Common variants at 9p21 and 8q22 are associated with increased susceptibility to optic nerve degeneration in glaucoma

Janey L. Wiggs, Brian L. Yaspan, Michael A. Hauser, Jae H. Kang, R. Rand Allingham, Lana M. Olson, Wael Abdrabou, Bao J. Fan, Dan Y. Wang, Wendy Brodeur, Donald L. Budenz, Joseph Caprioli, Andrew Crenshaw, Kristy Crooks, Elizabeth DelBono, Kimberly F. Doheny, David S. Friedman, Douglas Gaasterland, Terry Gaasterland, Cathy LaurieRichard K. Lee, Paul R. Lichter, Stephanie Loomis, Yutao Liu, Felipe A. Medeiros, Cathy McCarty, Daniel Mirel, Sayoko E. Moroi, David C. Musch, Anthony Realini, Frank W. Rozsa, Joel S. Schuman, Kathleen Scott, Kuldev Singh, Joshua D. Stein, Edward H. Trager, Paul VanVeldhuisen, Douglas Vollrath, Gadi Wollstein, Sachiko Yoneyama, Kang Zhang, Robert N. Weinreb, Jason Ernst, Manolis Kellis, Tomohiro Masuda, Don Zack, Julia E. Richards, Margaret Pericak-Vance, Louis R. Pasquale, Jonathan L. Haines

Research output: Contribution to journalArticle

177 Citations (Scopus)

Abstract

Optic nerve degeneration caused by glaucoma is a leading cause of blindness worldwide. Patients affected by the normal-pressure form of glaucoma are more likely to harbor risk alleles for glaucoma-related optic nerve disease. We have performed a meta-analysis of two independent genome-wide association studies for primary open angle glaucoma (POAG) followed by a normal-pressure glaucoma (NPG, defined by intraocular pressure (IOP) less than 22 mmHg) subgroup analysis. The single-nucleotide polymorphisms that showed the most significant associations were tested for association with a second form of glaucoma, exfoliation-syndrome glaucoma. The overall meta-analysis of the GLAUGEN and NEIGHBOR dataset results (3,146 cases and 3,487 controls) identified significant associations between two loci and POAG: the CDKN2BAS region on 9p21 (rs2157719 [G], OR = 0.69 [95%CI 0.63-0.75], p = 1.86×10-18), and the SIX1/SIX6 region on chromosome 14q23 (rs10483727 [A], OR = 1.32 [95%CI 1.21-1.43], p = 3.87×10-11). In sub-group analysis two loci were significantly associated with NPG: 9p21 containing the CDKN2BAS gene (rs2157719 [G], OR = 0.58 [95% CI 0.50-0.67], p = 1.17×10-12) and a probable regulatory region on 8q22 (rs284489 [G], OR = 0.62 [95% CI 0.53-0.72], p = 8.88×10-10). Both NPG loci were also nominally associated with a second type of glaucoma, exfoliation syndrome glaucoma (rs2157719 [G], OR = 0.59 [95% CI 0.41-0.87], p = 0.004 and rs284489 [G], OR = 0.76 [95% CI 0.54-1.06], p = 0.021), suggesting that these loci might contribute more generally to optic nerve degeneration in glaucoma. Because both loci influence transforming growth factor beta (TGF-beta) signaling, we performed a genomic pathway analysis that showed an association between the TGF-beta pathway and NPG (permuted p = 0.009). These results suggest that neuro-protective therapies targeting TGF-beta signaling could be effective for multiple forms of glaucoma.

Original languageEnglish (US)
Article numbere1002654
JournalPLoS Genetics
Volume8
Issue number4
DOIs
StatePublished - Apr 1 2012

Fingerprint

Nerve Degeneration
glaucoma
Optic Nerve
optics
Glaucoma
nerve tissue
meta-analysis
Exfoliation Syndrome
blindness
Transforming Growth Factor beta
targeting
chromosome
genomics
allele
transforming growth factor beta
harbor
polymorphism
genome
loci
Meta-Analysis

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

Cite this

Wiggs, J. L., Yaspan, B. L., Hauser, M. A., Kang, J. H., Allingham, R. R., Olson, L. M., ... Haines, J. L. (2012). Common variants at 9p21 and 8q22 are associated with increased susceptibility to optic nerve degeneration in glaucoma. PLoS Genetics, 8(4), [e1002654]. https://doi.org/10.1371/journal.pgen.1002654

