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Abstract:
Genetic factors have as large role as environmental factors in the
etiology of alcohol dependence (AD). Although genome-wide association
studies (GWAS) enable systematic searches for loci not hitherto
implicated in the etiology of AD, many true findings may be missed owing
to correction for multiple testing. The aim of the present study was to
circumvent this limitation by searching for biological system-level
differences, and then following up these findings in humans and animals.
Gene-set-based analysis of GWAS data from 1333 cases and 2168 controls
identified 19 significantly associated gene-sets, of which 5 could be
replicated in an independent sample. Clustered in these gene-sets were
novel and previously identified susceptibility genes. The most
frequently present gene, ie in 6 out of 19 gene-sets, was X-ray repair
complementing defective repair in Chinese hamster cells 5 (XRCC5).
Previous human and animal studies have implicated XRCC5 in alcohol
sensitivity. This phenotype is inversely correlated with the development
of AD, presumably as more alcohol is required to achieve the desired
effects. In the present study, the functional role of XRCC5 in AD was
further validated in animals and humans. Drosophila mutants with reduced
function of Ku80-the homolog of mammalian XRCC5-due to RNAi silencing
showed reduced sensitivity to ethanol. In humans with free access to
intravenous ethanol self-administration in the laboratory, the maximum
achieved blood alcohol concentration was influenced in an
allele-dose-dependent manner by genetic variation in XRCC5. In
conclusion, our convergent approach identified new candidates and
generated independent evidence for the involvement of XRCC5 in alcohol
dependence.
