Rare De Novo and Common Variations Affect Liability to Autism

Background: Early researchers hypothesized that Autism Spectrum Disorder (ASD) arises from polygenic inheritance. Subsequent results, however, such as the identification of mutations in certain genes that are responsible for syndromes associated with ASD, led others to propose that rare variants and de novo mutations of major effect would account for most cases. There is now ample evidence that both rare de novo and inherited variation play a role in risk for ASD. It is also well documented that common variation plays a substantial role in liability. How these two forces combine to determine liability in any particular individual is not yet well understood.

Objectives: I will discuss the current state of understanding of the interplay of rare and common variation.

Methods: We will integrate data and results from whole exome and genome wide association studies (GWAS), as well as a family studies, to describe statistically the relationship between rare and common variation and their relationship to heritability.

Results: While rare variation confers risk, both rare de novo and inherited variation acts within the context of a common-variant genetic load, and this load accounts for the largest portion of ASD liability. Even among individuals who carry rare highly damaging variants, there is often evidence for substantial common risk variation, a result that is contrary to popular beliefs.

Conclusions: “Although clinical geneticists have told parents for years that a certain mutation found in the DNA of their offspring was likely the cause of ASD, we can no longer ignore some elephants in the room: for the typical person with ASD, their genetic load of common variation accounts for a substantial portion of their liability, and even for individuals known to carry a damaging mutation associated with ASD, the load of common variants they carry appears to be high. We need a way to accurately quantify this load, because this information will be useful for clinical geneticists who offer advice about recurrence risk to families.” (Chaste et al., 2017, Annu Rev Genomics Hum Genet).