Common variants at 9p21 and 8q22 are associated with increased susceptibility to optic nerve degeneration in glaucoma. / Wiggs, Janey L.; Yaspan, Brian L.; Hauser, Michael A.; Kang, Jae H.; Allingham, R. Rand; Olson, Lana M.; Abdrabou, Wael; Fan, Bao J.; Wang, Dan Y.; Brodeur, Wendy; Budenz, Donald L.; Caprioli, Joseph; Crenshaw, Andrew; Crooks, Kristy; DelBono, Elizabeth; Doheny, Kimberly F.; Friedman, David S.; Gaasterland, Douglas; Gaasterland, Terry; Laurie, Cathy; Lee, Richard K.; Lichter, Paul R.; Loomis, Stephanie; Liu, Yutao; Medeiros, Felipe A.; McCarty, Cathy; Mirel, Daniel; Moroi, Sayoko E.; Musch, David C.; Realini, Anthony; Rozsa, Frank W.; Schuman, Joel S.; Scott, Kathleen; Singh, Kuldev; Stein, Joshua D.; Trager, Edward H.; VanVeldhuisen, Paul; Vollrath, Douglas; Wollstein, Gadi; Yoneyama, Sachiko; Zhang, Kang; Weinreb, Robert N.; Ernst, Jason; Kellis, Manolis; Masuda, Tomohiro; Zack, Don; Richards, Julia E.; Pericak-Vance, Margaret; Pasquale, Louis R.; Haines, Jonathan L.

In: PLoS Genetics, Vol. 8, No. 4, e1002654, 01.04.2012.

