Genetic Architecture of Cortical Thickness and White Matter hyperintensities: Evidence of Gene‐Environment Interaction with Cardiovascular Health and Late‐Life Depression

Abstract

AbstractBackgroundModifiable risk factors account for over 40% of dementias, offering potential for intervention. However, the impact of these risk factors, including depression and vascular disease, on brain health in the context of variable genetic influences is not well understood. Here we map the genetic landscape of brain structure, testing for gene‐by‐environment (GxE) interactions and relevance to cognitive performance in mid‐ and late‐life.MethodWe conducted genome‐wide association studies (GWAS) to identify genetic variants associated with cortical thickness in over 34,500 UK Biobank participants. We used postmortem bulk RNA sequencing of frontal cortex paired with antemortem MRI in a late‐life sample (n = 66) to directly corroborate implicated GWAS loci. Focusing on GWAS‐significant loci, we tested for GxE interactions and associations with cognition in 25,254 Canadian Longitudinal Study of Ageing (CLSA) participants.ResultWe identified 367 loci in the UK Biobank participants (age 45‐81), associated with global or regional cortical thickness (p<5×10−8), with genetic correlations between pairs of anatomical regions identifying three distinct modules. Corroboration with postmortem bulk RNA sequencing and MRI in a late‐life sample confirmed effects of STMN4, ARL17A and ARL17B genes on cortical thickness. Ten GWAS‐implicated loci from the UK Biobank were also associated with executive function or memory in CLSA, including rs1562330, a locus linked to the STMN4 gene. Notably, 37 variants also showed significant interactions with cardiovascular health or depression (P<2×10−4).ConclusionThese findings advance our understanding of the genetic architecture of brain structure and show that modifiable factors alter the effects of heritable genetic background on brain and cognitive health.