, et al
Examining and interpreting the female protective effect against autistic behavior
Proc Natl Acad Sci USA.
; doi:

Investigators from multiple institutions in the United States, United Kingdom (UK), and Sweden investigated whether the male preponderance in autism spectrum disorders (ASDs) is due to male-specific risk factors or female protective effects (FPE). Study participants were part of 2 large population cohorts of twins, including dizygotic twin pairs from the Twins Early Development Study (TEDS) in the UK and the Child and Adolescent Twin Study of Sweden (CATSS). Children in the TEDS cohort were assessed for ASD at age 12 years using the Childhood Autism Spectrum test (CAST), which was completed by parents. For those in the CATSS cohort, parents completed the autism-tics, attention deficit-hyperactivity disorder and other comorbidities (A-TAC) inventory to assay for autistic traits when the participants were 9 and 12 years old. Participants who scored above the 90th percentile on either instrument were classified as autistic. The overall and sex- and zygosity-normalized scores of twin siblings of females and males classified with autism were compared. In addition, the relative risks (RRs) for being classified as autistic in the twin siblings of females or males with autism were assessed.

The TEDS cohort included 3,842 twin pairs and there were 6,040 twin pairs in the CATSS cohort. Overall the CAST and A-TAC scores of the siblings of female autistic children were significantly higher than scores for the siblings of male autistic participants (P < .0001). The autism screening test scores of siblings of female autistic participants also deviated more from their sex- and zygosity-normed means than those of siblings of male autistic children in both TEDS (P = .002) and CATSS (P = .02) cohorts. Furthermore, in both the CATSS and TEDS cohorts, siblings of female autistic subjects had increased risk of having a sibling above the cutoff value on the test (RR of 1.50 and 1.29 in TEDS and CATSS, respectively).

The authors conclude that females require greater familial/genetic etiological load to manifest autistic behavior and are thus protected from autistic impairments by their female sex.

Dr Hamid has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.

ASDs are nearly 4 times more common in males than in females. This has been hypothesized to be either due to a female sex-specific protective effect or a male sex-specific increased risk.2,3  However, definitive data to support either of these hypotheses has been lacking. In this elegant study the authors provide the strongest population-based evidence to date to suggest a female sex-specific protective effect.

A FPE model suggests that females would require a much higher etiological load (genetic or environmental) than males (who would lack this protective effect) to manifest ASDs. Or, stated conversely,...

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