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Hypodopaminergic polygenic risk for polysubstance use.

Twin studies have shown substantial heritability for polysubstance use. Previous research has sought to pinpoint this genetic influence to variants in genes related to dopamine signaling, that are known to lower baseline dopamine levels (hypodopaminergic function). Candidategene studies often used single-gene designs and have yielded inconsistent results. Genome-wide association studies mainly include Single Nucleotide Polymorphisms (SNPs). In this study, a risk score was calculated based on both SNPs as well as Variable Number of Tandem Repeats (VNTRs).

Survey data on nicotine, alcohol and cannabis use from two family samples were analysed (N=2435 and N=1173). Moderate and problematic polysubstance uses were explored. A polygenic risk score was calculated by averaging the number of hypodopaminergic variants in three polymorphisms. Polysubstance use was regressed on this score with sex and age as covariates. Power was sufficient to detect small effect sizes (R2=0.4-0.8%).

The hypodopaminergic polygenic risk score (HPRS) was not related to polysubstance use in either sample. There were some indications for opposing effects of individual polymorphisms and separate substance use outcomes and for an interaction of the polygenic risk score with education level. There were no effects of a score extended with extra polymorphisms, and there were no quadratic effects of the HPRS.

The HPRS did not predict polysubstance use. Several explanations for these findings were ruled out. Future research might employ more comprehensive genetic models, thereby including geneenvironment interaction.

Author(s): Joelle A Pasman, Karin JH Verweij, Jorien L Treur, Gonneke Willemsen, Jouke-Jan Hottenga, Judith R Homberg, Sabine Spijker, Roy Otten, Rutger CME Engels, Eco JC de Geus, Jacqueline M Vink