Project Summary We propose a 5-year renewal of our African Ancestry-Genomic Psychiatry Cohort (AA-GPC) R01- MH104964. AA and other minority populations have been poorly represented in large-scale genomic studies, and yet these populations (i) have the largest disparities in health care and outcomes, and (ii) have the potential to broaden our knowledge of human genetics. In particular, AA genomes have nearly a million more variants per individual and are characterized by shorter haplotype blocks than European ancestry (EA) populations. As a consequence, genetic polymorphisms that are in perfect linkage disequilibrium (LD) in Europeans are broken-up by recombination events in AA genomes, allowing the contributions of smaller genomic intervals comprised of fewer variants to be assessed independently. Progress to date: During the initial funding period we will have enrolled and assessed ~10,000 new AA participants and have already completed 8,000 AA whole genome sequences (WGS). We recently demonstrated that among the 128 associated SNPs identified in the PGC-2 schizophrenia analysis, 41 increased in significance when combined with data from 10,000 AA-GPC participants, and for 12 of these regions, there was a reduction in the number of SNPs in the associated interval. In addition, this trans-ancestry meta-analysis of PGC-2 schizophrenia and AA-GPC results yielded 10 newly genome-wide significant loci. Similarly, the trans-ancestry meta-analysis results yielded the best polygenic risk score “training” dataset, explaining more variance in individuals of European and African ancestry, than scores based on either ancestry alone. In Phase 1 of this renewal: we will study genome-wide common variation in our existing AA-GPC and VA-CS#572 combined cohort of 36,322 AA participants. In Phase 2, we will perform an expanded analysis by adding 5,000 new participants ascertained in this project, 27,500 additional controls from the VA, and 34,000 cases and controls from the NeuroGap-Psychosis study (NeuroPsychiatric Genetics in African Populations; PI. Koenen). This meta-analysis will include over 100,000 AA participants, a sample of non-Caucasians with the potential for significant novel discovery.

Project Narrative African Ancestry and other minority populations have been poorly represented in large-scale genomic studies, and yet these populations have the largest disparities in health care and outcomes and have the potential to broaden our knowledge of human genetics. The African Ancestry-Genomic Psychiatry Cohort (AA-GPC) will combine the African Ancestry (AA) participants in this study, the VA-CSP study, and the NeuroGap-Psychosis study creating a study population over 100,000 AA participants. This analysis has the potential for significant novel discovery.