A Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure

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

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    Abstract

    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 × 10−8) 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 × 10−8). 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).
    Original languageEnglish
    Pages (from-to)375-400
    Number of pages26
    JournalAmerican Journal of Human Genetics
    Volume102
    Issue number3
    Early online date15 Feb 2018
    DOIs
    Publication statusPublished - 1 Mar 2018

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    Keywords

    • blood pressure
    • GWAS
    • GxE interactions
    • lifestyle
    • multi-ancestry
    • smoking
    • Genome-Wide Association Study
    • Reproducibility of Results
    • Humans
    • Male
    • Genetic Loci
    • Blood Pressure/genetics
    • Continental Population Groups/genetics
    • Smoking/genetics
    • Polymorphism, Single Nucleotide/genetics
    • Quantitative Trait Loci/genetics
    • Diastole/genetics
    • Epistasis, Genetic
    • Female
    • Systole/genetics
    • Cohort Studies

    Cite this

    Sung, Y. J., Winkler, T. W., De Las Fuentes, L., Bentley, A. R., Brown, M. R., Kraja, A. T., Schwander, K., Ntalla, I., Guo, X., Franceschini, N., Lu, Y., Cheng, C., Sim, X., Vojinovic, D., Marten, J., Musani, S. K., Li, C., Feitosa, M. F., Kilpeläinen, T. O., ... Chasman, D. I. (2018). A Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure. American Journal of Human Genetics, 102(3), 375-400. https://doi.org/10.1016/j.ajhg.2018.01.015