Variation in Genes Encoding the Neuroactive Steroid Synthetic Enzymes 5α-Reductase Type 1 and 3α-Reductase Type 2 Is Associated With Alcohol Dependence

Background: Studies of alcohol effects in rodents and in vitro implicate endogenous neuroactive steroids as key mediators of alcohol effects at GABA(A) receptors. We used a case-control sample to test the association with alcohol dependence (AD) of single nucleotide polymorphisms in the genes encoding two key enzymes required for the generation of endogenous neuroactive steroids: 5 alpha-reductase, type I (5 alpha-R), and 3 alpha-hydroxysteroid dehydrogenase, type 2 (3 alpha-HSD), both of which are expressed in human brain. Methods: We focused on markers previously associated with a biological phenotype. For 5 alpha-R, we examined the synonymous SRD5A1 exon 1 SNP rs248793, which has been associated with the ratio of dihydrotestosterone to testosterone. For 3 alpha-HSD, we examined the nonsynonymous AKR1C3 SNP rs12529 (H5Q), which has been associated with bladder cancer. The SNPs were genotyped in a sample of 1,083 non-Hispanic Caucasians including 552 controls and 531 subjects with AD. Results: The minor allele for both SNPs was more common among controls than subjects with AD: SRD5A1 rs248793 C-allele (chi 2(1) = 7.6, p = 0.006) and AKR1C3 rs12529 G-allele (chi 2(1) = 14.6, p = 0.0001). There was also an interaction of these alleles such that the "protective" effect of the minor allele at each marker for AD was conditional on the genotype of the second marker. Conclusions: We found evidence of an association with AD of polymorphisms in two genes encoding neuroactive steroid biosynthetic enzymes, providing indirect evidence that neuroactive steroids are important mediators of alcohol effects in humans.