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 - Associations of autozygosity with a broad range of human phenotypes. JF - Nat Commun Y1 - 2019 A1 - Clark, David W A1 - Okada, Yukinori A1 - Moore, Kristjan H S A1 - Mason, Dan A1 - Pirastu, Nicola A1 - Gandin, Ilaria A1 - Mattsson, Hannele A1 - Barnes, Catriona L K A1 - Lin, Kuang A1 - Zhao, Jing Hua A1 - Deelen, Patrick A1 - Rohde, Rebecca A1 - Schurmann, Claudia A1 - Guo, Xiuqing A1 - Giulianini, Franco A1 - Zhang, Weihua A1 - Medina-Gómez, Carolina A1 - Karlsson, Robert A1 - Bao, Yanchun A1 - Bartz, Traci M A1 - Baumbach, Clemens A1 - Biino, Ginevra A1 - Bixley, Matthew J A1 - Brumat, Marco A1 - Chai, Jin-Fang A1 - Corre, Tanguy A1 - Cousminer, Diana L A1 - Dekker, Annelot M A1 - Eccles, David A A1 - van Eijk, Kristel R A1 - Fuchsberger, Christian A1 - Gao, He A1 - Germain, Marine A1 - Gordon, Scott D A1 - de Haan, Hugoline G A1 - Harris, Sarah E A1 - Hofer, Edith A1 - Huerta-Chagoya, Alicia A1 - Igartua, Catherine A1 - Jansen, Iris E A1 - Jia, Yucheng A1 - Kacprowski, Tim A1 - Karlsson, Torgny A1 - Kleber, Marcus E A1 - Li, Shengchao Alfred A1 - Li-Gao, Ruifang A1 - Mahajan, Anubha A1 - Matsuda, Koichi A1 - Meidtner, Karina A1 - Meng, Weihua A1 - Montasser, May E A1 - van der Most, Peter J A1 - Munz, Matthias A1 - Nutile, Teresa A1 - Palviainen, Teemu A1 - Prasad, Gauri A1 - Prasad, Rashmi B A1 - Priyanka, Tallapragada Divya Sri A1 - Rizzi, Federica A1 - Salvi, Erika A1 - Sapkota, Bishwa R A1 - Shriner, Daniel A1 - Skotte, Line A1 - Smart, Melissa C A1 - Smith, Albert Vernon A1 - van der Spek, Ashley A1 - Spracklen, Cassandra N A1 - Strawbridge, Rona J A1 - Tajuddin, Salman M A1 - Trompet, Stella A1 - Turman, Constance A1 - Verweij, Niek A1 - Viberti, Clara A1 - Wang, Lihua A1 - Warren, Helen R A1 - Wootton, Robyn E A1 - Yanek, Lisa R A1 - Yao, Jie A1 - Yousri, Noha A A1 - Zhao, Wei A1 - Adeyemo, Adebowale A A1 - Afaq, Saima A1 - Aguilar-Salinas, Carlos Alberto A1 - Akiyama, Masato A1 - Albert, Matthew L A1 - Allison, Matthew A A1 - Alver, Maris A1 - Aung, Tin A1 - Azizi, Fereidoun A1 - Bentley, Amy R A1 - Boeing, Heiner A1 - Boerwinkle, Eric A1 - Borja, Judith B A1 - de Borst, Gert J A1 - Bottinger, Erwin P A1 - Broer, Linda A1 - Campbell, Harry A1 - Chanock, Stephen A1 - Chee, Miao-Li A1 - Chen, Guanjie A1 - Chen, Yii-der I A1 - Chen, Zhengming A1 - Chiu, Yen-Feng A1 - Cocca, Massimiliano A1 - Collins, Francis S A1 - Concas, Maria Pina A1 - Corley, Janie A1 - Cugliari, Giovanni A1 - van Dam, Rob M A1 - Damulina, Anna A1 - Daneshpour, Maryam S A1 - Day, Felix R A1 - Delgado, Graciela E A1 - Dhana, Klodian A1 - Doney, Alexander S F A1 - Dörr, Marcus A1 - Doumatey, Ayo P A1 - Dzimiri, Nduna A1 - Ebenesersdóttir, S Sunna A1 - Elliott, Joshua A1 - Elliott, Paul A1 - Ewert, Ralf A1 - Felix, Janine F A1 - Fischer, Krista A1 - Freedman, Barry I A1 - Girotto, Giorgia A1 - Goel, Anuj A1 - Gögele, Martin A1 - Goodarzi, Mark O A1 - Graff, Mariaelisa A1 - Granot-Hershkovitz, Einat A1 - Grodstein, Francine A1 - Guarrera, Simonetta A1 - Gudbjartsson, Daniel F A1 - Guity, Kamran A1 - Gunnarsson, Bjarni A1 - Guo, Yu A1 - Hagenaars, Saskia P A1 - Haiman, Christopher A A1 - Halevy, Avner A1 - Harris, Tamara B A1 - Hedayati, Mehdi A1 - van Heel, David A A1 - Hirata, Makoto A1 - Höfer, Imo A1 - Hsiung, Chao Agnes A1 - Huang, Jinyan A1 - Hung, Yi-Jen A1 - Ikram, M Arfan A1 - Jagadeesan, Anuradha A1 - Jousilahti, Pekka A1 - Kamatani, Yoichiro A1 - Kanai, Masahiro A1 - Kerrison, Nicola D A1 - Kessler, Thorsten A1 - Khaw, Kay-Tee A1 - Khor, Chiea Chuen A1 - de Kleijn, Dominique P V A1 - Koh, Woon-Puay A1 - Kolcic, Ivana A1 - Kraft, Peter A1 - Krämer, Bernhard K A1 - Kutalik, Zoltán A1 - Kuusisto, Johanna A1 - Langenberg, Claudia A1 - Launer, Lenore J A1 - Lawlor, Deborah A A1 - Lee, I-Te A1 - Lee, Wen-Jane A1 - Lerch, Markus M A1 - Li, Liming A1 - Liu, Jianjun A1 - Loh, Marie A1 - London, Stephanie J A1 - Loomis, Stephanie A1 - Lu, Yingchang A1 - Luan, Jian'an A1 - Mägi, Reedik A1 - Manichaikul, Ani W A1 - Manunta, Paolo A1 - Másson, Gísli A1 - Matoba, Nana A1 - Mei, Xue W A1 - Meisinger, Christa A1 - Meitinger, Thomas A1 - Mezzavilla, Massimo A1 - Milani, Lili A1 - Millwood, Iona Y A1 - Momozawa, Yukihide A1 - Moore, Amy A1 - Morange, Pierre-Emmanuel A1 - Moreno-Macias, Hortensia A1 - Mori, Trevor A A1 - Morrison, Alanna C A1 - Muka, Taulant A1 - Murakami, Yoshinori A1 - Murray, Alison D A1 - de