We found cognitive impairments in male mice related to genetic variants characterized by reduced Dys protein expression (pBonferroni = 0.0001), as well as in male humans through a COMT/Dys functional epistatic interaction involving PFC brain activity during working memory (t(23) = −3.21; pFDR = 0.004). The gene discussed is COMT; the disease is Cognitive impairment.