Genetic Variation in the Alpha Synuclein Gene (SNCA) Is Associated With BOLD Response to Alcohol Cues

Abstract

Preclinical studies implicate the gene encoding the alpha synuclein protein (SNCA) in the pathophysiology of alcohol dependence and dopamine neuron function. Results from clinical studies are less conclusive. Using neurobiological phenotypes in genetic studies, rather than typical heterogeneous diagnostic categories derived from self-report, may improve reliability across studies. This study aimed to examine whether polymorphisms in the SNCA gene were associated with alcohol taste cue-elicited responses in the brain, one such intermediate phenotype. A total of 326 heavy drinkers who underwent an alcohol taste task during functional magnetic resonance imaging (fMRI) also were genotyped. Analyses focused on two previously identified SNCA variants (rs2583985 and rs356168) as well as 27 other single nucleotide polymorphisms from the Illumina Human1M BeadChip that were used in an exploratory analysis of the whole gene. Neurobiological phenotypes were defined as fMRI blood oxygenation level-dependent (BOLD) responses to alcohol taste cue (vs. a control cue) in seven regions of interest known to be involved in cue processing and rich in dopaminergic axon terminals. Polymorphisms in the SNCA gene were significantly correlated with BOLD activation. Specifically, the largest effect sizes and significance were seen for rs2583985 in paracingulate and caudate (focused analysis) and for rs1372522 in paracingulate (exploratory analysis). Activation in all regions of interest was correlated with alcohol-dependence severity. SNCA genotype was found to be associated with the degree of fMRI BOLD response during exposure to the taste of alcohol versus a control taste. This study also further validates the use of this alcohol taste task as an intermediate phenotype for alcohol-dependence severity.