Recurrence Rates for Autism in Multiplex Families and Twins Demonstrate Sex Differences in Familial Genetic Liability

Background:   Autism spectrum disorders (ASDs) are more prevalent in males, suggesting a multiple threshold model for ASD liability. This model states that females in the population are protected by sex-differential mechanisms, and that a greater genetic burden is required for females to manifest an ASD phenotype than for males. Under this model, autistic females’ siblings are also predicted to share this greater genetic liability, whereas the siblings of autistic males are predicted to share comparatively lesser genetic liability. However, ASD recurrence rates reported in the literature have not demonstrated a significantly increased risk to siblings of affected girls as compared with siblings of boys.

Objectives:   Previous studies of recurrence risk utilized population cohorts or infant siblings of children with ASD, samples that include a combination of families with simplex and multiplex genetic architecture. Since sporadic cases from simplex families are enriched for de novorisk variants that are unlikely to be shared with siblings, including these families is likely to obscure recurrence patterns. The purpose of this study is therefore to utilize a strictly multiplex family sample from the Autism Genetic Resource Exchange (AGRE) to determine if recurrence risk in these families follows predictions from a female protective model.

Methods:   We assess recurrence rates and associated quantitative traits in full siblings from 1,120 multiplex nuclear families and concordance rates in 305 twin pairs from AGRE. We compare recurrence rates and phenotypes between males and females overall, and between twin pairs or families with at least one affected female (female-containing, FC), versus those with only affected males (male-only, MO).

Results:   We observe a significantly higher recurrence rate in males than females, siblings of female than male probands, and higher concordance in FC than MO twin pairs. Recurrence rates approach 50%, consistent with a dominant inheritance pattern in high-risk families as has been proposed. We also find a significant negative relationship between interbirth interval and ASD recurrence that is driven by male children in MO families.

Conclusions:   By classifying families as MO or FC post hoc, using full pedigree information, we observe significant recurrence rate differences between families harboring sex-differential familial liability. However, recurrence rates near 50% for females from FC families and for males overall suggest that simply conceptualizing females’ genetic risk as quantitatively greater than males’ may be insufficient. Consideration of the robustness of female protective factors and/or the sex-differential penetrance of specific risk variants is necessary. Furthermore, the male-specific relationship between shorter interbirth intervals and increased ASD risk speaks to the higher genetic risk load in females and potentially more frequent contributions from environmental, including maternal, risk factors in males. Understanding the mechanisms driving these sex-differential risk profiles will be useful for treatment development and prevention.