| Title: | Interactions between rare variants in DNA repair genes and cardiometabolic risk explain more variability in cognitive function |
| Journal: | GeroScience |
| Published: | 18 Apr 2026 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/41998431/ |
| DOI: | https://doi.org/10.1007/s11357-026-02238-3 |
| URL: | https://link.springer.com/content/pdf/10.1007/s11357-026-02238-3.pdf |
Publication 17949
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Abstract
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.Graphical Abstract</p>
10 Authors
- Nicolas Cherbuin
- Leticia Camargo Tavares
- Mark A. Fraser
- Yuan Li
- Claudia Navarro
- Erin I. Walsh
- Shea J. Andrews
- Richard A. Burns
- Anne Brüstle
- Lene Juel Rasmussen
1 Application
| Application ID | Title |
|---|---|
| 47813 | Towards a comprehensive predictive model of the contribution of individual and combination of risk factors to brain ageing, neurodegeneration, and cognitive decline. |
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