Associated and intermediate factors between genetic variants of the dopaminergic D2 receptor gene and harmful alcohol use in young adults

Abstract

Dopamine receptor D2 (DRD2) and ankyrin repeat and kinase domain-containing protein 1 (ANKK1) genes have received considerable attention for their involvement in alcohol use disorder (AUD), but many questions remain on their exact role. We conducted a population-based case-control and genetic association study in a large sample of young adults. Our aim was to assess the association between DRD2 and ANKK1 single nucleotide polymorphisms (SNPs) and harmful alcohol use, disentangling associated and possible intermediate factors. A total of 1841 college students from the French region Champagne-Ardennes, aged between 18 and 21 years and who reported at least one lifetime alcohol consumption, were included in this study. Allele frequencies were analysed according to harmful alcohol use (assessed through the Alcohol Use Disorder Identification Test [AUDIT] questionnaire). Different substance use disorders, including nicotine and cannabis dependences, were also assessed through questionnaires, as was a list of potential associated factors (e.g., major depressive episode, conduct disorder, attention-deficit/hyperactivity disorder [ADHD], school failure, sugar consumption, sexual trauma, parents' use of alcohol, tobacco or cannabis). We found that DRD2 rs1800498 was associated with harmful alcohol use. Many factors were detected, but a global path analysis revealed that DRD2 rs1800498 had a significant direct effect on harmful alcohol use and that early age at first alcohol consumption and depressive symptoms moderated this effect. This study suggests an interplay between harmful alcohol use, DRD2 genotypes and other risk factors that, with a full understanding, could be useful for preventive purposes.

Keywords: ANKK1 gene; DRD2 gene; addiction; alcohol use disorder; depression; harmful alcohol use.

FIGURE 1

Pairwise linkage disequilibrium between single nucleotide polymorphisms (SNPs) of the ankyrin repeat and kinase domain‐containing protein 1 (ANKK1) and dopamine receptor D2 (DRD2) genes. TC and GA refer to the nucleotides thymine, cytosine, guanine and adenine. Colour‐coding represents D′ values, and values in cells are D′ * 100. Block 1: ANKK1 gene; 1: rs4938015; 2: rs1800497; Block 2: DRD2 gene; 3: rs6277; 4: rs1800498. Arrows indicate gene directionality.

FIGURE 2

Structural equation model of the relationship between dopamine receptor D2 (DRD2) rs1800498 and harmful alcohol use. DRD2 rs1800498 has a significant direct effect on harmful alcohol use. This effect is significantly moderated by depressive symptoms and age at first alcohol consumption. Mediation of the effect of DRD2 rs1800498 on harmful alcohol use by nicotine dependence and DRD2 rs6277 is not significant. Numbers indicate standardized regression coefficients. Bold arrows represent significant effects. *p < 0.05, **p < 0.01, ***p < 0.001