Autism Genetics Phase II: Increasing Representation of Human Diversity

Abstract Autism Spectrum Disorder (ASD) is a common neurodevelopmental disorder whose genetic contributions are increasingly recognized. However, the vast majority of genetic research and discovery has occurred in populations of European (EU) origin, significantly underrepresenting communities of color and those of self- described African American (AA) ancestry. This disparity in genetics research, coupled with disparities in diagnosis and treatment, motivated the investigators in this Network to take a major new direction in their research, embarking on what has been a unique and highly successful recruitment of AA families with ASD (AA-ASD) into gene discovery research at multiple sites, conducted phenotyping—including information of critical relevance to the elucidation of race-based health disparities—while commencing genetic analysis to identify ASD susceptibility genes. Via this collaborative effort, we aim to fill significant gaps in ASD research by continuing to recruit and perform genetic research in this important population that has not previously been well represented in ASD genetics research. Our Network involves seven research sites and a DCC, collaborating in a systematic investigation of ASD genetics in order to identify rare mutations, chromosomal abnormalities, and common variation contributing to ASD susceptibility in the AA population, while leveraging this unique opportunity to understand and potentially remediate health disparities. Specifically, we will enrich existing resources by recruiting at least 720 AA probands and additional family members to ascertain a cohort of at least 2000 probands in total. Our recruitment plan includes an embedded health disparities project that continues to evaluate access and quality of care for AAs with ASD while increasing participation of AA individuals in genetic research. We will conduct whole-genome sequencing (WGS), which permits comprehensive investigation of genome-wide structural variation (SV) and coding and non-coding sequence variation (SNV) in ASD. We will employ novel methods to define the ancestral origin of specific chromosomal segments and ascertain the background on which susceptibility alleles occur and relate these features to quantitative phenotypes. In parallel, gene expression profiling and network analysis will be used to prioritize variants. Genetic risk factors identified in the mostly EU samples will be tested for association in the AA sample to determine whether these cohorts share the same genetic risk factors, using a sample size providing power to replicate previous associations and to identify rare, recurrent CNV and SNV. We will use local ancestry to boost power of polygenic risk scores derived from EU cohorts. The observation of new forms or different population frequencies of ASD-related variation in this sample as well as the sharing of most CNV and SNV with other cohorts are both outcomes that will have great significance for future studies and for clinical care. As has been our practice, our Network will make all phenotypic and genotype data accessible via the internet on a rolling basis, further enhancing the value of this resource to the community.