TY - JOUR
T1 - Role of Rare and Low-Frequency Variants in Gene-Alcohol Interactions on Plasma Lipid Levels
AU - Wang, Zhe
AU - Chen, Han
AU - Bartz, Traci M.
AU - Bielak, Lawrence F.
AU - Chasman, Daniel I.
AU - Feitosa, Mary F.
AU - Franceschini, Nora
AU - Guo, Xiuqing
AU - Lim, Elise
AU - Noordam, Raymond
AU - Richard, Melissa A.
AU - Wang, Heming
AU - Cade, Brian
AU - Cupples, L. Adrienne
AU - De Vries, Paul S.
AU - Giulanini, Franco
AU - Lee, Jiwon
AU - Lemaitre, Rozenn N.
AU - Martin, Lisa W.
AU - Reiner, Alex P.
AU - Rich, Stephen S.
AU - Schreiner, Pamela J.
AU - Sidney, Stephen
AU - Sitlani, Colleen M.
AU - Smith, Jennifer A.
AU - Willems Van Dijk, Ko
AU - Yao, Jie
AU - Zhao, Wei
AU - Fornage, Myriam
AU - Kardia, Sharon L.R.
AU - Kooperberg, Charles
AU - Liu, Ching Ti
AU - Mook-Kanamori, Dennis O.
AU - Province, Michael A.
AU - Psaty, Bruce M.
AU - Redline, Susan
AU - Ridker, Paul M.
AU - Rotter, Jerome I.
AU - Boerwinkle, Eric
AU - Morrison, Alanna C.
N1 - Publisher Copyright:
© 2020 Lippincott Williams and Wilkins. All rights reserved.
PY - 2020/8/1
Y1 - 2020/8/1
N2 - 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=6.65×10-6for 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.
AB - 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=6.65×10-6for 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.
KW - exome
KW - gene-environment interaction
KW - genome-wide association study
KW - lipids
KW - self-report
UR - http://www.scopus.com/inward/record.url?scp=85092661488&partnerID=8YFLogxK
U2 - 10.1161/CIRCGEN.119.002772
DO - 10.1161/CIRCGEN.119.002772
M3 - Article
C2 - 32510982
AN - SCOPUS:85092661488
SN - 2574-8300
VL - 13
SP - E002772
JO - Circulation: Genomic and Precision Medicine
JF - Circulation: Genomic and Precision Medicine
IS - 4
ER -