A multi-ancestry genome-wide study incorporating gene–smoking interactions identifies multiple new loci for pulse pressure and mean arterial pressure
Authors: Sung Yun Ju , de las Fuentes Lisa , Winkler Thomas W , Chasman Daniel I , Bentley Amy R , Kraja Aldi T , Ntalla Ioanna , Warren Helen R , Guo Xiuqing , Schwander Karen , Manning Alisa K , Brown Michael R , Aschard Hugues , Feitosa Mary F , Franceschini Nora , Lu Yingchang , Cheng Ching-Yu , Sim Xueling , Vojinovic Dina , Marten Jonathan , Musani Solomon K , Kilpeläinen Tuomas O , Richard Melissa A , Aslibekyan Stella , Bartz Traci M , Dorajoo Rajkumar , Li Changwei , Liu Yongmei , Rankinen Tuomo , Smith Albert Vernon , Tajuddin Salman M , Tayo Bamidele O , Zhao Wei , Zhou Yanhua , Matoba Nana , Sofer Tamar , Alver Maris , Amini Marzyeh , Boissel Mathilde , Chai Jin Fang , Chen Xu , Divers Jasmin , Gandin Ilaria , Gao Chuan , Giulianini Franco , Goel Anuj , Harris Sarah E , Hartwig Fernando P , He Meian , Horimoto Andrea R V R , Hsu Fang-Chi , Jackson Anne U , Kammerer Candace M , Kasturiratne Anuradhani , Komulainen Pirjo , Kühnel Brigitte , Leander Karin , Lee Wen-Jane , Lin Keng-Hung , Luan Jian’an , Lyytikäinen Leo-Pekka , McKenzie Colin A , Nelson Christopher P , Noordam Raymond , Scott Robert A , Sheu Wayne H H , Stančáková Alena , Takeuchi Fumihiko , van der Most Peter J , Varga Tibor V , Waken Robert J , Wang Heming , Wang Yajuan , Ware Erin B , Weiss Stefan , Wen Wanqing , Yanek Lisa R , Zhang Weihua , Zhao Jing Hua , Afaq Saima , Alfred Tamuno , Amin Najaf , Arking Dan E , Aung Tin , Barr R Graham , Bielak Lawrence F , Boerwinkle Eric , Bottinger Erwin P , Braund Peter S , Brody Jennifer A , Broeckel Ulrich , Cade Brian , Campbell Archie , Canouil Mickaël , Chakravarti Aravinda , Cocca Massimiliano , Collins Francis S , Connell John M , de Mutsert Renée , de Silva H Janaka , Dörr Marcus , Duan Qing , Eaton Charles B , Ehret Georg , Evangelou Evangelos , Faul Jessica D , Forouhi Nita G , Franco Oscar H , Friedlander Yechiel , Gao He , Gigante Bruna , Gu C Charles , Gupta Preeti , Hagenaars Saskia P , Harris Tamara B , He Jiang , Heikkinen Sami , Heng Chew-Kiat , Hofman Albert , Howard Barbara V , Hunt Steven C , Irvin Marguerite R , Jia Yucheng , Katsuya Tomohiro , Kaufman Joel , Kerrison Nicola D , Khor Chiea Chuen , Koh Woon-Puay , Koistinen Heikki A , Kooperberg Charles B , Krieger Jose E , Kubo Michiaki , Kutalik Zoltan , Kuusisto Johanna , Lakka Timo A , Langefeld Carl D , Langenberg Claudia , Launer Lenore J , Lee Joseph H , Lehne Benjamin , Levy Daniel , Lewis Cora E , Li Yize ,   Lifelines Cohort Study, Lim Sing Hui , Liu Ching-Ti , Liu Jianjun , Liu Jingmin , Liu Yeheng , Loh Marie , Lohman Kurt K , Louie Tin , Mägi Reedik , Matsuda Koichi , Meitinger Thomas , Metspalu Andres , Milani Lili , Momozawa Yukihide , Mosley, Jr Thomas H , Nalls Mike A , Nasri Ubaydah , O'Connell Jeff R , Ogunniyi Adesola , Palmas Walter R , Palmer Nicholette D , Pankow James S , Pedersen Nancy L , Peters Annette , Peyser Patricia A , Polasek Ozren , Porteous David , Raitakari Olli T , Renström Frida , Rice Treva K , Ridker Paul M , Robino Antonietta , Robinson Jennifer G , Rose Lynda M , Rudan Igor , Sabanayagam Charumathi , Salako Babatunde L , Sandow Kevin , Schmidt Carsten O , Schreiner Pamela J , Scott William R , Sever Peter , Sims Mario , Sitlani Colleen M , Smith Blair H , Smith Jennifer A , Snieder Harold , Starr John M , Strauch Konstantin , Tang Hua , Taylor Kent D , Teo Yik Ying , Tham Yih Chung , Uitterlinden André G , Waldenberger Melanie , Wang Lihua , Wang Ya Xing , Wei Wen Bin , Wilson Gregory , Wojczynski Mary K , Xiang Yong-Bing , Yao Jie , Yuan Jian-Min , Zonderman Alan B , Becker Diane M , Boehnke Michael , Bowden Donald W , Chambers John C , Chen Yii-Der Ida , Weir David R , de Faire Ulf , Deary Ian J , Esko Tõnu , Farrall Martin , Forrester Terrence , Freedman Barry I , Froguel Philippe , Gasparini Paolo , Gieger Christian , Horta Bernardo Lessa , Hung Yi-Jen , Jonas Jost Bruno , Kato Norihiro , Kooner Jaspal S , Laakso Markku , Lehtimäki Terho , Liang Kae-Woei , Magnusson Patrik K E , Oldehinkel Albertine J , Pereira Alexandre C , Perls Thomas , Rauramaa Rainer , Redline Susan , Rettig Rainer , Samani Nilesh J , Scott James , Shu Xiao-Ou , van der Harst Pim , Wagenknecht Lynne E , Wareham Nicholas J , Watkins Hugh , Wickremasinghe Ananda R , Wu Tangchun , Kamatani Yoichiro , Laurie Cathy C , Bouchard Claude , Cooper Richard S , Evans Michele K , Gudnason Vilmundur , Hixson James , Kardia Sharon L R , Kritchevsky Stephen B , Psaty Bruce M , van Dam Rob M , Arnett Donna K , Mook-Kanamori Dennis O , Fornage Myriam , Fox Ervin R , Hayward Caroline , van Duijn Cornelia M , Tai E Shyong , Wong Tien Yin , Loos Ruth J F , Reiner Alex P , Rotimi Charles N , Bierut Laura J , Zhu Xiaofeng , Cupples L Adrienne , Province Michael A , Rotter Jerome I , Franks Paul W , Rice Kenneth , Elliott Paul , Caulfield Mark J , Gauderman W James , Munroe Patricia B , Rao Dabeeru C , Morrison Alanna C 
Published: March 2019

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.