TY - JOUR T1 - Role of Rare and Low-Frequency Variants in Gene-Alcohol Interactions on Plasma Lipid Levels. JF - Circ Genom Precis Med Y1 - 2020 A1 - Wang, Zhe A1 - Chen, Han A1 - Bartz, Traci M A1 - Bielak, Lawrence F A1 - Chasman, Daniel I A1 - Feitosa, Mary F A1 - Franceschini, Nora A1 - Guo, Xiuqing A1 - Lim, Elise A1 - Noordam, Raymond A1 - Richard, Melissa A A1 - Wang, Heming A1 - Cade, Brian A1 - Cupples, L Adrienne A1 - de Vries, Paul S A1 - Giulanini, Franco A1 - Lee, Jiwon A1 - Lemaitre, Rozenn N A1 - Martin, Lisa W A1 - Reiner, Alex P A1 - Rich, Stephen S A1 - Schreiner, Pamela J A1 - Sidney, Stephen A1 - Sitlani, Colleen M A1 - Smith, Jennifer A A1 - Willems van Dijk, Ko A1 - Yao, Jie A1 - Zhao, Wei A1 - Fornage, Myriam A1 - Kardia, Sharon L R A1 - Kooperberg, Charles A1 - Liu, Ching-Ti A1 - Mook-Kanamori, Dennis O A1 - Province, Michael A A1 - Psaty, Bruce M A1 - Redline, Susan A1 - Ridker, Paul M A1 - Rotter, Jerome I A1 - Boerwinkle, Eric A1 - Morrison, Alanna C 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 (, , , , , , , and ) 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 (=6.65×10 for the interaction test) and replicated at nominal significance level (=0.013) in .

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.

VL - 13 IS - 4 ER -