The Effect of the X Chromosome Imbalance on  Sex Differences in Brain Variability and Autism Risk

Autism Spectrum Disorder (ASD) is a highly heritable disorder that is more prevalent in males than females. Genetic mechanisms of the sexual differentiation could therefore contribute to the sex differences in ASD. An unexplored pathway lies in the potential contribution of the direct effect of the X chromosome imbalance. Due to the X chromosome’s implications in brain structure, the imbalance in X chromosomes could contribute to recently discovered sex differences in brain structure variance. As males showed larger brain structure variance, they have generally larger brain structure deviations compared to females. If increasing brain structure deviations relate to increased ASD risk, this mechanism could explain why males show higher ASD prevalence compared to females. To assess an influence of the X chromosome imbalance on sex differences in brain structure variance, we assessed the sex difference in brain structure variance in brain regions with a high and low expression of the X...Show moreAutism Spectrum Disorder (ASD) is a highly heritable disorder that is more prevalent in males than females. Genetic mechanisms of the sexual differentiation could therefore contribute to the sex differences in ASD. An unexplored pathway lies in the potential contribution of the direct effect of the X chromosome imbalance. Due to the X chromosome’s implications in brain structure, the imbalance in X chromosomes could contribute to recently discovered sex differences in brain structure variance. As males showed larger brain structure variance, they have generally larger brain structure deviations compared to females. If increasing brain structure deviations relate to increased ASD risk, this mechanism could explain why males show higher ASD prevalence compared to females. To assess an influence of the X chromosome imbalance on sex differences in brain structure variance, we assessed the sex difference in brain structure variance in brain regions with a high and low expression of the X chromosome. We then assessed whether larger brain structure deviations related to increased ASD symptoms. This was examined in a population of typically developing individuals aged 7 to 14. The X chromosome expression did not affect sex differences in brain structure variance. Therefore, our results did not support an effect of the X chromosome imbalance on sex differences in brain structure variance. Additionally, brain deviation showed no relationship with ASD symptoms. Our results do not support a contribution of sex differences in brain structure variance to sex differences in ASD. Our findings could suggest potential influences of other downstream effects of the chromosomal imbalance and the high heterogeneity of ASD.Show less

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The Effect of the X Chromosome Imbalance on Sex Differences in Brain Variability and Autism Risk