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

• DOI: 10.1016/j.cell.2023.12.006
• Publication Date: 2024-01-18T15:35:52Z
• Authors: Shefali S. Verma; Harini V. Gudiseva; Venkata R.M. Chavali; Rebecca J. Salowe; Yuki Bradford; Lindsay Guare; Anastasia Lucas; David W. Collins; Vrathasha Vrathasha; Rohini M. Nair; Sonika Rathi; Bingxin Zhao; Jie He; Roy Lee; Selam Zenebe-Gete; Anita S. Bowman; Caitlin P. McHugh; Michael C. Zody; Maxwell Pistilli; Naira Khachatryan; Ebenezer Daniel; Windell Murphy; Jeffrey Henderer; Tyler G. Kinzy; Sudha K. Iyengar; Neal S. Peachey; Kent D. Taylor; Xiuqing Guo; Yii-Der Ida Chen; Linda Zangwill; Christopher Girkin; Radha Ayyagari; Jeffrey Liebmann; Chimd M. Chuka-Okosa; Susan E. Williams; Stephen Akafo; Donald L. Budenz; Olusola O. Olawoye; Michele Ramsay; Adeyinka Ashaye; Onoja M. Akpa; Tin Aung; Janey L. Wiggs; Ahmara G. Ross; Qi N. Cui; Victoria Addis; Amanda Lehman; Eydie Miller-Ellis; Prithvi S. Sankar; Scott M. Williams; Gui-shuang Ying; Jessica Cooke Bailey; Jerome I. Rotter; Robert Weinreb; Chiea Chuen Khor; Michael A. Hauser; Marylyn D. Ritchie; Joan M. O’Brien
• Keywords: Genome-wide Association Study; Genetic Association; Genetic genealogy; Genetic architecture

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.