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

Authors

  • Verica Milivojevic,

    1. From the Graduate Program in Neuroscience (VM), University of Connecticut Health Center, Farmington, Connecticut; Department of Psychiatry (HRK, LB, JC), Alcohol Research Center, University of Connecticut School of Medicine, Farmington, Connecticut; Department of Genetics and Developmental Biology (HRK), University of Connecticut School of Medicine, Farmington, Connecticut; and Departments of Psychiatry Neurobiology and Genetics (JG), Yale University School of Medicine, New Haven, Connecticut, and VA CT Healthcare System, West Haven, Connecticut.
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  • Henry R. Kranzler,

    1. From the Graduate Program in Neuroscience (VM), University of Connecticut Health Center, Farmington, Connecticut; Department of Psychiatry (HRK, LB, JC), Alcohol Research Center, University of Connecticut School of Medicine, Farmington, Connecticut; Department of Genetics and Developmental Biology (HRK), University of Connecticut School of Medicine, Farmington, Connecticut; and Departments of Psychiatry Neurobiology and Genetics (JG), Yale University School of Medicine, New Haven, Connecticut, and VA CT Healthcare System, West Haven, Connecticut.
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  • Joel Gelernter,

    1. From the Graduate Program in Neuroscience (VM), University of Connecticut Health Center, Farmington, Connecticut; Department of Psychiatry (HRK, LB, JC), Alcohol Research Center, University of Connecticut School of Medicine, Farmington, Connecticut; Department of Genetics and Developmental Biology (HRK), University of Connecticut School of Medicine, Farmington, Connecticut; and Departments of Psychiatry Neurobiology and Genetics (JG), Yale University School of Medicine, New Haven, Connecticut, and VA CT Healthcare System, West Haven, Connecticut.
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  • Linda Burian,

    1. From the Graduate Program in Neuroscience (VM), University of Connecticut Health Center, Farmington, Connecticut; Department of Psychiatry (HRK, LB, JC), Alcohol Research Center, University of Connecticut School of Medicine, Farmington, Connecticut; Department of Genetics and Developmental Biology (HRK), University of Connecticut School of Medicine, Farmington, Connecticut; and Departments of Psychiatry Neurobiology and Genetics (JG), Yale University School of Medicine, New Haven, Connecticut, and VA CT Healthcare System, West Haven, Connecticut.
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  • Jonathan Covault

    1. From the Graduate Program in Neuroscience (VM), University of Connecticut Health Center, Farmington, Connecticut; Department of Psychiatry (HRK, LB, JC), Alcohol Research Center, University of Connecticut School of Medicine, Farmington, Connecticut; Department of Genetics and Developmental Biology (HRK), University of Connecticut School of Medicine, Farmington, Connecticut; and Departments of Psychiatry Neurobiology and Genetics (JG), Yale University School of Medicine, New Haven, Connecticut, and VA CT Healthcare System, West Haven, Connecticut.
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Reprint requests: Jonathan Covault, Department of Psychiatry, Alcohol Research Center, University of Connecticut Health Center, Farmington, CT 06030-2103; Tel.: +1-860-679-7560; Fax: +1-860-679-1296; E-mail: jocovault@uchc.edu

Abstract

Background:  Studies of alcohol effects in rodents and in vitro implicate endogenous neuroactive steroids as key mediators of alcohol effects at GABAA 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: 5α–reductase, type I (5α-R), and 3α-hydroxysteroid dehydrogenase, type 2 (3α-HSD), both of which are expressed in human brain.

Methods:  We focused on markers previously associated with a biological phenotype. For 5α-R, we examined the synonymous SRD5A1 exon 1 SNP rs248793, which has been associated with the ratio of dihydrotestosterone to testosterone. For 3α-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 (χ2(1) = 7.6, p = 0.006) and AKR1C3 rs12529 G-allele (χ2(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.

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