Association of Genetic Variants with Primary Open-Angle Glaucoma among Individuals with African Ancestry

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. BromleyDonald L. Budenz, Trevor R. Carmichael, Pratap Challa, Yii Der Ida Chen, 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, Ruth J.F. Loos, 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, Caroline C.W. Klaver, Robert N. Weinreb, Allison E. Ashley Koch, John H. Fingert, Chiea Chuen Khor

Research output: Contribution to journalArticle

1 Citation (Scopus)

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 languageEnglish (US)
Pages (from-to)1682-1691
Number of pages10
JournalJAMA - Journal of the American Medical Association
Volume322
Issue number17
DOIs
StatePublished - Nov 5 2019

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Genome-Wide Association Study
Population
Alleles
Odds Ratio
Intraocular Pressure
Primary Open Angle Glaucoma
Mali
Democratic Republic of the Congo
Morocco
Cameroon
Optic Nerve Diseases
Ghana
Peru
Tanzania
Saudi Arabia
Nigeria
South Africa
Visual Fields
varespladib methyl
Glaucoma

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Hauser, M. A., Allingham, R. R., Aung, T., Van Der Heide, C. J., Taylor, K. D., Rotter, J. I., ... Khor, C. C. (2019). Association of Genetic Variants with Primary Open-Angle Glaucoma among Individuals with African Ancestry. JAMA - Journal of the American Medical Association, 322(17), 1682-1691. https://doi.org/10.1001/jama.2019.16161

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 journalArticle

Hauser, MA, Allingham, RR, Aung, T, Van Der Heide, CJ, Taylor, KD, Rotter, JI, Wang, SHJ, Bonnemaijer, PWM, Williams, SE, Abdullahi, SM, Abu-Amero, KK, Anderson, MG, Akafo, S, Alhassan, MB, Asimadu, I, Ayyagari, R, Bakayoko, S, Nyamsi, PB, Bowden, DW, Bromley, WC, Budenz, DL, Carmichael, TR, Challa, P, Chen, YDI, Chuka-Okosa, CM, Cooke Bailey, JN, Costa, VP, Cruz, DA, Dubiner, H, Ervin, JF, Feldman, RM, Flamme-Wiese, M, Gaasterland, DE, Garnai, SJ, Girkin, CA, Guirou, N, Guo, X, Haines, JL, Hammond, CJ, Herndon, L, Hoffmann, TJ, Hulette, CM, Hydara, A, Igo, RP, Jorgenson, E, Kabwe, J, Kilangalanga, NJ, Kizor-Akaraiwe, N, Kuchtey, RW, Lamari, H, Li, Z, Liebmann, JM, Liu, Y, Loos, RJF, Melo, MB, Moroi, SE, Msosa, JM, Mullins, RF, Nadkarni, G, Napo, A, Ng, MCY, Nunes, HF, Obeng-Nyarkoh, E, Okeke, A, Okeke, S, Olaniyi, O, Olawoye, O, Oliveira, MB, Pasquale, LR, Perez-Grossmann, RA, Pericak-Vance, MA, Qin, X, Ramsay, M, Resnikoff, S, Richards, JE, Schimiti, RB, Sim, KS, Sponsel, WE, Svidnicki, PV, Thiadens, AAHJ, Uche, NJ, Van Duijn, CM, De Vasconcellos, JPC, Wiggs, JL, Zangwill, LM, Risch, N, Milea, D, Ashaye, A, Klaver, CCW, Weinreb, RN, Ashley Koch, AE, Fingert, JH & Khor, CC 2019, 'Association of Genetic Variants with Primary Open-Angle Glaucoma among Individuals with African Ancestry', JAMA - Journal of the American Medical Association, vol. 322, no. 17, pp. 1682-1691. https://doi.org/10.1001/jama.2019.16161
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. / Association of Genetic Variants with Primary Open-Angle Glaucoma among Individuals with African Ancestry. In: JAMA - Journal of the American Medical Association. 2019 ; Vol. 322, No. 17. pp. 1682-1691.
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title = "Association of Genetic Variants with Primary Open-Angle Glaucoma among Individuals with African Ancestry",
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..",
author = "Hauser, {Michael A.} and Allingham, {R. Rand} and Tin Aung and {Van Der Heide}, {Carly J.} and Taylor, {Kent D.} and Rotter, {Jerome I.} and Wang, {Shih Hsiu J.} and Bonnemaijer, {Pieter W.M.} and Williams, {Susan E.} and Abdullahi, {Sadiq M.} and Abu-Amero, {Khaled K.} and Anderson, {Michael G.} and Stephen Akafo and Alhassan, {Mahmoud B.} and Ifeoma Asimadu and Radha Ayyagari and Saydou Bakayoko and Nyamsi, {Prisca Biangoup} and Bowden, {Donald W.} and Bromley, {William C.} and Budenz, {Donald L.} and Carmichael, {Trevor R.} and Pratap Challa and Chen, {Yii Der Ida} and Chuka-Okosa, {Chimdi M.} and {Cooke Bailey}, {Jessica N.} and Costa, {Vital Paulino} and Cruz, {Dianne A.} and Harvey Dubiner and Ervin, {John F.} and Feldman, {Robert M.} and Miles Flamme-Wiese and Gaasterland, {Douglas E.} and Garnai, {Sarah J.} and Girkin, {Christopher A.} and Nouhoum Guirou and Xiuqing Guo and Haines, {Jonathan L.} and Hammond, {Christopher J.} and Leon Herndon and Hoffmann, {Thomas J.} and Hulette, {Christine M.} and Abba Hydara and Igo, {Robert P.} and Eric Jorgenson and Joyce Kabwe and Kilangalanga, {Ngoy Janvier} and Nkiru Kizor-Akaraiwe and Kuchtey, {Rachel W.} and Hasnaa Lamari and Zheng Li and Liebmann, {Jeffrey M.} and Yutao Liu and Loos, {Ruth J.F.} and Melo, {Monica B.} and Moroi, {Sayoko E.} and Msosa, {Joseph M.} and Mullins, {Robert F.} and Girish Nadkarni and Abdoulaye Napo and Ng, {Maggie C.Y.} and Nunes, {Hugo Freire} and Ebenezer Obeng-Nyarkoh and Anthony Okeke and Suhanya Okeke and Olusegun Olaniyi and Olusola Olawoye and Oliveira, {Mariana Borges} and Pasquale, {Louise R.} and Perez-Grossmann, {Rodolfo A.} and Pericak-Vance, {Margaret A.} and Xue Qin and Michele Ramsay and Serge Resnikoff and Richards, {Julia E.} and Schimiti, {Rui Barroso} and Sim, {Kar Seng} and Sponsel, {William E.} and Svidnicki, {Paulo Vinicius} and Thiadens, {Alberta A.H.J.} and Uche, {Nkechinyere J.} and {Van Duijn}, {Cornelia M.} and {De Vasconcellos}, {Jos{\'e} Paulo Cabral} and Wiggs, {Janey L.} and Zangwill, {Linda M.} and Neil Risch and Dan Milea and Adeyinka Ashaye and Klaver, {Caroline C.W.} and Weinreb, {Robert N.} and {Ashley Koch}, {Allison E.} and Fingert, {John H.} and Khor, {Chiea Chuen}",
year = "2019",
month = "11",
day = "5",
doi = "10.1001/jama.2019.16161",
language = "English (US)",
volume = "322",
pages = "1682--1691",
journal = "JAMA - Journal of the American Medical Association",
issn = "0002-9955",
publisher = "American Medical Association",
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}

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

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 -