The Female Protective Effect Against Autistic Behavior: Evidence From Two Nationally-Representative Samples

Background:  Male preponderance in autistic behavioral impairment has been explained in terms of a hypothetical protective effect of female sex, yet little research has tested this hypothesis empirically. Autistic behaviors are highly familial. If more risk factors are required to produce autistic impairments in girls, the family members of affected females should, on average, carry more risk factors than the family members of affected males. In other words, the female protective effect hypothesis predicts that family members of female probands with autistic impairments should have higher autistic trait scores than the family members of male probands.

Objectives: The objective of this analysis was to conduct the first test the female protective effect hypothesis in the general population, using quantitative indicators of autistic impairment in two nationally-representative samples. 

Methods: We analyzed data from 3,842 12-year-old dizygotic twin pairs in the Twins Early Development Study (TEDS) and 6,040 9- and 12-year-old dizygotic twin pairs in the Child and Adolescent Twin Study of Sweden (CATSS). Autistic behaviors were measured using the Child Autism Spectrum Test in TEDS (CAST) and the Autism—Tics, ADHD and other comorbidities inventory (A-TAC) in CATSS. To include an adequate number of affected females for statistical comparison, probands were identified as individuals scoring in the top 10% of the overall population distributions of the CAST or A-TAC. We compared sibling autistic impairment between male and female probands.  

Results: In both TEDS and CATSS, siblings of female probands had significantly greater aggregation of autistic impairments than the siblings of male probands. Combining the cohorts, the average autistic trait scores of siblings of female and male probands were 0.64 and 0.37 standard deviations above the mean, respectively (p< .0001). The siblings of female probands also had greater risk of being in the top 10% themselves in both TEDS and CATSS (combined cohort risk ratio: 1.38, 95% confidence interval 1.11-1.72).

Conclusions: This study provides the first population-based evidence that familial etiologic factors relevant to autism are likely more concentrated in females that manifest the phenotype. This finding suggests that there is a component of female sex that protects girls from ASDs and requires that a greater number of risk factors be present for girls to show autistic behavioral impairment. An understanding of the biology underlying female advantage could greatly aid progress in identifying both causes and prevention factors for ASDs.