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

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

doi:10.1016/j.neuron.2022.06.020

Cited by 27 publications

(21 citation statements)

References 137 publications

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“…Previous heritability estimates are based on statistical models where equal variances for males and females are assumed, resulting in equal heritability, and where sex is included as a fixed factor to adjust for differences in prevalence (Figure 1B). Such models agree with the theory of female protective effect (FPE), where females require a higher genetic threshold to be diagnosed with ASD, resulting in a lower prevalence compared with males. However, existing research shows mixed support for the FPE model .…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, a model allowing for sex-specific heritability offers an alternative explanation of the difference in ASD prevalence . If males are more vulnerable to additive genetic risk, this model would be consistent with the GVM, and other models proposing an interaction between sex and genetic risk . The 2 theories of FPE and GVM are, however, not mutually exclusive and could coexist (Figure 2D).…”

Section: Discussionmentioning

confidence: 99%

“…In addition, ASD diagnoses may be confounded by sex and temporal trends. This is possible given that the norms in diagnostic procedures and societal changes across time may have affected males and females differently, even though the sex ratio has remained stable . To address this, we included fixed parameters not only for sex and birth year, but also for their interactions.…”

Section: Discussionmentioning

confidence: 99%

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Examining Sex Differences in Autism Heritability

Sandin,

Yip,

Yin

et al. 2024

JAMA Psychiatry

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ImportanceAutism 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.ObjectiveTo estimate the sex-specific heritability of ASD.Design, Setting, and ParticipantsThis 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 MeasuresModels 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.ResultsThe 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 RelevanceThese 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.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Examining Sex Differences in Autism Heritability

Sandin,

Yip,

Yin

et al. 2024

JAMA Psychiatry

Self Cite

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“…In summary, the mechanisms underlying why females are more tolerant of ASD’s genetic risk remain unclear. We need a new conceptual framework to understand the complex factors that contribute to ASD risk, and large-scale studies analyzing brain development and function at a molecular level can help uncover the mechanisms behind male–female differences in ASD ( 3 , 52 ).…”

Section: Discussionmentioning

confidence: 99%

Interactions of genetic risks for autism and the broad autism phenotypes

et al. 2023

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BackgroundCommon polygenic risk and de novo variants (DNVs) capture a small proportion of autism spectrum disorder (ASD) liability, and ASD phenotypic heterogeneity remains difficult to explain. Integrating multiple genetic factors contribute to clarifying the risk and clinical presentation of ASD.MethodsIn our study, we investigated the individual and combined effects of polygenic risk, damaging DNVs (including those in ASD risk genes), and sex among 2,591 ASD simplex families in the Simons Simplex Collection. We also explored the interactions among these factors, along with the broad autism phenotypes of ASD probands and their unaffected siblings. Finally, we combined the effects of polygenic risk, damaging DNVs in ASD risk genes, and sex to explain the total liability of ASD phenotypic spectrum.ResultsOur findings revealed that both polygenic risk and damaging DNVs contribute to an increased risk for ASD, with females exhibiting higher genetic burdens than males. ASD probands that carry damaging DNVs in ASD risk genes showed reduced polygenic risk. The effects of polygenic risk and damaging DNVs on autism broad phenotypes were inconsistent; probands with higher polygenic risk exhibited improvement in some behaviors, such as adaptive/cognitive behaviors, while those with damaging DNVs exhibited more severe phenotypes. Siblings with higher polygenic risk and damaging DNVs tended to have higher scores on broader autism phenotypes. Females exhibited more severe cognitive and behavioral problems compared to males among both ASD probands and siblings. The combination of polygenic risk, damaging DNVs in ASD risk genes, and sex explained 1–4% of the total liability of adaptive/cognitive behavior measurements.ConclusionOur study revealed that the risk for ASD and the autism broad phenotypes likely arises from a combination of common polygenic risk, damaging DNVs (including those in ASD risk genes), and sex.

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“…This sex bias is less pronounced when autism is accompanied by cognitive impairment or motor developmental delay. 4,5 The genetics of autism includes both rare and common variants. [6][7][8] The collective effect of the different genetic factors predisposing to autism on the trait prevalence is typically studied using the Liability Threshold Model.…”

Section: Introductionmentioning

confidence: 99%

Contribution of autosomal rare andde novovariants to sex differences in autism

Koko,

Satterstrom,

Warrier

et al. 2024

Preprint

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Autism is four times more prevalent in males than females. To study whether this reflects a difference in genetic predisposition attributed to autosomal rare variants, we evaluated the sex differences in effect size of damaging protein-truncating and missense variants on autism predisposition in 47,061 autistic individuals, then compared effect sizes between individuals with and without cognitive impairment or motor delay. Although these variants mediated differential likelihood of autism with versus without motor or cognitive impairment, their effect sizes on the liability scale did not differ significantly by sex exome-wide or in genes sex-differentially expressed in the cortex. Although de novo mutations were enriched in genes with male-biased expression in the fetal cortex, the liability they conferred did not differ significantly from other genes with similar loss-of-function intolerance and sex-averaged cortical expression. In summary, autosomal rare coding variants confer similar liability for autism in females and males.

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

Cited by 27 publications

References 137 publications

Examining Sex Differences in Autism Heritability

Examining Sex Differences in Autism Heritability

Interactions of genetic risks for autism and the broad autism phenotypes

Contribution of autosomal rare andde novovariants to sex differences in autism

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