Mutsert, Renée A1 - Mychaleckyj, Josyf C A1 - Nalls, Mike A A1 - Nauck, Matthias A1 - Neville, Matt J A1 - Nolte, Ilja M A1 - Ong, Ken K A1 - Orozco, Lorena A1 - Padmanabhan, Sandosh A1 - Pálsson, Gunnar A1 - Pankow, James S A1 - Pattaro, Cristian A1 - Pattie, Alison A1 - Polasek, Ozren A1 - Poulter, Neil A1 - Pramstaller, Peter P A1 - Quintana-Murci, Lluis A1 - Räikkönen, Katri A1 - Ralhan, Sarju A1 - Rao, Dabeeru C A1 - van Rheenen, Wouter A1 - Rich, Stephen S A1 - Ridker, Paul M A1 - Rietveld, Cornelius A A1 - Robino, Antonietta A1 - van Rooij, Frank J A A1 - Ruggiero, Daniela A1 - Saba, Yasaman A1 - Sabanayagam, Charumathi A1 - Sabater-Lleal, Maria A1 - Sala, Cinzia Felicita A1 - Salomaa, Veikko A1 - Sandow, Kevin A1 - Schmidt, Helena A1 - Scott, Laura J A1 - Scott, William R A1 - Sedaghati-Khayat, Bahareh A1 - Sennblad, Bengt A1 - van Setten, Jessica A1 - Sever, Peter J A1 - Sheu, Wayne H-H A1 - Shi, Yuan A1 - Shrestha, Smeeta A1 - Shukla, Sharvari Rahul A1 - Sigurdsson, Jon K A1 - Sikka, Timo Tonis A1 - Singh, Jai Rup A1 - Smith, Blair H A1 - Stančáková, Alena A1 - Stanton, Alice A1 - Starr, John M A1 - Stefansdottir, Lilja A1 - Straker, Leon A1 - Sulem, Patrick A1 - Sveinbjornsson, Gardar A1 - Swertz, Morris A A1 - Taylor, Adele M A1 - Taylor, Kent D A1 - Terzikhan, Natalie A1 - Tham, Yih-Chung A1 - Thorleifsson, Gudmar A1 - Thorsteinsdottir, Unnur A1 - Tillander, Annika A1 - Tracy, Russell P A1 - Tusié-Luna, Teresa A1 - Tzoulaki, Ioanna A1 - Vaccargiu, Simona A1 - Vangipurapu, Jagadish A1 - Veldink, Jan H A1 - Vitart, Veronique A1 - Völker, Uwe A1 - Vuoksimaa, Eero A1 - Wakil, Salma M A1 - Waldenberger, Melanie A1 - Wander, Gurpreet S A1 - Wang, Ya Xing A1 - Wareham, Nicholas J A1 - Wild, Sarah A1 - Yajnik, Chittaranjan S A1 - Yuan, Jian-Min A1 - Zeng, Lingyao A1 - Zhang, Liang A1 - Zhou, Jie A1 - Amin, Najaf A1 - Asselbergs, Folkert W A1 - Bakker, Stephan J L A1 - Becker, Diane M A1 - Lehne, Benjamin A1 - Bennett, David A A1 - van den Berg, Leonard H A1 - Berndt, Sonja I A1 - Bharadwaj, Dwaipayan A1 - Bielak, Lawrence F A1 - Bochud, Murielle A1 - Boehnke, Mike A1 - Bouchard, Claude A1 - Bradfield, Jonathan P A1 - Brody, Jennifer A A1 - Campbell, Archie A1 - Carmi, Shai A1 - Caulfield, Mark J A1 - Cesarini, David A1 - Chambers, John C A1 - Chandak, Giriraj Ratan A1 - Cheng, Ching-Yu A1 - Ciullo, Marina A1 - Cornelis, Marilyn A1 - Cusi, Daniele A1 - Smith, George Davey A1 - Deary, Ian J A1 - Dorajoo, Rajkumar A1 - van Duijn, Cornelia M A1 - Ellinghaus, David A1 - Erdmann, Jeanette A1 - Eriksson, Johan G A1 - Evangelou, Evangelos A1 - Evans, Michele K A1 - Faul, Jessica D A1 - Feenstra, Bjarke A1 - Feitosa, Mary A1 - Foisy, Sylvain A1 - Franke, Andre A1 - Friedlander, Yechiel A1 - Gasparini, Paolo A1 - Gieger, Christian A1 - Gonzalez, Clicerio A1 - Goyette, Philippe A1 - Grant, Struan F A A1 - Griffiths, Lyn R A1 - Groop, Leif A1 - Gudnason, Vilmundur A1 - Gyllensten, Ulf A1 - Hakonarson, Hakon A1 - Hamsten, Anders A1 - van der Harst, Pim A1 - Heng, Chew-Kiat A1 - Hicks, Andrew A A1 - Hochner, Hagit A1 - Huikuri, Heikki A1 - Hunt, Steven C A1 - Jaddoe, Vincent W V A1 - De Jager, Philip L A1 - Johannesson, Magnus A1 - Johansson, Asa A1 - Jonas, Jost B A1 - Jukema, J Wouter A1 - Junttila, Juhani A1 - Kaprio, Jaakko A1 - Kardia, Sharon L R A1 - Karpe, Fredrik A1 - Kumari, Meena A1 - Laakso, Markku A1 - van der Laan, Sander W A1 - Lahti, Jari A1 - Laudes, Matthias A1 - Lea, Rodney A A1 - Lieb, Wolfgang A1 - Lumley, Thomas A1 - Martin, Nicholas G A1 - März, Winfried A1 - Matullo, Giuseppe A1 - McCarthy, Mark I A1 - Medland, Sarah E A1 - Merriman, Tony R A1 - Metspalu, Andres A1 - Meyer, Brian F A1 - Mohlke, Karen L A1 - Montgomery, Grant W A1 - Mook-Kanamori, Dennis A1 - Munroe, Patricia B A1 - North, Kari E A1 - Nyholt, Dale R A1 - O'Connell, Jeffery R A1 - Ober, Carole A1 - Oldehinkel, Albertine J A1 - Palmas, Walter A1 - Palmer, Colin A1 - Pasterkamp, Gerard G A1 - Patin, Etienne A1 - Pennell, Craig E A1 - Perusse, Louis A1 - Peyser, Patricia A A1 - Pirastu, Mario A1 - Polderman, Tinca J C A1 - Porteous, David J A1 - Posthuma, Danielle A1 - Psaty, Bruce M A1 - Rioux, John D A1 - Rivadeneira, Fernando A1 - Rotimi, Charles A1 - Rotter, Jerome I A1 - Rudan, Igor A1 - den Ruijter, Hester M A1 - Sanghera, Dharambir K A1 - Sattar, Naveed A1 - Schmidt, Reinhold A1 - Schulze, Matthias B A1 - Schunkert, Heribert A1 - Scott, Robert A A1 - Shuldiner, Alan