Common variants near ABCA1, AFAP1 and GMDS confer risk of primary open-angle glaucoma

Puya Gharahkhani; Kathryn P. Burdon; Rhys Fogarty; Shiwani Sharma; Alex W. Hewitt; Sarah Martin; Matthew H. Law; Katie Cremin; Jessica N Cooke Bailey; Stephanie J. Loomis; Louis R. Pasquale; Jonathan L. Haines; Michael A. Hauser; Ananth C. Viswanathan; Peter McGuffin; Fotis Topouzis; Paul J. Foster; Stuart L. Graham; Robert J. Casson; Mark Chehade; Andrew J. White; Tiger Zhou; Emmanuelle Souzeau; John Landers; Jude T. Fitzgerald; Sonja Klebe; Jonathan B. Ruddle; Ivan Goldberg; Paul R. Healey; Richard A. Mills; Jie Jin Wang; Grant W. Montgomery; Nicholas G. Martin; Graham Radford-Smith; David C. Whiteman; Matthew A. Brown; Janey L. Wiggs; David A. Mackey; Paul Mitchell; Stuart Macgregor; Jamie E. Craig

doi:10.1038/ng.3079

Common variants near ABCA1, AFAP1 and GMDS confer risk of primary open-angle glaucoma

Puya Gharahkhani, Kathryn P. Burdon, Rhys Fogarty, Shiwani Sharma, Alex W. Hewitt, Sarah Martin, Matthew H. Law, Katie Cremin, Jessica N Cooke Bailey, Stephanie J. Loomis, Louis R. Pasquale, Jonathan L. Haines, Michael A. Hauser, Ananth C. Viswanathan, Peter McGuffin, Fotis Topouzis, Paul J. Foster, Stuart L. Graham, Robert J. Casson, Mark ChehadeAndrew J. White, Tiger Zhou, Emmanuelle Souzeau, John Landers, Jude T. Fitzgerald, Sonja Klebe, Jonathan B. Ruddle, Ivan Goldberg, Paul R. Healey, Richard A. Mills, Jie Jin Wang, Grant W. Montgomery, Nicholas G. Martin, Graham Radford-Smith, David C. Whiteman, Matthew A. Brown, Janey L. Wiggs, David A. Mackey, Paul Mitchell, Stuart Macgregor, Jamie E. Craig

Lifelong Health

Research output: Contribution to journal › Article › peer-review

104 Citations (Scopus)

Abstract

Primary open-angle glaucoma (POAG) is a major cause of irreversible blindness worldwide. We performed a genome-wide association study in an Australian discovery cohort comprising 1,155 cases with advanced POAG and 1,992 controls. We investigated the association of the top SNPs from the discovery stage in two Australian replication cohorts (932 cases and 6,862 controls total) and two US replication cohorts (2,616 cases and 2,634 controls total). Meta-analysis of all cohorts identified three loci newly associated with development of POAG. These loci are located upstream of ABCA1 (rs2472493[G], odds ratio (OR) = 1.31, P = 2.1 × 10 â '19), within AFAP1 (rs4619890[G], OR = 1.20, P = 7.0 × 10 â '10) and within GMDS (rs11969985[G], OR = 1.31, P = 7.7 × 10 â '10). Using RT-PCR and immunolabeling, we show that these genes are expressed within human retina, optic nerve and trabecular meshwork and that ABCA1 and AFAP1 are also expressed in retinal ganglion cells.

Original language	English
Pages (from-to)	1120-1125
Number of pages	6
Journal	Nature Genetics
Volume	46
Issue number	10
DOIs	https://doi.org/10.1038/ng.3079
Publication status	Published - 26 Sep 2014

ASJC Scopus subject areas

Genetics

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10.1038/ng.3079

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Cite this

Gharahkhani, P., Burdon, K. P., Fogarty, R., Sharma, S., Hewitt, A. W., Martin, S., Law, M. H., Cremin, K., Bailey, J. N. C., Loomis, S. J., Pasquale, L. R., Haines, J. L., Hauser, M. A., Viswanathan, A. C., McGuffin, P., Topouzis, F., Foster, P. J., Graham, S. L., Casson, R. J., ... Craig, J. E. (2014). Common variants near ABCA1, AFAP1 and GMDS confer risk of primary open-angle glaucoma. Nature Genetics, 46(10), 1120-1125. https://doi.org/10.1038/ng.3079

