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

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; Regeneron Genetics Center; Tyler G Kinzy; Sudha K Iyengar; Neal S Peachey; VA Million Veteran Program; 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

doi:10.1016/j.cell.2023.12.006

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

Cell. 2024 Jan 18;187(2):464-480.e10. doi: 10.1016/j.cell.2023.12.006.

Authors

Shefali S Verma¹, Harini V Gudiseva², Venkata R M Chavali², Rebecca J Salowe², Yuki Bradford³, Lindsay Guare³, Anastasia Lucas³, David W Collins², Vrathasha Vrathasha², Rohini M Nair², Sonika Rathi², Bingxin Zhao⁴, Jie He², Roy Lee², Selam Zenebe-Gete², Anita S Bowman², Caitlin P McHugh⁵, Michael C Zody⁵, Maxwell Pistilli², Naira Khachatryan², Ebenezer Daniel², Windell Murphy⁶, Jeffrey Henderer⁷; Regeneron Genetics Center⁸; Tyler G Kinzy⁹, Sudha K Iyengar⁹, Neal S Peachey¹⁰; VA Million Veteran Program; Kent D Taylor¹¹, Xiuqing Guo¹¹, Yii-Der Ida Chen¹¹, Linda Zangwill¹², Christopher Girkin¹³, Radha Ayyagari¹², Jeffrey Liebmann¹⁴, Chimd M Chuka-Okosa¹⁵, Susan E Williams¹⁶, Stephen Akafo¹⁷, Donald L Budenz¹⁸, Olusola O Olawoye¹⁹, Michele Ramsay²⁰, Adeyinka Ashaye¹⁹, Onoja M Akpa²¹, Tin Aung²², Janey L Wiggs²³, Ahmara G Ross², Qi N Cui², Victoria Addis², Amanda Lehman², Eydie Miller-Ellis², Prithvi S Sankar², Scott M Williams²⁴, Gui-Shuang Ying², Jessica Cooke Bailey²⁵, Jerome I Rotter¹¹, Robert Weinreb¹², Chiea Chuen Khor²⁶, Michael A Hauser²⁷, Marylyn D Ritchie³, Joan M O'Brien²⁸

Affiliations

¹ Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
² Scheie Eye Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
³ Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁴ Department of Statistics and Data Science, The Wharton School, University of Pennsylvania, Philadelphia, PA, USA.
⁵ New York Genome Center, New York, NY, USA.
⁶ Windell Murphy, MD, Philadelphia, PA, USA.
⁷ Department of Ophthalmology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA.
⁸ Tarrytown, NY, USA.
⁹ Department of Population and Quantitative Health Sciences, Cleveland Institute for Computational Biology, Case Western Reserve University, Cleveland, OH, USA; Louis Stokes Cleveland VA Medical Center, Cleveland, OH, USA.
¹⁰ Louis Stokes Cleveland VA Medical Center, Cleveland, OH, USA; Cole Eye Institute, Cleveland Clinic, Cleveland, OH, USA.
¹¹ Department of Pediatrics, The Institute for Translational Genomics and Population Sciences, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
¹² Viterbi Family Department of Ophthalmology, Shiley Eye Institute, University of California, San Diego, La Jolla, CA, USA.
¹³ Department of Ophthalmology and Visual Sciences, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
¹⁴ Department of Ophthalmology, Columbia University Medical Center, Columbia University, New York, NY, USA.
¹⁵ Department of Ophthalmology, University of Nigeria, Ituku, Nigeria.
¹⁶ Division of Ophthalmology, Department of Neurosciences, University of the Witwatersrand, Johannesburg, South Africa.
¹⁷ Unit of Ophthalmology, Department of Surgery, University of Ghana Medical School, Accra, Ghana.
¹⁸ Department of Ophthalmology, University of North Carolina, Chapel Hill, NC, USA.
¹⁹ Department of Ophthalmology, University of Ibadan, Ibadan, Nigeria.
²⁰ Sydney Brenner Institute for Molecular Bioscience, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
²¹ Department of Epidemiology and Medical Statistics, College of Medicine, University of Ibadan, Ibadan, Nigeria.
²² Singapore Eye Research Institute, Singapore, Singapore.
²³ Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA.
²⁴ Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA.
²⁵ Department of Population and Quantitative Health Sciences, Cleveland Institute for Computational Biology, Case Western Reserve University, Cleveland, OH, USA; Louis Stokes Cleveland VA Medical Center, Cleveland, OH, USA; Department of Pharmacology and Toxicology, Center for Health Disparities, Brody School of Medicine. East Carolina University, Greenville, NC, 27834, USA.
²⁶ Genome Institute of Singapore, Singapore, Singapore.
²⁷ Department of Medicine, Duke University, Durham, NC, USA.
²⁸ Scheie Eye Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Electronic address: joan.o'brien@pennmedicine.upenn.edu.

PMID: 38242088
DOI: 10.1016/j.cell.2023.12.006

Abstract

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.

Keywords: African ancestry; Black; genetic risk factors; genome-wide association study; glaucoma; health disparities; neurodegeneration; ophthalmology; optic nerve; primary open-angle glaucoma.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Black People / genetics
Genetic Predisposition to Disease
Genome-Wide Association Study*
Glaucoma, Open-Angle* / genetics
Humans
Polymorphism, Single Nucleotide / genetics

Abstract

Publication types

MeSH terms

Grants and funding