Abstract
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..
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1682-1691 |
| Number of pages | 10 |
| Journal | JAMA - Journal of the American Medical Association |
| Volume | 322 |
| Issue number | 17 |
| DOIs | |
| State | Published - Nov 5 2019 |
ASJC Scopus subject areas
- Medicine(all)
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Association of Genetic Variants with Primary Open-Angle Glaucoma among Individuals with African Ancestry. / Hauser, Michael A.; Allingham, R. Rand; Aung, Tin; Van Der Heide, Carly J.; Taylor, Kent D.; Rotter, Jerome I.; Wang, Shih Hsiu J.; Bonnemaijer, Pieter W.M.; Williams, Susan E.; Abdullahi, Sadiq M.; Abu-Amero, Khaled K.; Anderson, Michael G.; Akafo, Stephen; Alhassan, Mahmoud B.; Asimadu, Ifeoma; Ayyagari, Radha; Bakayoko, Saydou; Nyamsi, Prisca Biangoup; Bowden, Donald W.; Bromley, William C.; Budenz, Donald L.; Carmichael, Trevor R.; Challa, Pratap; Chen, Yii Der Ida; Chuka-Okosa, Chimdi M.; Cooke Bailey, Jessica N.; Costa, Vital Paulino; Cruz, Dianne A.; Dubiner, Harvey; Ervin, John F.; Feldman, Robert M.; Flamme-Wiese, Miles; Gaasterland, Douglas E.; Garnai, Sarah J.; Girkin, Christopher A.; Guirou, Nouhoum; Guo, Xiuqing; Haines, Jonathan L.; Hammond, Christopher J.; Herndon, Leon; Hoffmann, Thomas J.; Hulette, Christine M.; Hydara, Abba; Igo, Robert P.; Jorgenson, Eric; Kabwe, Joyce; Kilangalanga, Ngoy Janvier; Kizor-Akaraiwe, Nkiru; Kuchtey, Rachel W.; Lamari, Hasnaa; Li, Zheng; Liebmann, Jeffrey M.; Liu, Yutao; Loos, Ruth J.F.; Melo, Monica B.; Moroi, Sayoko E.; Msosa, Joseph M.; Mullins, Robert F.; Nadkarni, Girish; Napo, Abdoulaye; Ng, Maggie C.Y.; Nunes, Hugo Freire; Obeng-Nyarkoh, Ebenezer; Okeke, Anthony; Okeke, Suhanya; Olaniyi, Olusegun; Olawoye, Olusola; Oliveira, Mariana Borges; Pasquale, Louise R.; Perez-Grossmann, Rodolfo A.; Pericak-Vance, Margaret A.; Qin, Xue; Ramsay, Michele; Resnikoff, Serge; Richards, Julia E.; Schimiti, Rui Barroso; Sim, Kar Seng; Sponsel, William E.; Svidnicki, Paulo Vinicius; Thiadens, Alberta A.H.J.; Uche, Nkechinyere J.; Van Duijn, Cornelia M.; De Vasconcellos, José Paulo Cabral; Wiggs, Janey L.; Zangwill, Linda M.; Risch, Neil; Milea, Dan; Ashaye, Adeyinka; Klaver, Caroline C.W.; Weinreb, Robert N.; Ashley Koch, Allison E.; Fingert, John H.; Khor, Chiea Chuen.
