Gender-specific contribution of the GABAA subunit genes on 5q33 in methamphetamine use disorder

Abstract

Family and twins studies have suggested that genetic factors are involved in the development of substance use disorders. Several unrelated case/control association studies have reported associations of the GABA A subunit genes on 5q33 with the development of alcohol dependence. We hypothesized that these particular GABA A subunit genes also contribute to the development of methamphetamine use disorder. To test our hypothesis, we recruited cases using a series of questionnaires. Among the polymorphic SNPs, significant differences between cases and controls were identified in the female sample in the rs2279020 of the GABA A a1 subunit gene, and the novel SNP rs4480617 in the GABA A g2 subunit gene. No associations were found in the male sample. Further haplotype analysis identified several marker blocks significantly associated with methamphetamine use disorder in females; each block consists of the rs4480617. Our study provides preliminary evidence that the GABA A subunit genes on 5q33 may preferentially contribute to methamphetamine use disorder in females. There is increasing evidence that substance use disorders are familial and that genetic factors explain a substantial degree of the familial aggregation. 3 Grove et al 4 studied a sample of 32 pairs of monozygotic twins reared apart, and reported that inherited factors explained 45% of the variance in drug abuse and dependence. Pickens et al 5 found that the variance attributable to genetic factors in abuse of illicit drugs is 31% in males and 22% in females. Similarly, Tsuang et al 6 reported that genetic factors account for 34% of the variance in the individual's risk of developing a drug use disorder; for stimulant abuse, 44% of the variance is attributable to genetic factors. The pairwise concordance rate for stimulant abuse was 14.1% for monozygotic twins and 5.3% for dizygotic twins. 7 The supporting evidence is also derived from animal studies. For example, knockout of the dopamine D4 receptor gene in mice result in animals that are supersensitive to several substances, including methamphetamine. 8 For the GABA A a1 knockout mice, administration of amphetamine sulfate caused an

Haplotype association between GABAA receptor γ2 subunit gene (GABRG2) and methamphetamine use disorder

“…However, our data are partly in agreement with a recent report 10 that found the significant association between GABRG2 and METH use disorder in females. This provides further corroboration that our haplotypic association with METH uses disorder is not spurious, although potential sources of bias such as ascertainment bias still remain possible.…”

“…Recently, a significant association was reported between rs4480617 at the 5 0 -UTR of GABRG2 and METH use disorder in females. 10 Therefore, this SNP or other variants in the promoter region also can be another candidate. Given that the sample size of 96 used to identify SNPs in this study provides more than 80% power to detect SNPs with about 1% minor allele frequency, 33 we are almost unlikely to overlook common nonsynonymous SNPs predisposed to METH use disorder.…”

“…8 Second, QTL mapping for acute alcohol withdrawal severity suggests that a polymorphism in the GABA A receptor g2 subunit gene in mice is genetically correlated with this phenotype. 9 A third line of evidence involves several case-control association studies, suggesting that the human GABA A receptor g2 subunit gene (GABRG2) is marginally associated with METH use disorder, 10 and is also associated with alcoholism comorbid with antisocial personality disorder, 11 although there are conflicting results. 12,13 Therefore, it is possible that GABRG2 affects vulnerability to substance use disorder, including METH use disorder.…”

Association of Gamma-Aminobutyric Acid A Receptor α2 Gene (GABRA2) with Alcohol Use Disorder

“…One study (Lind et al, 2008) was excluded because it investigated families comprised of monozygotic and dizygotic twin pairs; one study (Khan et al, 2009) was excluded because the definition of alcoholism was based on alcohol consumption only; and four studies (Agrawal et al, 2006;Dick et al, 2005Dick et al, , 2006Edenberg et al, 2004) were excluded because the data were not made available after we contacted the authors to request access to the data. In the end, 27 studies (Chang et al, 2002;Covault et al, 2004Covault et al, , 2008Enoch et al, 2009;Fehr et al, 2006;Foley et al, 2004;Han et al, 2008;Hsu et al, 1998;Lappalainen et al, 2005;Li et al, 2002;Lin et al, 2003;Loh et al, 1999Loh et al, , 2000Loh et al, , 2007Lydall et al, 2011;Nishiyama et al, 2005;Onori et al, 2010;Park et al, 2006;Sander et al, 1999;Soyka et al, 2008) met our criteria for inclusion (Supplementary Table 3). These studies included a total of 4739 cases (AD, HD, or MD) and 4924 controls.…”

A Bayesian Decision-Theoretic Approach to Logically-Consistent Hypothesis Testing

“…Table 1. These numbers were taken from a study presented by [12] that had the aim of verifying the hypothesis that subunits of the gene GABA A contribute to a condition known as methamphetamine use disorder. Here, the set of all possible genotypes is G tAA, AB, BBu.…”