Genome-wide association analysis identifies TXNRD2, ATXN2 and FOXC1 as susceptibility loci for primary open-angle glaucoma

Jessica N Cooke Bailey, Stephanie J. Loomis, Jae H. Kang, R. Rand Allingham, Puya Gharahkhani, Chiea Chuen Khor, Kathryn P. Burdon, Hugues Aschard, Daniel I. Chasman, Robert P. Igo, Pirro G. Hysi, Craig A. Glastonbury, Allison Ashley-Koch, Murray Brilliant, Andrew A. Brown, Donald L. Budenz, Alfonso Buil, Ching Yu Cheng, Hyon Choi, William G. Christen & 60 others Gary Curhan, Immaculata De Vivo, John H. Fingert, Paul J. Foster, Charles Fuchs, Douglas Gaasterland, Terry Gaasterland, Alex W. Hewitt, Frank Hu, David J. Hunter, Anthony P. Khawaja, Richard K. Lee, Zheng Li, Paul R. Lichter, David A. Mackey, Peter McGuffin, Paul Mitchell, Sayoko E. Moroi, Shamira A. Perera, Keating W. Pepper, Qibin Qi, Tony Realini, Julia E. Richards, Paul M. Ridker, Eric Rimm, Robert Ritch, Marylyn Ritchie, Joel S. Schuman, William K. Scott, Kuldev Singh, Arthur J. Sit, Yeunjoo E. Song, Rulla M. Tamimi, Fotis Topouzis, Ananth C. Viswanathan, Shefali Setia Verma, Douglas Vollrath, Jie Jin Wang, Nicole Weisschuh, Bernd Wissinger, Gadi Wollstein, Tien Y. Wong, Brian L. Yaspan, Donald J Zack, Kang Zhang, Robert N. Weinreb, Margaret A. Pericak-Vance, Kerrin Small, Christopher J. Hammond, Tin Aung, Yutao Liu, Eranga N. Vithana, Stuart MacGregor, Jamie E. Craig, Peter Kraft, Gareth Howell, Michael A. Hauser, Louis R. Pasquale, Jonathan L. Haines, Janey L. Wiggs

Research output: Contribution to journalArticle

Abstract

Primary open-angle glaucoma (POAG) is a leading cause of blindness worldwide. To identify new susceptibility loci, we performed meta-analysis on genome-wide association study (GWAS) results from eight independent studies from the United States (3,853 cases and 33,480 controls) and investigated the most significantly associated SNPs in two Australian studies (1,252 cases and 2,592 controls), three European studies (875 cases and 4,107 controls) and a Singaporean Chinese study (1,037 cases and 2,543 controls). A meta-analysis of the top SNPs identified three new associated loci: rs35934224[T] in TXNRD2 (odds ratio (OR) = 0.78, P = 4.05 × 10 -11) encoding a mitochondrial protein required for redox homeostasis; rs7137828[T] in ATXN2 (OR = 1.17, P = 8.73 × 10 -10); and rs2745572[A] upstream of FOXC1 (OR = 1.17, P = 1.76 × 10 -10). Using RT-PCR and immunohistochemistry, we show TXNRD2 and ATXN2 expression in retinal ganglion cells and the optic nerve head. These results identify new pathways underlying POAG susceptibility and suggest new targets for preventative therapies.

Original languageEnglish (US)
Pages (from-to)189-194
Number of pages6
JournalNature Genetics
Volume48
Issue number2
DOIs
StatePublished - Feb 1 2016

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Genome-Wide Association Study
Odds Ratio
Single Nucleotide Polymorphism
Meta-Analysis
Retinal Ganglion Cells
Mitochondrial Proteins
Optic Disk
Blindness
Oxidation-Reduction
Homeostasis
Immunohistochemistry
Polymerase Chain Reaction
Primary Open Angle Glaucoma
Therapeutics

ASJC Scopus subject areas

  • Genetics

Cite this

Bailey, J. N. C., Loomis, S. J., Kang, J. H., Allingham, R. R., Gharahkhani, P., Khor, C. C., ... Wiggs, J. L. (2016). Genome-wide association analysis identifies TXNRD2, ATXN2 and FOXC1 as susceptibility loci for primary open-angle glaucoma. Nature Genetics, 48(2), 189-194. https://doi.org/10.1038/ng.3482

