The genetic architecture of autism spectrum disorder (ASD) includes rare protein-truncating variants with large effect sizes as well as common variation conferring much smaller effect sizes. In the past, these two types of variants were studied separately, but growing evidence supports that they additively contribute to ASD risk and are most appropriately studied together.

Hyejung Won, Kristen Brennand and Nan Yang have devised a new way to study the relationship between these rare and common variations. Together, the team plans to use neural cells derived from human-induced pluripotent stem cells (hiPSCs) to investigate how distinct variations interact with each other.

Noncoding variants, whether rare or common, contribute to a substantial proportion of the genetic architecture of ASD risk yet are poorly characterized. Thus, the team plans to first comprehensively catalog the effects of noncoding variations on the regulation of genes in human neurons. They will then contrast the regulatory activity of ASD-associated noncoding variants in human neurons with and without rare protein-truncating variants, to determine if there is an additive effect of rare mutations on the regulatory architecture of common variation.

Through this research, the team hopes to (1) find specific genetic changes that are linked to the risk of developing ASD, (2) better understand how rare and common variations interact to contribute to this risk and (3) identify new targets for future treatments.