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Meta-Analysis
. 2020 May;25(3):e12770.
doi: 10.1111/adb.12770. Epub 2019 May 31.

Parsing out the role of dopamine D4 receptor gene (DRD4) on alcohol-related phenotypes: A meta-analysis and systematic review

Allison M Daurio  1   2 , Sara L Deschaine  2 , Amirhossein Modabbernia  3 , Lorenzo Leggio  2   4
Affiliations
Meta-Analysis

Parsing out the role of dopamine D4 receptor gene (DRD4) on alcohol-related phenotypes: A meta-analysis and systematic review

Allison M Daurio et al. Addict Biol. 2020 May.

Abstract

Genetics account for moderate variation of individual differences in developing alcohol use disorder (AUD), but it is unclear which genetic variations contribute to AUD risk. One candidate gene investigated due to its association with AUD is the dopamine D4 receptor gene (DRD4), which contains a 48-base pair variable number tandem repeat (VNTR) in exon 3 of its coding region. To date, no quantitative synthesis of the published literature on the effects of DRD4 VNTR variation on alcohol-related phenotypes has been conducted. MEDLINE, Embase, Web of Science, and PsycInfo were searched for studies that reported on alcohol craving, alcohol consumption, severity of AUD, and case-control (AUD versus no diagnosis of AUD) studies in DRD4L (seven repeats or more) carriers compared with DRD4S (six repeats or less) homozygotes. Random-effects meta-analysis was used for all analyses. A pooled sample size of 655 to 13,360 of 28 studies were included. Compared with DRD4S homozygotes, DRD4L carriers had increased number of drinking days (SMD: 0.205; 95% CI: 0.008 to 0.402), binge drinking days (SMD: 0.217; 95% CI: 0.0532 to 0.380), and severity of AUD (SMD: 0.143; 95% CI: 0.028 to 0.259). There was no difference between DRD4 VNTR genotypes on drinks per drinking day, largest number of drinks per day/occasion, and case-control analysis. It was not possible to conduct a meta-analysis of the craving data, but a systematic review of this literature found mixed results on DRD4 VNTR genotype effect. The present meta-analysis suggests DRD4 VNTR variation may be a risk factor for problematic alcohol use. Our findings are limited, however, by the absence of ancestry data from studies included in our analysis, precluding our ability to adjust for population stratification. Due to the likelihood of type I error in candidate gene approaches, our work highlights the critical need for studies with larger and more inclusive samples that account for sex and genetic ancestry to fully understand this relationship.

Keywords: DRD4; alcohol use disorder; meta-analysis.

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Conflict of interest statement

Conflicts of Interest and Disclosures:

The authors report no biomedical financial interests or potential conflicts of interest. The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Figures

Figure 1:
Figure 1:
PRISMA flow diagram
Figure 2A/2B.
Figure 2A/2B.
Figure 2A: Severity of alcohol use disorder; Figure 2B: Case-control meta-analysis on DRD4L frequency
Figure 3A/3B/3C:
Figure 3A/3B/3C:
Figure 3A: Funnel Plot of Number of Drinks Per Drinking Day; Figure 3B: Severity of Alcohol Use Disorder; Figure 3C: Funnel Plot for Case-control Meta-Analysis on DRD4L Frequency
See this image and copyright information in PMC

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