A neurogenetic analysis of female autism

Abstract

Females versus males are less frequently diagnosed with autism spectrum disorder (ASD), and while understanding sex differences is critical to delineating the systems biology of the condition, female ASD is understudied. We integrated functional MRI and genetic data in a sex-balanced sample of ASD and typically developing youth (8–17 years old) to characterize female-specific pathways of ASD risk. Our primary objectives were to: (i) characterize female ASD (n = 45) brain response to human motion, relative to matched typically developing female youth (n = 45); and (ii) evaluate whether genetic data could provide further insight into the potential relevance of these brain functional differences. For our first objective we found that ASD females showed markedly reduced response versus typically developing females, particularly in sensorimotor, striatal, and frontal regions. This difference between ASD and typically developing females does not resemble differences between ASD (n = 47) and typically developing males (n = 47), even though neural response did not significantly differ between female and male ASD. For our second objective, we found that ASD females (n = 61), versus males (n = 66), showed larger median size of rare copy number variants containing gene(s) expressed in early life (10 postconceptual weeks to 2 years) in regions implicated by the typically developing female > female functional MRI contrast. Post hoc analyses suggested this difference was primarily driven by copy number variants containing gene(s) expressed in striatum. This striatal finding was reproducible among n = 2075 probands (291 female) from an independent cohort. Together, our findings suggest that striatal impacts may contribute to pathways of risk in female ASD and advocate caution in drawing conclusions regarding female ASD based on male-predominant cohorts.

Signaling Pathways and Sex Differential Processes in Autism Spectrum Disorder

“…This intriguing finding suggests that factors downstream of ASD risk genes likely interact with sex-differential processes to contribute to the sex bias in ASD. Second, a recent imaging genomics study from our group found that females with ASD show decreased activation of sensorimotor, striatal, and frontal brain regions in response to biological motion and have larger rare, genic CNVs containing genes expressed in these brain regions, particularly the striatum (54). In addition to finding a novel convergence in genetics and imaging data, this study further indicates that brain regions responsible for differences in the perception of social stimuli in typically developing females and males may also contribute to the female protective effect in ASD (54).…”

“…Second, a recent imaging genomics study from our group found that females with ASD show decreased activation of sensorimotor, striatal, and frontal brain regions in response to biological motion and have larger rare, genic CNVs containing genes expressed in these brain regions, particularly the striatum (54). In addition to finding a novel convergence in genetics and imaging data, this study further indicates that brain regions responsible for differences in the perception of social stimuli in typically developing females and males may also contribute to the female protective effect in ASD (54). Third, consistent with the "extreme male brain" theory, studies of prenatal exposure to sex steroid hormones in humans indicate that increased steroidogenic activity might be associated with increased ASD risk (60,61) [reviewed in (7,47)].…”

“…Imaging genomics is a cutting-edge approach to integrate neuroimaging and genomic data from individuals with ASD to gain a greater understanding of interactions between neural circuit and genetic mechanisms in ASD. Our group conducted an imaging-genomics analysis to characterize the female neural profile in ASD, which, in turn, could provide insights into potential female protective factors (54). To accomplish this, we integrated task-based functional MRI (fMRI) data obtained in response to point-light displays of whole-body human motion, a well-established measure of social perception (55), and genetic data regarding median size of rare, genic CNVs (i.e., those containing one or more genes) as a measure of mutation severity, in a sex-balanced cohort of ASD and typically-developing youth (8-17 years-old; total imaging n = 184, males = 94, females = 90).…”

The Diagnosis and Management of Autism Spectrum Disorder (ASD) in Adult Females in the Presence or Absence of an Intellectual Disability

“…This is supported by the fact that males, in general, have less spontaneous mutations associated with autism compared to females [22,23]. Autistic females also carry a larger size of rare copy number variations, containing genes that are expressed in the early development of the striatum [24].…”

Sex differences in age of diagnosis of autism spectrum disorder: Preliminary evidence from Uganda

“…Nonetheless, males are more likely to receive ASD diagnosis earlier than females (Halladay et al, 2015; Jamison et al, 2017). While the cause of this remains unclear (Constantino, 2017), some investigators have argued that molecular pathways that control sexual dimorphic brain development may be important targets for further investigation (Jack et al, 2021). It has also been suggested that the perception and interpretation of female social behavior could partially explain why females are diagnosed later and at lower rates than males (Jamison et al, 2017).…”