Polymorphisms of the dopamine beta-hydroxylase (DBH) gene show associations with cognitive flexibility in mentally healthy adults

The dopamine beta-hydroxylase (DBH) gene encodes the enzyme that converts noradrenaline into dopamine. It is predominantly expressed in prefrontal areas, the structure mostly implicated in cognitive functioning. Besides genetic associations with attention deficit disorder, positive evidence exists for genetic associations between DBH polymorphisms and neuropsychological phenotypes, e.g. working memory and executive function, thus underpinning the importance of dopaminergic action in cognition. Based on these reports we examined the hypothesis that polymorphisms of the DBH gene are associated with further cognitive domains. We analyzed 19 SNPs on the DBH gene in a mentally healthy control sample (n=543), that has been genotyped with the Illumina Bead Chip (300k). Subjects have been investigated with the Trail Making Test (TMT), and we analyzed the following variables: time TMT_A (speed component), time TMT_B (speed component, cognitive flexibility) and the difference between both scores (TMT_Diff: cognitive flexibility). Five SNPs survived the correction for multiple testing, with the best SNP displaying uncorrected p-values p=0.000007 (TMT_Diff) and 0.000009 (TMT_B), respectively, both for the allelic model. Of these, four SNPs map intronic and one SNP is synonymous-coding (exon 9). No associations could be found for the TMT_A variable. Our results provide first evidence that DBH polymorphisms are rather associated with cognitive flexibility than with motor speed.