - Evangelou, Evangelos A1 - Graff, Mariaelisa A1 - Alver, Maris A1 - Boissel, Mathilde A1 - Chai, Jin Fang A1 - Chen, Xu A1 - Divers, Jasmin A1 - Gandin, Ilaria A1 - Gao, Chuan A1 - Goel, Anuj A1 - Hagemeijer, Yanick A1 - Harris, Sarah E A1 - Hartwig, Fernando P A1 - He, Meian A1 - Horimoto, Andrea R V R A1 - Hsu, Fang-Chi A1 - Jackson, Anne U A1 - Kasturiratne, Anuradhani A1 - Komulainen, Pirjo A1 - Kuhnel, Brigitte A1 - Laguzzi, Federica A1 - Lee, Joseph H A1 - Luan, Jian'an A1 - Lyytikäinen, Leo-Pekka A1 - Matoba, Nana A1 - Nolte, Ilja M A1 - Pietzner, Maik A1 - Riaz, Muhammad A1 - Said, M Abdullah A1 - Scott, Robert A A1 - Sofer, Tamar A1 - Stančáková, Alena A1 - Takeuchi, Fumihiko A1 - Tayo, Bamidele O A1 - van der Most, Peter J A1 - Varga, Tibor V A1 - Wang, Yajuan A1 - Ware, Erin B A1 - Wen, Wanqing A1 - Yanek, Lisa R A1 - Zhang, Weihua A1 - Zhao, Jing Hua A1 - Afaq, Saima A1 - Amin, Najaf A1 - Amini, Marzyeh A1 - Arking, Dan E A1 - Aung, Tin A1 - Ballantyne, Christie A1 - Boerwinkle, Eric A1 - Broeckel, Ulrich A1 - Campbell, Archie A1 - Canouil, Mickaël A1 - Charumathi, Sabanayagam A1 - Chen, Yii-Der Ida A1 - Connell, John M A1 - de Faire, Ulf A1 - de Las Fuentes, Lisa A1 - de Mutsert, Renée A1 - de Silva, H Janaka A1 - Ding, Jingzhong A1 - Dominiczak, Anna F A1 - Duan, Qing A1 - Eaton, Charles B A1 - Eppinga, Ruben N A1 - Faul, Jessica D A1 - Fisher, Virginia A1 - Forrester, Terrence A1 - Franco, Oscar H A1 - Friedlander, Yechiel A1 - Ghanbari, Mohsen A1 - Giulianini, Franco A1 - Grabe, Hans J A1 - Grove, Megan L A1 - Gu, C Charles A1 - Harris, Tamara B A1 - Heikkinen, Sami A1 - Heng, Chew-Kiat A1 - Hirata, Makoto A1 - Hixson, James E A1 - Howard, Barbara V A1 - Ikram, M Arfan A1 - Jacobs, David R A1 - Johnson, Craig A1 - Jonas, Jost Bruno A1 - Kammerer, Candace M A1 - Katsuya, Tomohiro A1 - Khor, Chiea Chuen A1 - Kilpeläinen, Tuomas O A1 - Koh, Woon-Puay A1 - Koistinen, Heikki A A1 - Kolcic, Ivana A1 - Kooperberg, Charles A1 - Krieger, Jose E A1 - Kritchevsky, Steve B A1 - Kubo, Michiaki A1 - Kuusisto, Johanna A1 - Lakka, Timo A A1 - Langefeld, Carl D A1 - Langenberg, Claudia A1 - Launer, Lenore J A1 - Lehne, Benjamin A1 - Lemaitre, Rozenn N A1 - Li, Yize A1 - Liang, Jingjing A1 - Liu, Jianjun A1 - Liu, Kiang A1 - Loh, Marie A1 - Louie, Tin A1 - Mägi, Reedik A1 - Manichaikul, Ani W A1 - McKenzie, Colin A A1 - Meitinger, Thomas A1 - Metspalu, Andres A1 - Milaneschi, Yuri A1 - Milani, Lili A1 - Mohlke, Karen L A1 - Mosley, Thomas H A1 - Mukamal, Kenneth J A1 - Nalls, Mike A A1 - Nauck, Matthias A1 - Nelson, Christopher P A1 - Sotoodehnia, Nona A1 - O'Connell, Jeff R A1 - Palmer, Nicholette D A1 - Pazoki, Raha A1 - Pedersen, Nancy L A1 - Peters, Annette A1 - Peyser, Patricia A A1 - Polasek, Ozren A1 - Poulter, Neil A1 - Raffel, Leslie J A1 - Raitakari, Olli T A1 - Reiner, Alex P A1 - Rice, Treva K A1 - Rich, Stephen S A1 - Robino, Antonietta A1 - Robinson, Jennifer G A1 - Rose, Lynda M A1 - Rudan, Igor A1 - Schmidt, Carsten O A1 - Schreiner, Pamela J A1 - Scott, William R A1 - Sever, Peter A1 - Shi, Yuan A1 - Sidney, Stephen A1 - Sims, Mario A1 - Smith, Blair H A1 - Smith, Jennifer A A1 - Snieder, Harold A1 - Starr, John M A1 - Strauch, Konstantin A1 - Tan, Nicholas A1 - Taylor, Kent D A1 - Teo, Yik Ying A1 - Tham, Yih Chung A1 - Uitterlinden, André G A1 - van Heemst, Diana A1 - Vuckovic, Dragana A1 - Waldenberger, Melanie A1 - Wang, Lihua A1 - Wang, Yujie A1 - Wang, Zhe A1 - Wei, Wen Bin A1 - Williams, Christine A1 - Wilson, Gregory A1 - Wojczynski, Mary K A1 - Yao, Jie A1 - Yu, Bing A1 - Yu, Caizheng A1 - Yuan, Jian-Min A1 - Zhao, Wei A1 - Zonderman, Alan B A1 - Becker, Diane M A1 - Boehnke, Michael A1 - Bowden, Donald W A1 - Chambers, John C A1 - Deary, Ian J A1 - Esko, Tõnu A1 - Farrall, Martin A1 - Franks, Paul W A1 - Freedman, Barry I A1 - Froguel, Philippe A1 - Gasparini, Paolo A1 - Gieger, Christian A1 - Horta, Bernardo L A1 - Kamatani, Yoichiro A1 - Kato, Norihiro A1 - Kooner, Jaspal S A1 - Laakso, Markku A1 - Leander, Karin A1 - Lehtimäki, Terho A1 - Magnusson, Patrik K E A1 - Penninx, Brenda A1 - Pereira, Alexandre C A1 - Rauramaa, Rainer A1 - Samani, Nilesh J A1 - Scott, James A1 - Shu, Xiao-Ou A1 - van der Harst, Pim A1 - Wagenknecht, Lynne E A1 - Wang, Ya Xing A1 - Wareham, Nicholas J A1 - Watkins, Hugh A1 - Weir, David R A1 - Wickremasinghe, Ananda R A1 - Zheng, Wei A1 - Elliott, Paul A1 - North, Kari E A1 - Bouchard, Claude A1 - Evans, Michele K A1 - Gudnason, Vilmundur A1 - Liu, Ching-Ti A1 - Liu, Yongmei A1 - Psaty, Bruce M A1 - Ridker, Paul M A1 - van Dam, Rob M A1 - Kardia, Sharon L R A1 - Zhu, Xiaofeng A1 - Rotimi, Charles N A1 - Mook-Kanamori, Dennis O A1 - Fornage, Myriam A1 - Kelly, Tanika N A1 - Fox, Ervin R A1 - Hayward, Caroline A1 - van Duijn, Cornelia M A1 - Tai, E Shyong A1 - Wong, Tien Yin A1 - Liu, Jingmin A1 - Rotter, Jerome I A1 - Gauderman, W James A1 - Province, Michael A A1 - Munroe, Patricia B A1 - Rice, Kenneth A1 - Chasman, Daniel I A1 - Cupples, L Adrienne A1 - Rao, Dabeeru C A1 - Morrison, Alanna C AB -

