Examining Sex Differences in Autism Heritability

Abstract

Importance: Autism spectrum disorder (ASD) is a neurodevelopmental disorder more prevalent in males than in females. The cause of ASD is largely genetic, but the association of genetics with the skewed sex ratio is not yet understood. To our knowledge, no large population-based study has provided estimates of heritability by sex.

Objective: To estimate the sex-specific heritability of ASD.

Design, setting, and participants: This was a population-based, retrospective analysis using national health registers of nontwin siblings and cousins from Sweden born between January 1, 1985, and December 31, 1998, with follow-up to 19 years of age. Data analysis occurred from August 2022 to November 2023.

Main outcomes and measures: Models were fitted to estimate the relative variance in risk for ASD occurrence owing to sex-specific additive genetics, shared environmental effects, and a common residual term. The residual term conceptually captured other factors that promote individual behavioral variation (eg, maternal effects, de novo variants, rare genetic variants not additively inherited, or gene-environment interactions). Estimates were adjusted for differences in prevalence due to birth year and maternal and paternal age by sex.

Results: The sample included 1 047 649 individuals in 456 832 families (538 283 males [51.38%]; 509 366 females [48.62%]). Within the entire sample, 12 226 (1.17%) received a diagnosis of ASD, comprising 8128 (1.51%) males and 4098 (0.80%) females. ASD heritability was estimated at 87.0% (95% CI, 81.4%-92.6%) for males and 75.7% (95% CI, 68.4%-83.1%) for females with a difference in heritability estimated at 11.3% (95% CI, 1.0%-21.6%). There was no support for shared environmental contributions.

Conclusions and relevance: These findings suggest that the degree of phenotypic variation attributable to genetic differences (heritability) differs between males and females, indicating that some of the underlying causes of the condition may differ between the 2 sexes. The skewed sex ratio in ASD may be partly explained by differences in genetic variance between the sexes.

Figure 1.. Inverse Kaplan-Meier Curves Depicting Cumulative Probability of Autism Spectrum Disorder, Overall and by Sex and Birth Year

Kaplan-Meier curves based on incidence at 0, 5, 10, 15, and 19 years of age by sex (A) and by birth year (B).

Figure 2.. Possible Scenarios Under the Liability Threshold Model (LTM)

The LTM proposes that, for dichotomous traits (eg, ASD), there is an underlying continuous distribution of liability for that trait in a population, typically assumed to be Gaussian. If an individual’s liability (x-axis) exceeds a specific diagnostic threshold (represented by the black vertical solid line), the individual will be considered affected. The figures assume 1 single diagnostic threshold. Panel A illustrates the conventional assumption that males and females share the same liability distribution, with the same population mean and variance. In panel B, a female protective effect is illustrated, where males and females have the same distribution for ASD liability, but the male distribution is shifted toward the singular diagnostic threshold, resulting in more males than females exceeding the diagnostic threshold. Panel C shows the same mean for both sexes, suggesting no female protective effect (but instead males have a greater variance) resulting in more males than females exceeding the diagnostic threshold. In panel D, the liability distributions between males and females differ by their means and variances. The female mean is shifted toward the diagnostic threshold, but proportionally more males cross the liability threshold than females due to a greater variance. ASD indicates autism spectrum disorder.