Genetic evidence of gender difference in autism spectrum disorder supports the female-protective effect

Abstract

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with a male-to-female prevalence of 4:1. However, the genetic mechanisms underlying this gender difference remain unclear. Mutation burden analysis, a TADA model, and co-expression and functional network analyses were performed on de novo mutations (DNMs) and corresponding candidate genes. We found that the prevalence of putative functional DNMs (loss-of-function and predicted deleterious missense mutations) in females was significantly higher than that in males, suggesting that a higher genetic load was required in females to reach the threshold for a diagnosis. We then prioritized 174 candidate genes, including 60 shared genes, 91 male-specific genes, and 23 female-specific genes. All of the three subclasses of candidate genes were significantly more frequently co-expressed in female brains than male brains, suggesting that compensation effects of the deficiency of ASD candidate genes may be more likely in females. Nevertheless, the three subclasses of candidate genes were co-expressed with each other, suggesting a convergent functional network of male and female-specific genes. Our analysis of different aspects of genetic components provides suggestive evidence supporting the female-protective effect in ASD. Moreover, further study is needed to integrate neuronal and hormonal data to elucidate the underlying gender difference in ASD.

Perinatal Exposure to Diesel Exhaust-Origin Secondary Organic Aerosol Induces Autism-Like Behavior in Rats

“…Regarding ASD-related genes, we found Nlgn3 mRNA expression was significantly decreased in DE-SOA-exposed male rats, but not in the female rats in the present study. A recent report has indicated that developmental exposure to PM 2.5 caused autism-like behaviors, such as poor social interaction and repetitive behavior, accompanied by lower oxytocin receptor (OXTR) protein level, catalase activity, and glutathione (GSH) concentration, in 7-week-old male rats [ 59 ]. Different hormonal milieu, receptor type and function, and maturation of neural network may contribute the sex-specific effects in ASD.…”

Delineating the molecular and phenotypic spectrum of the SETD1B-related syndrome

“…However, ascertainment bias for the neurodevelopmental phenotype could also contribute to the male predominance. Nevertheless, it is tempting to speculate that sex-linked traits could affect susceptibility to clinical penetrance and spectrum of SETD1B variants, as female-protective effects have been proposed for other neurodevelopmental disorders 32,33 .…”

Challenged Motherhood: Mothers to Adult Daughters With Asperger Syndrome

“…The characteristics of AS are uniquely manifested in females, often resulting in difficulties in diagnosis. Females with AS are either diagnosed later in life or underdiagnosed (Milner et al, 2019;Sedgewick et al 2019), with a male to female early diagnosis ratio being 4:1 (Ferri et al, 2018;Lehnhardt, et al, 2016;Zhang et al, 2020 (Milner et al, 2019;Sedgewick et al, 2019), are able to engage in a reciprocal conversation, and have similar interest as their neurotypical (NT) peers (Milner et al, 2019). Moreover, females with AS were described as employing a strategy of 'camouflaging' in order to mask their autistic characteristics, consciously mimicking the behaviours of their NT peers (Cook et al, 2018;Milner et al, 2019;Sedgewick et al, 2019;Tharian et al, 2019).…”