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

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

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

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

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

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

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

VL - 10 IS - 1 ER - TY - JOUR T1 - Gene-educational attainment interactions in a multi-ancestry genome-wide meta-analysis identify novel blood pressure loci. JF - Mol Psychiatry Y1 - 2020 A1 - de Las Fuentes, Lisa A1 - Sung, Yun Ju A1 - Noordam, Raymond A1 - Winkler, Thomas A1 - Feitosa, Mary F A1 - Schwander, Karen A1 - Bentley, Amy R A1 - Brown, Michael R A1 - Guo, Xiuqing A1 - Manning, Alisa A1 - Chasman, Daniel I A1 - Aschard, Hugues A1 - Bartz, Traci M A1 - Bielak, Lawrence F A1 - Campbell, Archie A1 - Cheng, Ching-Yu A1 - Dorajoo, Rajkumar A1 - Hartwig, Fernando P A1 - Horimoto, A R V R A1 - Li, Changwei A1 - Li-Gao, Ruifang A1 - Liu, Yongmei A1 - Marten, Jonathan A1 - Musani, Solomon K A1 - Ntalla, Ioanna A1 - Rankinen, Tuomo A1 - Richard, Melissa A1 - Sim, Xueling A1 - Smith, Albert V A1 - Tajuddin, Salman M A1 - Tayo, Bamidele O A1 - Vojinovic, Dina A1 - Warren, Helen R A1 - Xuan, Deng A1 - Alver, Maris A1 - Boissel, Mathilde A1 - Chai, Jin-Fang A1 - Chen, Xu A1 - Christensen, Kaare A1 - Divers, Jasmin A1 - Evangelou, Evangelos A1 - Gao, Chuan A1 - Girotto, Giorgia A1 - Harris, Sarah E A1 - He, Meian A1 - Hsu, Fang-Chi A1 - Kuhnel, Brigitte A1 - Laguzzi, Federica A1 - Li, Xiaoyin A1 - Lyytikäinen, Leo-Pekka A1 - Nolte, Ilja M A1 - Poveda, Alaitz A1 - Rauramaa, Rainer A1 - Riaz, Muhammad A1 - Rueedi, Rico A1 - Shu, Xiao-Ou A1 - Snieder, Harold A1 - Sofer, Tamar A1 - Takeuchi, Fumihiko A1 - Verweij, Niek A1 - Ware, Erin B A1 - Weiss, Stefan A1 - Yanek, Lisa R A1 - Amin, Najaf A1 - Arking, Dan E A1 - Arnett, Donna K A1 - Bergmann, Sven A1 - Boerwinkle, Eric A1 - Brody, Jennifer A A1 - Broeckel, Ulrich A1 - Brumat, Marco A1 - Burke, Gregory A1 - Cabrera, Claudia P A1 - Canouil, Mickaël A1 - Chee, Miao Li A1 - Chen, Yii-Der Ida A1 - Cocca, Massimiliano A1 - Connell, John A1 - de Silva, H Janaka A1 - de Vries, Paul S A1 - Eiriksdottir, Gudny A1 - Faul, Jessica D A1 - Fisher, Virginia A1 - Forrester, Terrence A1 - Fox, Ervin F A1 - Friedlander, Yechiel A1 - Gao, He A1 - Gigante, Bruna A1 - Giulianini, Franco A1 - Gu, Chi Charles A1 - Gu, Dongfeng A1 - Harris, Tamara B A1 - He, Jiang A1 - Heikkinen, Sami A1 - Heng, Chew-Kiat A1 - Hunt, Steven A1 - Ikram, M Arfan A1 - Irvin, Marguerite R A1 - Kähönen, Mika A1 - Kavousi, Maryam A1 - Khor, Chiea Chuen A1 - Kilpeläinen, Tuomas O A1 - Koh, Woon-Puay A1 - Komulainen, Pirjo A1 - Kraja, Aldi T A1 - Krieger, J E A1 - Langefeld, Carl D A1 - Li, Yize A1 - Liang, Jingjing A1 - Liewald, David C M A1 - Liu, Ching-Ti A1 - Liu, Jianjun A1 - Lohman, Kurt K A1 - Mägi, Reedik A1 - McKenzie, Colin A A1 - Meitinger, Thomas A1 - Metspalu, Andres A1 - Milaneschi, Yuri A1 - Milani, Lili A1 - Mook-Kanamori, Dennis O A1 - Nalls, Mike A A1 - Nelson, Christopher P A1 - Norris, Jill M A1 - O'Connell, Jeff A1 - Ogunniyi, Adesola A1 - Padmanabhan, Sandosh A1 - Palmer, Nicholette D A1 - Pedersen, Nancy L A1 - Perls, Thomas A1 - Peters, Annette A1 - Petersmann, Astrid A1 - Peyser, Patricia A A1 - Polasek, Ozren A1 - Porteous, David J A1 - Raffel, Leslie J A1 - Rice, Treva K A1 - Rotter, Jerome I A1 - Rudan, Igor A1 - Rueda-Ochoa, Oscar-Leonel A1 - Sabanayagam, Charumathi A1 - Salako, Babatunde L A1 - Schreiner, Pamela J A1 - Shikany, James M A1 - Sidney, Stephen S A1 - Sims, Mario A1 - Sitlani, Colleen M A1 - Smith, Jennifer A A1 - Starr, John M A1 - Strauch, Konstantin A1 - Swertz, Morris A A1 - Teumer, Alexander A1 - Tham, Yih Chung A1 - Uitterlinden, André G A1 - Vaidya, Dhananjay A1 - van der Ende, M Yldau A1 - Waldenberger, Melanie A1 - Wang, Lihua A1 - Wang, Ya-Xing A1 - Wei, Wen-Bin A1 - Weir, David R A1 - Wen, Wanqing A1 - Yao, Jie A1 - Yu, Bing A1 - Yu, Caizheng A1 - Yuan, Jian-Min A1 - Zhao, Wei A1 - Zonderman, Alan B A1 - Becker, Diane M A1 - Bowden, Donald W A1 - Deary, Ian J A1 - Dörr, Marcus A1 - Esko, Tõnu A1 - Freedman, Barry I A1 - Froguel, Philippe A1 - Gasparini, Paolo A1 - Gieger, Christian A1 - Jonas, Jost Bruno A1 - Kammerer, Candace M A1 - Kato, Norihiro A1 - Lakka, Timo A A1 - Leander, Karin A1 - Lehtimäki, Terho A1 - Magnusson, Patrik K E A1 - Marques-Vidal, Pedro A1 - Penninx, Brenda W J H A1 - Samani, Nilesh J A1 - van der Harst, Pim A1 - Wagenknecht, Lynne E A1 - Wu, Tangchun A1 - Zheng, Wei A1 - Zhu, Xiaofeng A1 - Bouchard, Claude A1 - Cooper, Richard S A1 - Correa, Adolfo A1 - Evans, Michele K A1 - Gudnason, Vilmundur A1 - Hayward, Caroline A1 - Horta, Bernardo L A1 - Kelly, Tanika N A1 - Kritchevsky, Stephen B A1 - Levy, Daniel A1 - Palmas, Walter R A1 - Pereira, A C A1 - Province, Michael M A1 - Psaty, Bruce M A1 - Ridker, Paul M A1 - Rotimi, Charles N A1 - Tai, E Shyong A1 - van Dam, Rob M A1 - van Duijn, Cornelia M A1 - Wong, Tien Yin A1 - Rice, Kenneth A1 - Gauderman, W James A1 - Morrison, Alanna C A1 - North, Kari E A1 - Kardia, Sharon L R A1 - Caulfield, Mark J A1 - Elliott, Paul A1 - Munroe, Patricia B A1 - Franks, Paul W A1 - Rao, Dabeeru C A1 - Fornage, Myriam AB -

