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

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Title: A multi-ancestry genome-wide study incorporating gene-smoking interactions identifies multiple new loci for pulse pressure and mean arterial pressure
Authors: Sung, YJ
De Las Fuentes, L
Winkler, TW
Chasman, DI
Bentley, AR
Kraja, AT
Ntalla, I
Warren, HR
Guo, X
Schwander, K
Manning, AK
Brown, MR
Aschard, H
Feitosa, MF
Franceschini, N
Lu, Y
Cheng, C-Y
Sim, X
Vojinovic, D
Marten, J
Musani, SK
Kilpeläinen, TO
Richard, MA
Aslibekyan, S
Bartz, TM
Dorajoo, R
Li, C
Liu, Y
Rankinen, T
Smith, AV
Tajuddin, SM
Tayo, BO
Zhao, W
Zhou, Y
Matoba, N
Sofer, T
Alver, M
Amini, M
Boissel, M
Chai, JF
Chen, X
Divers, J
Gandin, I
Gao, C
Giulianini, F
Goel, A
Harris, SE
Hartwig, FP
He, M
Horimoto, ARVR
Hsu, F-C
Jackson, AU
Kammerer, CM
Kasturiratne, A
Komulainen, P
Kühnel, B
Leander, K
Lee, W-J
Lin, K-H
Luan, J
Lyytikäinen, L-P
McKenzie, CA
Nelson, CP
Noordam, R
Scott, RA
Sheu, WHH
Stančáková, A
Takeuchi, F
Van der Most, PJ
Varga, TV
Waken, RJ
Wang, H
Wang, Y
Ware, EB
Weiss, S
Wen, W
Yanek, LR
Zhang, W
Zhao, JH
Afaq, S
Alfred, T
Amin, N
Arking, DE
Aung, T
Barr, RG
Bielak, LF
Boerwinkle, E
Bottinger, EP
Braund, PS
Brody, JA
Broeckel, U
Cade, B
Campbell, A
Canouil, M
Chakravarti, A
Cocca, M
Collins, FS
Connell, JM
De Mutsert, R
De Silva, HJ
Dörr, M
Duan, Q
Eaton, CB
Ehret, G
Evangelou, E
Faul, JD
Forouhi, NG
Franco, OH
Friedlander, Y
Gao, H
Gigante, B
Gu, CC
Gupta, P
Hagenaars, SP
Harris, TB
He, J
Heikkinen, S
Heng, C-K
Hofman, A
Howard, BV
Hunt, SC
Irvin, MR
Jia, Y
Katsuya, T
Kaufman, J
Kerrison, ND
Khor, CC
Koh, W-P
Koistinen, HA
Kooperberg, CB
Krieger, JE
Kubo, M
Kutalik, Z
Kuusisto, J
Lakka, TA
Langefeld, CD
Langenberg, C
Launer, LJ
Lee, JH
Lehne, B
Levy, D
Lewis, CE
Li, Y
Lifelines Cohort Study
Lim, SH
Liu, C-T
Liu, J
Liu, J
Liu, Y
Loh, M
Lohman, KK
Louie, T
Mägi, R
Matsuda, K
Meitinger, T
Metspalu, A
Milani, L
Momozawa, Y
Mosley, TH
Nalls, MA
Nasri, U
O'Connell, JR
Ogunniyi, A
Palmas, WR
Palmer, ND
Pankow, JS
Pedersen, NL
Peters, A
Peyser, PA
Polasek, O
Porteous, D
Raitakari, OT
Renström, F
Rice, TK
Ridker, PM
Robino, A
Robinson, JG
Rose, LM
Rudan, I
Sabanayagam, C
Salako, BL
Sandow, K
Schmidt, CO
Schreiner, PJ
Scott, WR
Sever, P
Sims, M
Sitlani, CM
Smith, BH
Smith, JA
Snieder, H
Starr, JM
Strauch, K
Tang, H
Taylor, KD
Teo, YY
Tham, YC
Uitterlinden, AG
Waldenberger, M
Wang, L
Wang, YX
Wei, WB
Wilson, G
Wojczynski, MK
Xiang, Y-B
Yao, J
Yuan, J-M
Zonderman, AB
Becker, DM
Boehnke, M
Bowden, DW
Chambers, JC
Chen, Y-DI
Weir, DR
De Faire, U
Deary, IJ
Esko, T
Farrall, M
Forrester, T
Freedman, BI
Froguel, P
Gasparini, P
Gieger, C
Horta, BL
Hung, Y-J
Jonas, JB
Kato, N
Kooner, JS
Laakso, M
Lehtimäki, T
Liang, K-W
Magnusson, PKE
Oldehinkel, AJ
Pereira, AC
Perls, T
Rauramaa, R
Redline, S
Rettig, R
Samani, NJ
Scott, J
Shu, X-O
Van der Harst, P
Wagenknecht, LE
Wareham, NJ
Watkins, H
Wickremasinghe, AR
Wu, T
Kamatani, Y
Laurie, CC
Bouchard, C
Cooper, RS
Evans, MK
Gudnason, V
Hixson, J
Kardia, SLR
Kritchevsky, SB
Psaty, BM
Van Dam, RM
Arnett, DK
Mook-Kanamori, DO
Fornage, M
Fox, ER
Hayward, C
Van Duijn, CM
Tai, ES
Wong, TY
Loos, RJF
Reiner, AP
Rotimi, CN
Bierut, LJ
Zhu, X
Cupples, LA
Province, MA
Rotter, JI
Franks, PW
Rice, K
Elliott, P
Caulfield, MJ
Gauderman, WJ
Munroe, PB
Rao, DC
Morrison, AC
Item Type: Journal Article
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.
Issue Date: 1-Aug-2019
Date of Acceptance: 26-Mar-2019
DOI: 10.1093/hmg/ddz070
ISSN: 0964-6906
Publisher: Oxford University Press (OUP)
Start Page: 2615
End Page: 2633
Journal / Book Title: Human Molecular Genetics
Volume: 28
Issue: 15
Copyright Statement: © The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: This is a pre-copy-editing, author-produced version of an article accepted for publication in Human Molecular Genetics following peer review. The definitive publisher-authenticated version is available online at:
Sponsor/Funder: Medical Research Council (MRC)
Funder's Grant Number: MR/L01341X/1
Keywords: Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
Genetics & Heredity
Lifelines Cohort Study
Genetics & Heredity
06 Biological Sciences
11 Medical and Health Sciences
Publication Status: Published
Embargo Date: 2020-04-10
Online Publication Date: 2019-04-10
Appears in Collections:Clinical Sciences
National Heart and Lung Institute
Molecular Sciences
Faculty of Medicine
Epidemiology, Public Health and Primary Care

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