Gharahkhani, Puya ; Burdon, Kathryn P. ; Fogarty, Rhys ; Sharma, Shiwani ; Hewitt, Alex W. ; Martin, Sarah ; Law, Matthew H. ; Cremin, Katie ; Bailey, Jessica N Cooke ; Loomis, Stephanie J. ; Pasquale, Louis R. ; Haines, Jonathan L. ; Hauser, Michael A. ; Viswanathan, Ananth C. ; McGuffin, Peter ; Topouzis, Fotis ; Foster, Paul J. ; Graham, Stuart L. ; Casson, Robert J. ; Chehade, Mark ; White, Andrew J. ; Zhou, Tiger ; Souzeau, Emmanuelle ; Landers, John ; Fitzgerald, Jude T. ; Klebe, Sonja ; Ruddle, Jonathan B. ; Goldberg, Ivan ; Healey, Paul R. ; Mills, Richard A. ; Wang, Jie Jin ; Montgomery, Grant W. ; Martin, Nicholas G. ; Radford-Smith, Graham ; Whiteman, David C. ; Brown, Matthew A. ; Wiggs, Janey L. ; Mackey, David A. ; Mitchell, Paul ; Macgregor, Stuart ; Craig, Jamie E. / Common variants near ABCA1, AFAP1 and GMDS confer risk of primary open-angle glaucoma. In: Nature Genetics. 2014 ; Vol. 46, No. 10. pp. 1120-1125.

@article{5ec4d9aedeea49b6881a33396f82ce51,

title = "Common variants near ABCA1, AFAP1 and GMDS confer risk of primary open-angle glaucoma",

abstract = "Primary open-angle glaucoma (POAG) is a major cause of irreversible blindness worldwide. We performed a genome-wide association study in an Australian discovery cohort comprising 1,155 cases with advanced POAG and 1,992 controls. We investigated the association of the top SNPs from the discovery stage in two Australian replication cohorts (932 cases and 6,862 controls total) and two US replication cohorts (2,616 cases and 2,634 controls total). Meta-analysis of all cohorts identified three loci newly associated with development of POAG. These loci are located upstream of ABCA1 (rs2472493[G], odds ratio (OR) = 1.31, P = 2.1 × 10 {\^a} '19), within AFAP1 (rs4619890[G], OR = 1.20, P = 7.0 × 10 {\^a} '10) and within GMDS (rs11969985[G], OR = 1.31, P = 7.7 × 10 {\^a} '10). Using RT-PCR and immunolabeling, we show that these genes are expressed within human retina, optic nerve and trabecular meshwork and that ABCA1 and AFAP1 are also expressed in retinal ganglion cells.",

author = "Puya Gharahkhani and Burdon, {Kathryn P.} and Rhys Fogarty and Shiwani Sharma and Hewitt, {Alex W.} and Sarah Martin and Law, {Matthew H.} and Katie Cremin and Bailey, {Jessica N Cooke} and Loomis, {Stephanie J.} and Pasquale, {Louis R.} and Haines, {Jonathan L.} and Hauser, {Michael A.} and Viswanathan, {Ananth C.} and Peter McGuffin and Fotis Topouzis and Foster, {Paul J.} and Graham, {Stuart L.} and Casson, {Robert J.} and Mark Chehade and White, {Andrew J.} and Tiger Zhou and Emmanuelle Souzeau and John Landers and Fitzgerald, {Jude T.} and Sonja Klebe and Ruddle, {Jonathan B.} and Ivan Goldberg and Healey, {Paul R.} and Mills, {Richard A.} and Wang, {Jie Jin} and Montgomery, {Grant W.} and Martin, {Nicholas G.} and Graham Radford-Smith and Whiteman, {David C.} and Brown, {Matthew A.} and Wiggs, {Janey L.} and Mackey, {David A.} and Paul Mitchell and Stuart Macgregor and Craig, {Jamie E.}",

