A genome-wide association study of alcohol-dependence symptom counts in extended pedigrees identifies C15orf53

Abstract

Several studies have identified genes associated with alcohol use disorders, but the variation in each of these genes explains only a small portion of the genetic vulnerability. The goal of the present study was to perform a genome-wide association study (GWAS) in extended families from the Collaborative Study on the Genetics of Alcoholism (COGA) to identify novel genes affecting risk for alcohol dependence. To maximize the power of the extended family design we used a quantitative endophenotype, measured in all individuals: number of alcohol dependence symptoms endorsed (symptom count). Secondary analyses were performed to determine if the single nucleotide polymorphisms (SNPs) associated with symptom count were also associated with the dichotomous phenotype, DSM-IV alcohol dependence. This family-based GWAS identified SNPs in C15orf53 that are strongly associated with DSM-IV alcohol (p=4.5×10−8, inflation corrected p=9.4×10−7). Results with DSM-IV alcohol dependence in the regions of interest support our findings with symptom count, though the associations were less significant. Attempted replications of the most promising association results were conducted in two independent samples: non-overlapping subjects from the Study of Addiction: Genes and Environment (SAGE) and the Australian twin-family study of alcohol use disorders (OZALC). Nominal association of C15orf53 with symptom count was observed in SAGE. The variant that showed strongest association with symptom count, rs12912251 and its highly correlated variants (D′=1, r2≥ 0.95), has previously been associated with risk for bipolar disorder.

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:significant findings in African- and European-Americans including novel risk loci

“…Using a symptom count phenotype, Wang et al . 15 identified a significant association of AD with C15orf53 .…”

Genetics of Alcohol Dependence: A Review of Clinical Studies

“…A potential future challenge might be posed by the change in diagnostic criteria with the publication of DSM-V [6]. While merging the diagnostic criteria into a single entity ‘substance use disorders' with varying degrees of severity might ease the definition of endophenotypes or of semiquantitative approaches like symptom count [176], great care must be taken when comparing studies based on DSM-V with previously published DSM-IV-based work. Also, GxE interactions must be considered [189,190,191], although keeping in mind that the GxE approach is one of the most challenging and complex of all conceptual frameworks applied in the genetic investigation of AUDs [197].…”

“…A potential endophenotype solely based on clinical criteria is the symptom count as a crude, but straightforward measure of disease severity that can be applied in both patients and healthy controls. In a GWAS directed at alcohol dependence symptom count, Wang et al [176] found converging evidence for a role of the thus far poorly characterized C15ORF53 gene in the etiology of alcohol dependence-related phenotypes. Other endophenotypes show a weaker statistical association with the clinical phenotype of interest, but might be more directly related to the underlying pathophysiological mechanisms.…”