Assessment of the Association of D2 Dopamine Receptor Gene and Reported Allele Frequencies With Alcohol Use Disorders

Abstract

IMPORTANCE The association between the D2 dopamine receptor gene (DRD2) Taq1A locus (rs1800497) and alcohol use disorder (AUD) is enduring but the subject of long-standing controversy; meta-analysis of studies across 3 decades shows an association between rs1800497 and AUD, but genome-wide analyses have detected no role for rs1800497 in any phenotype. No evidence has emerged that rs1800497, which is located in ANKK1, perturbs the expression or function of DRD2. OBJECTIVE To resolve contradictions in previous studies by identifying hidden confounders and assaying for functional effects of rs1800497 and other loci in the DRD2 region. DATA SOURCES PubMed (882 studies), Embase (1056 studies), and Web of Science (501 studies) databases were searched through August 2018. Three clinical populations-Finnish, Native American, and African American participants-were genotyped for 208 to 277 informative singlenucleotide polymorphisms (SNPs) across the DRD2 region to test the associations of SNPs in this region with AUD. STUDY SELECTION Eligible studies had diagnosis of AUD made by accepted criteria, reliable genotyping methods, sufficient genotype data to calculate odds ratios and 95% CIs, and availability of control allele frequencies or genotype frequencies. DATA EXTRACTION AND SYNTHESIS After meta-analysis of 62 studies, metaregression was performed to detect between-study heterogeneity and to explore the effects of moderators, including deviations of cases and controls from allele frequencies in large population databases (ExAC and 1000 Genomes). Linkage to AUD and the effect on gene expression of rs1800497 were evaluated in the context of other SNPs in the DRD2 region. Data analysis was performed from August 2018 to March 2019. This study follows the Preferred Reporting Items for Systematic Reviews and Meta-analyses reporting guideline. MAIN OUTCOMES AND MEASURES The effects of rs1800497 and other SNPs in the DRD2 region on gene expression were measured in human postmortem brain samples via differential allelic expression and evaluated in other tissues via publicly available expression quantitative locus data. RESULTS A total of 62 studies of DRD2 and AUD with 16 294 participants were meta-analyzed. The rs1800497 SNP was associated with AUD (odds ratio, 1.23; 95% CI, 1.14-1.31; P < .001). However, the association was attributable to spuriously low allele frequencies in controls in positive studies, which also accounted for some between-study heterogeneity (I 2 = 43%; 95% CI, 23%-58%; Q 61 = 107.20).

Extra-striatal D2/3 receptor availability in youth at risk for addiction

“…One possibility is that increased extra-striatal DA 2/3 R levels reflect an adaptation to chronically low extracellular DA levels. Alternatively, the greater density of DA 2/3 R in high EXT individuals may be an inherited feature; indeed, the prior evidence of genetic predispositions to low DA 2 receptor function in addiction susceptible populations has now been shown to reflect biased allele frequencies in healthy control samples [ 58 ]. In either scenario, the widespread increases in DA 2/3 Rs could lead to elevated DA 2/3 R-mediated signaling, disrupting better calibrated reward processing [ 59 , 60 ].…”

DRD2 and BDNF Polymorphisms Are Associated With Binge Eating Disorder (BED) in Patients With Weight Regain After Bariatric Surgery

“…The analysis combining genotypes of the two studied polymorphisms revealed that the presence of at least one T allele for the DRD2 gene polymorphism (rs1800497) and an A allele for the BDNF gene polymorphism (rs6265) were predominant in the BED group (p = 0.002). The literature evaluating the combination of these polymorphisms is scarce, however in view of the data obtained in this study, a possible synergism was observed between these genetic variants, since the function of both genes is related to the addiction of chemical substances such as alcohol and cocaine [50][51][52], psychiatric disorders [53][54] and eating disorders [38,49].…”

Ankyrin Repeat and Kinase Domain Containing 1 Gene, and Addiction Vulnerability

“…Another study of common SNVs underlying drug addiction found that TaqIA is the third most significant genetic variation associated with alcohol-related phenotypes [52]. The most recent study meta-analyzed 62 reports followed by a meta-regression to identify hidden confounders [53]. The pooled odds ratio (OR) not only estimates that the TaqIA A1 allele increases the risk of alcohol dependence but also claims that the relationship between this SNV and alcoholism, is one of the largest effects ever observed for a polymorphic genetic variant in psychiatry (OR, 1.23; p < 0.001).…”

“…The pooled odds ratio (OR) not only estimates that the TaqIA A1 allele increases the risk of alcohol dependence but also claims that the relationship between this SNV and alcoholism, is one of the largest effects ever observed for a polymorphic genetic variant in psychiatry (OR, 1.23; p < 0.001). The authors state that the association is not attributable to dopamine receptor D2 (D2R) functional differences [53].…”