Educational attainment is widely used as a surrogate for socioeconomic status (SES). Low SES is a risk factor for hypertension and high blood pressure (BP). To identify novel BP loci, we performed multi-ancestry meta-analyses accounting for gene-educational attainment interactions using two variables, "Some College" (yes/no) and "Graduated College" (yes/no). Interactions were evaluated using both a 1 degree of freedom (DF) interaction term and a 2DF joint test of genetic and interaction effects. Analyses were performed for systolic BP, diastolic BP, mean arterial pressure, and pulse pressure. We pursued genome-wide interrogation in Stage 1 studies (N = 117 438) and follow-up on promising variants in Stage 2 studies (N = 293 787) in five ancestry groups. Through combined meta-analyses of Stages 1 and 2, we identified 84 known and 18 novel BP loci at genome-wide significance level (P < 5 × 10). Two novel loci were identified based on the 1DF test of interaction with educational attainment, while the remaining 16 loci were identified through the 2DF joint test of genetic and interaction effects. Ten novel loci were identified in individuals of African ancestry. Several novel loci show strong biological plausibility since they involve physiologic systems implicated in BP regulation. They include genes involved in the central nervous system-adrenal signaling axis (ZDHHC17, CADPS, PIK3C2G), vascular structure and function (GNB3, CDON), and renal function (HAS2 and HAS2-AS1, SLIT3). Collectively, these findings suggest a role of educational attainment or SES in further dissection of the genetic architecture of BP.

