Zhe Wang1, Han Chen1, Traci M Bartz2, Lawrence F Bielak3, Daniel I Chasman4, Mary F Feitosa5, Nora Franceschini6, Xiuqing Guo7, Elise Lim8, Raymond Noordam9, Melissa A Richard10, Heming Wang11,12, Brian Cade11,12, L Adrienne Cupples8,13, Paul S de Vries1, Franco Giulanini4, Jiwon Lee11,12, Rozenn N Lemaitre14, Lisa W Martin15, Alex P Reiner16, Stephen S Rich17, Pamela J Schreiner18, Stephen Sidney19, Colleen M Sitlani14, Jennifer A Smith3,20, Ko Willems van Dijk21,22, Jie Yao7, Wei Zhao3, Myriam Fornage1,10, Sharon L R Kardia3, Charles Kooperberg1, Ching-Ti Liu1, Dennis O Mook-Kanamori23,24, Michael A Province5, Bruce M Psaty25,26, Susan Redline11,12, Paul M Ridker11,12, Jerome I Rotter7, Eric Boerwinkle1,27, Alanna C Morrison1. 1. Department of Epidemiology, Human Genetics Center, Human Genetics and Environmental Sciences, School of Public Health (Z.W., H.C., P.S.d.V., M.F., E.B., A.C.M.), University of Texas Health Science Center at Houston, Houston, TX. 2. Cardiovascular Health Research Unit, Department of Biostatistics and Medicine (T.M.B.), University of Washington, Seattle, WA. 3. Department of Epidemiology, School of Public Health (L.F.B., J.A.S., W.Z., S.L.R.K.), University of Michigan, Ann Arbor, MI. 4. Division of Preventive Medicine (D.I.C., F.G.), Brigham and Women's Hospital, Boston, MA. 5. Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO (M.F.F., M.A.P.). 6. Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill (N.F.). 7. Department of Pediatrics, Institute for Translational Genomics and Population Sciences, The Lundquist Institute at Harbor-UCLA Medical Center, Torrance, CA (X.G., J.Y., J.I.R.). 8. Biostatistics Department, Boston University School of Public Health, MA (E.L., L.A.C., C.-T.L.). 9. Section of Gerontology and Geriatrics, Department of Internal Medicine (R.N.), Leiden University Medical Center, the Netherlands. 10. Brown Foundation Institute of Molecular Medicine (M.A.R., M.F.), University of Texas Health Science Center at Houston, Houston, TX. 11. Division of Sleep and Circadian Disorders, Department of Medicine (H.W., B.C., J.L., S.R., P.M.R.), Brigham and Women's Hospital, Boston, MA. 12. Harvard Medical School, Boston, MA (D.I.C., H.W., B.C., J.L., S.R., P.M.R.). 13. NHLBI Framingham Heart Study, MA (L.A.C.). 14. Cardiovascular Health Research Unit, Department of Medicine (R.N.L., C.M.S.), University of Washington, Seattle, WA. 15. George Washington University School of Medicine and Health Sciences, DC (L.W.M.). 16. Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA (A.P.R., C.K.). 17. Department of Public Health Sciences, Center for Public Health Genomics, University of Virginia, Charlottesville (S.S.R.). 18. Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis (P.J.S.). 19. Division of Research, Kaiser Permanente Northern California, Oakland (S.S.). 20. Institute for Social Research, Survey Research Center (J.A.S.), University of Michigan, Ann Arbor, MI. 21. Department of Human Genetics (K.W.v.D.), Leiden University Medical Center, the Netherlands. 22. Division of Endocrinology, Department of Internal Medicine (K.W.v.D.), Leiden University Medical Center, the Netherlands. 23. Department of Clinical Epidemiology (D.O.M.-K.), Leiden University Medical Center, the Netherlands. 24. Department of Public Health and Primary Care (D.O.M.-K.), Leiden University Medical Center, the Netherlands. 25. Cardiovascular Health Research Unit, Department of Medicine, Epidemiology and Health Services (B.M.P.), University of Washington, Seattle, WA. 26. Kaiser Permanente Washington Health Research Institute, Seattle, WA (B.M.P.). 27. Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX (E.B.).
Abstract
BACKGROUND: Alcohol intake influences plasma lipid levels, and such effects may be moderated by genetic variants. We aimed to characterize the role of aggregated rare and low-frequency protein-coding variants in gene by alcohol consumption interactions associated with fasting plasma lipid levels. METHODS: In the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, fasting plasma triglycerides and high- and low-density lipoprotein cholesterol were measured in 34 153 individuals with European ancestry from 5 discovery studies and 32 277 individuals from 6 replication studies. Rare and low-frequency functional protein-coding variants (minor allele frequency, ≤5%) measured by an exome array were aggregated by genes and evaluated by a gene-environment interaction test and a joint test of genetic main and gene-environment interaction effects. Two dichotomous self-reported alcohol consumption variables, current drinker, defined as any recurrent drinking behavior, and regular drinker, defined as the subset of current drinkers who consume at least 2 drinks per week, were considered. RESULTS: We discovered and replicated 21 gene-lipid associations at 13 known lipid loci through the joint test. Eight loci (PCSK9, LPA, LPL, LIPG, ANGPTL4, APOB, APOC3, and CD300LG) remained significant after conditioning on the common index single-nucleotide polymorphism identified by previous genome-wide association studies, suggesting an independent role for rare and low-frequency variants at these loci. One significant gene-alcohol interaction on triglycerides in a novel locus was significantly discovered (P=6.65×10-6 for the interaction test) and replicated at nominal significance level (P=0.013) in SMC5. CONCLUSIONS: In conclusion, this study applied new gene-based statistical approaches and suggested that rare and low-frequency genetic variants interacted with alcohol consumption on lipid levels.
BACKGROUND:Alcohol intake influences plasma lipid levels, and such effects may be moderated by genetic variants. We aimed to characterize the role of aggregated rare and low-frequency protein-coding variants in gene by alcohol consumption interactions associated with fasting plasma lipid levels. METHODS: In the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, fasting plasma triglycerides and high- and low-density lipoprotein cholesterol were measured in 34 153 individuals with European ancestry from 5 discovery studies and 32 277 individuals from 6 replication studies. Rare and low-frequency functional protein-coding variants (minor allele frequency, ≤5%) measured by an exome array were aggregated by genes and evaluated by a gene-environment interaction test and a joint test of genetic main and gene-environment interaction effects. Two dichotomous self-reported alcohol consumption variables, current drinker, defined as any recurrent drinking behavior, and regular drinker, defined as the subset of current drinkers who consume at least 2 drinks per week, were considered. RESULTS: We discovered and replicated 21 gene-lipid associations at 13 known lipid loci through the joint test. Eight loci (PCSK9, LPA, LPL, LIPG, ANGPTL4, APOB, APOC3, and CD300LG) remained significant after conditioning on the common index single-nucleotide polymorphism identified by previous genome-wide association studies, suggesting an independent role for rare and low-frequency variants at these loci. One significant gene-alcohol interaction on triglycerides in a novel locus was significantly discovered (P=6.65×10-6 for the interaction test) and replicated at nominal significance level (P=0.013) in SMC5. CONCLUSIONS: In conclusion, this study applied new gene-based statistical approaches and suggested that rare and low-frequency genetic variants interacted with alcohol consumption on lipid levels.
Entities:
Keywords:
exome; gene-environment interaction; genome-wide association study; lipids; self-report
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