Common genetic variants, acting additively, are a major source of risk for autism

TLDR

Autism spectrum disorders are early‑onset neurodevelopmental syndromes marked by social, communicative, and repetitive‑behavior deficits, and while rare de‑novo variants are known contributors, the role of common genetic polymorphisms and environmental factors remains uncertain, especially across simplex and multiplex families. The study aims to quantify the proportion of ASD liability attributable to additive genetic effects (narrow‑sense heritability) and assess how this varies between simplex and multiplex families. Using quantitative genetics on genome‑wide common variants, the authors compare ASD cases to controls, evaluate additive model assumptions in relatives, and partition families by simplex/multiplex status to estimate heritability changes. They find that common variants explain over 60 % of liability in multiplex families and about 40 % in simplex families, with simplex data fitting additive models well, while multiplex data show slight deviations likely due to assortative mating, underscoring that many small‑effect common variants contribute to ASD risk.

Abstract

Abstract Background Autism spectrum disorders (ASD) are early onset neurodevelopmental syndromes typified by impairments in reciprocal social interaction and communication, accompanied by restricted and repetitive behaviors. While rare and especially de novo genetic variation are known to affect liability, whether common genetic polymorphism plays a substantial role is an open question and the relative contribution of genes and environment is contentious. It is probable that the relative contributions of rare and common variation, as well as environment, differs between ASD families having only a single affected individual (simplex) versus multiplex families who have two or more affected individuals. Methods By using quantitative genetics techniques and the contrast of ASD subjects to controls, we estimate what portion of liability can be explained by additive genetic effects, known as narrow-sense heritability. We evaluate relatives of ASD subjects using the same methods to evaluate the assumptions of the additive model and partition families by simplex/multiplex status to determine how heritability changes with status. Results By analyzing common variation throughout the genome, we show that common genetic polymorphism exerts substantial additive genetic effects on ASD liability and that simplex/multiplex family status has an impact on the identified composition of that risk. As a fraction of the total variation in liability, the estimated narrow-sense heritability exceeds 60% for ASD individuals from multiplex families and is approximately 40% for simplex families. By analyzing parents, unaffected siblings and alleles not transmitted from parents to their affected children, we conclude that the data for simplex ASD families follow the expectation for additive models closely. The data from multiplex families deviate somewhat from an additive model, possibly due to parental assortative mating. Conclusions Our results, when viewed in the context of results from genome-wide association studies, demonstrate that a myriad of common variants of very small effect impacts ASD liability.