ER - TY - JOUR T1 - Inherited causes of clonal haematopoiesis in 97,691 whole genomes. JF - Nature Y1 - 2020 A1 - Bick, Alexander G A1 - Weinstock, Joshua S A1 - Nandakumar, Satish K A1 - Fulco, Charles P A1 - Bao, Erik L A1 - Zekavat, Seyedeh M A1 - Szeto, Mindy D A1 - Liao, Xiaotian A1 - Leventhal, Matthew J A1 - Nasser, Joseph A1 - Chang, Kyle A1 - Laurie, Cecelia A1 - Burugula, Bala Bharathi A1 - Gibson, Christopher J A1 - Lin, Amy E A1 - Taub, Margaret A A1 - Aguet, Francois A1 - Ardlie, Kristin A1 - Mitchell, Braxton D A1 - Barnes, Kathleen C A1 - Moscati, Arden A1 - Fornage, Myriam A1 - Redline, Susan A1 - Psaty, Bruce M A1 - Silverman, Edwin K A1 - Weiss, Scott T A1 - Palmer, Nicholette D A1 - Vasan, Ramachandran S A1 - Burchard, Esteban G A1 - Kardia, Sharon L R A1 - He, Jiang A1 - Kaplan, Robert C A1 - Smith, Nicholas L A1 - Arnett, Donna K A1 - Schwartz, David A A1 - Correa, Adolfo A1 - de Andrade, Mariza A1 - Guo, Xiuqing A1 - Konkle, Barbara A A1 - Custer, Brian A1 - Peralta, Juan M A1 - Gui, Hongsheng A1 - Meyers, Deborah A A1 - McGarvey, Stephen T A1 - Chen, Ida Yii-Der A1 - Shoemaker, M Benjamin A1 - Peyser, Patricia A A1 - Broome, Jai G A1 - Gogarten, Stephanie M A1 - Wang, Fei Fei A1 - Wong, Quenna A1 - Montasser, May E A1 - Daya, Michelle A1 - Kenny, Eimear E A1 - North, Kari E A1 - Launer, Lenore J A1 - Cade, Brian E A1 - Bis, Joshua C A1 - Cho, Michael H A1 - Lasky-Su, Jessica A1 - Bowden, Donald W A1 - Cupples, L Adrienne A1 - Mak, Angel C Y A1 - Becker, Lewis C A1 - Smith, Jennifer A A1 - Kelly, Tanika N A1 - Aslibekyan, Stella A1 - Heckbert, Susan R A1 - Tiwari, Hemant K A1 - Yang, Ivana V A1 - Heit, John A A1 - Lubitz, Steven A A1 - Johnsen, Jill M A1 - Curran, Joanne E A1 - Wenzel, Sally E A1 - Weeks, Daniel E A1 - Rao, Dabeeru C A1 - Darbar, Dawood A1 - Moon, Jee-Young A1 - Tracy, Russell P A1 - Buth, Erin J A1 - Rafaels, Nicholas A1 - Loos, Ruth J F A1 - Durda, Peter A1 - Liu, Yongmei A1 - Hou, Lifang A1 - Lee, Jiwon A1 - Kachroo, Priyadarshini A1 - Freedman, Barry I A1 - Levy, Daniel A1 - Bielak, Lawrence F A1 - Hixson, James E A1 - Floyd, James S A1 - Whitsel, Eric A A1 - Ellinor, Patrick T A1 - Irvin, Marguerite R A1 - Fingerlin, Tasha E A1 - Raffield, Laura M A1 - Armasu, Sebastian M A1 - Wheeler, Marsha M A1 - Sabino, Ester C A1 - Blangero, John A1 - Williams, L Keoki A1 - Levy, Bruce D A1 - Sheu, Wayne Huey-Herng A1 - Roden, Dan M A1 - Boerwinkle, Eric A1 - Manson, JoAnn E A1 - Mathias, Rasika A A1 - Desai, Pinkal A1 - Taylor, Kent D A1 - Johnson, Andrew D A1 - Auer, Paul L A1 - Kooperberg, Charles A1 - Laurie, Cathy C A1 - Blackwell, Thomas W A1 - Smith, Albert V A1 - Zhao, Hongyu A1 - Lange, Ethan A1 - Lange, Leslie A1 - Rich, Stephen S A1 - Rotter, Jerome I A1 - Wilson, James G A1 - Scheet, Paul A1 - Kitzman, Jacob O A1 - Lander, Eric S A1 - Engreitz, Jesse M A1 - Ebert, Benjamin L A1 - Reiner, Alexander P A1 - Jaiswal, Siddhartha A1 - Abecasis, Goncalo A1 - Sankaran, Vijay G A1 - Kathiresan, Sekar A1 - Natarajan, Pradeep AB -

Age is the dominant risk factor for most chronic human diseases, but the mechanisms through which ageing confers this risk are largely unknown. The age-related acquisition of somatic mutations that lead to clonal expansion in regenerating haematopoietic stem cell populations has recently been associated with both haematological cancer and coronary heart disease-this phenomenon is termed clonal haematopoiesis of indeterminate potential (CHIP). Simultaneous analyses of germline and somatic whole-genome sequences provide the opportunity to identify root causes of CHIP. Here we analyse high-coverage whole-genome sequences from 97,691 participants of diverse ancestries in the National Heart, Lung, and Blood Institute Trans-omics for Precision Medicine (TOPMed) programme, and identify 4,229 individuals with CHIP. We identify associations with blood cell, lipid and inflammatory traits that are specific to different CHIP driver genes. Association of a genome-wide set of germline genetic variants enabled the identification of three genetic loci associated with CHIP status, including one locus at TET2 that was specific to individuals of African ancestry. In silico-informed in vitro evaluation of the TET2 germline locus enabled the identification of a causal variant that disrupts a TET2 distal enhancer, resulting in increased self-renewal of haematopoietic stem cells. Overall, we observe that germline genetic variation shapes haematopoietic stem cell function, leading to CHIP through mechanisms that are specific to clonal haematopoiesis as well as shared mechanisms that lead to somatic mutations across tissues.

VL - 586 IS - 7831 ER - TY - JOUR T1 - Multi-ancestry genome-wide gene-sleep interactions identify novel loci for blood pressure. JF - Mol Psychiatry Y1 - 2021 A1 - Wang, Heming A1 - Noordam, Raymond A1 - Cade, Brian E A1 - Schwander, Karen A1 - Winkler, Thomas W A1 - Lee, Jiwon A1 - Sung, Yun Ju A1 - Bentley, Amy R A1 - Manning, Alisa K A1 - Aschard, Hugues A1 - Kilpeläinen, Tuomas O A1 - Ilkov, Marjan A1 - Brown, Michael R A1 - Horimoto, Andrea R A1 - Richard, Melissa A1 - Bartz, Traci M A1 - Vojinovic, Dina A1 - Lim, Elise A1 - Nierenberg, Jovia L A1 - Liu, Yongmei A1 - Chitrala, Kumaraswamynaidu A1 - Rankinen, Tuomo A1 - Musani, Solomon K A1 - Franceschini, Nora A1 - Rauramaa, Rainer A1 - Alver, Maris A1 - Zee, Phyllis C A1 - Harris, Sarah E A1 - van der Most, Peter J A1 - Nolte, Ilja M A1 - Munroe, Patricia B A1 - Palmer, Nicholette D A1 - Kuhnel, Brigitte A1 - Weiss, Stefan A1 - Wen, Wanqing A1 - Hall, Kelly A A1 - Lyytikäinen, Leo-Pekka A1 - O'Connell, Jeff A1 - Eiriksdottir, Gudny A1 - Launer, Lenore J A1 - de Vries, Paul S A1 - Arking, Dan E A1 - Chen, Han A1 - Boerwinkle, Eric A1 - Krieger, Jose E A1 - Schreiner, Pamela J A1 - Sidney, Stephen A1 - Shikany, James M A1 - Rice, Kenneth A1 - Chen, Yii-Der Ida A1 - Gharib, Sina A A1 - Bis, Joshua C A1 - Luik, Annemarie I A1 - Ikram, M Arfan A1 - Uitterlinden, André G A1 - Amin, Najaf A1 - Xu, Hanfei A1 - Levy, Daniel A1 - He, Jiang A1 - Lohman, Kurt K A1 - Zonderman, Alan B A1 - Rice, Treva K A1 - Sims, Mario A1 - Wilson, Gregory A1 - Sofer, Tamar A1 - Rich, Stephen S A1 - Palmas, Walter A1 - Yao, Jie A1 - Guo, Xiuqing A1 - Rotter, Jerome I A1 - Biermasz, Nienke R A1 - Mook-Kanamori, Dennis O A1 - Martin, Lisa W A1 - Barac, Ana A1 - Wallace, Robert B A1 - Gottlieb, Daniel J A1 - Komulainen, Pirjo A1 - Heikkinen, Sami A1 - Mägi, Reedik A1 - Milani, Lili A1 - Metspalu, Andres A1 - Starr, John M A1 - Milaneschi, Yuri A1 - Waken, R J A1 - Gao, Chuan A1 - Waldenberger, Melanie A1 - Peters, Annette A1 - Strauch, Konstantin A1 - Meitinger, Thomas A1 - Roenneberg, Till A1 - Völker, Uwe A1 - Dörr, Marcus A1 - Shu, Xiao-Ou A1 - Mukherjee, Sutapa A1 - Hillman, David R A1 - Kähönen, Mika A1 - Wagenknecht, Lynne E A1 - Gieger, Christian A1 - Grabe, Hans J A1 - Zheng, Wei A1 - Palmer, Lyle J A1 - Lehtimäki, Terho A1 - Gudnason, Vilmundur A1 - Morrison, Alanna C A1 - Pereira, Alexandre C A1 - Fornage, Myriam A1 - Psaty, Bruce M A1 - van Duijn, Cornelia M A1 - Liu, Ching-Ti A1 - Kelly, Tanika N A1 - Evans, Michele K A1 - Bouchard, Claude A1 - Fox, Ervin R A1 - Kooperberg, Charles A1 - Zhu, Xiaofeng A1 - Lakka, Timo A A1 - Esko, Tõnu A1 - North, Kari E A1 - Deary, Ian J A1 - Snieder, Harold A1 - Penninx, Brenda W J H A1 - Gauderman, W James A1 - Rao, Dabeeru C A1 - Redline, Susan A1 - van Heemst, Diana AB -

