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

Joseph D. Dougherty, Natasha Marrus, Susan E. Maloney, Benjamin Yip, Sven Sandin, Tychele N. Turner, Din Selmanovic, Kristen L. Kroll, David H. Gutmann, John N. Constantino, Lauren A. Weiss

Research output: Contribution to journalReview articlepeer-review

Abstract

Male 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.

Original languageEnglish
Pages (from-to)3243-3262
Number of pages20
JournalNeuron
Volume110
Issue number20
DOIs
StatePublished - 19 Oct 2022
Externally publishedYes

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