note = "Funding Information: Blue Mountains Eye Study (BMES): BMES was supported by the NHMRC, Funding Information: support for recruitment of ANZRAG was provided by the Royal Australian and New Zealand College of Ophthalmology (RANZCO) Eye Foundation. Genotyping was funded by the National Health and Medical Research Council (NHMRC) of Australia (#535074 and #1023911). This work was also supported by funding from NHMRC #1031362 awarded to J.E.C., NHMRC #1037838 awarded to A.W.H., NHMRC #1048037 awarded to S.L.G., NHMRC #1009844 awarded to R.J.C. and I.G., NHMRC #1031920 and an Alcon Research Institute grant awarded to D.A.M., an Allergan Unrestricted grant awarded to A.J.W., the BrightFocus Foundation and a Ramaciotti Establishment Grant. The authors acknowledge the support of B. Usher-Ridge in patient recruitment and data collection and P. Danoy and J. Hadler for genotyping. Controls for the ANZRAG discovery cohort were drawn from the Australian Cancer Study, the Study of Digestive Health and a study of inflammatory bowel diseases. The Australian Cancer Study was supported by the Queensland Cancer Fund and the NHMRC of Australia (program number 199600, awarded to D.C.W., A.C. Green, N.K. Hayward, P.G. Parsons, D.M. Purdie and P.M. Webb, and program number 552429, awarded to D.C.W.). The Study of Digestive Health was supported by grant number 5 R01 CA 001833 from the US National Cancer Institute (awarded to D.C.W.). The Barrett{\textquoteright}s and Esophageal Adenocarcinoma Genetic Susceptibility Study (BEAGESS) sponsored the genotyping of cases with esophageal cancer and Barrett{\textquoteright}s esophagus, which were used as unscreened controls in the ANZRAG discovery cohort. BEAGESS was funded by grant R01 CA136725 from the US National Cancer Institute. Genotyping for part of the Australian twin control sample included in the ANZRAG replication cohort was funded by an NHMRC Medical Genomics Grant. Genotyping for the remainder of twin controls was performed by the US National Institutes of Health (NIH) Center for Inherited Research (CIDR) as part of NIH/National Eye Institute (NEI) grant 1RO1EY018246, and we are grateful to C. Day and staff. We acknowledge with appreciation all women who participated in the QIMR endometriosis study. We thank Endometriosis Associations for supporting study recruitment. We thank S. Nicolaides and the Queensland Medical Laboratory for pro bono collection and delivery of blood samples and other pathology services for assistance with blood collection. The QIMR twin and endometriosis studies were supported by grants from the NHMRC of Australia (241944, 339462, 389927, 389875, 389891, 389892, 389938, 443036, 442915, 442981, 496610, 496739, 552485 and 552498), the Cooperative Research Centre for Discovery of Genes for Common Human Diseases (CRC), Cerylid Biosciences (Melbourne) and donations from N. and S. Hawkins. We thank M.J. Wright, M.J. Campbell, A. Caracella, S. Gordon, D.R. Nyholt, A.K. Henders, B. Haddon, D. Smyth, H. Beeby, O. Zheng and B. Chapman for their input into project management, databases, sample processing and genotyping. We are grateful to the many research assistants and interviewers for assistance with the studies contributing to the QIMR twin collection. Funding Information: MEEI case-control sample: genotyping for the Massachusetts Eye and Ear Infirmary (MEEI) case-control sample was performed at the Broad Institute of MIT and Harvard with funding support from the NIH GEI (Gene Environment Initiative) (U01HG04424 and U01HG004728). The GENEVA Coordinating Center (U01HG004446) assisted with genotype cleaning. Imputation was supported by NIH EY022305. Collection of cases and controls was supported by NIH EY015872. Support for molecular analysis of the associated genes was provided by the Ophthalmic Research Institute of Australia. The authors acknowledge the support of M. Philpott in collection of cadaveric human eye tissues and N. Mabarrack for initial optimization of the antibody to AFAP. S. MacGregor is supported by Australian Research Council (ARC) and NHMRC Fellowships. G.W.M., M.A.B., K.P.B., D.C.W. and J.E.C. are supported by Australian NHMRC Fellowships. D.C.W. was funded by the ARC and G.R.-S. was funded by NHMRC during the period of this study. The authors acknowledge C. Abbot (Alcon Research Ltd.) for providing normal and glaucomatous trabecular meshwork cell lines, NTM-5 and GTM-3, respectively, as a kind gift. Funding Information: Canberra Australia (974159, 211069, 457349, 512423, 475604 and 529912), the Centre for Clinical Research Excellence in Translational Clinical Research in Eye Diseases, NHMRC Senior Research Fellowships (358702 and 632909 to J.J.W.) and the Wellcome Trust, UK, as part of Wellcome Trust Case Control Consortium 2 (A.C.V., P. McGuffin, P. Mitchell, F.T. and P.J.F.) for genotyping costs of the entire BMES population (085475B08Z, 08547508Z, 076113). P.J.F. is also supported by Medical Research Council (MRC) G0401527, Research Into Ageing (Ref 262) and NIHR (UK) Biomedical Research Centre at Moorfields Eye Hospital and University College London Institute of Ophthalmology (BRC2_009) funds. The BMES acknowledges E. Rochtchina from the Centre for Vision Research, Department of Ophthalmology and Westmead Millennium Institute University of Sydney, J. Attia, R. Scott and E.G. Holliday from the University of Newcastle, J. Xie and P.N. Baird from the Centre for Eye Research Australia, University of Melbourne, M.T. Inouye, Medical Systems Biology, Department of Pathology and Department of Microbiology and Immunology, University of Melbourne and X. Sim, National University of Singapore. Funding Information: services for the NEIGHBOR study were provided by the CIDR and were supported by the NEI through grant HG005259-01 (J.L.W.). Additionally, CIDR is funded through a federal contract from the NIH to The Johns Hopkins University, contract number HHSN268200782096C. Collecting and processing samples for the NEIGHBOR data set was supported by the NEI through American Recovery and Reinvestment Act (ARRA) grants 3R01EY015872-05S1 (J.L.W.) and 3R01EY019126-02S1 (M.A.H.). Genotype imputation and meta-analysis were supported by EY022305 (J.L.W.). Funding for the collection of cases and controls was provided by the following NIH grants: EY015543 (R.R. Allingham); EY006827 (D. Gaasterland); HL73042, HL073389, EY13315, EY023646 (M.A.H.); CA87969, CA49449, CA55075 (J.H. Kang); EY009149 (P.R. Lichter); HG004608 (C. McCarty); EY008208 (F.A. Medeiros); EY015473 (L.R.P.); EY012118 (M. Pericak-Vance); EY015682 (A. Realini); EY011671, EY09580 (J.E. Richards); EY013178 (J.S. Schuman); RR015574, EY015872, EY010886, EY009847, EY014104 (J.L.W.); EY011008, EY144428, EY144448 and EY18660 (K. Zhang). J.L.W. and L.R.P. are also supported by the Harvard Glaucoma Center for Excellence and the Margolis Fund. Y. Liu is supported by the Glaucoma Research Foundation, the American Health Assistance Foundation and the Glaucoma Foundation. J.L.W., L.R.P., D.C. Musch and J.E. Richards are supported by Research to Prevent Blindness. J.N.C.B. is supported by NIH T32 EY007157 (CWRU) and T32 EY21453-2 (VUMC).",

