A multi-ancestry genome-wide study incorporating gene-smoking interactions identifies multiple new loci for pulse pressure and mean arterial pressure

Yun Ju Sung, Lisa De Las Fuentes, Thomas W. Winkler, Daniel I. Chasman, Amy R. Bentley, Aldi T. Kraja, Ioanna Ntalla, Helen R. Warren, Xiuqing Guo, Karen Schwander, Alisa K. Manning, Michael R. Brown, Hugues Aschard, Mary F. Feitosa, Nora Franceschini, Yingchang Lu, Ching Yu Cheng, Xueling Sim, Dina Vojinovic, Jonathan MartenSolomon K. Musani, Tuomas O. Kilpeläinen, Melissa A. Richard, Stella Aslibekyan, Traci M. Bartz, Rajkumar Dorajoo, Changwei Li, Yongmei Liu, Tuomo Rankinen, Albert Vernon Smith, Salman M. Tajuddin, Bamidele O. Tayo, 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 P. Hartwig, Meian He, Andrea R.V.R. Horimoto, Fang Chi Hsu, Anne U. Jackson, Candace M. Kammerer, Anuradhani Kasturiratne, Pirjo Komulainen, Brigitte Kühnel, Karin Leander, Wen Jane Lee, Keng Hung Lin, Jian'an Luan, Leo Pekka Lyytikäinen, Colin A. McKenzie, Christopher P. Nelson, Raymond Noordam, Robert A. Scott, Wayne H.H. Sheu, Alena Stančáková, Fumihiko Takeuchi, Peter J. Van Der Most, Tibor V. Varga, Robert J. Waken, 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 E. Arking, Tin Aung, R. Graham Barr, Lawrence F. Bielak, Eric Boerwinkle, Erwin P. Bottinger, Peter S. Braund, Jennifer A. Brody, Ulrich Broeckel, Brian Cade, Archie Campbell, Mickaël Canouil, Aravinda Chakravarti, Massimiliano Cocca, Francis S. Collins, John M. Connell, Renée De Mutsert, H. Janaka De Silva, Marcus Dörr, Qing Duan, Charles B. Eaton, Georg Ehret, Evangelos Evangelou, Jessica D. Faul, Nita G. Forouhi, Oscar H. Franco, Yechiel Friedlander, He Gao, Bruna Gigante, C. Charles Gu, Preeti Gupta, Saskia P. Hagenaars, Tamara B. Harris, Jiang He, Sami Heikkinen, Chew Kiat Heng, Albert Hofman, Barbara V. Howard, Steven C. Hunt, Marguerite R. Irvin, Yucheng Jia, Tomohiro Katsuya, Joel Kaufman, Nicola D. Kerrison, Chiea Chuen Khor, Woon Puay Koh, Heikki A. Koistinen, Charles B. Kooperberg, Jose E. Krieger, Michiaki Kubo, Zoltan Kutalik, Johanna Kuusisto, Timo A. Lakka, Carl D. Langefeld, Claudia Langenberg, Lenore J. Launer, Joseph H. Lee, Benjamin Lehne, Daniel Levy, Cora E. Lewis, Yize Li, Sing Hui Lim, Ching Ti Liu, Jianjun Liu, Jingmin Liu, Yeheng Liu, Marie Loh, Kurt K. Lohman, Tin Louie, Reedik Mägi, Koichi Matsuda, Thomas Meitinger, Andres Metspalu, Lili Milani, Yukihide Momozawa, Thomas H. Thomas, Mike A. Nalls, Ubaydah Nasri, Jeff R. O'Connell, Adesola Ogunniyi, Walter R. Palmas, Nicholette D. Palmer, James S. Pankow, Nancy L. Pedersen, Annette Peters, Patricia A. Peyser, Ozren Polasek, David Porteous, 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, Peter Sever, Mario Sims, Colleen M. Sitlani, Blair H. Smith, 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 Xing Wang, Wen Bin Wei, Gregory Wilson, Mary K. Wojczynski, Yong Bing Xiang, Jie Yao, Jian Min Yuan, Alan B. Zonderman, Diane M. Becker, Michael Boehnke, Donald W. Bowden, John C. Chambers, Yii Der Ida Chen, David R. Weir, Ulf De Faire, Ian J. Deary, Tõnu Esko, Martin Farrall, Terrence Forrester, Barry I. Freedman, Philippe Froguel, Paolo Gasparini, Christian Gieger, Bernardo Lessa Horta, Yi Jen Hung, Jost Bruno Jonas, Norihiro Kato, Jaspal S. Kooner, Markku Laakso, Terho Lehtimäki, Kae Woei Liang, Patrik K.E. Magnusson, Albertine J. Oldehinkel, Alexandre C. Pereira, Thomas Perls, Rainer Rauramaa, Susan Redline, Rainer Rettig, Nilesh J. Samani, James Scott, Xiao Ou Shu, Pim Van Der Harst, Lynne E. Wagenknecht, Nicholas J. Wareham, Hugh Watkins, Ananda R. Wickremasinghe, Tangchun Wu, Yoichiro Kamatani, Cathy C. Laurie, Claude Bouchard, Richard S. Cooper, Michele K. Evans, Vilmundur Gudnason, James Hixson, Sharon L.R. Kardia, Stephen B. Kritchevsky, Bruce M. Psaty, Rob M. Van Dam, Donna K. Arnett, Dennis O. Mook-Kanamori, Myriam Fornage, Ervin R. Fox, Caroline Hayward, Cornelia M. Van Duijn, E. Shyong Tai, Tien Yin Wong, Ruth J.F. Loos, Alex P. Reiner, Charles N. Rotimi, Laura J. Bierut, Xiaofeng Zhu, L. Adrienne Cupples, Michael A. Province, Jerome I. Rotter, Paul W. Franks, Kenneth Rice, Paul Elliott, Mark J. Caulfield, W. James Gauderman, Patricia B. Munroe, Dabeeru C. Rao, Alanna C. Morrison

