Multiancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions

Vries, P.S. de; Brown, M.R.; Bentley, A.R.; Sung, Y.J.; Winkler, T.W.; Ntalla, I.; ... ; LifeLines Cohort Study Grp (2019)

Article / Letter to editor

A person's lipid profile is influenced by genetic variants and alcohol consumption, but the contribution of interactions between these exposures has not been studied. We therefore incorporated gene-alcohol interactions into a multiancestry genome-wide association study of levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. We included 45 studies in stage 1 (genome-wide discovery) and 66 studies in stage 2 (focused follow-up), for a total of 394,584 individuals from 5 ancestry groups. Analyses covered the period July 2014-November 2017. Genetic main effects and interaction effects were jointly assessed by means of a 2-degrees-of-freedom (df) test, and a 1-df test was used to assess the interaction effects alone. Variants at 495 loci were at least suggestively associated (P < 1 x 10(-6)) with lipid levels in stage 1 and were evaluated in stage 2, followed by combined analyses of stage 1 and stage 2. In the combined analysis of stages 1 and 2, a total of 147 independent loci were associated with lipid levels at P < 5 x 10(-8) using 2-df tests, of which 18 were novel. No genome-wide-significant associations were found testing the interaction effect alone. The novel loci included several genes (proprotein convertase subtilisin/kexin type 5 (PCSK5), vascular endothelial growth factor B (VEGFB), and apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1 (APOBEC1) complementation factor (A1CF)) that have a putative role in lipid metabolism on the basis of existing evidence from cellular and experimental models.

• alcohol consumption
• cholesterol
• gene-environment interactions
• gene-lifestyle interactions
• genome-wide association studies
• lipids
• triglycerides

