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

MedStar author(s):
Citation: American Journal of Epidemiology. 188(6):1033-1054, 2019 06 01.PMID: 30698716Institution: MedStar Health Research InstituteForm of publication: Journal ArticleMedline article type(s): Journal ArticleSubject headings: *Alcohol Drinking/ep [Epidemiology] | *Lipids/bl [Blood] | Adolescent | Adult | Aged | Cholesterol, HDL/bl [Blood] | Cholesterol, LDL/bl [Blood] | Continental Population Groups | Female | Genome-Wide Association Study | Genotype | Humans | Life Style | Male | Middle Aged | Phenotype | Triglycerides/bl [Blood] | Vascular Endothelial Growth Factor B | Young AdultYear: 2019Local holdings: Available online from MWHC library: 1996 - present, Available in print through MWHC library: 1996 - 2006ISSN:
  • 0002-9262
Name of journal: American journal of epidemiologyAbstract: An individual'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 multi-ancestry 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 five ancestry groups. Genetic main and interaction effects were jointly assessed by 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 Stage 1 and Stage 2, 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 (PCSK5, VEGFB, and A1CF) with a putative role in lipid metabolism based on existing evidence from cellular and experimental models.All authors: Afaq S, Alver M, Amin N, Amini M, Arking DE, Aschard H, Aung T, Ballantyne C, Bartz TM, Becker DM, Bentley AR, Bielak LF, Boehnke M, Boerwinkle E, Boissel M, Bouchard C, Bowden DW, Broeckel U, Brown MR, Campbell A, Canouil M, Chai JF, Chambers JC, Charumathi S, Chasman DI, Chen X, Chen YI, Cheng CY, Connell JM, Cupples LA, de Faire U, de Las Fuentes L, de Mutsert R, de Silva HJ, de Vries PS, Deary IJ, Deng X, Ding J, Divers J, Dominiczak AF, Dorajoo R, Duan Q, Eaton CB, Elliott P, Eppinga RN, Esko T, Evangelou E, Evans MK, Farrall M, Faul JD, Feitosa MF, Fisher V, Fornage M, Forrester T, Fox ER, Franceschini N, Franco OH, Franks PW, Freedman BI, Friedlander Y, Froguel P, Gandin I, Gao C, Gasparini P, Gauderman WJ, Ghanbari M, Gieger C, Giulianini F, Goel A, Grabe HJ, Graff M, Grove ML, Gu CC, Gudnason V, Guo X, Hagemeijer Y, Harris SE, Harris TB, Hartwig FP, Hayward C, He M, Heikkinen S, Heng CK, Hirata M, Hixson JE, Horimoto ARVR, Horta BL, Howard BV, Hsu FC, Huffman JE, Ikram MA, InterAct Consortium, Jackson AU, Jacobs DR Jr, Johnson C, Jonas JB, Kamatani Y, Kammerer CM, Kardia SLR, Kasturiratne A, Kato N, Katsuya T, Kelly TN, Khor CC, Kilpelainen TO, Koh WP, Koistinen HA, Kolcic I, Komulainen P, Kooner JS, Kooperberg C, Kraja AT, Krieger JE, Kritchevsky SB, Kubo M, Kuhnel B, Kuusisto J, Laakso M, Laguzzi F, Lakka TA, Langefeld CD, Langenberg C, Launer LJ, Leander K, Lee JH, Lehne B, Lehtimaki T, Lemaitre RN, Li C, Li Y, Liang J, Lifelines Cohort, Groningen, The Netherlands (Lifelines Cohort Study), Liu CT, Liu J, Liu J, Liu K, Liu Y, Loh M, Lohman KK, Louie T, Luan J, Lyytikainen LP, Magi R, Magnusson PKE, Manichaikul AW, Manning AK, Matoba N, McKenzie CA, Meitinger T, Metspalu A, Milaneschi Y, Milani L, Mohlke KL, Mook-Kanamori DO, Morrison AC, Mosley TH Jr, Mukamal KJ, Munroe PB, Musani SK, Nalls MA, Nauck M, Nelson CP, Nolte IM, Noordam R, North KE, Ntalla I, O'Connell JR, Palmer ND, Pazoki R, Pedersen NL, Penninx B, Pereira AC, Peters A, Peyser PA, Pietzner M, Polasek O, Poulter N, Province MA, Psaty BM, Raffel LJ, Raitakari OT, Rankinen T, Rao DC, Rauramaa R, Reiner AP, Riaz M, Rice K, Rice TK, Rich SS, Richard MA, Ridker PM, Robino A, Robinson JG, Rose LM, Rotimi CN, Rotter JI, Rudan I, Said MA, Samani NJ, Schmidt CO, Schreiner PJ, Schwander K, Scott J, Scott RA, Scott WR, Sever P, Shi Y, Shu XO, Sidney S, Sim X, Sims M, Smith AV, Smith BH, Smith JA, Snieder H, Sofer T, Sotoodehnia N, Stancakova A, Starr JM, Strauch K, Sung YJ, Tai ES, Tajuddin SM, Takeuchi F, Tan N, Taylor KD, Tayo BO, Teo YY, Tham YC, Uitterlinden AG, van Dam RM, van der Harst P, van der Most PJ, van Duijn CM, van Heemst D, Varga TV, Vojinovic D, Vuckovic D, Wagenknecht LE, Waldenberger M, Wang L, Wang Y, Wang Y, Wang YX, Wang Z, Ware EB, Wareham NJ, Watkins H, Wei WB, Weir DR, Wen W, Wickremasinghe AR, Williams C, Wilson G Sr, Winkler TW, Wojczynski MK, Wong TY, Yanek LR, Yao J, Yu B, Yu C, Yuan JM, Zhang W, Zhao JH, Zhao W, Zheng W, Zhu X, Zonderman ABOriginally published: American Journal of Epidemiology. 2019 Jan 29Fiscal year: FY2019Digital Object Identifier: Date added to catalog: 2019-03-14
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Item type Current library Collection Call number Status Date due Barcode
Journal Article MedStar Authors Catalog Article 30698716 Available 30698716

Available online from MWHC library: 1996 - present, Available in print through MWHC library: 1996 - 2006

An individual'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 multi-ancestry 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 five ancestry groups. Genetic main and interaction effects were jointly assessed by 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 Stage 1 and Stage 2, 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 (PCSK5, VEGFB, and A1CF) with a putative role in lipid metabolism based on existing evidence from cellular and experimental models.

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