year = "2014",

month = sep,

day = "26",

doi = "10.1038/ng.3079",

language = "English",

volume = "46",

pages = "1120--1125",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "10",

}

Gharahkhani, P, Burdon, KP, Fogarty, R, Sharma, S, Hewitt, AW, Martin, S, Law, MH, Cremin, K, Bailey, JNC, Loomis, SJ, Pasquale, LR, Haines, JL, Hauser, MA, Viswanathan, AC, McGuffin, P, Topouzis, F, Foster, PJ, Graham, SL, Casson, RJ, Chehade, M, White, AJ, Zhou, T, Souzeau, E, Landers, J, Fitzgerald, JT, Klebe, S, Ruddle, JB, Goldberg, I, Healey, PR, Mills, RA, Wang, JJ, Montgomery, GW, Martin, NG, Radford-Smith, G, Whiteman, DC, Brown, MA, Wiggs, JL, Mackey, DA, Mitchell, P, Macgregor, S & Craig, JE 2014, 'Common variants near ABCA1, AFAP1 and GMDS confer risk of primary open-angle glaucoma', Nature Genetics, vol. 46, no. 10, pp. 1120-1125. https://doi.org/10.1038/ng.3079

Common variants near ABCA1, AFAP1 and GMDS confer risk of primary open-angle glaucoma. / Gharahkhani, Puya; Burdon, Kathryn P.; Fogarty, Rhys; Sharma, Shiwani; Hewitt, Alex W.; Martin, Sarah; Law, Matthew H.; Cremin, Katie; Bailey, Jessica N Cooke; Loomis, Stephanie J.; Pasquale, Louis R.; Haines, Jonathan L.; Hauser, Michael A.; Viswanathan, Ananth C.; McGuffin, Peter; Topouzis, Fotis; Foster, Paul J.; Graham, Stuart L.; Casson, Robert J.; Chehade, Mark; White, Andrew J.; Zhou, Tiger; Souzeau, Emmanuelle; Landers, John; Fitzgerald, Jude T.; Klebe, Sonja; Ruddle, Jonathan B.; Goldberg, Ivan; Healey, Paul R.; Mills, Richard A.; Wang, Jie Jin; Montgomery, Grant W.; Martin, Nicholas G.; Radford-Smith, Graham; Whiteman, David C.; Brown, Matthew A.; Wiggs, Janey L.; Mackey, David A.; Mitchell, Paul; Macgregor, Stuart; Craig, Jamie E.

In: Nature Genetics, Vol. 46, No. 10, 26.09.2014, p. 1120-1125.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Common variants near ABCA1, AFAP1 and GMDS confer risk of primary open-angle glaucoma

AU - Gharahkhani, Puya

AU - Burdon, Kathryn P.

AU - Fogarty, Rhys

AU - Sharma, Shiwani

AU - Hewitt, Alex W.

AU - Martin, Sarah

AU - Law, Matthew H.

AU - Cremin, Katie

AU - Bailey, Jessica N Cooke

AU - Loomis, Stephanie J.

AU - Pasquale, Louis R.

AU - Haines, Jonathan L.

AU - Hauser, Michael A.

AU - Viswanathan, Ananth C.

AU - McGuffin, Peter

AU - Topouzis, Fotis

AU - Foster, Paul J.

AU - Graham, Stuart L.

AU - Casson, Robert J.

AU - Chehade, Mark

AU - White, Andrew J.

AU - Zhou, Tiger

AU - Souzeau, Emmanuelle

AU - Landers, John

AU - Fitzgerald, Jude T.

AU - Klebe, Sonja

AU - Ruddle, Jonathan B.

AU - Goldberg, Ivan

AU - Healey, Paul R.

AU - Mills, Richard A.

AU - Wang, Jie Jin

AU - Montgomery, Grant W.

AU - Martin, Nicholas G.

AU - Radford-Smith, Graham

AU - Whiteman, David C.

AU - Brown, Matthew A.

AU - Wiggs, Janey L.

AU - Mackey, David A.

AU - Mitchell, Paul

AU - Macgregor, Stuart

AU - Craig, Jamie E.

