The Contribution of Autism-Related Common Variants to the Familial Aggregation of Quantitative Autistic Traits

Abstract

\n Background: Autism spectrum disorder (ASD) polygenic risk scores (PRS), derived from genome-wide association studies (GWAS), have been employed to predict ASD diagnosis in the general population (Nagelkerke’s R2=2.45%). Critically, large genetic epidemiological studies have demonstrated that family members of affected individuals exhibit subclinical quantitative autistic traits (QAT), suggesting that diagnosed ASD is the pathological tail of a continuous distribution of QAT. Recent molecular genetic studies have reinforced these findings by uncovering a genetic correlation between ASD and QAT in the general population, emphasizing the importance of employing QAT in GWAS. Yet no study to date has examined the extent to which aggregated effects of common variants contributes to variance in QAT in a familial multiplex sample—one enriched for inherited ASD risk.Methods: Given the elevation of QAT among unaffected members in multiplex families, we examined the contribution of ASD-PRS to QAT, as measured by the Social Responsiveness Scale (SRS), in 1491 subjects from multiplex families in the Autism Genetic Resource Exchange (AGRE)—with (N=538) and without (N=921) an ASD diagnosis. Using the iPSYCH-ASD-GWAS as our discovery dataset, comprised of cases (N=8,605) and controls (N=19,526), we estimated how much variance in QAT that the ASD-PRS explained in our target dataset, AGRE. We also examined if there were interaction effects of diagnosis and sex.Results: The ASD-PRS explained 0.34% of the variance in QAT (p=0.017). There was no significant interaction effect of disorder status (p=0.511), but there was a significant interaction of sex (p=0.027) and a significant interaction effect of ASD and sex (p=0.031).Limitations: The primary limitation of this study is the small size of the discovery GWAS (iPSYCH).Conclusions: Our results reveal that autism-related polygenic load, as measured via the ASD-PRS, significantly predicts QAT—critically, in both affected and unaffected family members. Further, the association of ASD-PRS with QAT in females was modified by diagnosis, indicating that this relationship was the strongest among affected females.The unique nature of this study’s multiplex familial sample enables a novel demonstration that common polygenic variation in ASD contributes to familial QAT, particularly among affected females.