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

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.

• Authors: 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 Marten, Solomon 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, Lifelines Cohort Study, 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 Mosley Jr, 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
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 28 Issue 15 Pg. 2615-2633 (08 01 2019) ISSN: 1460-2083 [Electronic] England
• PMID: 31127295 (Publication Type: Journal Article, Multicenter Study, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected].

Chemical References

• AVPR1A protein, human
• Antiporters
• CSMD1 protein, human
• Membrane Proteins
• Receptors, Vasopressin
• SLC26A7 protein, human
• Sulfate Transporters
• Tumor Suppressor Proteins
• CASP9 protein, human
• Caspase 9

Topics

• Adolescent
• Adult
• Aged
• Aged, 80 and over
• Antiporters (genetics)
• Arterial Pressure (genetics)
• Blood Pressure (genetics)
• Caspase 9 (genetics)
• Ethnicity (genetics)
• Female
• Gene-Environment Interaction
• Genome-Wide Association Study
• Humans
• Hypertension (etiology, genetics)
• Male
• Membrane Proteins (genetics)
• Middle Aged
• Polymorphism, Genetic
• Racial Groups (genetics)
• Receptors, Vasopressin (genetics)
• Smoking (adverse effects)
• Sulfate Transporters (genetics)
• Tumor Suppressor Proteins (genetics)
• Young Adult