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 (ρ_p) were observed between type 2 diabetes and measures of attention (Continuous Performance Test [CPT d′]: ρ_p = −0.143, p = 0.001), verbal memory (California Verbal Learning Test [CVLT] recall: ρ_p = −0.111, p = 0.004) and face memory (Penn Face Memory Test [PFMT]: ρ_p = −0.127, p = 0.002; PFMT Delayed: ρ_p = −0.148, p = 2 × 10⁻⁴), replicating findings of cognitive impairment in type 2 diabetes. Negative genetic correlations (ρ_g) were also observed between type 2 diabetes and measures of attention (CPT d′: ρ_g = −0.401, p = 0.001), working memory (digit span backward test: ρ_g = −0.380, p = 0.005), and face memory (PFMT: ρ_g = −0.476, p = 2 × 10⁻⁴; PFMT Delayed: ρ_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′: β = −0.219, p = 0.005), working memory (digit span backward: β = −0.326, p = 0.035), and face memory (PFMT: β = −0.171, p = 0.023; PFMT Delayed: β = −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.