Gene-educational attainment interactions in a multi-ancestry genome-wide meta-analysis identify novel blood pressure loci

Lisa de Las Fuentes (1) , Yun Ju Sung (1) , Raymond Noordam (2) , Thomas Winkler (3) , Mary Feitosa (4) , Karen Schwander (4) , Amy Bentley (5) , Michael Brown , Xiuqing Guo (6) , Alisa Manning (7) , Daniel Chasman , Hugues Aschard (8, 9) , Traci Bartz , Lawrence Bielak , Archie Campbell , Ching-Yu Cheng , Rajkumar Dorajoo , Fernando Hartwig , A. Horimoto , Changwei Li , Ruifang Li-Gao , Yongmei Liu , Jonathan Marten , Solomon Musani , Ioanna Ntalla , Tuomo Rankinen , Melissa Richard , Xueling Sim , Albert Smith , Salman Tajuddin , Bamidele Tayo , Dina Vojinovic , Helen Warren , Deng Xuan , Maris Alver , Mathilde Boissel (10) , Jin-Fang Chai , Xu Chen , Kaare Christensen , Jasmin Divers , Evangelos Evangelou , Chuan Gao , Giorgia Girotto , Sarah Harris , Meian He , Fang-Chi Hsu , Brigitte Kühnel , Federica Laguzzi , Xiaoyin Li , Leo-Pekka Lyytikäinen , Ilja Nolte , Alaitz Poveda , Rainer Rauramaa , Muhammad Riaz , Rico Rueedi , Xiao-Ou Shu , Harold Snieder , Tamar Sofer , Fumihiko Takeuchi , Niek Verweij , Erin Ware , Stefan Weiss , Lisa Yanek , Najaf Amin , Dan Arking , Donna Arnett , Sven Bergmann , Eric Boerwinkle , Jennifer Brody , Ulrich Broeckel , Marco Brumat , Gregory Burke , Claudia Cabrera , Mickaël Canouil , Miao Li Chee , Yii-Der Ida Chen , Massimiliano Cocca , John Connell , H Janaka de Silva , Paul de Vries , Gudny Eiriksdottir , Jessica Faul , Virginia Fisher , Terrence Forrester , Ervin Fox , Yechiel Friedlander , He Gao , Bruna Gigante , Franco Giulianini , Chi Charles Gu , Dongfeng Gu , Tamara Harris , Jiang He , Sami Heikkinen , Chew-Kiat Heng , Steven Hunt , M Arfan Ikram , Marguerite Irvin , Mika Kähönen , Maryam Kavousi , Chiea Chuen Khor , Tuomas Kilpeläinen , Woon-Puay Koh , Pirjo Komulainen , Aldi Kraja , J. Krieger , Carl Langefeld , Yize Li , Jingjing Liang , David Liewald , Ching-Ti Liu , Jianjun Liu , Kurt Lohman , Reedik Mägi , Colin Mckenzie , Thomas Meitinger , Andres Metspalu , Yuri Milaneschi , Lili Milani , Dennis Mook-Kanamori , Mike Nalls , Christopher Nelson , Jill Norris , Jeff O'Connell , Adesola Ogunniyi , Sandosh Padmanabhan , Nicholette Palmer , Nancy Pedersen , Thomas Perls , Annette Peters , Astrid Petersmann , Patricia Peyser , Ozren Polasek , David Porteous , Leslie Raffel , Treva Rice , Jerome Rotter , Igor Rudan , Oscar-Leonel Rueda-Ochoa , Charumathi Sabanayagam , Babatunde Salako , Pamela Schreiner , James Shikany , Stephen Sidney , Mario Sims , Colleen Sitlani , Jennifer Smith , John Starr , Konstantin Strauch , Morris Swertz , Alexander Teumer , Yih Chung Tham , André Uitterlinden , Dhananjay Vaidya , M Yldau van Der Ende , Melanie Waldenberger , Lihua Wang , Ya-Xing Wang , Wen-Bin Wei , David Weir , Wanqing Wen , Jie Yao , Bing Yu , Caizheng Yu , Jian-Min Yuan , Wei Zhao , Alan Zonderman , Diane Becker , Donald Bowden , Ian Deary , Marcus Dörr , Tõnu Esko , Barry Freedman , Philippe Froguel , Paolo Gasparini , Christian Gieger , Jost Bruno Jonas , Candace Kammerer , Norihiro Kato , Timo Lakka , Karin Leander , Terho Lehtimäki , Patrik Magnusson , Pedro Marques-Vidal , Brenda Penninx , Nilesh Samani , Pim van Der Harst , Lynne Wagenknecht , Tangchun Wu , Wei Zheng , Xiaofeng Zhu , Claude Bouchard , Richard Cooper , Adolfo Correa , Michele Evans , Vilmundur Gudnason , Caroline Hayward , Bernardo Horta , Tanika Kelly , Stephen Kritchevsky , Daniel Levy , Walter Palmas , A. Pereira , Michael Province , Bruce Psaty , Paul Ridker , Charles Rotimi , E Shyong Tai , Rob van Dam , Cornelia van Duijn , Tien Yin Wong , Kenneth Rice , W James Gauderman , Alanna Morrison , Kari North , Sharon Kardia , Mark Caulfield , Paul Elliott , Patricia Munroe , Paul Franks , Dabeeru Rao , Myriam Fornage (11)

