Multiancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions.
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., Stančáková 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 None., 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) None., 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.
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.