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

Published

Journal Article

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 × 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 × 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.

Full Text

Duke Authors

Cited Authors

  • de Vries, PS; Brown, MR; Bentley, AR; Sung, YJ; Winkler, TW; Ntalla, I; Schwander, K; Kraja, AT; Guo, X; Franceschini, N; Cheng, C-Y; Sim, X; Vojinovic, D; Huffman, JE; Musani, SK; Li, C; Feitosa, MF; Richard, MA; Noordam, R; Aschard, H; Bartz, TM; Bielak, LF; Deng, X; Dorajoo, R; Lohman, KK; Manning, AK; Rankinen, T; Smith, AV; Tajuddin, SM; Evangelou, E; Graff, M; Alver, M; Boissel, M; Chai, JF; Chen, X; Divers, J; Gandin, I; Gao, C; Goel, A; Hagemeijer, Y; Harris, SE; Hartwig, FP; He, M; Horimoto, ARVR; Hsu, F-C; Jackson, AU; Kasturiratne, A; Komulainen, P; Kühnel, B; Laguzzi, F; Lee, JH; Luan, J; Lyytikäinen, L-P; Matoba, N; Nolte, IM; Pietzner, M; Riaz, M; Said, MA; Scott, RA; Sofer, T; StanĨáková, A; Takeuchi, F; Tayo, BO; van der Most, PJ; Varga, TV; Wang, Y; Ware, EB; Wen, W; Yanek, LR; Zhang, W; Zhao, JH; Afaq, S; Amin, N; Amini, M; Arking, DE; Aung, T; Ballantyne, C; Boerwinkle, E; Broeckel, U; Campbell, A; Canouil, M; Charumathi, S; Chen, Y-DI; Connell, JM; de Faire, U; de Las Fuentes, L; de Mutsert, R; de Silva, HJ; Ding, J; Dominiczak, AF; Duan, Q; Eaton, CB; Eppinga, RN; Faul, JD; Fisher, V; Forrester, T; Franco, OH; Friedlander, Y; Ghanbari, M; Giulianini, F; Grabe, HJ; Grove, ML; Gu, CC; Harris, TB; Heikkinen, S; Heng, C-K; Hirata, M; Hixson, JE; Howard, BV; Ikram, MA; InterAct Consortium, ; Jacobs, DR; Johnson, C; Jonas, JB; Kammerer, CM; Katsuya, T; Khor, CC; Kilpeläinen, TO; Koh, W-P; Koistinen, HA; Kolcic, I; Kooperberg, C; Krieger, JE; Kritchevsky, SB; Kubo, M; Kuusisto, J; Lakka, TA; Langefeld, CD; Langenberg, C; Launer, LJ; Lehne, B; Lemaitre, RN; Li, Y; Liang, J; Liu, J; Liu, K; Loh, M; Louie, T; Mägi, R; Manichaikul, AW; McKenzie, CA; Meitinger, T; Metspalu, A; Milaneschi, Y; Milani, L; Mohlke, KL; Mosley, TH; Mukamal, KJ; Nalls, MA; Nauck, M; Nelson, CP; Sotoodehnia, N; O'Connell, JR; Palmer, ND; Pazoki, R; Pedersen, NL; Peters, A; Peyser, PA; Polasek, O; Poulter, N; Raffel, LJ; Raitakari, OT; Reiner, AP; Rice, TK; Rich, SS; Robino, A; Robinson, JG; Rose, LM; Rudan, I; Schmidt, CO; Schreiner, PJ; Scott, WR; Sever, P; Shi, Y; Sidney, S; Sims, M; Smith, BH; Smith, JA; Snieder, H; Starr, JM; Strauch, K; Tan, N; Taylor, KD; Teo, YY; Tham, YC; Uitterlinden, AG; van Heemst, D; Vuckovic, D; Waldenberger, M; Wang, L; Wang, Y; Wang, Z; Wei, WB; Williams, C; Wilson, G; Wojczynski, MK; Yao, J; Yu, B; Yu, C; Yuan, J-M; Zhao, W; Zonderman, AB; Becker, DM; Boehnke, M; Bowden, DW; Chambers, JC; Deary, IJ; Esko, T; Farrall, M; Franks, PW; Freedman, BI; Froguel, P; Gasparini, P; Gieger, C; Horta, BL; Kamatani, Y; Kato, N; Kooner, JS; Laakso, M; Leander, K; Lehtimäki, T; Lifelines Cohort, Groningen, The Netherlands (Lifelines Cohort Study), ; Magnusson, PKE; Penninx, B; Pereira, AC; Rauramaa, R; Samani, NJ; Scott, J; Shu, X-O; van der Harst, P; Wagenknecht, LE; Wang, YX; Wareham, NJ; Watkins, H; Weir, DR; Wickremasinghe, AR; Zheng, W; Elliott, P; North, KE; Bouchard, C; Evans, MK; Gudnason, V; Liu, C-T; Liu, Y; Psaty, BM; Ridker, PM; van Dam, RM; Kardia, SLR; Zhu, X; Rotimi, CN; Mook-Kanamori, DO; Fornage, M; Kelly, TN; Fox, ER; Hayward, C; van Duijn, CM; Tai, ES; Wong, TY; Liu, J; Rotter, JI; Gauderman, WJ; Province, MA; Munroe, PB; Rice, K; Chasman, DI; Cupples, LA; Rao, DC; Morrison, AC

Published Date

  • June 1, 2019

Published In

Volume / Issue

  • 188 / 6

Start / End Page

  • 1033 - 1054

PubMed ID

  • 30698716

Pubmed Central ID

  • 30698716

Electronic International Standard Serial Number (EISSN)

  • 1476-6256

Digital Object Identifier (DOI)

  • 10.1093/aje/kwz005

Language

  • eng

Conference Location

  • United States