How rare and common risk variation jointly affect liability for autism spectrum disorder

Background: Genetic studies have implicated rare and common variation in liability for autism spectrum disorder (ASD). Of the discovered risk variants, those rare in the population invariably have large impact on liability, while common variants have small effects. Yet, collectively, common risk variants account for the majority of population-level variability. How these rare and common risk variants jointly affect liability for individuals requires further study. Methods: To explore how common and rare variants jointly affect liability, we assessed two cohorts of ASD families characterized for rare and common genetic variation (Simons Simplex Collection and Population-Based Autism Genetics & Environment Study). We analyzed data from 3,011 affected subjects, as well as two cohorts of unaffected individuals characterized for common genetic variation: 3,011 subjects matched for ancestry to ASD subjects; and 11,950 subjects for estimating allele frequencies. We used genetic scores, which assessed the relative burden of common genetic variation affecting risk for ASD (henceforth burden), and determined how this burden was distributed among three subpopulations: ASD subjects who carry a rare damaging variant implicated in risk for ASD (mutation carriers); ASD subjects who do not (non-carriers); and unaffected subjects, who are assumed to be non-carriers. Results: Burden harbored by ASD subjects is stochastically greater than that harbored by control subjects. For mutation carriers, their average burden is intermediate between non-carrier ASD and control subjects. Both carrier and non-carrier ASD subjects have greater burden, on average, than control subjects. The effects of common and rare variants likely combine additively to determine individual-level liability. Limitations: Only 258 ASD subjects were known mutation carriers. This relatively small subpopulation limits this study to characterizing general patterns of burden, as opposed to effects of specific mutations or genes. Also, a small fraction of subjects that are categorized as non-carriers could be mutation carriers. Conclusions: Liability arising from common and rare risk variation likely combine additively to determine risk for any individual diagnosed with ASD. On average, ASD subjects carry a substantial burden of common risk variation, even if they also carry a rare mutation affecting risk.