Dr. Hyejung Won (Assistant Professor, Genetics) received a three-year grant from the Simons Foundation Autism Research Initiative 2022 Program:聽 Genomics of ASD: Pathways to Biological Convergence and Genetic Therapies.
Dr.聽Won鈥檚 project is titled 鈥淩eciprocal impacts of rate聽and聽common polygenic risk architecture for autism into biological measures鈥�.聽聽Project abstract:聽 Genetic architecture of autism spectrum disorder (ASD) shows that both rare聽and聽common variation contributes to the significant proportion of heritability. While these two sets of variation in the opposite allelic spectrum have been traditionally studied in separation, the fact that rare variants with a large effect size do not have a perfect penetrance raises the idea that rare variant effects need to be understood in the polygenic background. However, the interplay between common聽and聽rare variation in ASD has not been systematically interrogated. Here, we propose a novel experimental paradigm in which we can systematically investigate the convergent effects of rare聽and聽common non-coding variants (Aim 1), together with impact of rare variants on regulatory function of common variants (Aim 2: rare to common) as well as the functional impact of rare variants under polygenic background (Aim 3: common to rare) within human neuronal context. To test the rare variant impact on regulatory architecture of common variation, we will introduce ASD-associated GWAS variants into human neurons with rare ASD gene perturbations聽and聽measure their allelic regulatory activity using massively parallel reporter assays (MPRA). To test the impact of polygenic architecture on rare variant function, we will introduce rare ASD risk genes into human neurons with extreme polygenic risk scores (PRS). The observed interplay between common聽and聽rare variants will shape our view of how variants across allelic spectrum can be studied in a unified framework than separate entities.
Simons Foundation Award announcement