Genome-wide association analysis identifies TXNRD2, ATXN2 and FOXC1 as susceptibility loci for primary open-angle glaucoma. / Bailey, Jessica N Cooke; Loomis, Stephanie J.; Kang, Jae H.; Allingham, R. Rand; Gharahkhani, Puya; Khor, Chiea Chuen; Burdon, Kathryn P.; Aschard, Hugues; Chasman, Daniel I.; Igo, Robert P.; Hysi, Pirro G.; Glastonbury, Craig A.; Ashley-Koch, Allison; Brilliant, Murray; Brown, Andrew A.; Budenz, Donald L.; Buil, Alfonso; Cheng, Ching Yu; Choi, Hyon; Christen, William G.; Curhan, Gary; De Vivo, Immaculata; Fingert, John H.; Foster, Paul J.; Fuchs, Charles; Gaasterland, Douglas; Gaasterland, Terry; Hewitt, Alex W.; Hu, Frank; Hunter, David J.; Khawaja, Anthony P.; Lee, Richard K.; Li, Zheng; Lichter, Paul R.; Mackey, David A.; McGuffin, Peter; Mitchell, Paul; Moroi, Sayoko E.; Perera, Shamira A.; Pepper, Keating W.; Qi, Qibin; Realini, Tony; Richards, Julia E.; Ridker, Paul M.; Rimm, Eric; Ritch, Robert; Ritchie, Marylyn; Schuman, Joel S.; Scott, William K.; Singh, Kuldev; Sit, Arthur J.; Song, Yeunjoo E.; Tamimi, Rulla M.; Topouzis, Fotis; Viswanathan, Ananth C.; Verma, Shefali Setia; Vollrath, Douglas; Wang, Jie Jin; Weisschuh, Nicole; Wissinger, Bernd; Wollstein, Gadi; Wong, Tien Y.; Yaspan, Brian L.; Zack, Donald J; Zhang, Kang; Weinreb, Robert N.; Pericak-Vance, Margaret A.; Small, Kerrin; Hammond, Christopher J.; Aung, Tin; Liu, Yutao; Vithana, Eranga N.; MacGregor, Stuart; Craig, Jamie E.; Kraft, Peter; Howell, Gareth; Hauser, Michael A.; Pasquale, Louis R.; Haines, Jonathan L.; Wiggs, Janey L.

In: Nature Genetics, Vol. 48, No. 2, 01.02.2016, p. 189-194.