R A1 - Sim, Xueling A1 - Small, Neil A1 - Smith, Jennifer A A1 - Sotoodehnia, Nona A1 - Tai, E-Shyong A1 - Teumer, Alexander A1 - Timpson, Nicholas J A1 - Toniolo, Daniela A1 - Trégouët, David-Alexandre A1 - Tuomi, Tiinamaija A1 - Vollenweider, Peter A1 - Wang, Carol A A1 - Weir, David R A1 - Whitfield, John B A1 - Wijmenga, Cisca A1 - Wong, Tien-Yin A1 - Wright, John A1 - Yang, Jingyun A1 - Yu, Lei A1 - Zemel, Babette S A1 - Zonderman, Alan B A1 - Perola, Markus A1 - Magnusson, Patrik K E A1 - Uitterlinden, André G A1 - Kooner, Jaspal S A1 - Chasman, Daniel I A1 - Loos, Ruth J F A1 - Franceschini, Nora A1 - Franke, Lude A1 - Haley, Chris S A1 - Hayward, Caroline A1 - Walters, Robin G A1 - Perry, John R B A1 - Esko, Tõnu A1 - Helgason, Agnar A1 - Stefansson, Kari A1 - Joshi, Peter K A1 - Kubo, Michiaki A1 - Wilson, James F AB -

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

VL - 10 IS - 1 ER - TY - JOUR T1 - A catalog of genetic loci associated with kidney function from analyses of a million individuals. JF - Nat Genet Y1 - 2019 A1 - Wuttke, Matthias A1 - Li, Yong A1 - Li, Man A1 - Sieber, Karsten B A1 - Feitosa, Mary F A1 - Gorski, Mathias A1 - Tin, Adrienne A1 - Wang, Lihua A1 - Chu, Audrey Y A1 - Hoppmann, Anselm A1 - Kirsten, Holger A1 - Giri, Ayush A1 - Chai, Jin-Fang A1 - Sveinbjornsson, Gardar A1 - Tayo, Bamidele O A1 - Nutile, Teresa A1 - Fuchsberger, Christian A1 - Marten, Jonathan A1 - Cocca, Massimiliano A1 - Ghasemi, Sahar A1 - Xu, Yizhe A1 - Horn, Katrin A1 - Noce, Damia A1 - van der Most, Peter J A1 - Sedaghat, Sanaz A1 - Yu, Zhi A1 - Akiyama, Masato A1 - Afaq, Saima A1 - Ahluwalia, Tarunveer S A1 - Almgren, Peter A1 - Amin, Najaf A1 - Arnlöv, Johan A1 - Bakker, Stephan J L A1 - Bansal, Nisha A1 - Baptista, Daniela A1 - Bergmann, Sven A1 - Biggs, Mary L A1 - Biino, Ginevra A1 - Boehnke, Michael A1 - Boerwinkle, Eric A1 - Boissel, Mathilde A1 - Bottinger, Erwin P A1 - Boutin, Thibaud S A1 - Brenner, Hermann A1 - Brumat, Marco A1 - Burkhardt, Ralph A1 - Butterworth, Adam S A1 - Campana, Eric A1 - Campbell, Archie A1 - Campbell, Harry A1 - Canouil, Mickaël A1 - Carroll, Robert J A1 - Catamo, Eulalia A1 - Chambers, John C A1 - Chee, Miao-Ling A1 - Chee, Miao-Li A1 - Chen, Xu A1 - Cheng, Ching-Yu A1 - Cheng, Yurong A1 - Christensen, Kaare A1 - Cifkova, Renata A1 - Ciullo, Marina A1 - Concas, Maria Pina A1 - Cook, James P A1 - Coresh, Josef A1 - Corre, Tanguy A1 - Sala, Cinzia Felicita A1 - Cusi, Daniele A1 - Danesh, John A1 - Daw, E Warwick A1 - de Borst, Martin H A1 - De Grandi, Alessandro A1 - de Mutsert, Renée A1 - de Vries, Aiko P J A1 - Degenhardt, Frauke A1 - Delgado, Graciela A1 - Demirkan, Ayse A1 - Di Angelantonio, Emanuele A1 - Dittrich, Katalin A1 - Divers, Jasmin A1 - Dorajoo, Rajkumar A1 - Eckardt, Kai-Uwe A1 - Ehret, Georg A1 - Elliott, Paul A1 - Endlich, Karlhans A1 - Evans, Michele K A1 - Felix, Janine F A1 - Foo, Valencia Hui Xian A1 - Franco, Oscar H A1 - Franke, Andre A1 - Freedman, Barry I A1 - Freitag-Wolf, Sandra A1 - Friedlander, Yechiel A1 - Froguel, Philippe A1 - Gansevoort, Ron T A1 - Gao, He A1 - Gasparini, Paolo A1 - Gaziano, J Michael A1 - Giedraitis, Vilmantas A1 - Gieger, Christian A1 - Girotto, Giorgia A1 - Giulianini, Franco A1 - Gögele, Martin A1 - Gordon, Scott D A1 - Gudbjartsson, Daniel F A1 - Gudnason, Vilmundur A1 - Haller, Toomas A1 - Hamet, Pavel A1 - Harris, Tamara B A1 - Hartman, Catharina A A1 - Hayward, Caroline A1 - Hellwege, Jacklyn N A1 - Heng, Chew-Kiat A1 - Hicks, Andrew A A1 - Hofer, Edith A1 - Huang, Wei A1 - Hutri-Kähönen, Nina A1 - Hwang, Shih-Jen A1 - Ikram, M Arfan A1 - Indridason, Olafur S A1 - Ingelsson, Erik A1 - Ising, Marcus A1 - Jaddoe, Vincent W V A1 - Jakobsdottir, Johanna A1 - Jonas, Jost B A1 - Joshi, Peter K A1 - Josyula, Navya Shilpa A1 - Jung, Bettina A1 - Kähönen, Mika A1 - Kamatani, Yoichiro A1 - Kammerer, Candace M A1 - Kanai, Masahiro A1 - Kastarinen, Mika A1 - Kerr, Shona M A1 - Khor, Chiea-Chuen A1 - Kiess, Wieland A1 - Kleber, Marcus E A1 - Koenig, Wolfgang A1 - Kooner, Jaspal S A1 - Körner, Antje A1 - Kovacs, Peter A1 - Kraja, Aldi T A1 - Krajcoviechova, Alena A1 - Kramer, Holly A1 - Krämer, Bernhard K A1 - Kronenberg, Florian A1 - Kubo, Michiaki A1 - Kuhnel, Brigitte A1 - Kuokkanen, Mikko A1 - Kuusisto, Johanna A1 - La Bianca, Martina A1 - Laakso, Markku A1 - Lange, Leslie A A1 - Langefeld, Carl D A1 - Lee, Jeannette Jen-Mai A1 - Lehne, Benjamin A1 - Lehtimäki, Terho A1 - Lieb, Wolfgang A1 - Lim, Su-Chi A1 - Lind, Lars A1 - Lindgren, Cecilia M A1 - Liu, Jun A1 - Liu, Jianjun A1 - Loeffler, Markus A1 - Loos, Ruth J F A1 - Lucae, Susanne A1 - Lukas, Mary Ann A1 - Lyytikäinen, Leo-Pekka A1 - Mägi, Reedik A1 - Magnusson, Patrik K E A1 - Mahajan, Anubha A1 - Martin, Nicholas G A1 - Martins, Jade A1 - März, Winfried A1 - Mascalzoni, Deborah A1 - Matsuda, Koichi A1 - Meisinger, Christa A1 - Meitinger, Thomas A1 - Melander, Olle A1 - Metspalu, Andres A1 - Mikaelsdottir, Evgenia K A1 - Milaneschi, Yuri A1 - Miliku, Kozeta A1 - Mishra, Pashupati P A1 - Mohlke, Karen L A1 - Mononen, Nina A1 - Montgomery, Grant W A1 - Mook-Kanamori, Dennis O A1 - Mychaleckyj, Josyf C A1 - Nadkarni, Girish N A1 - Nalls, Mike A A1 - Nauck, Matthias A1 - Nikus, Kjell A1 - Ning, Boting A1 - Nolte, Ilja M A1 - Noordam, Raymond A1 - O'Connell, Jeffrey A1 - O'Donoghue, Michelle L A1 - Olafsson, Isleifur A1 - Oldehinkel, Albertine J A1 - Orho-Melander, Marju A1 - Ouwehand, Willem H A1 - Padmanabhan, Sandosh A1 - Palmer, Nicholette D A1 - Palsson, Runolfur A1 - Penninx, Brenda W J H A1 - Perls, Thomas A1 - Perola, Markus A1 - Pirastu, Mario A1 - Pirastu, Nicola A1 - Pistis, Giorgio A1 - Podgornaia, Anna I A1 - Polasek, Ozren A1 - Ponte, Belen A1 - Porteous, David J A1 - Poulain, Tanja A1 - Pramstaller, Peter P A1 - Preuss, Michael H A1 - Prins, Bram P A1 - Province, Michael A A1 - Rabelink, Ton J A1 - Raffield, Laura M A1 - Raitakari, Olli T A1 - Reilly, Dermot F A1 - Rettig, Rainer A1 - Rheinberger, Myriam A1 - Rice, Kenneth M A1 - Ridker, Paul M A1 - Rivadeneira, Fernando A1 - Rizzi, Federica A1 - Roberts, David J A1 - Robino, Antonietta A1 - Rossing, Peter A1 - Rudan, Igor A1 - Rueedi, Rico A1 - Ruggiero, Daniela A1 - Ryan, Kathleen A A1 - Saba, Yasaman A1 - Sabanayagam, Charumathi A1 - Salomaa, Veikko A1 - Salvi, Erika A1 - Saum, Kai-Uwe A1 - Schmidt, Helena A1 - Schmidt, Reinhold A1 - Schöttker, Ben A1 - Schulz, Christina-Alexandra A1 - Schupf, Nicole A1 - Shaffer, Christian M A1 - Shi, Yuan A1 - Smith, Albert V A1 - Smith, Blair H A1 - Soranzo, Nicole A1 - Spracklen, Cassandra N A1 - Strauch, Konstantin A1 - Stringham, Heather M A1 - Stumvoll, Michael A1 - Svensson, Per O A1 - Szymczak, Silke A1 - Tai, E-Shyong A1 - Tajuddin, Salman M A1 - Tan, Nicholas Y Q A1 - Taylor, Kent D A1 - Teren, Andrej A1 - Tham, Yih-Chung A1 - Thiery, Joachim A1 - Thio, Chris H L A1 - Thomsen, Hauke A1 - Thorleifsson, Gudmar A1 - Toniolo, Daniela A1 - Tönjes, Anke A1 - Tremblay, Johanne A1 - Tzoulaki, Ioanna A1 - Uitterlinden, André G A1 - Vaccargiu, Simona A1 - van Dam, Rob M A1 - van der Harst, Pim A1 - van Duijn, Cornelia M A1 - Velez Edward, Digna R A1 - Verweij, Niek A1 - Vogelezang, Suzanne A1 - Völker, Uwe A1 - Vollenweider, Peter A1 - Waeber, Gérard A1 - Waldenberger, Melanie A1 - Wallentin, Lars A1 - Wang, Ya Xing A1 - Wang, Chaolong A1 - Waterworth, Dawn M A1 - Bin Wei, Wen A1 - White, Harvey A1 - Whitfield, John B A1 - Wild, Sarah H A1 - Wilson, James F A1 - Wojczynski, Mary K A1 - Wong, Charlene A1 - Wong, Tien-Yin A1 - Xu, Liang A1 - Yang, Qiong A1 - Yasuda, Masayuki A1 - Yerges-Armstrong, Laura M A1 - Zhang, Weihua A1 - Zonderman, Alan B A1 - Rotter, Jerome I A1 - Bochud, Murielle A1 - Psaty, Bruce M A1 - Vitart, Veronique A1 - Wilson, James G A1 - Dehghan, Abbas A1 - Parsa, Afshin A1 - Chasman, Daniel I A1 - Ho, Kevin A1 - Morris, Andrew P A1 - Devuyst, Olivier A1 - Akilesh, Shreeram A1 - Pendergrass, Sarah A A1 - Sim, Xueling A1 - Böger, Carsten A A1 - Okada, Yukinori A1 - Edwards, Todd L A1 - Snieder, Harold A1 - Stefansson, Kari A1 - Hung, Adriana M A1 - Heid, Iris M A1 - Scholz, Markus A1 - Teumer, Alexander A1 - Köttgen, Anna A1 - Pattaro, Cristian KW - Chromosome Mapping KW - European Continental Ancestry Group KW - Genetic Association Studies KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Glomerular Filtration Rate KW - Humans KW - Inheritance Patterns KW - Kidney Function Tests KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci KW - Quantitative Trait, Heritable KW - Renal Insufficiency, Chronic KW - Uromodulin AB -

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

