Genome-wide association and genetic functional studies identify <i>autism susceptibility candidate 2</i> gene ( <i>AUTS2</i> ) in the regulation of alcohol consumption

TLDR

Alcohol consumption is moderately heritable yet its genetic determinants remain largely unknown, despite its clinical and societal importance. The authors performed a genome‑wide association meta‑analysis of ~2.5 million SNPs in 26,316 European‑ancestry individuals, with replication in 21,185 participants, assessing alcohol intake per kilogram body weight. They identified a genome‑wide significant association of SNP rs6943555 in AUTS2 with alcohol consumption, demonstrated genotype‑dependent AUTS2 expression in human prefrontal cortex and mouse brain, and showed that AUTS2 knockdown in Drosophila reduces alcohol sensitivity, establishing AUTS2 as a regulator of alcohol drinking behavior.

Abstract

Alcohol consumption is a moderately heritable trait, but the genetic basis in humans is largely unknown, despite its clinical and societal importance. We report a genome-wide association study meta-analysis of ∼2.5 million directly genotyped or imputed SNPs with alcohol consumption (gram per day per kilogram body weight) among 12 population-based samples of European ancestry, comprising 26,316 individuals, with replication genotyping in an additional 21,185 individuals. SNP rs6943555 in autism susceptibility candidate 2 gene ( AUTS2 ) was associated with alcohol consumption at genome-wide significance ( P = 4 × 10 −8 to P = 4 × 10 −9 ). We found a genotype-specific expression of AUTS2 in 96 human prefrontal cortex samples ( P = 0.026) and significant ( P &lt; 0.017) differences in expression of AUTS2 in whole-brain extracts of mice selected for differences in voluntary alcohol consumption. Down-regulation of an AUTS2 homolog caused reduced alcohol sensitivity in Drosophila ( P &lt; 0.001). Our finding of a regulator of alcohol consumption adds knowledge to our understanding of genetic mechanisms influencing alcohol drinking behavior.