Understanding vulnerability through variability: A longitudinal twin study linking sex differences in neurodiversity, neurodevelopment and X-linked genetic mechanisms

There are marked sex differences in the prevalence and expression of neurodiverse conditions, including autism and ADHD. Yet, it is unclear how sex-related mechanisms may affect differences in the expression of symptoms. In the present study, we examine whether previously reported greater male than female variability in neuroanatomy extends to brain development and if X-linked mechanisms are involved, using twin modeling. We further tested whether these observed patterns may be behavioral relevant and linked to symptoms of autism and ADHD. The present study included data from the L-CID study with up to three longitudinal imaging scans from 990 same-sex twin pairs (56% monozygotic, 7-14 yo, 49% females). We replicated greater male than female variability in both cross-sectional and longitudinal data, which was most pronounced for cortical surface area. In line with our hypothesis, twin modeling results support a significant role of X-chromosome expression related to sex differences in neuroanatomical variation. In addition, normative modeling analysis showed that, as predicted, deviations in brain anatomy at both upper and lower ends of the distribution were associated with symptoms of neurodiversity. These findings support a significant and understudied role of the X-chromosome in sex differences in the brain and the need to move beyond binary models to better understand sex-linked vulnerability and protective mechanisms in mental health.