VL - 51 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 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 - Mendelian randomization analysis does not support causal associations of birth weight with hypertension risk and blood pressure in adulthood. JF - Eur J Epidemiol Y1 - 2020 A1 - Zheng, Yan A1 - Huang, Tao A1 - Wang, Tiange A1 - Mei, Zhendong A1 - Sun, Zhonghan A1 - Zhang, Tao A1 - Ellervik, Christina A1 - Chai, Jin-Fang A1 - Sim, Xueling A1 - van Dam, Rob M A1 - Tai, E-Shyong A1 - Koh, Woon-Puay A1 - Dorajoo, Rajkumar A1 - Saw, Seang-Mei A1 - Sabanayagam, Charumathi A1 - Wong, Tien Yin A1 - Gupta, Preeti A1 - Rossing, Peter A1 - Ahluwalia, Tarunveer S A1 - Vinding, Rebecca K A1 - Bisgaard, Hans A1 - Bønnelykke, Klaus A1 - Wang, Yujie A1 - Graff, Mariaelisa A1 - Voortman, Trudy A1 - van Rooij, Frank J A A1 - Hofman, Albert A1 - van Heemst, Diana A1 - Noordam, Raymond A1 - Estampador, Angela C A1 - Varga, Tibor V A1 - Enzenbach, Cornelia A1 - Scholz, Markus A1 - Thiery, Joachim A1 - Burkhardt, Ralph A1 - Orho-Melander, Marju A1 - Schulz, Christina-Alexandra A1 - Ericson, Ulrika A1 - Sonestedt, Emily A1 - Kubo, Michiaki A1 - Akiyama, Masato A1 - Zhou, Ang A1 - Kilpeläinen, Tuomas O A1 - Hansen, Torben A1 - Kleber, Marcus E A1 - Delgado, Graciela A1 - McCarthy, Mark A1 - Lemaitre, Rozenn N A1 - Felix, Janine F A1 - Jaddoe, Vincent W V A1 - Wu, Ying A1 - Mohlke, Karen L A1 - Lehtimäki, Terho A1 - Wang, Carol A A1 - Pennell, Craig E A1 - Schunkert, Heribert A1 - Kessler, Thorsten A1 - Zeng, Lingyao A1 - Willenborg, Christina A1 - Peters, Annette A1 - Lieb, Wolfgang A1 - Grote, Veit A1 - Rzehak, Peter A1 - Koletzko, Berthold A1 - Erdmann, Jeanette A1 - Munz, Matthias A1 - Wu, Tangchun A1 - He, Meian A1 - Yu, Caizheng A1 - Lecoeur, Cécile A1 - Froguel, Philippe A1 - Corella, Dolores A1 - Moreno, Luis A A1 - Lai, Chao-Qiang A1 - Pitkänen, Niina A1 - Boreham, Colin A A1 - Ridker, Paul M A1 - Rosendaal, Frits R A1 - de Mutsert, Renée A1 - Power, Chris A1 - Paternoster, Lavinia A1 - Sørensen, Thorkild I A A1 - Tjønneland, Anne A1 - Overvad, Kim A1 - Djoussé, Luc A1 - Rivadeneira, Fernando A1 - Lee, Nanette R A1 - Raitakari, Olli T A1 - Kähönen, Mika A1 - Viikari, Jorma A1 - Langhendries, Jean-Paul A1 - Escribano, Joaquin A1 - Verduci, Elvira A1 - Dedoussis, George A1 - König, Inke A1 - Balkau, Beverley A1 - Coltell, Oscar A1 - Dallongeville, Jean A1 - Meirhaeghe, Aline A1 - Amouyel, Philippe A1 - Gottrand, Frédéric A1 - Pahkala, Katja A1 - Niinikoski, Harri A1 - Hyppönen, Elina A1 - März, Winfried A1 - Mackey, David A A1 - Gruszfeld, Dariusz A1 - Tucker, Katherine L A1 - Fumeron, Frédéric A1 - Estruch, Ramon A1 - Ordovas, Jose M A1 - Arnett, Donna K A1 - Mook-Kanamori, Dennis O A1 - Mozaffarian, Dariush A1 - Psaty, Bruce M A1 - North, Kari E A1 - Chasman, Daniel I A1 - Qi, Lu AB -

Epidemiology studies suggested that low birthweight was associated with a higher risk of hypertension in later life. However, little is known about the causality of such associations. In our study, we evaluated the causal association of low birthweight with adulthood hypertension following a standard analytic protocol using the study-level data of 183,433 participants from 60 studies (CHARGE-BIG consortium), as well as that with blood pressure using publicly available summary-level genome-wide association data from EGG consortium of 153,781 participants, ICBP consortium and UK Biobank cohort together of 757,601 participants. We used seven SNPs as the instrumental variable in the study-level analysis and 47 SNPs in the summary-level analysis. In the study-level analyses, decreased birthweight was associated with a higher risk of hypertension in adults (the odds ratio per 1 standard deviation (SD) lower birthweight, 1.22; 95% CI 1.16 to 1.28), while no association was found between genetically instrumented birthweight and hypertension risk (instrumental odds ratio for causal effect per 1 SD lower birthweight, 0.97; 95% CI 0.68 to 1.41). Such results were consistent with that from the summary-level analyses, where the genetically determined low birthweight was not associated with blood pressure measurements either. One SD lower genetically determined birthweight was not associated with systolic blood pressure (β = - 0.76, 95% CI - 2.45 to 1.08 mmHg), 0.06 mmHg lower diastolic blood pressure (β = - 0.06, 95% CI - 0.93 to 0.87 mmHg), or pulse pressure (β = - 0.65, 95% CI - 1.38 to 0.69 mmHg, all p > 0.05). Our findings suggest that the inverse association of birthweight with hypertension risk from observational studies was not supported by large Mendelian randomization analyses.

