Rare and Common Genetic Variations Confer Liability for Autism Spectrum Disorder

Among scientists working in the field of autism spectrum disorder research, two models represent the most common understanding of the disorder’s genetic underpinnings: one posits that rare risk variants invariably have large impact on liability; the other emphasizes the major role played by common variations with small effects. On a population level, the common variation likely plays the dominant role in liability, but for an individual, a rare mutation potentially makes the greatest contribution to liability.

In a study published in Molecular Autism, investigators including first author Lambertus Klei, PhD (Research Scientist), Nadine Melhem, PhD (Associate Professor of Psychiatry), and corresponding author Bernie Devlin, PhD (Professor of Psychiatry and Clinical and Translational Science) from Pitt Psychiatry examined how common and rare variations combine, perhaps additively, to confer risk for autism. 

The study included 17,972 genetic samples from individuals of European descent, with approximately 17% of the individuals having been diagnosed with autism, and the remaining 83% not diagnosed with autism. The team analyzed both groups for rare and common genetic risk variants. They used genetic scores, which assessed the relative burden of common genetic variation affecting risk of autism, and determined how this burden was distributed among three subpopulations: subjects with autism who carry a potentially damaging variant implicated in risk for the disorder; subjects with autism who do not carry a potentially damaging variant; and unaffected subjects who are assumed to be non-carriers. The results of the analysis revealed that that rare and common risk variation combine additively in their effects on autism liability.

“Our results are intriguing, some of them complement the work of others, and yet I believe we have a long way to go before we completely understand how rare and common risk variation combine to affect liability for individuals diagnosed with autism and in the larger population,” said Dr. Devlin.

How Rare and Common Risk Variation Jointly Affect Liability for Autism Spectrum Disorder
Klei L, McClain LL, Mahjani B, Panayidou K, De Rubeis S, Grahnat ACS, Karlsson G, Lu Y, Melhem N, Xu X, Reichenberg A, Sandin S, Hultman CM, Buxbaum JD, Roeder K, Devlin B. 
Molecular Autism 12, 66 (2021) https://doi.org/10.1186/s13229-021-00466-2