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

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

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

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

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

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

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

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

VL - 63 ER - TY - JOUR T1 - Insights From a Large-Scale Whole-Genome Sequencing Study of Systolic Blood Pressure, Diastolic Blood Pressure, and Hypertension. JF - Hypertension Y1 - 2022 A1 - Kelly, Tanika N A1 - Sun, Xiao A1 - He, Karen Y A1 - Brown, Michael R A1 - Taliun, Sarah A Gagliano A1 - Hellwege, Jacklyn N A1 - Irvin, Marguerite R A1 - Mi, Xuenan A1 - Brody, Jennifer A A1 - Franceschini, Nora A1 - Guo, Xiuqing A1 - Hwang, Shih-Jen A1 - de Vries, Paul S A1 - Gao, Yan A1 - Moscati, Arden A1 - Nadkarni, Girish N A1 - Yanek, Lisa R A1 - Elfassy, Tali A1 - Smith, Jennifer A A1 - Chung, Ren-Hua A1 - Beitelshees, Amber L A1 - Patki, Amit A1 - Aslibekyan, Stella A1 - Blobner, Brandon M A1 - Peralta, Juan M A1 - Assimes, Themistocles L A1 - Palmas, Walter R A1 - Liu, Chunyu A1 - Bress, Adam P A1 - Huang, Zhijie A1 - Becker, Lewis C A1 - Hwa, Chii-Min A1 - O'Connell, Jeffrey R A1 - Carlson, Jenna C A1 - Warren, Helen R A1 - Das, Sayantan A1 - Giri, Ayush A1 - Martin, Lisa W A1 - Craig Johnson, W A1 - Fox, Ervin R A1 - Bottinger, Erwin P A1 - Razavi, Alexander C A1 - Vaidya, Dhananjay A1 - Chuang, Lee-Ming A1 - Chang, Yen-Pei C A1 - Naseri, Take A1 - Jain, Deepti A1 - Kang, Hyun Min A1 - Hung, Adriana M A1 - Srinivasasainagendra, Vinodh A1 - Snively, Beverly M A1 - Gu, Dongfeng A1 - Montasser, May E A1 - Reupena, Muagututi'a Sefuiva A1 - Heavner, Benjamin D A1 - LeFaive, Jonathon A1 - Hixson, James E A1 - Rice, Kenneth M A1 - Wang, Fei Fei A1 - Nielsen, Jonas B A1 - Huang, Jianfeng A1 - Khan, Alyna T A1 - Zhou, Wei A1 - Nierenberg, Jovia L A1 - Laurie, Cathy C A1 - Armstrong, Nicole D A1 - Shi, Mengyao A1 - Pan, Yang A1 - Stilp, Adrienne M A1 - Emery, Leslie A1 - Wong, Quenna A1 - Hawley, Nicola L A1 - Minster, Ryan L A1 - Curran, Joanne E A1 - Munroe, Patricia B A1 - Weeks, Daniel E A1 - North, Kari E A1 - Tracy, Russell P A1 - Kenny, Eimear E A1 - Shimbo, Daichi A1 - Chakravarti, Aravinda A1 - Rich, Stephen S A1 - Reiner, Alex P A1 - Blangero, John A1 - Redline, Susan A1 - Mitchell, Braxton D A1 - Rao, Dabeeru C A1 - Ida Chen, Yii-Der A1 - Kardia, Sharon L R A1 - Kaplan, Robert C A1 - Mathias, Rasika A A1 - He, Jiang A1 - Psaty, Bruce M A1 - Fornage, Myriam A1 - Loos, Ruth J F A1 - Correa, Adolfo A1 - Boerwinkle, Eric A1 - Rotter, Jerome I A1 - Kooperberg, Charles A1 - Edwards, Todd L A1 - Abecasis, Goncalo R A1 - Zhu, Xiaofeng A1 - Levy, Daniel A1 - Arnett, Donna K A1 - Morrison, Alanna C AB -