VL - 35 IS - 7 ER - TY - JOUR T1 - Differential and shared genetic effects on kidney function between diabetic and non-diabetic individuals. JF - Commun Biol Y1 - 2022 A1 - Winkler, Thomas W A1 - Rasheed, Humaira A1 - Teumer, Alexander A1 - Gorski, Mathias A1 - Rowan, Bryce X A1 - Stanzick, Kira J A1 - Thomas, Laurent F A1 - Tin, Adrienne A1 - Hoppmann, Anselm A1 - Chu, Audrey Y A1 - Tayo, Bamidele A1 - Thio, Chris H L A1 - Cusi, Daniele A1 - Chai, Jin-Fang A1 - Sieber, Karsten B A1 - Horn, Katrin A1 - Li, Man A1 - Scholz, Markus A1 - Cocca, Massimiliano A1 - Wuttke, Matthias A1 - van der Most, Peter J A1 - Yang, Qiong A1 - Ghasemi, Sahar A1 - Nutile, Teresa A1 - Li, Yong A1 - Pontali, Giulia A1 - Günther, Felix A1 - Dehghan, Abbas A1 - Correa, Adolfo A1 - Parsa, Afshin A1 - Feresin, Agnese A1 - de Vries, Aiko P J A1 - Zonderman, Alan B A1 - Smith, Albert V A1 - Oldehinkel, Albertine J A1 - De Grandi, Alessandro A1 - Rosenkranz, Alexander R A1 - Franke, Andre A1 - Teren, Andrej A1 - Metspalu, Andres A1 - Hicks, Andrew A A1 - Morris, Andrew P A1 - Tönjes, Anke A1 - Morgan, Anna A1 - Podgornaia, Anna I A1 - Peters, Annette A1 - Körner, Antje A1 - Mahajan, Anubha A1 - Campbell, Archie A1 - Freedman, Barry I A1 - Spedicati, Beatrice A1 - Ponte, Belen A1 - Schöttker, Ben A1 - Brumpton, Ben A1 - Banas, Bernhard A1 - Krämer, Bernhard K A1 - Jung, Bettina A1 - Åsvold, Bjørn Olav A1 - Smith, Blair H A1 - Ning, Boting A1 - Penninx, Brenda W J H A1 - Vanderwerff, Brett R A1 - Psaty, Bruce M A1 - Kammerer, Candace M A1 - Langefeld, Carl D A1 - Hayward, Caroline A1 - Spracklen, Cassandra N A1 - Robinson-Cohen, Cassianne A1 - Hartman, Catharina A A1 - Lindgren, Cecilia M A1 - Wang, Chaolong A1 - Sabanayagam, Charumathi A1 - Heng, Chew-Kiat A1 - Lanzani, Chiara A1 - Khor, Chiea-Chuen A1 - Cheng, Ching-Yu A1 - Fuchsberger, Christian A1 - Gieger, Christian A1 - Shaffer, Christian M A1 - Schulz, Christina-Alexandra A1 - Willer, Cristen J A1 - Chasman, Daniel I A1 - Gudbjartsson, Daniel F A1 - Ruggiero, Daniela A1 - Toniolo, Daniela A1 - Czamara, Darina A1 - Porteous, David J A1 - Waterworth, Dawn M A1 - Mascalzoni, Deborah A1 - Mook-Kanamori, Dennis O A1 - Reilly, Dermot F A1 - Daw, E Warwick A1 - Hofer, Edith A1 - Boerwinkle, Eric A1 - Salvi, Erika A1 - Bottinger, Erwin P A1 - Tai, E-Shyong A1 - Catamo, Eulalia A1 - Rizzi, Federica A1 - Guo, Feng A1 - Rivadeneira, Fernando A1 - Guilianini, Franco A1 - Sveinbjornsson, Gardar A1 - Ehret, Georg A1 - Waeber, Gérard A1 - Biino, Ginevra A1 - Girotto, Giorgia A1 - Pistis, Giorgio A1 - Nadkarni, Girish N A1 - Delgado, Graciela E A1 - Montgomery, Grant W A1 - Snieder, Harold A1 - Campbell, Harry A1 - White, Harvey D A1 - Gao, He A1 - Stringham, Heather M A1 - Schmidt, Helena A1 - Li, Hengtong A1 - Brenner, Hermann A1 - Holm, Hilma A1 - Kirsten, Holgen A1 - Kramer, Holly A1 - Rudan, Igor A1 - Nolte, Ilja M A1 - Tzoulaki, Ioanna A1 - Olafsson, Isleifur A1 - Martins, Jade A1 - Cook, James P A1 - Wilson, James F A1 - Halbritter, Jan A1 - Felix, Janine F A1 - Divers, Jasmin A1 - Kooner, Jaspal S A1 - Lee, Jeannette Jen-Mai A1 - O'Connell, Jeffrey A1 - Rotter, Jerome I A1 - Liu, Jianjun A1 - Xu, Jie A1 - Thiery, Joachim A1 - Arnlöv, Johan A1 - Kuusisto, Johanna A1 - Jakobsdottir, Johanna A1 - Tremblay, Johanne A1 - Chambers, John C A1 - Whitfield, John B A1 - Gaziano, John M A1 - Marten, Jonathan A1 - Coresh, Josef A1 - Jonas, Jost B A1 - Mychaleckyj, Josyf C A1 - Christensen, Kaare A1 - Eckardt, Kai-Uwe A1 - Mohlke, Karen L A1 - Endlich, Karlhans A1 - Dittrich, Katalin A1 - Ryan, Kathleen A A1 - Rice, Kenneth M A1 - Taylor, Kent D A1 - Ho, Kevin A1 - Nikus, Kjell A1 - Matsuda, Koichi A1 - Strauch, Konstantin A1 - Miliku, Kozeta A1 - Hveem, Kristian A1 - Lind, Lars A1 - Wallentin, Lars A1 - Yerges-Armstrong, Laura M A1 - Raffield, Laura M A1 - Phillips, Lawrence S A1 - Launer, Lenore J A1 - Lyytikäinen, Leo-Pekka A1 - Lange, Leslie A A1 - Citterio, Lorena A1 - Klaric, Lucija A1 - Ikram, M Arfan A1 - Ising, Marcus A1 - Kleber, Marcus E A1 - Francescatto, Margherita A1 - Concas, Maria Pina A1 - Ciullo, Marina A1 - Piratsu, Mario A1 - Orho-Melander, Marju A1 - Laakso, Markku A1 - Loeffler, Markus A1 - Perola, Markus A1 - de Borst, Martin H A1 - Gögele, Martin A1 - Bianca, Martina La A1 - Lukas, Mary Ann A1 - Feitosa, Mary F A1 - Biggs, Mary L A1 - Wojczynski, Mary K A1 - Kavousi, Maryam A1 - Kanai, Masahiro A1 - Akiyama, Masato A1 - Yasuda, Masayuki A1 - Nauck, Matthias A1 - Waldenberger, Melanie A1 - Chee, Miao-Li A1 - Chee, Miao-Ling A1 - Boehnke, Michael A1 - Preuss, Michael H A1 - Stumvoll, Michael A1 - Province, Michael A A1 - Evans, Michele K A1 - O'Donoghue, Michelle L A1 - Kubo, Michiaki A1 - Kähönen, Mika A1 - Kastarinen, Mika A1 - Nalls, Mike A A1 - Kuokkanen, Mikko A1 - Ghanbari, Mohsen A1 - Bochud, Murielle A1 - Josyula, Navya Shilpa A1 - Martin, Nicholas G A1 - Tan, Nicholas Y Q A1 - Palmer, Nicholette D A1 - Pirastu, Nicola A1 - Schupf, Nicole A1 - Verweij, Niek A1 - Hutri-Kähönen, Nina A1 - Mononen, Nina A1 - Bansal, Nisha A1 - Devuyst, Olivier A1 - Melander, Olle A1 - Raitakari, Olli T A1 - Polasek, Ozren A1 - Manunta, Paolo A1 - Gasparini, Paolo A1 - Mishra, Pashupati P A1 - Sulem, Patrick A1 - Magnusson, Patrik K E A1 - Elliott, Paul A1 - Ridker, Paul M A1 - Hamet, Pavel A1 - Svensson, Per O A1 - Joshi, Peter K A1 - Kovacs, Peter A1 - Pramstaller, Peter P A1 - Rossing, Peter A1 - Vollenweider, Peter A1 - van der Harst, Pim A1 - Dorajoo, Rajkumar A1 - Sim, Ralene Z H A1 - Burkhardt, Ralph A1 - Tao, Ran A1 - Noordam, Raymond A1 - Mägi, Reedik A1 - Schmidt, Reinhold A1 - de Mutsert, Renée A1 - Rueedi, Rico A1 - van Dam, Rob M A1 - Carroll, Robert J A1 - Gansevoort, Ron T A1 - Loos, Ruth J F A1 - Felicita, Sala Cinzia A1 - Sedaghat, Sanaz A1 - Padmanabhan, Sandosh A1 - Freitag-Wolf, Sandra A1 - Pendergrass, Sarah A A1 - Graham, Sarah E A1 - Gordon, Scott D A1 - Hwang, Shih-Jen A1 - Kerr, Shona M A1 - Vaccargiu, Simona A1 - Patil, Snehal B A1 - Hallan, Stein A1 - Bakker, Stephan J L A1 - Lim, Su-Chi A1 - Lucae, Susanne A1 - Vogelezang, Suzanne A1 - Bergmann, Sven A1 - Corre, Tanguy A1 - Ahluwalia, Tarunveer S A1 - Lehtimäki, Terho A1 - Boutin, Thibaud S A1 - Meitinger, Thomas A1 - Wong, Tien-Yin A1 - Bergler, Tobias A1 - Rabelink, Ton J A1 - Esko, Tõnu A1 - Haller, Toomas A1 - Thorsteinsdottir, Unnur A1 - Völker, Uwe A1 - Foo, Valencia Hui Xian A1 - Salomaa, Veikko A1 - Vitart, Veronique A1 - Giedraitis, Vilmantas A1 - Gudnason, Vilmundur A1 - Jaddoe, Vincent W V A1 - Huang, Wei A1 - Zhang, Weihua A1 - Wei, Wen Bin A1 - Kiess, Wieland A1 - März, Winfried A1 - Koenig, Wolfgang A1 - Lieb, Wolfgang A1 - Gào, Xīn A1 - Sim, Xueling A1 - Wang, Ya Xing A1 - Friedlander, Yechiel A1 - Tham, Yih-Chung A1 - Kamatani, Yoichiro A1 - Okada, Yukinori A1 - Milaneschi, Yuri A1 - Yu, Zhi A1 - Stark, Klaus J A1 - Stefansson, Kari A1 - Böger, Carsten A A1 - Hung, Adriana M A1 - Kronenberg, Florian A1 - Köttgen, Anna A1 - Pattaro, Cristian A1 - Heid, Iris M KW - Creatinine KW - Diabetes Mellitus KW - Diabetic Nephropathies KW - Genome-Wide Association Study KW - Glomerular Filtration Rate KW - Humans KW - Kidney AB -

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

VL - 5 IS - 1 ER - TY - JOUR T1 - Gene-educational attainment interactions in a multi-population genome-wide meta-analysis identify novel lipid loci. JF - Front Genet Y1 - 2023 A1 - de Las Fuentes, Lisa A1 - Schwander, Karen L A1 - Brown, Michael R A1 - Bentley, Amy R A1 - Winkler, Thomas W A1 - Sung, Yun Ju A1 - Munroe, Patricia B A1 - Miller, Clint L A1 - Aschard, Hugo A1 - Aslibekyan, Stella A1 - Bartz, Traci M A1 - Bielak, Lawrence F A1 - Chai, Jin Fang A1 - Cheng, Ching-Yu A1 - Dorajoo, Rajkumar A1 - Feitosa, Mary F A1 - Guo, Xiuqing A1 - Hartwig, Fernando P A1 - Horimoto, Andrea A1 - Kolcic, Ivana A1 - Lim, Elise A1 - Liu, Yongmei A1 - Manning, Alisa K A1 - Marten, Jonathan A1 - Musani, Solomon K A1 - Noordam, Raymond A1 - Padmanabhan, Sandosh A1 - Rankinen, Tuomo A1 - Richard, Melissa A A1 - Ridker, Paul M A1 - Smith, Albert V A1 - Vojinovic, Dina A1 - Zonderman, Alan B A1 - Alver, Maris A1 - Boissel, Mathilde A1 - Christensen, Kaare A1 - Freedman, Barry I A1 - Gao, Chuan A1 - Giulianini, Franco 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 - Robino, Antonietta A1 - Sofer, Tamar A1 - Takeuchi, Fumihiko A1 - Tayo, Bamidele O A1 - van der Most, Peter J A1 - Verweij, Niek A1 - Ware, Erin B A1 - Weiss, Stefan A1 - Wen, Wanqing A1 - Yanek, Lisa R A1 - Zhan, Yiqiang A1 - Amin, Najaf A1 - Arking, Dan E A1 - Ballantyne, Christie A1 - Boerwinkle, Eric A1 - Brody, Jennifer A A1 - Broeckel, Ulrich A1 - Campbell, Archie A1 - Canouil, Mickaël A1 - Chai, Xiaoran A1 - Chen, Yii-Der Ida A1 - Chen, Xu A1 - Chitrala, Kumaraswamy Naidu A1 - Concas, Maria Pina A1 - de Faire, Ulf A1 - de Mutsert, Renée