Investigation of sex-differential genetic risk factors for autism spectrum disorders

Autism spectrum disorders (ASDs) are pervasive neurodevelopmental disorders that affect more males than females, and the mechanisms responsible for increasing males' risk or protecting females are not understood. This sex biased prevalence is consistent across time and populations, suggesting that an understanding of the processes driving sex-differential risk would likely be informative of fundamental pathophysiology in ASD. One known component of ASD risk is genetic variation. Thus, here I apply several approaches that leverage current knowledge of ASD genetics to investigate the role and mechanisms of sex-differential biology in ASD risk. First, I evaluate a cohort of families with more than one autistic child for evidence of sex-differential, familial risk variation. Second, I use genetic linkage analysis to identify sex-differential risk loci in families from the same multiplex cohort. Third, I characterize gene expression patterns in typical human neocortex to identify points of interaction between typical sexual dimorphism and genes known to carry risk variants for ASD.I find that recurrence rates for ASD diagnoses in multiplex families are consistent with a female protective model, in which females require more deleterious genetic variation to be affected with ASD and this greater genetic load is shared with females' siblings. I also identify several chromosomal loci with evidence of genetic linkage in families either with (chromosome 8p21.2 and 8p12), or without (chromosome 1p31.3), an autistic female. No significant common variants are found in either region that can account for this linkage; these loci will be further investigated by targeted sequencing to identify rare risk variants. Gene expression analyses show that known ASD risk genes are not differentially expressed in males or females in the prenatal or adult human neocortex. However, astrocyte markers and gene sets implicated in immune function and inflammatory processes are expressed at higher levels in males. This suggests that sex-differential factors may operate downstream from, or interact with, ASD risk genes, as opposed to directly regulating the expression of these genes. Overall, findings from these multiple approaches provide valuable context for the function of sex-differential biology in ASD etiology, and suggest promising directions for future research