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

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

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

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

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

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

VL - 13 IS - 1 ER - TY - JOUR T1 - Whole genome sequence association analysis of fasting glucose and fasting insulin levels in diverse cohorts from the NHLBI TOPMed program. JF - Commun Biol Y1 - 2022 A1 - DiCorpo, Daniel A1 - Gaynor, Sheila M A1 - Russell, Emily M A1 - Westerman, Kenneth E A1 - Raffield, Laura M A1 - Majarian, Timothy D A1 - Wu, Peitao A1 - Sarnowski, Chloe A1 - Highland, Heather M A1 - Jackson, Anne A1 - Hasbani, Natalie R A1 - de Vries, Paul S A1 - Brody, Jennifer A A1 - Hidalgo, Bertha A1 - Guo, Xiuqing A1 - Perry, James A A1 - O'Connell, Jeffrey R A1 - Lent, Samantha A1 - Montasser, May E A1 - Cade, Brian E A1 - Jain, Deepti A1 - Wang, Heming A1 - D'Oliveira Albanus, Ricardo A1 - Varshney, Arushi A1 - Yanek, Lisa R A1 - Lange, Leslie A1 - Palmer, Nicholette D A1 - Almeida, Marcio A1 - Peralta, Juan M A1 - Aslibekyan, Stella A1 - Baldridge, Abigail S A1 - Bertoni, Alain G A1 - Bielak, Lawrence F A1 - Chen, Chung-Shiuan A1 - Chen, Yii-Der Ida A1 - Choi, Won Jung A1 - Goodarzi, Mark O A1 - Floyd, James S A1 - Irvin, Marguerite R A1 - Kalyani, Rita R A1 - Kelly, Tanika N A1 - Lee, Seonwook A1 - Liu, Ching-Ti A1 - Loesch, Douglas A1 - Manson, JoAnn E A1 - Minster, Ryan L A1 - Naseri, Take A1 - Pankow, James S A1 - Rasmussen-Torvik, Laura J A1 - Reiner, Alexander P A1 - Reupena, Muagututi'a Sefuiva A1 - Selvin, Elizabeth A1 - Smith, Jennifer A A1 - Weeks, Daniel E A1 - Xu, Huichun A1 - Yao, Jie A1 - Zhao, Wei A1 - Parker, Stephen A1 - Alonso, Alvaro A1 - Arnett, Donna K A1 - Blangero, John A1 - Boerwinkle, Eric A1 - Correa, Adolfo A1 - Cupples, L Adrienne A1 - Curran, Joanne E A1 - Duggirala, Ravindranath A1 - He, Jiang A1 - Heckbert, Susan R A1 - Kardia, Sharon L R A1 - Kim, Ryan W A1 - Kooperberg, Charles A1 - Liu, Simin A1 - Mathias, Rasika A A1 - McGarvey, Stephen T A1 - Mitchell, Braxton D A1 - Morrison, Alanna C A1 - Peyser, Patricia A A1 - Psaty, Bruce M A1 - Redline, Susan A1 - Shuldiner, Alan R A1 - Taylor, Kent D A1 - Vasan, Ramachandran S A1 - Viaud-Martinez, Karine A A1 - Florez, Jose C A1 - Wilson, James G A1 - Sladek, Robert A1 - Rich, Stephen S A1 - Rotter, Jerome I A1 - Lin, Xihong A1 - Dupuis, Josée A1 - Meigs, James B A1 - Wessel, Jennifer A1 - Manning, Alisa K KW - Diabetes Mellitus, Type 2 KW - Fasting KW - Glucose KW - Humans KW - Insulin KW - National Heart, Lung, and Blood Institute (U.S.) KW - Nerve Tissue Proteins KW - Polymorphism, Single Nucleotide KW - Precision Medicine KW - Receptors, Immunologic KW - United States AB -

The genetic determinants of fasting glucose (FG) and fasting insulin (FI) have been studied mostly through genome arrays, resulting in over 100 associated variants. We extended this work with high-coverage whole genome sequencing analyses from fifteen cohorts in NHLBI's Trans-Omics for Precision Medicine (TOPMed) program. Over 23,000 non-diabetic individuals from five race-ethnicities/populations (African, Asian, European, Hispanic and Samoan) were included. Eight variants were significantly associated with FG or FI across previously identified regions MTNR1B, G6PC2, GCK, GCKR and FOXA2. We additionally characterize suggestive associations with FG or FI near previously identified SLC30A8, TCF7L2, and ADCY5 regions as well as APOB, PTPRT, and ROBO1. Functional annotation resources including the Diabetes Epigenome Atlas were compiled for each signal (chromatin states, annotation principal components, and others) to elucidate variant-to-function hypotheses. We provide a catalog of nucleotide-resolution genomic variation spanning intergenic and intronic regions creating a foundation for future sequencing-based investigations of glycemic traits.

VL - 5 IS - 1 ER - TY - JOUR T1 - Whole-Exome Sequencing Study Identifies Four Novel Gene Loci Associated with Diabetic Kidney Disease. JF - Hum Mol Genet Y1 - 2022 A1 - Pan, Yang A1 - Sun, Xiao A1 - Mi, Xuenan A1 - Huang, Zhijie A1 - Hsu, Yenchih A1 - Hixson, James E A1 - Munzy, Donna A1 - Metcalf, Ginger A1 - Franceschini, Nora A1 - Tin, Adrienne A1 - Köttgen, Anna A1 - Francis, Michael A1 - Brody, Jennifer A A1 - Kestenbaum, Bryan A1 - Sitlani, Colleen M A1 - Mychaleckyj, Josyf C A1 - Kramer, Holly A1 - Lange, Leslie A A1 - Guo, Xiuqing A1 - Hwang, Shih-Jen A1 - Irvin, Marguerite R A1 - Smith, Jennifer A A1 - Yanek, Lisa R A1 - Vaidya, Dhananjay A1 - Chen, Yii-Der Ida A1 - Fornage, Myriam A1 - Lloyd-Jones, Donald M A1 - Hou, Lifang A1 - Mathias, Rasika A A1 - Mitchell, Braxton D A1 - Peyser, Patricia A A1 - Kardia, Sharon L R A1 - Arnett, Donna K A1 - Correa, Adolfo A1 - Raffield, Laura M A1 - Vasan, Ramachandran S A1 - Cupple, L Adrienne A1 - Levy, Daniel A1 - Kaplan, Robert C A1 - North, Kari E A1 - Rotter, Jerome I A1 - Kooperberg, Charles A1 - Reiner, Alexander P A1 - Psaty, Bruce M A1 - Tracy, Russell P A1 - Gibbs, Richard A A1 - Morrison, Alanna C A1 - Feldman, Harold A1 - Boerwinkle, Eric A1 - He, Jiang A1 - Kelly, Tanika N AB -