A1 - de Silva, H Janaka A1 - de Vries, Paul S A1 - Do, Ahn A1 - Faul, Jessica D A1 - Fisher, Virginia A1 - Floyd, James S A1 - Forrester, Terrence A1 - Friedlander, Yechiel A1 - Girotto, Giorgia A1 - Gu, C Charles A1 - Hallmans, Göran A1 - Heikkinen, Sami A1 - Heng, Chew-Kiat A1 - Homuth, Georg A1 - Hunt, Steven A1 - Ikram, M Arfan A1 - Jacobs, David R A1 - Kavousi, Maryam A1 - Khor, Chiea Chuen A1 - Kilpeläinen, Tuomas O A1 - Koh, Woon-Puay A1 - Komulainen, Pirjo A1 - Langefeld, Carl D A1 - Liang, Jingjing A1 - Liu, Kiang A1 - Liu, Jianjun A1 - Lohman, Kurt A1 - Mägi, Reedik A1 - Manichaikul, Ani W A1 - McKenzie, Colin A A1 - Meitinger, Thomas A1 - Milaneschi, Yuri A1 - Nauck, Matthias A1 - Nelson, Christopher P A1 - O'Connell, Jeffrey R A1 - Palmer, Nicholette D A1 - Pereira, Alexandre C A1 - Perls, Thomas A1 - Peters, Annette A1 - Polasek, Ozren A1 - Raitakari, Olli T A1 - Rice, Kenneth A1 - Rice, Treva K A1 - Rich, Stephen S A1 - Sabanayagam, Charumathi A1 - Schreiner, Pamela J A1 - Shu, Xiao-Ou A1 - Sidney, Stephen A1 - Sims, Mario A1 - Smith, Jennifer A A1 - Starr, John M A1 - Strauch, Konstantin A1 - Tai, E Shyong A1 - Taylor, Kent D A1 - Tsai, Michael Y A1 - Uitterlinden, André G A1 - van Heemst, Diana A1 - Waldenberger, Melanie A1 - Wang, Ya-Xing A1 - Wei, Wen-Bin A1 - Wilson, Gregory A1 - Xuan, Deng A1 - Yao, Jie A1 - Yu, Caizheng A1 - Yuan, Jian-Min A1 - Zhao, Wei A1 - Becker, Diane M A1 - Bonnefond, Amélie A1 - Bowden, Donald W A1 - Cooper, Richard S A1 - Deary, Ian J A1 - Divers, Jasmin A1 - Esko, Tõnu A1 - Franks, Paul W A1 - Froguel, Philippe A1 - Gieger, Christian A1 - Jonas, Jost B A1 - Kato, Norihiro A1 - Lakka, Timo A A1 - Leander, Karin A1 - Lehtimäki, Terho A1 - Magnusson, Patrik K E A1 - North, Kari E A1 - Ntalla, Ioanna A1 - Penninx, Brenda A1 - Samani, Nilesh J A1 - Snieder, Harold A1 - Spedicati, Beatrice A1 - van der Harst, Pim A1 - Völzke, Henry A1 - Wagenknecht, Lynne E A1 - Weir, David R A1 - Wojczynski, Mary K A1 - Wu, Tangchun A1 - Zheng, Wei A1 - Zhu, Xiaofeng A1 - Bouchard, Claude A1 - Chasman, Daniel I A1 - Evans, Michele K A1 - Fox, Ervin R A1 - Gudnason, Vilmundur A1 - Hayward, Caroline A1 - Horta, Bernardo L A1 - Kardia, Sharon L R A1 - Krieger, Jose Eduardo A1 - Mook-Kanamori, Dennis O A1 - Peyser, Patricia A A1 - Province, Michael M A1 - Psaty, Bruce M A1 - Rudan, Igor A1 - Sim, Xueling A1 - Smith, Blair H A1 - van Dam, Rob M A1 - van Duijn, Cornelia M A1 - Wong, Tien Yin A1 - Arnett, Donna K A1 - Rao, Dabeeru C A1 - Gauderman, James A1 - Liu, Ching-Ti A1 - Morrison, Alanna C A1 - Rotter, Jerome I A1 - Fornage, Myriam AB -

Educational attainment, widely used in epidemiologic studies as a surrogate for socioeconomic status, is a predictor of cardiovascular health outcomes. A two-stage genome-wide meta-analysis of low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), and triglyceride (TG) levels was performed while accounting for gene-educational attainment interactions in up to 226,315 individuals from five population groups. We considered two educational attainment variables: "Some College" (yes/no, for any education beyond high school) and "Graduated College" (yes/no, for completing a 4-year college degree). Genome-wide significant ( < 5 × 10) and suggestive ( < 1 × 10) variants were identified in Stage 1 (in up to 108,784 individuals) through genome-wide analysis, and those variants were followed up in Stage 2 studies (in up to 117,531 individuals). In combined analysis of Stages 1 and 2, we identified 18 novel lipid loci (nine for LDL, seven for HDL, and two for TG) by two degree-of-freedom (2 DF) joint tests of main and interaction effects. Four loci showed significant interaction with educational attainment. Two loci were significant only in cross-population analyses. Several loci include genes with known or suggested roles in adipose (), brain (), and liver () biology, highlighting the potential importance of brain-adipose-liver communication in the regulation of lipid metabolism. An investigation of the potential druggability of genes in identified loci resulted in five gene targets shown to interact with drugs approved by the Food and Drug Administration, including genes with roles in adipose and brain tissue. Genome-wide interaction analysis of educational attainment identified novel lipid loci not previously detected by analyses limited to main genetic effects.

VL - 14 ER -