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

Lisa de las Fuentes*, Yun Ju Sung*, Lifelines Cohort Study, 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. HorimotoChangwei Li, Ruifang 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, Muhammad Riaz, Niek Verweij, Najaf Amin, M. Arfan Ikram, Maryam Kavousi, Oscar Leonel Rueda-Ochoa, Alexander Teumer, André G. Uitterlinden, Ya Xing Wang, Wei Zhao, A. C. Pereira, Cornelia M. van Duijn, Tien Yin Wong, Dabeeru C. Rao, Myriam Fornage

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

5 Citations (Scopus)

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
Pages (from-to)2111-2125
Number of pages15
JournalMolecular Psychiatry
Volume26
Issue number6
Early online date5 May 2020
DOIs
Publication statusPublished - Jun 2021

Bibliographical note

Funding Information:
Acknowledgements This project was largely supported by a grant from the U.S. National Heart, Lung, and Blood Institute (NHLBI), the National Institutes of Health, R01HL118305. A Career Development Award (K25HL121091), also from the NHLBI, enabled Dr. Sung to play a major role on this project. Dr. Kilpeläinen was supported by the Novo Nordisk Foundation (NNF18CC0034900 and NNF17OC0026848). Full set of study-specific funding sources and acknowledgments appear in the Supplementary Material. These authors constitute the writing group: L.d.l.F., Y.J.S., R.N., T.W., M.F.F., K.S., P.B.M., P.W.F., D.C.R., M.F.

Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature Limited.

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