Research output: Contribution to journalArticle

Bailey, JNC, Loomis, SJ, Kang, JH, Allingham, RR, Gharahkhani, P, Khor, CC, Burdon, KP, Aschard, H, Chasman, DI, Igo, RP, Hysi, PG, Glastonbury, CA, Ashley-Koch, A, Brilliant, M, Brown, AA, Budenz, DL, Buil, A, Cheng, CY, Choi, H, Christen, WG, Curhan, G, De Vivo, I, Fingert, JH, Foster, PJ, Fuchs, C, Gaasterland, D, Gaasterland, T, Hewitt, AW, Hu, F, Hunter, DJ, Khawaja, AP, Lee, RK, Li, Z, Lichter, PR, Mackey, DA, McGuffin, P, Mitchell, P, Moroi, SE, Perera, SA, Pepper, KW, Qi, Q, Realini, T, Richards, JE, Ridker, PM, Rimm, E, Ritch, R, Ritchie, M, Schuman, JS, Scott, WK, Singh, K, Sit, AJ, Song, YE, Tamimi, RM, Topouzis, F, Viswanathan, AC, Verma, SS, Vollrath, D, Wang, JJ, Weisschuh, N, Wissinger, B, Wollstein, G, Wong, TY, Yaspan, BL, Zack, DJ, Zhang, K, Weinreb, RN, Pericak-Vance, MA, Small, K, Hammond, CJ, Aung, T, Liu, Y, Vithana, EN, MacGregor, S, Craig, JE, Kraft, P, Howell, G, Hauser, MA, Pasquale, LR, Haines, JL & Wiggs, JL 2016, 'Genome-wide association analysis identifies TXNRD2, ATXN2 and FOXC1 as susceptibility loci for primary open-angle glaucoma', Nature Genetics, vol. 48, no. 2, pp. 189-194. https://doi.org/10.1038/ng.3482
Bailey, Jessica N Cooke ; Loomis, Stephanie J. ; Kang, Jae H. ; Allingham, R. Rand ; Gharahkhani, Puya ; Khor, Chiea Chuen ; Burdon, Kathryn P. ; Aschard, Hugues ; Chasman, Daniel I. ; Igo, Robert P. ; Hysi, Pirro G. ; Glastonbury, Craig A. ; Ashley-Koch, Allison ; Brilliant, Murray ; Brown, Andrew A. ; Budenz, Donald L. ; Buil, Alfonso ; Cheng, Ching Yu ; Choi, Hyon ; Christen, William G. ; Curhan, Gary ; De Vivo, Immaculata ; Fingert, John H. ; Foster, Paul J. ; Fuchs, Charles ; Gaasterland, Douglas ; Gaasterland, Terry ; Hewitt, Alex W. ; Hu, Frank ; Hunter, David J. ; Khawaja, Anthony P. ; Lee, Richard K. ; Li, Zheng ; Lichter, Paul R. ; Mackey, David A. ; McGuffin, Peter ; Mitchell, Paul ; Moroi, Sayoko E. ; Perera, Shamira A. ; Pepper, Keating W. ; Qi, Qibin ; Realini, Tony ; Richards, Julia E. ; Ridker, Paul M. ; Rimm, Eric ; Ritch, Robert ; Ritchie, Marylyn ; Schuman, Joel S. ; Scott, William K. ; Singh, Kuldev ; Sit, Arthur J. ; Song, Yeunjoo E. ; Tamimi, Rulla M. ; Topouzis, Fotis ; Viswanathan, Ananth C. ; Verma, Shefali Setia ; Vollrath, Douglas ; Wang, Jie Jin ; Weisschuh, Nicole ; Wissinger, Bernd ; Wollstein, Gadi ; Wong, Tien Y. ; Yaspan, Brian L. ; Zack, Donald J ; Zhang, Kang ; Weinreb, Robert N. ; Pericak-Vance, Margaret A. ; Small, Kerrin ; Hammond, Christopher J. ; Aung, Tin ; Liu, Yutao ; Vithana, Eranga N. ; MacGregor, Stuart ; Craig, Jamie E. ; Kraft, Peter ; Howell, Gareth ; Hauser, Michael A. ; Pasquale, Louis R. ; Haines, Jonathan L. ; Wiggs, Janey L. / Genome-wide association analysis identifies TXNRD2, ATXN2 and FOXC1 as susceptibility loci for primary open-angle glaucoma. In: Nature Genetics. 2016 ; Vol. 48, No. 2. pp. 189-194.
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abstract = "Primary open-angle glaucoma (POAG) is a leading cause of blindness worldwide. To identify new susceptibility loci, we performed meta-analysis on genome-wide association study (GWAS) results from eight independent studies from the United States (3,853 cases and 33,480 controls) and investigated the most significantly associated SNPs in two Australian studies (1,252 cases and 2,592 controls), three European studies (875 cases and 4,107 controls) and a Singaporean Chinese study (1,037 cases and 2,543 controls). A meta-analysis of the top SNPs identified three new associated loci: rs35934224[T] in TXNRD2 (odds ratio (OR) = 0.78, P = 4.05 × 10 -11) encoding a mitochondrial protein required for redox homeostasis; rs7137828[T] in ATXN2 (OR = 1.17, P = 8.73 × 10 -10); and rs2745572[A] upstream of FOXC1 (OR = 1.17, P = 1.76 × 10 -10). Using RT-PCR and immunohistochemistry, we show TXNRD2 and ATXN2 expression in retinal ganglion cells and the optic nerve head. These results identify new pathways underlying POAG susceptibility and suggest new targets for preventative therapies.",
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T1 - Genome-wide association analysis identifies TXNRD2, ATXN2 and FOXC1 as susceptibility loci for primary open-angle glaucoma

AU - Bailey, Jessica N Cooke

AU - Loomis, Stephanie J.

