Genomics of Autism in Latinx Ancestries

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.

Grant Number: 5R01MH128813-04
NIH Institute/Center: NIH
Principal Investigator: Joseph Buxbaum