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

ER - TY - JOUR T1 - Multi-ancestry transcriptome-wide association analyses yield insights into tobacco use biology and drug repurposing. JF - Nat Genet Y1 - 2023 A1 - Chen, Fang A1 - Wang, Xingyan A1 - Jang, Seon-Kyeong A1 - Quach, Bryan C A1 - Weissenkampen, J Dylan A1 - Khunsriraksakul, Chachrit A1 - Yang, Lina A1 - Sauteraud, Renan A1 - Albert, Christine M A1 - Allred, Nicholette D D A1 - Arnett, Donna K A1 - Ashley-Koch, Allison E A1 - Barnes, Kathleen C A1 - Barr, R Graham A1 - Becker, Diane M A1 - Bielak, Lawrence F A1 - Bis, Joshua C A1 - Blangero, John A1 - Boorgula, Meher Preethi A1 - Chasman, Daniel I A1 - Chavan, Sameer A1 - Chen, Yii-der I A1 - Chuang, Lee-Ming A1 - Correa, Adolfo A1 - Curran, Joanne E A1 - David, Sean P A1 - Fuentes, Lisa de Las A1 - Deka, Ranjan A1 - Duggirala, Ravindranath A1 - Faul, Jessica D A1 - Garrett, Melanie E A1 - Gharib, Sina A A1 - Guo, Xiuqing A1 - Hall, Michael E A1 - Hawley, Nicola L A1 - He, Jiang A1 - Hobbs, Brian D A1 - Hokanson, John E A1 - Hsiung, Chao A A1 - Hwang, Shih-Jen A1 - Hyde, Thomas M A1 - Irvin, Marguerite R A1 - Jaffe, Andrew E A1 - Johnson, Eric O A1 - Kaplan, Robert A1 - Kardia, Sharon L R A1 - Kaufman, Joel D A1 - Kelly, Tanika N A1 - Kleinman, Joel E A1 - Kooperberg, Charles A1 - Lee, I-Te A1 - Levy, Daniel A1 - Lutz, Sharon M A1 - Manichaikul, Ani W A1 - Martin, Lisa W A1 - Marx, Olivia A1 - McGarvey, Stephen T A1 - Minster, Ryan L A1 - Moll, Matthew A1 - Moussa, Karine A A1 - Naseri, Take A1 - North, Kari E A1 - Oelsner, Elizabeth C A1 - Peralta, Juan M A1 - Peyser, Patricia A A1 - Psaty, Bruce M A1 - Rafaels, Nicholas A1 - Raffield, Laura M A1 - Reupena, Muagututi'a Sefuiva A1 - Rich, Stephen S A1 - Rotter, Jerome I A1 - Schwartz, David A A1 - Shadyab, Aladdin H A1 - Sheu, Wayne H-H A1 - Sims, Mario A1 - Smith, Jennifer A A1 - Sun, Xiao A1 - Taylor, Kent D A1 - Telen, Marilyn J A1 - Watson, Harold A1 - Weeks, Daniel E A1 - Weir, David R A1 - Yanek, Lisa R A1 - Young, Kendra A A1 - Young, Kristin L A1 - Zhao, Wei A1 - Hancock, Dana B A1 - Jiang, Bibo A1 - Vrieze, Scott A1 - Liu, Dajiang J KW - Biology KW - Drug Repositioning KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Polymorphism, Single Nucleotide KW - Tobacco Use KW - Transcriptome AB -

Most transcriptome-wide association studies (TWASs) so far focus on European ancestry and lack diversity. To overcome this limitation, we aggregated genome-wide association study (GWAS) summary statistics, whole-genome sequences and expression quantitative trait locus (eQTL) data from diverse ancestries. We developed a new approach, TESLA (multi-ancestry integrative study using an optimal linear combination of association statistics), to integrate an eQTL dataset with a multi-ancestry GWAS. By exploiting shared phenotypic effects between ancestries and accommodating potential effect heterogeneities, TESLA improves power over other TWAS methods. When applied to tobacco use phenotypes, TESLA identified 273 new genes, up to 55% more compared with alternative TWAS methods. These hits and subsequent fine mapping using TESLA point to target genes with biological relevance. In silico drug-repurposing analyses highlight several drugs with known efficacy, including dextromethorphan and galantamine, and new drugs such as muscle relaxants that may be repurposed for treating nicotine addiction.

VL - 55 IS - 2 ER - TY - JOUR T1 - Rare variants in long non-coding RNAs are associated with blood lipid levels in the TOPMed Whole Genome Sequencing Study. JF - medRxiv Y1 - 2023 A1 - Wang, Yuxuan A1 - Selvaraj, Margaret Sunitha A1 - Li, Xihao A1 - Li, Zilin A1 - Holdcraft, Jacob A A1 - Arnett, Donna K A1 - Bis, Joshua C A1 - Blangero, John A1 - Boerwinkle, Eric A1 - Bowden, Donald W A1 - Cade, Brian E A1 - Carlson, Jenna C A1 - Carson, April P A1 - Chen, Yii-Der Ida A1 - Curran, Joanne E A1 - de Vries, Paul S A1 - Dutcher, Susan K A1 - Ellinor, Patrick T A1 - Floyd, James S A1 - Fornage, Myriam A1 - Freedman, Barry I A1 - Gabriel, Stacey A1 - Germer, Soren A1 - Gibbs, Richard A A1 - Guo, Xiuqing A1 - He, Jiang A1 - Heard-Costa, Nancy A1 - Hildalgo, Bertha A1 - Hou, Lifang A1 - Irvin, Marguerite R A1 - Joehanes, Roby A1 - Kaplan, Robert C A1 - Kardia, Sharon Lr A1 - Kelly, Tanika N A1 - Kim, Ryan A1 - Kooperberg, Charles A1 - Kral, Brian G A1 - Levy, Daniel A1 - Li, Changwei A1 - Liu, Chunyu A1 - Lloyd-Jone, Don A1 - Loos, Ruth Jf A1 - Mahaney, Michael C A1 - Martin, Lisa W A1 - Mathias, Rasika A A1 - Minster, Ryan L A1 - Mitchell, Braxton D A1 - Montasser, May E A1 - Morrison, Alanna C A1 - Murabito, Joanne M A1 - Naseri, Take A1 - O'Connell, Jeffrey R A1 - Palmer, Nicholette D A1 - Preuss, Michael H A1 - Psaty, Bruce M A1 - Raffield, Laura M A1 - Rao, Dabeeru C A1 - Redline, Susan A1 - Reiner, Alexander P A1 - Rich, Stephen S A1 - Ruepena, Muagututi'a Sefuiva A1 - Sheu, Wayne H-H A1 - Smith, Jennifer A A1 - Smith, Albert A1 - Tiwari, Hemant K A1 - Tsai, Michael Y A1 - Viaud-Martinez, Karine A A1 - Wang, Zhe A1 - Yanek, Lisa R A1 - Zhao, Wei A1 - Rotter, Jerome I A1 - Lin, Xihong A1 - Natarajan, Pradeep A1 - Peloso, Gina M AB -