In: JAMA - Journal of the American Medical Association, Vol. 322, No. 17, 05.11.2019, p. 1682-1691.Research output: Contribution to journal › Article › peer-review
}
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 - Funding Information: Funding/Support: Funding for the discovery genome-wide association study was provided by Duke-National University of Singapore. Additional support was provided by the National Eye Institute/ National Institutes of Health (grant numbers EY023704, P30EY022589, EY110008, EY019869, EY021818, EY023242, EY028671, EY015473, EY022305, P30 EY014104, and EY023512) and the National Institutes of Health (grant numbers R01 DK087914, R01 DK066358, R01 DK053591, U01 DK105556, R01 HL56266, R01 DK070941, DRC DK063491, CTSI UL1TR001881, R01DK110113, R01DK101855, R01DK107786, U01HG007417, and 1U54-HG009826); the Combined Ophthalmic Research Rotterdam, Algemene Nederlandse Vereniging ter Voorkoming van Blindheid, Landelijke Stichting voor Blinden en Slechtzienden, Stichting Beheer Het Schild, Prof Dr Henkes Stichting, Rotterdamse Stichting Blindenbelangen, Stichting Glaucoomfonds, The Andrea and Charles Bronfman Philanthropies, the National Research Foundation of Singapore (NRF-NRFI2018-01), the São Paulo Research Foundation (FAPESP 10/ 18353-9, FAPESP 02/11575-0), the EyeSight Foundation of Alabama (Dr Girkin), Research to Prevent Blindness (Dr Girkin), the Carnegie Corporation Transformation project at the University of the Witwatersrand grant, the BrightFocus Foundation, the Glaucoma Foundation, the Glaucoma Research Foundation, the International Glaucoma Foundation, and Leonard and Marlene Hadley. Some samples used in this study were provided by the Kathleen Price Bryan Brain Bank of the Joseph and Kathleen Bryan Alzheimer’s Disease Research Center at Duke University (NIA P30 AG028377). Funding Information: reported receiving grants from the National Institutes of Health (NIH) during the conduct of the study. Dr Williams reported receiving grants from the Carnegie Corporation Transformation project at the University of the Witwatersrand and grants and personal fees from the Carnegie Corporation Clinician Scientist Fellowship during the conduct of the study. Dr Anderson reported receiving grants from the National Eye Institute (NEI)/NIH and the US Department of Veterans Affairs Rehabilitation Research and Development Service during the conduct of the study. Dr Nyamsi reported receiving nonfinancial support from the Singapore Eye Research Institute during the conduct of the study. Dr Bromley reported collaboration with the University of Michigan W.K. Kellogg Eye Center. Dr Chen reported receiving grants from NIH during the conduct of the study. Dr Cooke Bailey reported being supported by the Clinical and Translational Science Collaborative of Cleveland (KL2TR0002547) from the National Center for Advancing Translational Sciences/NIH and the NIH Roadmap for Medical Research during the conduct of the study. Dr Flamme-Wiese reported receiving grants from NIH (P30EY025580) during the conduct of the study. Dr Haines reported receiving grants from NIH during the conduct of the study. Dr Hammond reported receiving grants from the International Glaucoma Association during the conduct of the study. Dr Kizor-Akaraiwe reported receiving nonfinancial support from Singapore Eye Research Institute/Singapore National Eye Center outside the submitted work. Dr Liebmann reported receiving grants from NEI/NIH during the conduct of the study. Dr Melo reported receiving grants from São Paulo Research Foundation during the conduct of the study. Dr Nadkarni reported receiving personal fees from Renalytix AI BioVie outside the submitted work. Dr Napo reported receiving personal fees from IOTA during the conduct of the study. Dr Pasquale reported receiving personal fees from Bausch & Lomb and Verily outside the submitted work. Dr Resnikoff reported receiving personal fees from Laboratoires Thea outside the submitted work. Dr Richards reported receiving grants from NIH and Research to Prevent Blindness during the conduct of the study and royalties from Elsevier outside the submitted work. Dr Cabral de Vasconcellos reported receiving grants from São Paulo Research Foundation during the conduct of the study. Dr Wiggs reported receiving grants from NEI during the conduct of the study and consulting for Aerpio Pharmaceuticals outside the submitted work. Dr Zangwill reported receiving grants from NEI during the conduct of the study and grants and nonfinancial support from Heidelberg Engineering, Topcon Inc, Carl Zeiss Meditec, and Optovue outside the submitted work. Funding Information: Dr Weinreb reported receiving personal fees from Aerie Pharmaceuticals, Allergan, Eyenovia, and Implantdata; nonfinancial support from Heidelberg Engineering and Carl Zeiss Meditec; and grants from Genentech, Konan, Optovue, Topcon, Optos, Cetervue, and Bausch & Lomb outside the submitted work. No other disclosures were reported. 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
UR - http://www.scopus.com/inward/citedby.url?scp=85074550267&partnerID=8YFLogxK
U2 - 10.1001/jama.2019.16161
DO - 10.1001/jama.2019.16161
M3 - Article
C2 - 31688885
AN - SCOPUS:85074550267
VL - 322
SP - 1682
EP - 1691
JO - JAMA - Journal of the American Medical Association
JF - JAMA - Journal of the American Medical Association
SN - 0002-9955
IS - 17
ER -