Can the "female protective effect" liability threshold model explain sex differences in autism spectrum disorder?

TitleCan the "female protective effect" liability threshold model explain sex differences in autism spectrum disorder?
Publication TypeJournal Article
Year of Publication2022
AuthorsDougherty JD, Marrus N, Maloney SE, Yip B, Sandin S, Turner TN, Selmanovic D, Kroll KL, Gutmann DH, Constantino JN, Weiss LA
JournalNeuron
Volume110
Pagination3243-3262
Date Published10
ISSN1097-4199
AbstractMale sex is a strong risk factor for autism spectrum disorder (ASD). The leading theory for a "female protective effect" (FPE) envisions males and females have "differing thresholds" under a "liability threshold model" (DT-LTM). Specifically, this model posits that females require either a greater number or larger magnitude of risk factors (i.e., greater liability) to manifest ASD, which is supported by the finding that a greater proportion of females with ASD have highly penetrant genetic mutations. Herein, we derive testable hypotheses from the DT-LTM for ASD, investigating heritability, familial recurrence, correlation between ASD penetrance and sex ratio, population traits, clinical features, the stability of the sex ratio across diagnostic changes, and highlight other key prerequisites. Our findings reveal that several key predictions of the DT-LTM are not supported by current data, requiring us to establish a different conceptual framework for evaluating alternate models that explain sex differences in ASD.
DOI10.1016/j.neuron.2022.06.020