N1 - Funding Information: Blue Mountains Eye Study (BMES): BMES was supported by the NHMRC, Funding Information: support for recruitment of ANZRAG was provided by the Royal Australian and New Zealand College of Ophthalmology (RANZCO) Eye Foundation. Genotyping was funded by the National Health and Medical Research Council (NHMRC) of Australia (#535074 and #1023911). This work was also supported by funding from NHMRC #1031362 awarded to J.E.C., NHMRC #1037838 awarded to A.W.H., NHMRC #1048037 awarded to S.L.G., NHMRC #1009844 awarded to R.J.C. and I.G., NHMRC #1031920 and an Alcon Research Institute grant awarded to D.A.M., an Allergan Unrestricted grant awarded to A.J.W., the BrightFocus Foundation and a Ramaciotti Establishment Grant. The authors acknowledge the support of B. Usher-Ridge in patient recruitment and data collection and P. Danoy and J. Hadler for genotyping. Controls for the ANZRAG discovery cohort were drawn from the Australian Cancer Study, the Study of Digestive Health and a study of inflammatory bowel diseases. The Australian Cancer Study was supported by the Queensland Cancer Fund and the NHMRC of Australia (program number 199600, awarded to D.C.W., A.C. Green, N.K. Hayward, P.G. Parsons, D.M. Purdie and P.M. Webb, and program number 552429, awarded to D.C.W.). The Study of Digestive Health was supported by grant number 5 R01 CA 001833 from the US National Cancer Institute (awarded to D.C.W.). The Barrett’s and Esophageal Adenocarcinoma Genetic Susceptibility Study (BEAGESS) sponsored the genotyping of cases with esophageal cancer and Barrett’s esophagus, which were used as unscreened controls in the ANZRAG discovery cohort. BEAGESS was funded by grant R01 CA136725 from the US National Cancer Institute. Genotyping for part of the Australian twin control sample included in the ANZRAG replication cohort was funded by an NHMRC Medical Genomics Grant. Genotyping for the remainder of twin controls was performed by the US National Institutes of Health (NIH) Center for Inherited Research (CIDR) as part of NIH/National Eye Institute (NEI) grant 1RO1EY018246, and we are grateful to C. Day and staff. We acknowledge with appreciation all women who participated in the QIMR endometriosis study. We thank Endometriosis Associations for supporting study recruitment. We thank S. Nicolaides and the Queensland Medical Laboratory for pro bono collection and delivery of blood samples and other pathology services for assistance with blood collection. The QIMR twin and endometriosis studies were supported by grants from the NHMRC of Australia (241944, 339462, 389927, 389875, 389891, 389892, 389938, 443036, 442915, 442981, 496610, 496739, 552485 and 552498), the Cooperative Research Centre for Discovery of Genes for Common Human Diseases (CRC), Cerylid Biosciences (Melbourne) and donations from N. and S. Hawkins. We thank M.J. Wright, M.J. Campbell, A. Caracella, S. Gordon, D.R. Nyholt, A.K. Henders, B. Haddon, D. Smyth, H. Beeby, O. Zheng and B. Chapman for their input into project management, databases, sample processing and genotyping. We are grateful to the many research assistants and interviewers for assistance with the studies contributing to the QIMR twin collection. Funding Information: MEEI case-control sample: genotyping for the Massachusetts Eye and Ear Infirmary (MEEI) case-control sample was performed at the Broad Institute of MIT and Harvard with funding support from the NIH GEI (Gene Environment Initiative) (U01HG04424 and U01HG004728). The GENEVA Coordinating Center (U01HG004446) assisted with genotype cleaning. Imputation was supported by NIH EY022305. Collection of cases and controls was supported by NIH EY015872. Support for molecular analysis of the associated genes was provided by the Ophthalmic Research Institute of Australia. The authors acknowledge the support of M. Philpott in collection of cadaveric human eye tissues and N. Mabarrack for initial optimization of the antibody to AFAP. S. MacGregor is supported by Australian Research Council (ARC) and NHMRC Fellowships. G.W.M., M.A.B., K.P.B., D.C.W. and J.E.C. are supported by Australian NHMRC Fellowships. D.C.W. was funded by the ARC and G.R.-S. was funded by NHMRC during the period of this study. The authors acknowledge C. Abbot (Alcon Research Ltd.) for providing normal and glaucomatous trabecular meshwork cell lines, NTM-5 and GTM-3, respectively, as a kind gift. Funding Information: Canberra Australia (974159, 211069, 457349, 512423, 475604 and 529912), the Centre for Clinical Research Excellence in Translational Clinical Research in Eye Diseases, NHMRC Senior Research Fellowships (358702 and 632909 to J.J.W.) and the Wellcome Trust, UK, as part of Wellcome Trust Case Control Consortium 2 (A.C.V., P. McGuffin, P. Mitchell, F.T. and P.J.F.) for genotyping costs of the entire BMES population (085475B08Z, 08547508Z, 076113). P.J.F. is also supported by Medical Research Council (MRC) G0401527, Research Into Ageing (Ref 262) and NIHR (UK) Biomedical Research Centre at Moorfields Eye Hospital and University College London Institute of Ophthalmology (BRC2_009) funds. The BMES acknowledges E. Rochtchina from the Centre for Vision Research, Department of Ophthalmology and Westmead Millennium Institute University of Sydney, J. Attia, R. Scott and E.G. Holliday from the University of Newcastle, J. Xie and P.N. Baird from the Centre for Eye Research Australia, University of Melbourne, M.T. Inouye, Medical Systems Biology, Department of Pathology and Department of Microbiology and Immunology, University of Melbourne and X. Sim, National University of Singapore. Funding Information: services for the NEIGHBOR study were provided by the CIDR and were supported by the NEI through grant HG005259-01 (J.L.W.). Additionally, CIDR is funded through a federal contract from the NIH to The Johns Hopkins University, contract number HHSN268200782096C. Collecting and processing samples for the NEIGHBOR data set was supported by the NEI through American Recovery and Reinvestment Act (ARRA) grants 3R01EY015872-05S1 (J.L.W.) and 3R01EY019126-02S1 (M.A.H.). Genotype imputation and meta-analysis were supported by EY022305 (J.L.W.). Funding for the collection of cases and controls was provided by the following NIH grants: EY015543 (R.R. Allingham); EY006827 (D. Gaasterland); HL73042, HL073389, EY13315, EY023646 (M.A.H.); CA87969, CA49449, CA55075 (J.H. Kang); EY009149 (P.R. Lichter); HG004608 (C. McCarty); EY008208 (F.A. Medeiros); EY015473 (L.R.P.); EY012118 (M. Pericak-Vance); EY015682 (A. Realini); EY011671, EY09580 (J.E. Richards); EY013178 (J.S. Schuman); RR015574, EY015872, EY010886, EY009847, EY014104 (J.L.W.); EY011008, EY144428, EY144448 and EY18660 (K. Zhang). J.L.W. and L.R.P. are also supported by the Harvard Glaucoma Center for Excellence and the Margolis Fund. Y. Liu is supported by the Glaucoma Research Foundation, the American Health Assistance Foundation and the Glaucoma Foundation. J.L.W., L.R.P., D.C. Musch and J.E. Richards are supported by Research to Prevent Blindness. J.N.C.B. is supported by NIH T32 EY007157 (CWRU) and T32 EY21453-2 (VUMC).

