Sex-stratified insights into the genetics of brain volumes in late adulthood

Abstract

BackgroundThe prevalence, timing and disease course of mental and neurological disorders vary according to sex, yet the neurogenetic mechanisms underlying sex differences in these disorders remain poorly understood. Methods. Here, we explored the genetic architecture of the anatomical volumes of 257 regions of interest across the brain using multivariate genome-wide analyses in 15,740 male and 15,740 female participants from the UK Biobank, matched on age and scan site. ResultsOur findings revealed that the genetics of brain volume is highly similar between females and males in late adulthood. Yet, we found evidence of possible autosomal sex heterogeneity, particularly in the number of brain-volume associated genes, which was higher in females than in males. Variability in the number of identified genes were marked in limbic regions such as the insula, the cingulate cortex, the hippocampus and the amygdala. Conclusion.Overall, our findings contribute to a better understanding of the genetic determinants of brain volumes in males and females. Because neurogenetics may also influence the risk for sex-prevalent brain disorders, the current findings have the potential to facilitate precision medicine approaches in improving prevention strategies and targeted treatments. Plain English summaryMental and neurobiological disorders often differ between females and males. Some disorders are more common in one sex than the other, and symptoms can present or evolve differently. Variation in brain biology, partly shaped by genetic factors, may contribute to these observed patterns. In this study, we investigated genetic factors linked to brain structure in females and males separately. We focused on the volumes of 257 brain regions and analyzed genetic data from more than 30,000 adults from the UK Biobank. Overall, we found that the patterns of association between genetics and brain volumes are largely similar between females and males in late adulthood. At the same time, we observed evidence of sex-dependent patterns, particularly in the number of genes associated with brain volume, which tended to be higher in females than in males. These differences were marked in brain regions involved in the limbic system. Together, our findings improve our understanding of how genetics contribute to brain structure in females and males. HighlightsGenetic influences on brain volumes are largely shared between females and males in late adulthood. Gene-level variability was observed, with a higher number of brain volumes associated genes identified in females than in male, in both multivariate and univariate analyses. This gene-level variability was most pronounced in limbic regions, such as the insular and cingulate cortices.