Interactions between rare variants in DNA repair genes and cardiometabolic risk explain more variability in cognitive...

The brain is vulnerable to DNA damage and cardiometabolic risk. Yet, whether genetic variation in DNA repair interacts with cardiometabolic factors to explain cognitive variability remains unclear. Participants (n = 376,533) of white-British ancestry from the UK biobank with cognitive, neuroimaging, and whole-exome sequencing data were included. Six cognitive outcomes were assessed: fluid intelligence (FIQ), symbol-digit matching task (SDMT), visual matching (MATCH), trail making (TRAIL1 and TRAIL2), and prospective memory (PMEM). Seven brain regions of interest were assessed: total brain (TBV), grey matter (GMV), left and right white matter (LWM/RWM), left and right hippocampi (LHC/RHC), and white matter hyperintensities (WMH) volumes. A total of 3487 genetic variants across 39 DNA repair genes were tested. SNP and gene/gene-set level associations were tested using regression models adjusted for age, sex, APOE ε4, ancestry, and outcome-specific covariates. Genetic interactions with a multidimensional cardiometabolic risk index (CMRI), encompassing established risk factors, were assessed. We detected 107 genetic variants (mostly extremely rare) across 36 DNA repair genes associated at Bonferroni-significance (p ≤ 1.4 × 10^-5) with neurocognitive and brain outcomes. Most associations were observed for WMH (43 variants across 27 genes) and SDMT (26 variants across 17 genes). Most associations (60.8% of variants) were identified only in interaction models with CMRI. Associations across 35 of the 36 previously identified genes were also observed (p < 0.05) for dementia. Interactions between rare genetic variants involved in DNA repair mechanisms and cardiometabolic risk may explain some of the observed cognitive variability.