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Abstract
BackgroundThere 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).MethodsTo 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.ResultsThe 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.
Highlights
Cognitive decline is a part of normal aging, the rate of cognitive decline can be influenced by factors such as lifestyle, health, and genetics
This study aimed to examine the functional effects of dopaminergic polymorphisms in a type 2 diabetes (T2D)-affected population on cognitive performance, individuals whose performance was indicative of mild cognitive impairment or dementia were not excluded
Characteristics of candidate SNPs and DAT1 VNTR are summarized in Table 2 with a brief description of gene function and relevant references
Summary
Cognitive decline is a part of normal aging, the rate of cognitive decline can be influenced by factors such as lifestyle, health, and genetics. 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, b = À0.45). Secondary analysis of genome-wide and imputed data uncovered another DOPA decarboxylase variant, rs62445903, associated with retroactive interference (P = 7.21 9 10À7, b = 0.3). These data suggest a role for dopaminergic genes, a gene involved in regulation of dopamine synthesis, in cognitive performance in type 2 diabetes
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