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

Proc Natl Acad Sci U S A. 2011 Apr 26;108(17):7119-24. doi: 10.1073/pnas.1017288108. Epub 2011 Apr 6.

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 < 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 < 0.001). Our finding of a regulator of alcohol consumption adds knowledge to our understanding of genetic mechanisms influencing alcohol drinking behavior.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alcohol Drinking / genetics*
  • Alcohol Drinking / metabolism
  • Animals
  • Cytoskeletal Proteins
  • Drosophila melanogaster / genetics
  • Drosophila melanogaster / metabolism
  • European Continental Ancestry Group / genetics*
  • Female
  • Gene Expression Regulation / genetics
  • Genome-Wide Association Study
  • Genotype
  • Humans
  • Male
  • Mice
  • Nuclear Proteins / biosynthesis
  • Nuclear Proteins / genetics
  • Polymorphism, Single Nucleotide*
  • Proteins / genetics*
  • Proteins / metabolism
  • Quantitative Trait, Heritable*
  • Transcription Factors

Substances

  • AUTS2 protein, human
  • Auts2 protein, mouse
  • Cytoskeletal Proteins
  • Nuclear Proteins
  • Proteins
  • Transcription Factors