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

Fuentes, L. de las; Sung, Y.J.; Noordam, R.; Winkler, T.; Feitosa, M.F.; Schwander, K.; ... ; Lifelines Cohort Study (2020)

Article / Letter to editor

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 x 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.

• All authors: Fuentes, L. de las; Sung, Y.J.; Noordam, R.; Winkler, T.; Feitosa, M.F.; Schwander, K.; Bentley, A.R.; Brown, M.R.; Guo, X.Q.; Manning, A.; Chasman, D.I.; Aschard, H.; Bartz, T.M.; Bielak, L.F.; Campbell, A.; Cheng, C.Y.; Dorajoo, R.; Hartwig, F.P.; Horimoto, A.R.V.R.; Li, C.W.; Li-Gao, R.; Liu, Y.M.; Marten, J.; Musani, S.K.; Ntalla, I.; Rankinen, T.; Richard, M.; Sim, X.; Smith, A.V.; Tajuddin, S.M.; Tayo, B.O.; Vojinovic, D.; Warren, H.R.; Xuan, D.; Alver, M.; Boissel, M.; Chai, J.F.; Chen, X.; Christensen, K.; Divers, J.; Evangelou, E.; Gao, C.; Girotto, G.; Harris, S.E.; He, M.A.; Hsu, F.C.; Kuhnel, B.; Laguzzi, F.; Li, X.Y.; Lyytikainen, L.P.; Nolte, I.M.; Poveda, A.; Rauramaa, R.; Riaz, M.; Rueedi, R.; Shu, X.O.; Snieder, H.; Sofer, T.; Takeuchi, F.; Verweij, N.; Ware, E.B.; Weiss, S.; Yanek, L.R.; Amin, N.; Arking, D.E.; Arnett, D.K.; Bergmann, S.; Boerwinkle, E.; Brody, J.A.; Broeckel, U.; Brumat, M.; Burke, G.; Cabrera, C.P.; Canouil, M.; Chee, M.L.; Chen, Y.D.I.; Cocca, M.; Connell, J.; Silva, H.J. de; Vries, P.S. de; Eiriksdottir, G.; Faul, J.D.; Fisher, V.; Forrester, T.; Fox, E.F.; Friedlander, Y.; Gao, H.; Gigante, B.; Giulianini, F.; Gu, C.C.; Gu, D.F.; Harris, T.B.; He, J.; Heikkinen, S.; Heng, C.K.; Hunt, S.; Ikram, M.A.; Irvin, M.R.; Kahonen, M.; Kavousi, M.; Khor, C.C.; Kilpelainen, T.O.; Koh, W.P.; Komulainen, P.; Kraja, A.T.; Krieger, J.E.; Langefeld, C.D.; Li, Y.Z.; Liang, J.J.; Liewald, D.C.M.; Liu, C.T.; Liu, J.J.; Lohman, K.K.; Magi, R.; McKenzie, C.A.; Meitinger, T.; Metspalu, A.; Milaneschi, Y.; Milani, L.; Mook-Kanamori, D.O.; Nalls, M.A.; Nelson, C.P.; Norris, J.M.; O'Connell, J.; Ogunniyi, A.; Padmanabhan, S.; Palmer, N.D.; Pedersen, N.L.; Perls, T.; Peters, A.; Petersmann, A.; Peyser, P.A.; Polasek, O.; Porteous, D.J.; Raffel, L.J.; Rice, T.K.; Rotter, J.I.; Rudan, I.; Rueda-Ochoa, O.L.; Sabanayagam, C.; Salako, B.L.; Schreiner, P.J.; Shikany, J.M.; Sidney, S.S.; Sims, M.; Sitlani, C.M.; Smith, J.A.; Starr, J.M.; Strauch, K.; Swertz, M.A.; Teumer, A.; Tham, Y.C.; Uitterlinden, A.G.; Vaidya, D.; Ende, M.Y. van der; Waldenberger, M.; Wang, L.H.; Wang, Y.X.; Wei, W.B.; Weir, D.R.; Wen, W.Q.; Yao, J.; Yu, B.; Yu, C.Z.; Yuan, J.M.; Zhao, W.; Zonderman, A.B.; Becker, D.M.; Bowden, D.W.; Deary, I.J.; Dorr, M.; Esko, T.; Freedman, B.I.; Froguel, P.; Gasparini, P.; Gieger, C.; Jonas, J.B.; Kammerer, C.M.; Kato, N.; Lakka, T.A.; Leander, K.; Lehtimaki, T.; Magnusson, P.K.E.; Marques-Vidal, P.; Penninx, B.W.J.H.; Samani, N.J.; Harst, P. van der; Wagenknecht, L.E.; Wu, T.C.; Zheng, W.; Zhu, X.F.; Bouchard, C.; Cooper, R.S.; Correa, A.; Evans, M.K.; Gudnason, V.; Hayward, C.; Horta, B.L.; Kelly, T.N.; Kritchevsky, S.B.; Levy, D.; Palmas, W.R.; Pereira, A.C.; Province, M.M.; Psaty, B.M.; Ridker, P.M.; Rotimi, C.N.; Tai, E.S.; Dam, R.M. van; Duijn, C.M. van; Wong, T.Y.; Rice, K.; Gauderman, W.J.; Morrison, A.C.; North, K.E.; Kardia, S.L.R.; Caulfield, M.J.; Elliott, P.; Munroe, P.B.; Franks, P.W.; Rao, D.C.; Fornage, M.; Lifelines Cohort Study
• Date: 2020-05-05
• Journal: Molecular Psychiatry
• Volume: 26
• Pages: 2111 - 2125
• DOI: doi:10.1038/s41380-020-0719-3
• Link: https://www.nature.com/articles/s41380-020-0719-3