• All authors: Vries, P.S. de; Brown, M.R.; Bentley, A.R.; Sung, Y.J.; Winkler, T.W.; Ntalla, I.; Schwander, K.; Kraja, A.T.; Guo, X.Q.; Franceschini, N.; Cheng, C.Y.; Sim, X.L.; Vojinovic, D.; Huffman, J.E.; Musani, S.K.; Li, C.W.; Feitosa, M.F.; Richard, M.A.; Noordam, R.; Aschard, H.; Bartz, T.M.; Bielak, L.F.; Deng, X.; Dorajoo, R.; Lohman, K.K.; Manning, A.K.; Rankinen, T.; Smith, A.V.; Tajuddin, S.M.; Evangelou, E.; Graff, M.; Alver, M.; Boissel, M.; Chai, J.F.; Chen, X.; Divers, J.; Gandin, I.; Gao, C.; Goel, A.; Hagemeijer, Y.; Harris, S.E.; Hartwig, F.P.; He, M.A.; Horimoto, A.R.V.R.; Hsu, F.C.; Jackson, A.U.; Kasturiratne, A.; Komulainen, P.; Kuhnel, B.; Laguzzi, F.; Lee, J.H.; Luan, J.A.; Lyytikainen, L.P.; Matoba, N.; Nolte, I.M.; Pietzner, M.; Riaz, M.; Said, M.A.; Scott, R.A.; Sofer, T.; Stancakova, A.; Takeuchi, F.; Tayo, B.O.; Most, P.J. van der; Varga, T.V.; Wang, Y.J.; Ware, E.B.; Wen, W.Q.; Yanek, L.R.; Zhang, W.H.; Zhao, J.H.; Afaq, S.; Amin, N.; Amini, M.; Arking, D.E.; Aung, T.; Ballantyne, C.; Boerwinkle, E.; Broeckel, U.; Campbell, A.; Canouil, M.; Charumathi, S.; Chen, Y.D.I.; Connell, J.M.; Faire, U. de; Fuentes, L. de las; Mutsert, R. de; Silva, H.J. de; Ding, J.Z.; Dominiczak, A.F.; Duan, Q.; Eaton, C.B.; Eppinga, R.N.; Faul, J.D.; Fisher, V.; Forrester, T.; Franco, O.H.; Friedlander, Y.; Ghanbari, M.; Giulianini, F.; Grabe, H.J.; Grove, M.L.; Gu, C.C.; Harris, T.B.; Heikkinen, S.; Heng, C.K.; Hirata, M.; Hixson, J.E.; Howard, B.V.; Ikram, M.A.; Jacobs, D.R.; Johnson, C.; Jonas, J.B.; Kammerer, C.M.; Katsuya, T.; Khor, C.C.; Kilpelainen, T.O.; Koh, W.P.; Koistinen, H.A.; Kolcic, I.; Kooperberg, C.; Krieger, J.E.; Kritchevsky, S.B.; Kubo, M.; Kuusisto, J.; Lakka, T.A.; Langefeld, C.D.; Langenberg, C.; Launer, L.J.; Lehne, B.; Lemaitre, R.N.; Li, Y.Z.; Liang, J.J.; Liu, J.J.; Liu, K.; Loh, M.; Louie, T.; Magi, R.; Manichaikul, A.W.; McKenzie, C.A.; Meitinger, T.; Metspalu, A.; Milaneschi, Y.; Milani, L.; Mohlke, K.L.; Mosley, T.H.; Mukamal, K.J.; Nalls, M.A.; Nauck, M.; Nelson, C.P.; Sotoodehnia, N.; O'Connell, J.R.; Palmer, N.D.; Pazoki, R.; Pedersen, N.L.; Peters, A.; Peyser, P.A.; Polasek, O.; Poulter, N.; Raffel, L.J.; Raitakari, O.T.; Reiner, A.P.; Rice, T.K.; Rich, S.S.; Robino, A.; Robinson, J.G.; Rose, L.M.; Rudan, I.; Schmidt, C.O.; Schreiner, P.J.; Scott, W.R.; Sever, P.; Shi, Y.; Sidney, S.; Sims, M.; Smith, B.H.; Smith, J.A.; Snieder, H.; Starr, J.M.; Strauch, K.; Tan, N.; Taylor, K.D.; Teo, Y.Y.; Tham, Y.C.; Uitterlinden, A.G.; Heemst, D. van; Vuckovic, D.; Waldenberger, M.; Wang, L.H.; Wang, Z.; Wei, W.B.; Williams, C.; Wilson, G.; Wojczynski, M.K.; Yao, J.; Yu, B.; Yu, C.Z.; Yuan, J.M.; Zhao, W.; Zonderman, A.B.; Becker, D.M.; Boehnke, M.; Bowden, D.W.; Chambers, J.C.; Deary, I.J.; Esko, T.; Farrall, M.; Franks, P.W.; Freedman, B.I.; Froguel, P.; Gasparini, P.; Gieger, C.; Horta, B.L.; Kamatani, Y.; Kato, N.; Kooner, J.S.; Laakso, M.; Leander, K.; Lehtimaki, T.; Magnusson, P.K.E.; Penninx, B.; Pereira, A.C.; Rauramaa, R.; Samani, N.J.; Scott, J.; Shu, X.O.; Harst, P. van der; Wagenknecht, L.E.; Wang, Y.X.; Wareham, N.J.; Watkins, H.; Weir, D.R.; Wickremasinghe, A.R.; Zheng, W.; Elliott, P.; North, K.E.; Bouchard, C.; Evans, M.K.; Gudnason, V.; Liu, C.T.; Liu, Y.M.; Psaty, B.M.; Ridker, P.M.; Dam, R.M. van; Kardia, S.L.R.; Zhu, X.F.; Rotimi, C.N.; Mook-Kanamori, D.O.; Fornage, M.; Kelly, T.N.; Fox, E.R.; Hayward, C.; Duijn, C.M. van; Tai, E.S.; Wong, T.Y.; Liu, J.M.; Rotter, J.I.; Gauderman, W.J.; Province, M.A.; Munroe, P.B.; Rice, K.; Chasman, D.I.; Cupples, L.A.; Rao, D.C.; Morrison, A.C.; InterAct Consortium; LifeLines Cohort Study Grp
• Date: 2019-06-01
• Journal: American Journal of Epidemiology
• Volume: 188
• Issue: 6
• Pages: 1033 - 1054
• DOI: doi:10.1093/aje/kwz005