Neurocognitive Impairment in Type 2 Diabetes: Evidence for Shared Genetic Aetiology.

Aims/hypothesis Type 2 diabetes is associated with cognitive impairments, but it is unclear whether common genetic factors influence both type 2 diabetes risk and cognition. Methods Using data from 1892 Mexican-American individuals from extended pedigrees, including 402 with type 2 diabetes, we examined possible pleiotropy between type 2 diabetes and cognitive functioning, as measured by a comprehensive neuropsychological test battery. Results Negative phenotypic correlations (rho(p)) were observed between type 2 diabetes and measures of attention (Continuous Performance Test [CPT d ']: rho(p) = -0.143, p = 0.001), verbal memory (California Verbal Learning Test [CVLT] recall: rho(p) = -0.111, p = 0.004) and face memory (Penn Face Memory Test [PFMT]: rho(p) = -0.127, p = 0.002; PFMT Delayed: rho(p) = -0.148, p = 2 x 10(-4)), replicating findings of cognitive impairment in type 2 diabetes. Negative genetic correlations (rho(g)) were also observed between type 2 diabetes and measures of attention (CPT d ': rho(g) = -0.401, p = 0.001), working memory (digit span backward test: rho(g) = -0.380, p = 0.005), and face memory (PFMT: rho(g) = -0.476, p = 2 x 10(-4); PFMT Delayed: rho(g) = -0.376, p = 0.005), suggesting that the same genetic factors underlying risk for type 2 diabetes also influence poor cognitive performance in these domains. Performance in these domains was also associated with type 2 diabetes risk using an endophenotype ranking value approach. Specifically, on measures of attention (CPT d ': beta = -0.219, p = 0.005), working memory (digit span backward: beta = -0.326, p = 0.035), and face memory (PFMT: beta = -0.171, p = 0.023; PFMT Delayed: beta = -0.215, p = 0.005), individuals with type 2 diabetes showed the lowest performance, while unaffected/unrelated individuals showed the highest performance, and those related to an individual with type 2 diabetes performed at an intermediate level. Conclusions/interpretation These findings suggest that cognitive impairment may be a useful endophenotype of type 2 diabetes and, therefore, help to elucidate the pathophysiological underpinnings of this chronic disease. Data availability The data analysed in this study is available in dbGaP: www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs001215.v2.p2.