Dopamine pathway gene variants may modulate cognitive performance in the DHS - Mind Study

Abstract

Background: There is an established association between type 2 diabetes and accelerated cognitive decline. The exact mechanism linking type 2 diabetes and reduced cognitive function is less clear. The monoamine system, which is extensively involved in cognition, can be altered by type 2 diabetes status. Thus, this study hypothesized that sequence variants in genes linked to dopamine metabolism and associated pathways are associated with cognitive function as assessed by the Digit Symbol Substitution Task, the Modified Mini-Mental State Examination, the Stroop Task, the Rey Auditory-Verbal Learning Task, and the Controlled Oral Word Association Task for Phonemic and Semantic Fluency in the Diabetes Heart Study, a type 2 diabetes-enriched familial cohort (n = 893).

Methods: To determine the effects of candidate variants on cognitive performance, genetic association analyses were performed on the well-documented variable number tandem repeat located in the 3' untranslated region of the dopamine transporter, as well as on single-nucleotide polymorphisms covering genes in the dopaminergic pathway, the insulin signaling pathway, and the convergence of both. Next, polymorphisms in loci of interest with strong evidence for involvement in dopamine processing were extracted from genetic datasets available in a subset of the cohort (n = 572) derived from Affymetrix(®) Genome-Wide Human SNP Array 5.0 and 1000 Genomes imputation from this array.

Results: The candidate gene analysis revealed one variant from the DOPA decarboxylase gene, rs10499695, to be associated with poorer performance on a subset of Rey Auditory-Verbal Learning Task measuring retroactive interference (P = 0.001, β = -0.45). Secondary analysis of genome-wide and imputed data uncovered another DOPA decarboxylase variant, rs62445903, also associated with retroactive interference (P = 7.21 × 10(-7), β = 0.3). These data suggest a role for dopaminergic genes, specifically a gene involved in regulation of dopamine synthesis, in cognitive performance in type 2 diabetes.

Keywords: Cognition; DAT1 VNTR; DOPA decarboxylase; dopamine; polymorphism; type 2 diabetes.

Figure 1

Locus plots for GWAS and Imputed associations with (A) RAVLT‐RI (B) Stroop‐II and (C) Stroop‐IV. Association analyses were performed assuming an additive model of inheritance with adjustment for age, sex, T2D affected status, and education; additional adjustment for recall performance after first exposure to the word list was included for RAVLT‐RI. Abbreviations: GWAS, genome‐wide association study; RAVLT‐RI, Rey Auditory‐verbal Learning Task—retroactive interference; T2D, type 2 diabetes.