Association analysis of the DRD4 and COMT genes in methamphetamine abuse

Abstract

We analyzed two polymorphisms in genes encoding proteins of the dopamine system, the Val158Met polymorphism in the catechol-O-methyltransferase gene and the 120-bp VNTR polymorphism in the promoter of the dopamine D4 receptor gene for association with methamphetamine abuse. We used a case/control design with 416 methamphetamine abusing subjects and 435 normal controls. All subjects were Han Chinese from Taiwan. We found an excess of the high activity Val158 allele in the methamphetamine abuser group, consistent with several previous reports of association of this allele with drug abuse. The 120-bp VNTR polymorphism in the promoter of the dopamine D4 receptor gene itself did not show significant association with methamphetamine abuse. However, analysis of the 120-bp VNTR polymorphism and the exon 3 VNTR in the dopamine D4 receptor as a haplotype showed significant association with methamphetamine abuse, which gave an empirical P value 0.0034 for a heterogeneity model. Moreover, there were significant interactive effects between polymorphisms in the catechol-O-methyltransferase and dopamine D4 genes. The evidence of interaction between COMT 158 Val/Met and DRD4 48-bp VNTR polymorphisms (P = 0.0003, OR = 1.45, 95% CI: 1.148-1.77), and between COMT 158 Val/Met and DRD4 120 bp promoter polymorphisms (P = 0.01, OR = 1.10, 95% CI: 1.10-1.18) were significant but the latter was weak. We conclude that genetic variation in the dopamine system may encode an additive effect on risk of becoming a methamphetamine abuser.

Association of p.Val158Met COMT polymorphism with paranoid ideation in drug addicts

“…These results are in accordance with the literature [20,21,31]. But other authors have not replicated these findings [18,32,33].…”

“…Although this polymorphism has been already studied in drug addicts [19,20,30], to our knowledge, this is the first screening to include a correlation with paranoid ideation.…”

“…Individual genetic differences modulating COMT activity might therefore influence the vulnerability to substance use disorders. The high-activity COMT variant, the Val allele, was found in higher rates in subjects with polysubstance abuse and addiction to nicotine and methamphetamine [19][20][21].…”

Functional polymorphisms in dopamine and serotonin pathway genes

“…Other evidence supporting an association of this polymorphism together with a haplotype of markers in the 5 0 end of the gene and ADHD has been reported (P 5 0.03) . Additionally, studies have reported associations of this repeat with schizophrenia (P 5 0.003) [Xing et al, 2003] and (less robustly) methamphetamine abuse (P 5 0.01) [Li et al, 2004]. Other studies have reported an association with novelty seeking in bipolar (P 5 0.01) and alcoholic families (P 5 0.006) [Rogers et al, 2004].…”

Evidence for a two-stage model of dependence using the NESARC and its implications for genetic association studies

“…While pitfalls such as small samples and confounding (i.e., population stratification) have been blamed (Lachman, 2006), the lack of replication may also be due, in part, to differences in selection criteria for the control groups across studies, particularly with respect to the inclusion of abstainers (Buckland, 2001;Tsuang et al, 1999), i.e., individuals who never used the substance. Some studies restricted control subjects to abstainers (Gerra et al, 2004;Li et al, 2004;Liu et al, 2005;Uhl et al, 2001) or those with extremely low frequency of use (Morita et al, 2005;Xu et al, 2002). Other studies specifically included users, i.e., those exposed to the substance (Kohnke et al, 2005;Sullivan et al, 2001a) and attempted to match on level of drug use (Franke et al, 2003).…”