AU - Kang, Jae H.

AU - Allingham, R. Rand

AU - Gharahkhani, Puya

AU - Khor, Chiea Chuen

AU - Burdon, Kathryn P.

AU - Aschard, Hugues

AU - Chasman, Daniel I.

AU - Igo, Robert P.

AU - Hysi, Pirro G.

AU - Glastonbury, Craig A.

AU - Ashley-Koch, Allison

AU - Brilliant, Murray

AU - Brown, Andrew A.

AU - Budenz, Donald L.

AU - Buil, Alfonso

AU - Cheng, Ching Yu

AU - Choi, Hyon

AU - Christen, William G.

AU - Curhan, Gary

AU - De Vivo, Immaculata

AU - Fingert, John H.

AU - Foster, Paul J.

AU - Fuchs, Charles

AU - Gaasterland, Douglas

AU - Gaasterland, Terry

AU - Hewitt, Alex W.

AU - Hu, Frank

AU - Hunter, David J.

AU - Khawaja, Anthony P.

AU - Lee, Richard K.

AU - Li, Zheng

AU - Lichter, Paul R.

AU - Mackey, David A.

AU - McGuffin, Peter

AU - Mitchell, Paul

AU - Moroi, Sayoko E.

AU - Perera, Shamira A.

AU - Pepper, Keating W.

AU - Qi, Qibin

AU - Realini, Tony

AU - Richards, Julia E.

AU - Ridker, Paul M.

AU - Rimm, Eric

AU - Ritch, Robert

AU - Ritchie, Marylyn

AU - Schuman, Joel S.

AU - Scott, William K.

AU - Singh, Kuldev

AU - Sit, Arthur J.

AU - Song, Yeunjoo E.

AU - Tamimi, Rulla M.

AU - Topouzis, Fotis

AU - Viswanathan, Ananth C.

AU - Verma, Shefali Setia

AU - Vollrath, Douglas

AU - Wang, Jie Jin

AU - Weisschuh, Nicole

AU - Wissinger, Bernd

AU - Wollstein, Gadi

AU - Wong, Tien Y.

AU - Yaspan, Brian L.

AU - Zack, Donald J

AU - Zhang, Kang

AU - Weinreb, Robert N.

AU - Pericak-Vance, Margaret A.

AU - Small, Kerrin

AU - Hammond, Christopher J.

AU - Aung, Tin

AU - Liu, Yutao

AU - Vithana, Eranga N.

AU - MacGregor, Stuart

AU - Craig, Jamie E.

AU - Kraft, Peter

AU - Howell, Gareth

AU - Hauser, Michael A.

AU - Pasquale, Louis R.

AU - Haines, Jonathan L.

AU - Wiggs, Janey L.

PY - 2016/2/1

Y1 - 2016/2/1

N2 - Primary open-angle glaucoma (POAG) is a leading cause of blindness worldwide. To identify new susceptibility loci, we performed meta-analysis on genome-wide association study (GWAS) results from eight independent studies from the United States (3,853 cases and 33,480 controls) and investigated the most significantly associated SNPs in two Australian studies (1,252 cases and 2,592 controls), three European studies (875 cases and 4,107 controls) and a Singaporean Chinese study (1,037 cases and 2,543 controls). A meta-analysis of the top SNPs identified three new associated loci: rs35934224[T] in TXNRD2 (odds ratio (OR) = 0.78, P = 4.05 × 10 -11) encoding a mitochondrial protein required for redox homeostasis; rs7137828[T] in ATXN2 (OR = 1.17, P = 8.73 × 10 -10); and rs2745572[A] upstream of FOXC1 (OR = 1.17, P = 1.76 × 10 -10). Using RT-PCR and immunohistochemistry, we show TXNRD2 and ATXN2 expression in retinal ganglion cells and the optic nerve head. These results identify new pathways underlying POAG susceptibility and suggest new targets for preventative therapies.

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