1 WUSTL - Washington University in Saint Louis
2 Leiden University Medical Center (LUMC)
3 University of Regensburg
4 Washington University School of Medicine in St. Louis
5 NIH - National Institutes of Health [Bethesda]
6 Harbor UCLA Medical Center [Torrance, Ca.]
7 Massachusetts General Hospital [Boston]
8 Département de Biologie Computationnelle - Department of Computational Biology
9 Harvard School of Public Health
10 EGENODIA (GI3M) - Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283
11 UTHealth - The University of Texas Health Science Center at Houston

Educational attainment is widely used as a surrogate for socioeconomic status (SES). Low SES is a risk factor for hypertension and high blood pressure (BP). To identify novel BP loci, we performed multi-ancestry meta-analyses accounting for gene-educational attainment interactions using two variables, "Some College" (yes/no) and "Graduated College" (yes/no). Interactions were evaluated using both a 1 degree of freedom (DF) interaction term and a 2DF joint test of genetic and interaction effects. Analyses were performed for systolic BP, diastolic BP, mean arterial pressure, and pulse pressure. We pursued genome-wide interrogation in Stage 1 studies (N = 117 438) and follow-up on promising variants in Stage 2 studies (N = 293 787) in five ancestry groups. Through combined meta-analyses of Stages 1 and 2, we identified 84 known and 18 novel BP loci at genome-wide significance level (P < 5 × 10-8). Two novel loci were identified based on the 1DF test of interaction with educational attainment, while the remaining 16 loci were identified through the 2DF joint test of genetic and interaction effects. Ten novel loci were identified in individuals of African ancestry. Several novel loci show strong biological plausibility since they involve physiologic systems implicated in BP regulation. They include genes involved in the central nervous system-adrenal signaling axis (ZDHHC17, CADPS, PIK3C2G), vascular structure and function (GNB3, CDON), and renal function (HAS2 and HAS2-AS1, SLIT3). Collectively, these findings suggest a role of educational attainment or SES in further dissection of the genetic architecture of BP.

Domains: Life Sciences [q-bio]; Genetics; Human genetics; Life Sciences [q-bio]; Santé publique et épidémiologie; Statistics [stat]; Methodology [stat.ME]; Statistics [stat]; Applications [stat.AP]; Computer Science [cs]; Bioinformatics [q-bio.QM]

Lisa de Las Fuentes, Yun Ju Sung, Raymond Noordam, Thomas Winkler, Mary Feitosa, et al.. Gene-educational attainment interactions in a multi-ancestry genome-wide meta-analysis identify novel blood pressure loci. Molecular Psychiatry, 2020, ⟨10.1038/s41380-020-0719-3⟩. ⟨pasteur-03278567⟩