Forward and reverse genomic screens enhance the understanding of phenotypic variation in a large Chinese rhesus macaque cohort

Combining genotype and phenotype data promises to greatly increase the value of macaque as biomedical models for human disease. Here we launch the Macaque Biobank project by deeply sequencing 919 captive Chinese rhesus macaques (CRM) while assessing 52 phenotypic traits. Genomic analyses revealed CRMs exhibit 1.7-fold higher nucleotide diversity and significantly lower mutational load than their Indian counterparts. We identified hundreds of loss-of-function variants linked to human inherited disease and drug targets, and at least seven exert significant effects on phenotypes using forward genomic screens. Genome-wide association analyses revealed 30 independent loci associated with phenotypic variations. Using reverse genomic approaches, we identified DISC1 (p.Arg517Trp) as a genetic risk factor for neuropsychiatric disorders, with macaques carrying this deleterious allele exhibiting impairments in working memory and cortical architecture. This study demonstrates the potential of macaque cohorts for the investigation of genotype-phenotype relationships and exploring potential spontaneous models of human genetic disease.