A multi-cohort genome-wide association study in African ancestry individuals reveals risk loci for primary open-angle glaucoma.

Primary open-angle glaucoma (POAG), the leading cause of irreversible blindness worldwide, disproportionately affects individuals of African ancestry. We conducted a genome-wide association study (GWAS) for POAG in 11,275 individuals of African ancestry (6,003 cases; 5,272 controls). We detected 46 risk loci associated with POAG at genome-wide significance. Replication and post-GWAS analyses, including functionally informed fine-mapping, multiple trait co-localization, and in silico validation, implicated two previously undescribed variants (rs1666698 mapping to DBF4P2 ; rs34957764 mapping to ROCK1P1) and one previously associated variant (rs11824032 mapping to ARHGEF12) as likely causal. For individuals of African ancestry, a polygenic risk score (PRS) for POAG from our mega-analysis (African ancestry individuals) outperformed a PRS from summary statistics of a much larger GWAS derived from European ancestry individuals. This study quantifies the genetic architecture similarities and differences between African and non-African ancestry populations for this blinding disease. [Display omitted] • A comprehensive GWAS on African ancestry individuals with glaucoma was conducted • 46 risk loci significantly associated with glaucoma were detected • Variants in ROCK1P1 , ARHGEF12 , and DBF4P2 demonstrated likely causal pathophysiology • Polygenic risk scores derived from African ancestry individuals show enhanced strength Glaucoma represents a pressing public health need among African ancestry individuals. This study provides novel insight into the genetic architecture of glaucoma in this population by identifying gene variants with pathophysiological significance. [ABSTRACT FROM AUTHOR]