PY - 2014/9/26

Y1 - 2014/9/26

N2 - Primary open-angle glaucoma (POAG) is a major cause of irreversible blindness worldwide. We performed a genome-wide association study in an Australian discovery cohort comprising 1,155 cases with advanced POAG and 1,992 controls. We investigated the association of the top SNPs from the discovery stage in two Australian replication cohorts (932 cases and 6,862 controls total) and two US replication cohorts (2,616 cases and 2,634 controls total). Meta-analysis of all cohorts identified three loci newly associated with development of POAG. These loci are located upstream of ABCA1 (rs2472493[G], odds ratio (OR) = 1.31, P = 2.1 × 10 â '19), within AFAP1 (rs4619890[G], OR = 1.20, P = 7.0 × 10 â '10) and within GMDS (rs11969985[G], OR = 1.31, P = 7.7 × 10 â '10). Using RT-PCR and immunolabeling, we show that these genes are expressed within human retina, optic nerve and trabecular meshwork and that ABCA1 and AFAP1 are also expressed in retinal ganglion cells.

AB - Primary open-angle glaucoma (POAG) is a major cause of irreversible blindness worldwide. We performed a genome-wide association study in an Australian discovery cohort comprising 1,155 cases with advanced POAG and 1,992 controls. We investigated the association of the top SNPs from the discovery stage in two Australian replication cohorts (932 cases and 6,862 controls total) and two US replication cohorts (2,616 cases and 2,634 controls total). Meta-analysis of all cohorts identified three loci newly associated with development of POAG. These loci are located upstream of ABCA1 (rs2472493[G], odds ratio (OR) = 1.31, P = 2.1 × 10 â '19), within AFAP1 (rs4619890[G], OR = 1.20, P = 7.0 × 10 â '10) and within GMDS (rs11969985[G], OR = 1.31, P = 7.7 × 10 â '10). Using RT-PCR and immunolabeling, we show that these genes are expressed within human retina, optic nerve and trabecular meshwork and that ABCA1 and AFAP1 are also expressed in retinal ganglion cells.

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U2 - 10.1038/ng.3079

DO - 10.1038/ng.3079

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