TY - JOUR
T1 - Association of Genetic Variants with Primary Open-Angle Glaucoma among Individuals with African Ancestry
AU - Hauser, Michael A.
AU - Allingham, R. Rand
AU - Aung, Tin
AU - Van Der Heide, Carly J.
AU - Taylor, Kent D.
AU - Rotter, Jerome I.
AU - Wang, Shih Hsiu J.
AU - Bonnemaijer, Pieter W.M.
AU - Williams, Susan E.
AU - Abdullahi, Sadiq M.
AU - Abu-Amero, Khaled K.
AU - Anderson, Michael G.
AU - Akafo, Stephen
AU - Alhassan, Mahmoud B.
AU - Asimadu, Ifeoma
AU - Ayyagari, Radha
AU - Bakayoko, Saydou
AU - Nyamsi, Prisca Biangoup
AU - Bowden, Donald W.
AU - Bromley, William C.
AU - Budenz, Donald L.
AU - Carmichael, Trevor R.
AU - Challa, Pratap
AU - Chen, Yii Der Ida
AU - Chuka-Okosa, Chimdi M.
AU - Cooke Bailey, Jessica N.
AU - Costa, Vital Paulino
AU - Cruz, Dianne A.
AU - Dubiner, Harvey
AU - Ervin, John F.
AU - Feldman, Robert M.
AU - Flamme-Wiese, Miles
AU - Gaasterland, Douglas E.
AU - Garnai, Sarah J.
AU - Girkin, Christopher A.
AU - Guirou, Nouhoum
AU - Guo, Xiuqing
AU - Haines, Jonathan L.
AU - Hammond, Christopher J.
AU - Herndon, Leon
AU - Hoffmann, Thomas J.
AU - Hulette, Christine M.
AU - Hydara, Abba
AU - Igo, Robert P.
AU - Jorgenson, Eric
AU - Kabwe, Joyce
AU - Kilangalanga, Ngoy Janvier
AU - Kizor-Akaraiwe, Nkiru
AU - Kuchtey, Rachel W.
AU - Lamari, Hasnaa
AU - Li, Zheng
AU - Liebmann, Jeffrey M.
AU - Liu, Yutao
AU - Loos, Ruth J.F.
AU - Melo, Monica B.
AU - Moroi, Sayoko E.
AU - Msosa, Joseph M.
AU - Mullins, Robert F.
AU - Nadkarni, Girish
AU - Napo, Abdoulaye
AU - Ng, Maggie C.Y.
AU - Nunes, Hugo Freire
AU - Obeng-Nyarkoh, Ebenezer
AU - Okeke, Anthony
AU - Okeke, Suhanya
AU - Olaniyi, Olusegun
AU - Olawoye, Olusola
AU - Oliveira, Mariana Borges
AU - Pasquale, Louise R.
AU - Perez-Grossmann, Rodolfo A.
AU - Pericak-Vance, Margaret A.
AU - Qin, Xue
AU - Ramsay, Michele
AU - Resnikoff, Serge
AU - Richards, Julia E.
AU - Schimiti, Rui Barroso
AU - Sim, Kar Seng
AU - Sponsel, William E.
AU - Svidnicki, Paulo Vinicius
AU - Thiadens, Alberta A.H.J.
AU - Uche, Nkechinyere J.
AU - Van Duijn, Cornelia M.
AU - De Vasconcellos, José Paulo Cabral
AU - Wiggs, Janey L.
AU - Zangwill, Linda M.
AU - Risch, Neil
AU - Milea, Dan
AU - Ashaye, Adeyinka
AU - Klaver, Caroline C.W.
AU - Weinreb, Robert N.
AU - Ashley Koch, Allison E.
AU - Fingert, John H.
AU - Khor, Chiea Chuen
N1 - Publisher Copyright:
© 2019 American Medical Association. All rights reserved.
PY - 2019/11/5
Y1 - 2019/11/5
N2 - Importance: Primary 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. Objectives: To 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 Participants: A 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 14917 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. Exposures: Genetic variants associated with primary open-angle glaucoma. Main Outcomes and Measures: Presence 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. Results: A 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 14917 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 Relevance: In 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..
AB - Importance: Primary 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. Objectives: To 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 Participants: A 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 14917 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. Exposures: Genetic variants associated with primary open-angle glaucoma. Main Outcomes and Measures: Presence 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. Results: A 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 14917 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 Relevance: In 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..
UR - http://www.scopus.com/inward/record.url?scp=85074550267&partnerID=8YFLogxK
U2 - 10.1001/jama.2019.16161
DO - 10.1001/jama.2019.16161
M3 - Article
C2 - 31688885
AN - SCOPUS:85074550267
SN - 0098-7484
VL - 322
SP - 1682
EP - 1691
JO - JAMA - Journal of the American Medical Association
JF - JAMA - Journal of the American Medical Association
IS - 17
ER -