A Quantitative-Trait Genome-Wide Association Study of Alcoholism Risk in the Community: Findings and Implications

Abstract

Background Given moderately strong genetic contributions to variation in alcoholism and heaviness of drinking (50–60% heritability), with high correlation of genetic influences, we have conducted a quantitative trait genomewide association study for phenotypes related to alcohol use and dependence. Methods Diagnostic interview and blood/buccal samples were obtained from sibships ascertained through the Australian Twin Registry. Genomewide SNP genotyping was performed with 8754 individuals [2062 alcohol dependent cases] selected for informativeness for alcohol use disorder and associated quantitative traits. Family-based association tests were performed for alcohol dependence, dependence factor score and heaviness of drinking factor score, with confirmatory case-population control comparisons using an unassessed population control series of 3393 Australians with genomewide SNP data. Results No findings reached genomewide significance (p=8.4×10−8 for this study), with lowest p-value for primary phenotypes of 1.2×10−7. Convergent findings for quantitative consumption and diagnostic and quantitative dependence measures suggest possible roles for a transmembrane protein gene (TMEM108) and for ANKS1A. The major finding, however, was small effect sizes estimated for individual SNPs, suggesting that hundreds of genetic variants make modest contributions (1/4% of variance or less) to alcohol dependence risk. Conclusions We conclude that (i) meta-analyses of consumption data may contribute usefully to gene-discovery; (ii) translation of human alcoholism GWAS results to drug discovery or clinically useful prediction of risk will be challenging; (iii) through accumulation across studies, GWAS data may become valuable for improved genetic risk differentiation in research in biological psychiatry (e.g. prospective high-risk or resilience studies).

Association of Gamma-Aminobutyric Acid A Receptor α2 Gene (GABRA2) with Alcohol Use Disorder

“…The genetic contribution to vulnerability to develop alcohol or drug dependence has generally been estimated in the range 40-70%, depending on the substance, consistent with complex inheritance in which multiple genes exert a small effect of vulnerability or protection, A genetic meta-analysis D Li et al along with the environment (Frank et al, 2012;Gelernter and Kranzler, 2009;Goldman et al, 2005;Heath et al, 2011;Kendler et al, 2007;Wang et al, 2013). By analyzing potential associations between specific alleles and multiple substance phenotypes, our analyses may represent a necessary step toward identifying the effects of phenotypeinfluencing genes with improved certainty.…”

Genome-Wide Association Study of Alcohol Dependence Implicates KIAA0040 on Chromosome 1q

“…Candidate gene studies have shown that a large number of risk loci exist for AD in the dopaminergic, serotonergic, GABAergic, cholinergic, opioidergic, and endocannabinoidergic systems, as well as in the ethanol metabolic pathway. Several genome-wide association studies (GWASs) have reported additional risk loci for alcoholism (Treutlein et al, 2009;Bierut et al, 2010;Edenberg et al, 2010;Heath et al, 2011). The first GWAS in German males reported that 15 top-ranked SNPs (in PECR, ADH1C, CAST, ERAP1, PPP2R2B, ESR1, GATA4, CCDC41, and CDH13) (5.6 Â 10 À6 ppp2.2 Â 10…”

A translational systems biology approach in both animals and humans identifies a functionally related module of accumbal genes involved in the regulation of reward processing and binge drinking in males

“…7,8 The ex ploratory nature of GWAS is proving to be instrumental in fur thering our understanding of the precise mechanisms in the brain that regulate alcoholrelated phenotypes, particularly when combined with extensive followup functional work. In a recent GWAS metaanalysis of alcohol consumption (n > 20 000) we identified a novel malespecific signal in the RASGRF2 gene, 9 and in further support of this, a followup candidatebased analysis in a sample of male adolescents re vealed a significant association between a RASGRF2 polymor phism and frequency of binge drinking episodes.…”