Investigations into the genetic basis of autism spectrum disorder (ASD) have focused on the opposite extremes of rare de novo mutations and common polygenic risk. A portion of the unexplained genetic risk for ASD lies between these extremes and could consist of rare inherited variants with moderate-to-large effects. Recent studies have demonstrated that rare inherited coding and cis-regulatory variants contribute to ASD susceptibility. The segregation of rare variants in families is consistent with complex genetic inheritance in which both fathers and mothers carry a substantial proportion of risk. However, mechanisms of complex genetic inheritance are not well understood.

Jonathan Sebat and his laboratory at University of California, San Diego (UCSD) are investigating the nature of complex genetic inheritance by assembling a large combined data set of whole-exome sequencing and genome-wide genotyping data from more than 9,000 affected individuals and 7,000 non-affected family members from SPARK, the Simons Simplex Collection (SSC) and ongoing genome sequencing studies at UCSD. Within the combined data, they are defining distinct components of the genetic architecture of ASD, including de novo mutations, rare inherited variants and polygenic risk scores, and determining the joint contributions of multiple rare variants and polygenic risk in families. Sebat’s team is also investigating the influence of inherited genetic risk on neuropsychiatric traits in affected individuals and their parents. Lastly, functional characteristics of inherited risk are being compared to that of known ASD genes to determine if inherited risk is driven by distinct time periods in development.

By finding direct evidence of a multifactorial etiology in ASD families, Sebat aims to elucidate specific mechanisms of complex genetic inheritance and to expand knowledge of the genes and regulatory elements that control neurodevelopment and influence human social behavior.