The role of sex-differential biology in risk for autism spectrum disorder

Abstract

Autism spectrum disorder (ASD) is a developmental condition that affects approximately four times as many males as females, a strong sex bias that has not yet been fully explained. Understanding the causes of this biased prevalence may highlight novel avenues for treatment development that could benefit patients with diverse genetic backgrounds, and the expertise of sex differences researchers will be invaluable in this endeavor. In this review, I aim to assess current evidence pertaining to the sex difference in ASD prevalence and to identify outstanding questions and remaining gaps in our understanding of how males come to be more frequently affected and/or diagnosed with ASD. Though males consistently outnumber females in ASD prevalence studies, prevalence estimates generated using different approaches report male/female ratios of variable magnitude that suggest that ascertainment or diagnostic biases may contribute to the male skew in ASD. Here, I present the different methods applied and implications of their findings. Additionally, even as prevalence estimations challenge the degree of male bias in ASD, support is growing for the long-proposed female protective effect model of ASD risk, and I review the relevant results from recurrence rate, quantitative trait, and genetic analyses. Lastly, I describe work investigating several sex-differential biological factors and pathways that may be responsible for females’ protection and/or males’ increased risk predicted by the female protective effect model, including sex steroid hormone exposure and regulation and sex-differential activity of certain neural cell types. However, much future work from both the ASD and sex differences research communities will be required to flesh out our understanding of how these factors act to influence the developing brain and modulate ASD risk.

Large-scale exome sequencing study implicates both developmental and functional changes in the neurobiology of autism

“…1B; 14 Table S3). This result is consistent with the female protective effect (FPE) model, which 15 postulates that females require an increased genetic load (in this case, high-liability PTVs) to 16 reach the threshold for a diagnosis (Werling, 2016). The converse hypothesis is that risk 17 variation has larger effects in males than in females so that females require a higher genetic 18 burden to reach the same diagnostic threshold as males; however, across all classes of genetic 19 variants, we observed no significant sex differences in trait liability, consistent with the FPE 20 model (STAR Methods; Fig.…”

Integration of Brain and Behavior Measures for Identification of Data-Driven Groups Cutting Across Children with ASD, ADHD, or OCD

“…Biological sex is an important source of heterogeneity in NDDs [11] and aspects of sex-specific brain structure and functional connectivity patterns have been found in ASD [51] and to a lesser degree in ADHD [52] or OCD [53]. Previous evidence has suggested a protective effect for females, or required increased biological 'hit' related to resilience to developing NDDs [54,55]. However, interpretation of any differences found amongst males versus females in the current study is limited due to the small numbers of represented females with NDDs.…”

Intrinsic excitation-inhibition imbalance affects medial prefrontal cortex differently in autistic men versus women

“…Future work changing E:I balance in vMPFC may provide a useful avenue for ameliorating daily life social-communication adaptation and coping difficulties in autistic males and enable them to optimally engage in compensatory processes such as camouflaging to the similar extent as autistic females, despite the underlying potentially sex-differential neurobiological bases of autism. It may also be fruitful to examine how intact E:I balance in vMPFC of females may be an expression of protective factors that are hypothesized to buffer risk for autism in females 48,49 .…”