• Genetics of Glaucoma in People of African Descent (GGLAD) Consortium, Michael A Hauser, R Rand Allingham, Tin Aung, Carly J Van Der Heide, Kent D Taylor, Jerome I Rotter, Shih-Hsiu J Wang, Pieter W M Bonnemaijer, Susan E Williams, Sadiq M Abdullahi, Khaled K Abu-Amero, Michael G Anderson, Stephen Akafo, Mahmoud B Alhassan, Ifeoma Asimadu, Radha Ayyagari, Saydou Bakayoko, Prisca Biangoup Nyamsi, Donald W Bowden, William C Bromley, Donald L Budenz, Trevor R Carmichael, Pratap Challa, ChenYii-Der IdaYIThe Institute for Translational Genomics and Population Sciences, Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California.Department of Pediatrics, Harbor-University of Calif, Chimdi M Chuka-Okosa, Jessica N Cooke Bailey, Vital Paulino Costa, Dianne A Cruz, Harvey DuBiner, John F Ervin, Robert M Feldman, Miles Flamme-Wiese, Douglas E Gaasterland, Sarah J Garnai, Christopher A Girkin, Nouhoum Guirou, Xiuqing Guo, Jonathan L Haines, Christopher J Hammond, Leon Herndon, Thomas J Hoffmann, Christine M Hulette, Abba Hydara, Robert P Igo, Eric Jorgenson, Joyce Kabwe, Ngoy Janvier Kilangalanga, Nkiru Kizor-Akaraiwe, Rachel W Kuchtey, Hasnaa Lamari, Zheng Li, Jeffrey M Liebmann, Yutao Liu, LoosRuth J FRJFThe Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York.The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York., Monica B Melo, Sayoko E Moroi, Joseph M Msosa, Robert F Mullins, Girish Nadkarni, Abdoulaye Napo, Maggie C Y Ng, Hugo Freire Nunes, Ebenezer Obeng-Nyarkoh, Anthony Okeke, Suhanya Okeke, Olusegun Olaniyi, Olusola Olawoye, Mariana Borges Oliveira, Louise R Pasquale, Rodolfo A Perez-Grossmann, Margaret A Pericak-Vance, Xue Qin, Michele Ramsay, Serge Resnikoff, Julia E Richards, Rui Barroso Schimiti, Kar Seng Sim, William E Sponsel, Paulo Vinicius Svidnicki, Alberta A H J Thiadens, Nkechinyere J Uche, Cornelia M van Duijn, José Paulo Cabral de Vasconcellos, Janey L Wiggs, Linda M Zangwill, Neil Risch, Dan Milea, Adeyinka Ashaye, KlaverCaroline C WCCWDepartment of Epidemiology, Erasmus MC, Rotterdam, the Netherlands.Department of Ophthalmology, Erasmus MC, Rotterdam, the Netherlands.Department of Ophthalmology, Radboud University Medical Center, Nijmegen, the Netherlands., Robert N Weinreb, Allison E Ashley Koch, John H Fingert, and Chiea Chuen Khor.
• Department of Medicine, Duke University, Durham, North Carolina.
• JAMA. 2019 Nov 5; 322 (17): 168216911682-1691.

ImportancePrimary open-angle glaucoma presents with increased prevalence and a higher degree of clinical severity in populations of African ancestry compared with European or Asian ancestry. Despite this, individuals of African ancestry remain understudied in genomic research for blinding disorders.ObjectivesTo perform a genome-wide association study (GWAS) of African ancestry populations and evaluate potential mechanisms of pathogenesis for loci associated with primary open-angle glaucoma.Design, Settings, And ParticipantsA 2-stage GWAS with a discovery data set of 2320 individuals with primary open-angle glaucoma and 2121 control individuals without primary open-angle glaucoma. The validation stage included an additional 6937 affected individuals and 14 917 unaffected individuals using multicenter clinic- and population-based participant recruitment approaches. Study participants were recruited from Ghana, Nigeria, South Africa, the United States, Tanzania, Britain, Cameroon, Saudi Arabia, Brazil, the Democratic Republic of the Congo, Morocco, Peru, and Mali from 2003 to 2018. Individuals with primary open-angle glaucoma had open iridocorneal angles and displayed glaucomatous optic neuropathy with visual field defects. Elevated intraocular pressure was not included in the case definition. Control individuals had no elevated intraocular pressure and no signs of glaucoma.ExposuresGenetic variants associated with primary open-angle glaucoma.Main Outcomes And MeasuresPresence of primary open-angle glaucoma. Genome-wide significance was defined as P < 5 × 10-8 in the discovery stage and in the meta-analysis of combined discovery and validation data.ResultsA total of 2320 individuals with primary open-angle glaucoma (mean [interquartile range] age, 64.6 [56-74] years; 1055 [45.5%] women) and 2121 individuals without primary open-angle glaucoma (mean [interquartile range] age, 63.4 [55-71] years; 1025 [48.3%] women) were included in the discovery GWAS. The GWAS discovery meta-analysis demonstrated association of variants at amyloid-β A4 precursor protein-binding family B member 2 (APBB2; chromosome 4, rs59892895T>C) with primary open-angle glaucoma (odds ratio [OR], 1.32 [95% CI, 1.20-1.46]; P = 2 × 10-8). The association was validated in an analysis of an additional 6937 affected individuals and 14 917 unaffected individuals (OR, 1.15 [95% CI, 1.09-1.21]; P < .001). Each copy of the rs59892895*C risk allele was associated with increased risk of primary open-angle glaucoma when all data were included in a meta-analysis (OR, 1.19 [95% CI, 1.14-1.25]; P = 4 × 10-13). The rs59892895*C risk allele was present at appreciable frequency only in African ancestry populations. In contrast, the rs59892895*C risk allele had a frequency of less than 0.1% in individuals of European or Asian ancestry.Conclusions And RelevanceIn this genome-wide association study, variants at the APBB2 locus demonstrated differential association with primary open-angle glaucoma by ancestry. If validated in additional populations this finding may have implications for risk assessment and therapeutic strategies.

35 keywords...

hide…