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

Lisa de las Fuentes*, Yun Ju Sung, Raymond Noordam, Thomas Winkler, Mary F. Feitosa, Karen Schwander, Amy R. Bentley, Michael R. Brown, Xiuqing Guo, Alisa Manning, Daniel I. Chasman, Hugues Aschard, Traci M. Bartz, Lawrence F. Bielak, Archie Campbell, Ching Yu Cheng, Rajkumar Dorajoo, Fernando P. Hartwig, A. R.V.R. Horimoto, Changwei LiRuifang Li-Gao, Yongmei Liu, Jonathan Marten, Solomon K. Musani, Ioanna Ntalla, Tuomo Rankinen, Melissa Richard, Xueling Sim, Albert V. Smith, Salman M. Tajuddin, Bamidele O. Tayo, Dina Vojinovic, Helen R. Warren, Deng Xuan, Maris Alver, Mathilde Boissel, Jin Fang Chai, Xu Chen, Kaare Christensen, Jasmin Divers, Evangelos Evangelou, Chuan Gao, Giorgia Girotto, Sarah E. Harris, Meian He, Fang Chi Hsu, Brigitte Kühnel, Federica Laguzzi, Xiaoyin Li, Leo Pekka Lyytikäinen, Ilja M. Nolte, Alaitz Poveda, Rainer Rauramaa, Muhammad Riaz, Rico Rueedi, Xiao ou Shu, Harold Snieder, Tamar Sofer, Fumihiko Takeuchi, Niek Verweij, Erin B. Ware, Stefan Weiss, Lisa R. Yanek, Najaf Amin, Dan E. Arking, Donna K. Arnett, Sven Bergmann, Eric Boerwinkle, Jennifer A. Brody, Ulrich Broeckel, Marco Brumat, Gregory Burke, Claudia P. Cabrera, Mickaël Canouil, Miao Li Chee, Yii Der Ida Chen, Massimiliano Cocca, John Connell, H. Janaka de Silva, Paul S. de Vries, Gudny Eiriksdottir, Jessica D. Faul, Virginia Fisher, Terrence Forrester, Ervin F. Fox, Yechiel Friedlander, He Gao, Bruna Gigante, Franco Giulianini, Chi Charles Gu, Dongfeng Gu, Tamara B. Harris, Jiang He, Sami Heikkinen, Chew Kiat Heng, Steven Hunt, M. Arfan Ikram, Marguerite R. Irvin, Mika Kähönen, Maryam Kavousi, Chiea Chuen Khor, Tuomas O. Kilpeläinen, Woon Puay Koh, Pirjo Komulainen, Aldi T. Kraja, J. E. Krieger, Carl D. Langefeld, Yize Li, Jingjing Liang, David C.M. Liewald, Ching Ti Liu, Jianjun Liu, Kurt K. Lohman, Reedik Mägi, Colin A. McKenzie, Thomas Meitinger, Andres Metspalu, Yuri Milaneschi, Lili Milani, Dennis O. Mook-Kanamori, Mike A. Nalls, Christopher P. Nelson, Jill M. Norris, Jeff O’Connell, Adesola Ogunniyi, Sandosh Padmanabhan, Nicholette D. Palmer, Nancy L. Pedersen, Thomas Perls, Annette Peters, Astrid Petersmann, Patricia A. Peyser, Ozren Polasek, David J. Porteous, Leslie J. Raffel, Treva K. Rice, Jerome I. Rotter, Igor Rudan, Oscar Leonel Rueda-Ochoa, Charumathi Sabanayagam, Babatunde L. Salako, Pamela J. Schreiner, James M. Shikany, Stephen S. Sidney, Mario Sims, Colleen M. Sitlani, Jennifer A. Smith, John M. Starr, Konstantin Strauch, Morris A. Swertz, Alexander Teumer, Yih Chung Tham, André G. Uitterlinden, Dhananjay Vaidya, M. Yldau van der Ende, Melanie Waldenberger, Lihua Wang, Ya Xing Wang, Wen Bin Wei, David R. Weir, Wanqing Wen, Jie Yao, Bing Yu, Caizheng Yu, Jian Min Yuan, Wei Zhao, Alan B. Zonderman, Diane M. Becker, Donald W. Bowden, Ian J. Deary, Marcus Dörr, Tõnu Esko, Barry I. Freedman, Philippe Froguel, Paolo Gasparini, Christian Gieger, Jost Bruno Jonas, Candace M. Kammerer, Norihiro Kato, Timo A. Lakka, Karin Leander, Terho Lehtimäki, Patrik K.E. Magnusson, Pedro Marques-Vidal, Brenda W.J.H. Penninx, Nilesh J. Samani, Pim van der Harst, Lynne E. Wagenknecht, Tangchun Wu, Wei Zheng, Xiaofeng Zhu, Claude Bouchard, Richard S. Cooper, Adolfo Correa, Michele K. Evans, Vilmundur Gudnason, Caroline Hayward, Bernardo L. Horta, Tanika N. Kelly, Stephen B. Kritchevsky, Daniel Levy, Walter R. Palmas, A. C. Pereira, Michael M. Province, Bruce M. Psaty, Paul M. Ridker, Charles N. Rotimi, E. Shyong Tai, Rob M. van Dam, Cornelia M. van Duijn, Tien Yin Wong, Kenneth Rice, W. James Gauderman, Alanna C. Morrison, Kari E. North, Sharon L.R. Kardia, Mark J. Caulfield, Paul Elliott, Patricia B. Munroe, Paul W. Franks, Dabeeru C. Rao, Myriam Fornage, Lifelines Cohort Study

*Corresponding author for this work

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Abstract

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.

Original languageEnglish
JournalMolecular Psychiatry
DOIs
Publication statusAccepted/In press - 1 Jan 2020

Cite this

de las Fuentes, L., Sung, Y. J., Noordam, R., Winkler, T., Feitosa, M. F., Schwander, K., ... Lifelines Cohort Study (Accepted/In press). Gene-educational attainment interactions in a multi-ancestry genome-wide meta-analysis identify novel blood pressure loci. Molecular Psychiatry. https://doi.org/10.1038/s41380-020-0719-3