Abstract
Genome-wide association studies (GWAS) have revealed many single nucleotide polymorphisms (SNPs) associated with complex traits. Although these studies frequently fail to identify statistically significant associations, the top association signals from GWAS may be enriched for true associations. We therefore investigated the association of alcohol dependence with 43 SNPs selected from association signals in the first two published GWAS of alcoholism. Our analysis of 808 alcohol-dependent cases and 1,248 controls provided evidence of association of alcohol dependence with SNP rs1614972 in the ADH1C gene (unadjusted p = 0.0017). Because the GWAS study that originally reported association of alcohol dependence with this SNP [1] included only men, we also performed analyses in sex-specific strata. The results suggest that this SNP has a similar effect in both sexes (men: OR (95%CI) = 0.80 (0.66, 0.95); women: OR (95%CI) = 0.83 (0.66, 1.03)). We also observed marginal evidence of association of the rs1614972 minor allele with lower alcohol consumption in the non-alcoholic controls (p = 0.081), and independently in the alcohol-dependent cases (p = 0.046). Despite a number of potential differences between the samples investigated by the prior GWAS and the current study, data presented here provide additional support for the association of SNP rs1614972 in ADH1C with alcohol dependence and extend this finding by demonstrating association with consumption levels in both non-alcoholic and alcohol-dependent populations. Further studies should investigate the association of other polymorphisms in this gene with alcohol dependence and related alcohol-use phenotypes.
Highlights
Alcohol dependence is known to be under considerable genetic influence [2,3], yet few genetic risk factors have been discovered and confirmed
For the alcohol withdrawal studies, in addition to establishing a diagnosis of alcohol dependence, a standardized questionnaire was used to collect alcohol consumption data, including average number of drinks per drinking day measured in units of standard drinks, with standard drink defined according to the National Institute on Alcohol Abuse and Alcoholism (NIAAA) as 14 g of alcohol
The strongest evidence of association with alcohol dependence was obtained for single nucleotide polymorphisms (SNPs) rs1614972 in the alcohol dehydrogenase 1C (ADH1C) gene (OR = 0.80, 95% CI = (0.70, 0.92), p = 0.0017)
Summary
Alcohol dependence is known to be under considerable genetic influence [2,3], yet few genetic risk factors have been discovered and confirmed. Genome-wide association studies (GWAS) have successfully identified many single nucleotide polymorphisms (SNPs) associated with complex traits. GWAS generally have low power to detect individual SNP effects. Many of these studies fail to identify associations that are statistically significant at the genome-wide level. The top association signals from GWAS are expected to be enriched for true associations and provide good candidates for further followup. Replication of the top GWAS signals in independent data sets is an important strategy for identifying genetic factors contributing to complex traits
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