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

LifeLines Cohort Study, Yun Ju Sung (Lead / Corresponding author), Lisa de Las Fuentes (Lead / Corresponding author), Thomas W. Winkler (Lead / Corresponding author), Daniel I. Chasman (Lead / Corresponding author), Amy R. Bentley, Aldi T. Kraja (Lead / Corresponding author), Ioanna Ntalla (Lead / Corresponding author), Helen R. Warren (Lead / Corresponding author), Xiuqing Guo (Lead / Corresponding author), Karen Schwander, Alisa K. Manning, Michael R. Brown, Hugues Aschard, Mary F. Feitosa, Nora Franceschini, Yingchang Lu, Ching-Yu Cheng, Xueling Sim, Dina VojinovicJonathan 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, John M. Connell, Blair H. Smith, 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
Pages (from-to)2615-2633
Number of pages19
JournalHuman Molecular Genetics
Volume28
Issue number15
Early online date10 Apr 2019
DOIs
Publication statusPublished - 1 Aug 2019

Keywords

  • smoking
  • hypertension
  • genes
  • genome
  • life style
  • genetics
  • kidney
  • mean arterial pressure
  • blood pressure regulation
  • pulse pressure
  • genome-wide association study

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