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Background <p>The prevalence, timing and disease course of mental and neurological disorders vary according to sex, yet the neurogenetic mechanisms underlying sex differences in brain disorders remain poorly understood. While sex chromosomes and hormones contribute to sex differences in brain biology, previous studies suggest a role for autosomal genetic variation as well.</p> Methods <p>We investigated autosomal genetic associations with brain volumes in 15,740 females and 15,740 males from the UK Biobank, matched for age and scan site, using sex-stratified genome-wide association analyses. We applied a multivariate genome-wide approach (MOSTest) across 257 brain regions and complemented these analyses with region-specific univariate genome-wide association studies.</p> Results <p>Heritability estimates and genetic correlations were highly similar between females and males in late adulthood, indicating largely shared genetic influences on brain volumes. Many loci reaching genome-wide significance in one sex also showed signal in the other. Gene mapping in these loci yielded a greater total number of brain-volumes associated genes in females than in males. Variability in the number of mapped genes was particularly pronounced in limbic regions such as the insula, cingulate cortex, hippocampus and amygdala.</p> Conclusion <p>Overall, our findings contribute to a better understanding of autosomal genetic influences on brain volumes in males and females and may inform future studies examining sex variability in neurobiological mechanisms relevant to brain disorders.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月14日

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  • Édith Breton,
  • Elleke Tissink,
  • Gloria Matte Bon,
  • Dennis van der Meer,
  • Ole A. Andreassen,
  • Tobias Kaufmann

摘要

Background

The prevalence, timing and disease course of mental and neurological disorders vary according to sex, yet the neurogenetic mechanisms underlying sex differences in brain disorders remain poorly understood. While sex chromosomes and hormones contribute to sex differences in brain biology, previous studies suggest a role for autosomal genetic variation as well.

Methods

We investigated autosomal genetic associations with brain volumes in 15,740 females and 15,740 males from the UK Biobank, matched for age and scan site, using sex-stratified genome-wide association analyses. We applied a multivariate genome-wide approach (MOSTest) across 257 brain regions and complemented these analyses with region-specific univariate genome-wide association studies.

Results

Heritability estimates and genetic correlations were highly similar between females and males in late adulthood, indicating largely shared genetic influences on brain volumes. Many loci reaching genome-wide significance in one sex also showed signal in the other. Gene mapping in these loci yielded a greater total number of brain-volumes associated genes in females than in males. Variability in the number of mapped genes was particularly pronounced in limbic regions such as the insula, cingulate cortex, hippocampus and amygdala.

Conclusion

Overall, our findings contribute to a better understanding of autosomal genetic influences on brain volumes in males and females and may inform future studies examining sex variability in neurobiological mechanisms relevant to brain disorders.