Examining and interpreting the female protective effect against autistic behavior

Abstract

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. If females are protected, they should require greater etiologic load to manifest the same degree of impairment as males. The objective of this analysis was to examine whether greater familial etiologic load was associated with quantitative autistic impairments in females compared with males. Subjects included 3,842 dizygotic twin pairs from the Twins Early Development Study (TEDS) and 6,040 dizygotic twin pairs from the Child and Adolescent Twin Study of Sweden (CATSS). In both samples, we compared sibling autistic traits between female and male probands, who were identified as children scoring in the top 90th and 95th percentiles of the population autistic trait distributions. In both TEDS and CATSS, siblings of female probands above the 90th percentile had significantly more autistic impairments than the siblings of male probands above the 90th percentile. The siblings of female probands above the 90th percentile also had greater categorical recurrence risk in both TEDS and CATSS. Results were similar in probands above the 95th percentile. This finding, replicated across two nationally-representative samples, suggests that female sex protects girls from autistic impairments and that girls may require greater familial etiologic load to manifest the phenotype. It provides empirical support for the hypothesis of a female protective effect against autistic behavior and can be used to inform and interpret future gene finding efforts in autism spectrum disorders.

Fig. 1.

Increase in risk to siblings of female probands above the 90th percentile. Probands were 34.2% female in TEDS and 32.9% female in CATSS. Error bars indicate 95% confidence interval around group mean. P values indicate the multiple-testing–corrected strength of the difference between the group mean noted in the cell and the group mean in one or more of the cohort-specific rows below, indicated by the symbols (*, comparison with male probands; §, comparison with female probands). For example, “0.42 (p=0.002 §)” indicates that, in the TEDS cohort, the P value for the difference in means between the siblings of male (0.42) and female (0.78) probands was 0.002.