Genomics of Autism in Latinx Ancestries

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Project Summary The genetic architecture of autism spectrum disorder (ASD) is complex and ongoing efforts to decipher it have focused on both common and rare genetic variants. Our investigative team has added significantly to current understanding of ASD genetic risk and to the functional impact of identified genes. Despite our large-scale genetic analyses, there remains a number of unanswered questions, one of which is whether its genetic architecture differs across ancestral populations. Notably, there has been no systematic effort to investigate this in Hispanic and Latina/Latino populations, the largest minority population in the United States (~60 million, 18% of the total population), and growing rapidly. Inclusion of under-represented populations in genetic studies is important both for scientific reasons and for parity. This proposal therefore encapsulates 2 NIMH priorities: we will investigate genetic risk for ASD in people of Hispanic/Latinx ancestry. To further our understanding of ASD in Hispanic/Latinx populations, we propose to: 1) recruit, phenotype and sample at least 1,600 additional Hispanic/Latinx ASD trios, thereby expanding our existing sample set of well-characterized Hispanic/Latinx ASD samples; 2) genotype and sequence all samples in the cohort and combine results with the Autism Sequencing Consortium and the Psychiatric Genomics Consortium, large-scale efforts on rare and common genetic variation, respectively; 3) analyze common genetic variation in the cohort using cross-ancestry genome-wide association studies (GWAS), develop ancestry-informed polygenic risk scores, and contribute to fine-mapping and colocalization of top GWAS findings; and, 4) carry out genetic association studies for rare genetic variants in the cohort, taking special care to account for ancestry, especially for rare inherited variation. At the successful conclusion of the proposed studies, we will have four important results: a deeper understanding of how rare and common variation contribute to risk for ASD across ancestries; enhanced fine-mapping of ASD GWAS loci; better, more portable PRS for diverse ancestries; and a larger number of known ASD risk genes. In addition, we will have contributed to improving methods for integrating samples of diverse ancestry in genomic studies and will have enhanced recruitment of under-represented populations in such studies.