Long non-coding RNAs (lncRNAs) are known to perform important regulatory functions. Large-scale whole genome sequencing (WGS) studies and new statistical methods for variant set tests now provide an opportunity to assess the associations between rare variants in lncRNA genes and complex traits across the genome. In this study, we used high-coverage WGS from 66,329 participants of diverse ancestries with blood lipid levels (LDL-C, HDL-C, TC, and TG) in the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) program to investigate the role of lncRNAs in lipid variability. We aggregated rare variants for 165,375 lncRNA genes based on their genomic locations and conducted rare variant aggregate association tests using the STAAR (variant-Set Test for Association using Annotation infoRmation) framework. We performed STAAR conditional analysis adjusting for common variants in known lipid GWAS loci and rare coding variants in nearby protein coding genes. Our analyses revealed 83 rare lncRNA variant sets significantly associated with blood lipid levels, all of which were located in known lipid GWAS loci (in a ±500 kb window of a Global Lipids Genetics Consortium index variant). Notably, 61 out of 83 signals (73%) were conditionally independent of common regulatory variations and rare protein coding variations at the same loci. We replicated 34 out of 61 (56%) conditionally independent associations using the independent UK Biobank WGS data. Our results expand the genetic architecture of blood lipids to rare variants in lncRNA, implicating new therapeutic opportunities.

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

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

VL - 14 ER - TY - JOUR T1 - WHOLE GENOME SEQUENCING ANALYSIS OF BODY MASS INDEX IDENTIFIES NOVEL AFRICAN ANCESTRY-SPECIFIC RISK ALLELE. JF - medRxiv Y1 - 2023 A1 - Zhang, Xinruo A1 - Brody, Jennifer A A1 - Graff, Mariaelisa A1 - Highland, Heather M A1 - Chami, Nathalie A1 - Xu, Hanfei A1 - Wang, Zhe A1 - Ferrier, Kendra A1 - Chittoor, Geetha A1 - Josyula, Navya S A1 - Li, Xihao A1 - Li, Zilin A1 - Allison, Matthew A A1 - Becker, Diane M A1 - Bielak, Lawrence F A1 - Bis, Joshua C A1 - Boorgula, Meher Preethi A1 - Bowden, Donald W A1 - Broome, Jai G A1 - Buth, Erin J A1 - Carlson, Christopher S A1 - Chang, Kyong-Mi A1 - Chavan, Sameer A1 - Chiu, Yen-Feng A1 - Chuang, Lee-Ming A1 - Conomos, Matthew P A1 - DeMeo, Dawn L A1 - Du, Margaret A1 - Duggirala, Ravindranath A1 - Eng, Celeste A1 - Fohner, Alison E A1 - Freedman, Barry I A1 - Garrett, Melanie E A1 - Guo, Xiuqing A1 - Haiman, Chris A1 - Heavner, Benjamin D A1 - Hidalgo, Bertha A1 - Hixson, James E A1 - Ho, Yuk-Lam A1 - Hobbs, Brian D A1 - Hu, Donglei A1 - Hui, Qin A1 - Hwu, Chii-Min A1 - Jackson, Rebecca D A1 - Jain, Deepti A1 - Kalyani, Rita R A1 - Kardia, Sharon L R A1 - Kelly, Tanika N A1 - Lange, Ethan M A1 - LeNoir, Michael A1 - Li, Changwei A1 - Marchand, Loic Le A1 - McDonald, Merry-Lynn N A1 - McHugh, Caitlin P A1 - Morrison, Alanna C A1 - Naseri, Take A1 - O'Connell, Jeffrey A1 - O'Donnell, Christopher J A1 - Palmer, Nicholette D A1 - Pankow, James S A1 - Perry, James A A1 - Peters, Ulrike A1 - Preuss, Michael H A1 - Rao, D C A1 - Regan, Elizabeth A A1 - Reupena, Sefuiva M A1 - Roden, Dan M A1 - Rodriguez-Santana, Jose A1 - Sitlani, Colleen M A1 - Smith, Jennifer A A1 - Tiwari, Hemant K A1 - Vasan, Ramachandran S A1 - Wang, Zeyuan A1 - Weeks, Daniel E A1 - Wessel, Jennifer A1 - Wiggins, Kerri L A1 - Wilkens, Lynne R A1 - Wilson, Peter W F A1 - Yanek, Lisa R A1 - Yoneda, Zachary T A1 - Zhao, Wei A1 - Zöllner, Sebastian A1 - Arnett, Donna K A1 - Ashley-Koch, Allison E A1 - Barnes, Kathleen C A1 - Blangero, John A1 - Boerwinkle, Eric A1 - Burchard, Esteban G A1 - Carson, April P A1 - Chasman, Daniel I A1 - Chen, Yii-Der Ida A1 - Curran, Joanne E A1 - Fornage, Myriam A1 - Gordeuk, Victor R A1 - He, Jiang A1 - Heckbert, Susan R A1 - Hou, Lifang A1 - Irvin, Marguerite R A1 - Kooperberg, Charles A1 - Minster, Ryan L A1 - Mitchell, Braxton D A1 - Nouraie, Mehdi A1 - Psaty, Bruce M A1 - Raffield, Laura M A1 - Reiner, Alexander P A1 - Rich, Stephen S A1 - Rotter, Jerome I A1 - Shoemaker, M Benjamin A1 - Smith, Nicholas L A1 - Taylor, Kent D A1 - Telen, Marilyn J A1 - Weiss, Scott T A1 - Zhang, Yingze A1 - Costa, Nancy Heard- A1 - Sun, Yan V A1 - Lin, Xihong A1 - Cupples, L Adrienne A1 - Lange, Leslie A A1 - Liu, Ching-Ti A1 - Loos, Ruth J F A1 - North, Kari E A1 - Justice, Anne E AB -

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

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