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

PURPOSE: 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.

HIGHLIGHTS: * 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

SUMMARY: 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.

*Author(s): Shefali S. Verma, Harini V. Gudiseva, Venkata R.M. Chavali, Michael A. Hauser, Marylyn D. Ritchie, Joan M. O’Brien

Clinical Paper of the Month manager: Anthony Khawaja