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Abstract

Elevated blood pressure (BP), a leading cause of global morbidity and mortality, is influenced by both genetic and lifestyle factors. Cigarette smoking is one such lifestyle factor. Across five ancestries, we performed a genome-wide gene-smoking interaction study of mean arterial pressure (MAP) and pulse pressure (PP) in 129 913 individuals in stage 1 and follow-up analysis in 480 178 additional individuals in stage 2. We report here 136 loci significantly associated with MAP and/or PP. Of these, 61 were previously published through main-effect analysis of BP traits, 37 were recently reported by us for systolic BP and/or diastolic BP through gene-smoking interaction analysis and 38 were newly identified (P < 5 × 10-8, false discovery rate < 0.05). We also identified nine new signals near known loci. Of the 136 loci, 8 showed significant interaction with smoking status. They include CSMD1 previously reported for insulin resistance and BP in the spontaneously hypertensive rats. Many of the 38 new loci show biologic plausibility for a role in BP regulation. SLC26A7 encodes a chloride/bicarbonate exchanger expressed in the renal outer medullary collecting duct. AVPR1A is widely expressed, including in vascular smooth muscle cells, kidney, myocardium and brain. FHAD1 is a long non-coding RNA overexpressed in heart failure. TMEM51 was associated with contractile function in cardiomyocytes. CASP9 plays a central role in cardiomyocyte apoptosis. Identified only in African ancestry were 30 novel loci. Our findings highlight the value of multi-ancestry investigations, particularly in studies of interaction with lifestyle factors, where genomic and lifestyle differences may contribute to novel findings.

Original languageEnglish (US)
Pages (from-to)2615-2633
Number of pages19
JournalHuman molecular genetics
Volume28
Issue number15
DOIs
StatePublished - Aug 1 2019

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    Sung, Y. J., De Las Fuentes, L., Winkler, T. W., Chasman, D. I., Bentley, A. R., Kraja, A. T., Ntalla, I., Warren, H. R., Guo, X., Schwander, K., Manning, A. K., Brown, M. R., Aschard, H., Feitosa, M. F., Franceschini, N., Lu, Y., Cheng, C. Y., Sim, X., Vojinovic, D., ... Morrison, A. C. (2019). A multi-ancestry genome-wide study incorporating gene-smoking interactions identifies multiple new loci for pulse pressure and mean arterial pressure. Human molecular genetics, 28(15), 2615-2633. https://doi.org/10.1093/hmg/ddz070