Genome-wide Association Study of Alcohol Dependence

Abstract

Context Identification of genes contributing to alcohol dependence will improve our understanding of the mechanisms underlying this disorder. Objective To identify susceptibility genes for alcohol dependence through a genome-wide association study (GWAS) and follow-up study in a population of German male inpatients with an early age at onset. Design The GWAS included 487 male inpatients with DSM-IV alcohol dependence with an age at onset below 28 years and 1,358 population based control individuals. The follow-up study included 1,024 male inpatients and 996 age-matched male controls. All subjects were of German descent. The GWAS tested 524,396 single nucleotide polymorphisms (SNPs). All SNPs with p<10-4 were subjected to the follow-up study. In addition, nominally significant SNPs from those genes that had also shown expression changes in rat brains after chronic alcohol consumption were selected for the follow-up step. Results The GWAS produced 121 SNPs with nominal p<10-4. These, together with 19 additional SNPs from homologs of rat genes showing differential expression, were genotyped in the follow-up sample. Fifteen SNPs showed significant association with the same allele as in the GWAS. In the combined analysis, two closely linked intergenic SNPs met genome-wide significance (rs7590720 p=9.72×10-9; rs1344694 p=1.69×10-8). They are located on chromosome 2q35, a region which has been implicated in linkage studies for alcohol phenotypes. Nine SNPs were located in genes, including CDH13 and ADH1C genes which have been reported to be associated with alcohol dependence. Conclusion This is the first GWAS and follow-up study to identify a genome-wide significant association in alcohol dependence. Further independent studies are required to confirm these findings.

A genome-wide association study of alcohol dependence

“…We also show association results (Table S4) from our study for the SNPs recently reported in the independent GWAS of alcoholdependent men by Treutlein and colleagues (24). Only one SNP, rs13160562, shows modest evidence of replication [0.88; 95% confidence interval (CI) 0.78-0.99, P = 0.03].…”

“…Their top two findings, rs7590720 and rs1344694, were not associated with alcohol dependence in our study in our primary analysis or in secondary analyses stratified by ancestry and sex. In comparing our findings for the top 15 signals reported by Treutlein et al (24), our results modestly support one finding, rs13160562 in the endoplasmic reticulum aminopeptidase 1 (ERAP1) gene (metaanalysis OR = 0.83, 95% CI 0.77-0.90, P = 2.74 × 10 −6 ).…”

“…Overall, no newly identified variants were associated with alcohol dependence at the genome-wide significance threshold; however, this interpretation of our results is conservative. Our top 15 association signals were not replicated in the independent datasets, nor did the present study replicate the two genome-wide significant results reported by Treutlein and colleagues (24), who examined alcohol-dependent men in treatment and compared them with individuals from the community. Their top two findings, rs7590720 and rs1344694, were not associated with alcohol dependence in our study in our primary analysis or in secondary analyses stratified by ancestry and sex.…”

“…In our family-based association analyses, none of the SNPs demonstrated association with a P value < 0.05; however, rs1386449 and rs10224675, which in our primary analyses are associated with alcohol dependence only in AfricanAmericans, have a P value < 0.10 in the family-based analysis with a small number of African-American families. The top results also were examined in alcohol-dependent case and community-based comparison subjects of German ancestry (24). Of the seven SNPs that were genotyped and tested in the sample, none reached a significance level of P < 0.05.…”

“…Case-control sample. Replication analyses were performed in the GWAS sample of alcohol-dependent subjects reported by Treutlein et al (24). Alcoholdependent men (n = 487) were recruited from consecutive admissions to treatment facilities as part of the German Addiction Research Network (GARN; http://www.bw-suchtweb.de).…”