Research output: Contribution to journalArticle

Wiggs, JL, Yaspan, BL, Hauser, MA, Kang, JH, Allingham, RR, Olson, LM, Abdrabou, W, Fan, BJ, Wang, DY, Brodeur, W, Budenz, DL, Caprioli, J, Crenshaw, A, Crooks, K, DelBono, E, Doheny, KF, Friedman, DS, Gaasterland, D, Gaasterland, T, Laurie, C, Lee, RK, Lichter, PR, Loomis, S, Liu, Y, Medeiros, FA, McCarty, C, Mirel, D, Moroi, SE, Musch, DC, Realini, A, Rozsa, FW, Schuman, JS, Scott, K, Singh, K, Stein, JD, Trager, EH, VanVeldhuisen, P, Vollrath, D, Wollstein, G, Yoneyama, S, Zhang, K, Weinreb, RN, Ernst, J, Kellis, M, Masuda, T, Zack, D, Richards, JE, Pericak-Vance, M, Pasquale, LR & Haines, JL 2012, 'Common variants at 9p21 and 8q22 are associated with increased susceptibility to optic nerve degeneration in glaucoma', PLoS Genetics, vol. 8, no. 4, e1002654. https://doi.org/10.1371/journal.pgen.1002654
Wiggs, Janey L. ; Yaspan, Brian L. ; Hauser, Michael A. ; Kang, Jae H. ; Allingham, R. Rand ; Olson, Lana M. ; Abdrabou, Wael ; Fan, Bao J. ; Wang, Dan Y. ; Brodeur, Wendy ; Budenz, Donald L. ; Caprioli, Joseph ; Crenshaw, Andrew ; Crooks, Kristy ; DelBono, Elizabeth ; Doheny, Kimberly F. ; Friedman, David S. ; Gaasterland, Douglas ; Gaasterland, Terry ; Laurie, Cathy ; Lee, Richard K. ; Lichter, Paul R. ; Loomis, Stephanie ; Liu, Yutao ; Medeiros, Felipe A. ; McCarty, Cathy ; Mirel, Daniel ; Moroi, Sayoko E. ; Musch, David C. ; Realini, Anthony ; Rozsa, Frank W. ; Schuman, Joel S. ; Scott, Kathleen ; Singh, Kuldev ; Stein, Joshua D. ; Trager, Edward H. ; VanVeldhuisen, Paul ; Vollrath, Douglas ; Wollstein, Gadi ; Yoneyama, Sachiko ; Zhang, Kang ; Weinreb, Robert N. ; Ernst, Jason ; Kellis, Manolis ; Masuda, Tomohiro ; Zack, Don ; Richards, Julia E. ; Pericak-Vance, Margaret ; Pasquale, Louis R. ; Haines, Jonathan L. / Common variants at 9p21 and 8q22 are associated with increased susceptibility to optic nerve degeneration in glaucoma. In: PLoS Genetics. 2012 ; Vol. 8, No. 4.
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abstract = "Optic nerve degeneration caused by glaucoma is a leading cause of blindness worldwide. Patients affected by the normal-pressure form of glaucoma are more likely to harbor risk alleles for glaucoma-related optic nerve disease. We have performed a meta-analysis of two independent genome-wide association studies for primary open angle glaucoma (POAG) followed by a normal-pressure glaucoma (NPG, defined by intraocular pressure (IOP) less than 22 mmHg) subgroup analysis. The single-nucleotide polymorphisms that showed the most significant associations were tested for association with a second form of glaucoma, exfoliation-syndrome glaucoma. The overall meta-analysis of the GLAUGEN and NEIGHBOR dataset results (3,146 cases and 3,487 controls) identified significant associations between two loci and POAG: the CDKN2BAS region on 9p21 (rs2157719 [G], OR = 0.69 [95{\%}CI 0.63-0.75], p = 1.86×10-18), and the SIX1/SIX6 region on chromosome 14q23 (rs10483727 [A], OR = 1.32 [95{\%}CI 1.21-1.43], p = 3.87×10-11). In sub-group analysis two loci were significantly associated with NPG: 9p21 containing the CDKN2BAS gene (rs2157719 [G], OR = 0.58 [95{\%} CI 0.50-0.67], p = 1.17×10-12) and a probable regulatory region on 8q22 (rs284489 [G], OR = 0.62 [95{\%} CI 0.53-0.72], p = 8.88×10-10). Both NPG loci were also nominally associated with a second type of glaucoma, exfoliation syndrome glaucoma (rs2157719 [G], OR = 0.59 [95{\%} CI 0.41-0.87], p = 0.004 and rs284489 [G], OR = 0.76 [95{\%} CI 0.54-1.06], p = 0.021), suggesting that these loci might contribute more generally to optic nerve degeneration in glaucoma. Because both loci influence transforming growth factor beta (TGF-beta) signaling, we performed a genomic pathway analysis that showed an association between the TGF-beta pathway and NPG (permuted p = 0.009). These results suggest that neuro-protective therapies targeting TGF-beta signaling could be effective for multiple forms of glaucoma.",
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T1 - Common variants at 9p21 and 8q22 are associated with increased susceptibility to optic nerve degeneration in glaucoma

AU - Wiggs, Janey L.

AU - Yaspan, Brian L.

AU - Hauser, Michael A.

AU - Kang, Jae H.

AU - Allingham, R. Rand

AU - Olson, Lana M.

AU - Abdrabou, Wael

AU - Fan, Bao J.

AU - Wang, Dan Y.

AU - Brodeur, Wendy

AU - Budenz, Donald L.

AU - Caprioli, Joseph

AU - Crenshaw, Andrew

AU - Crooks, Kristy

AU - DelBono, Elizabeth

AU - Doheny, Kimberly F.

AU - Friedman, David S.

AU - Gaasterland, Douglas

AU - Gaasterland, Terry

AU - Laurie, Cathy

AU - Lee, Richard K.

AU - Lichter, Paul R.

AU - Loomis, Stephanie

AU - Liu, Yutao

AU - Medeiros, Felipe A.

AU - McCarty, Cathy

AU - Mirel, Daniel

AU - Moroi, Sayoko E.

AU - Musch, David C.

AU - Realini, Anthony

AU - Rozsa, Frank W.

AU - Schuman, Joel S.

AU - Scott, Kathleen

AU - Singh, Kuldev

AU - Stein, Joshua D.

AU - Trager, Edward H.

AU - VanVeldhuisen, Paul

AU - Vollrath, Douglas

AU - Wollstein, Gadi

AU - Yoneyama, Sachiko

AU - Zhang, Kang

AU - Weinreb, Robert N.

AU - Ernst, Jason

AU - Kellis, Manolis

AU - Masuda, Tomohiro

AU - Zack, Don

AU - Richards, Julia E.

AU - Pericak-Vance, Margaret

AU - Pasquale, Louis R.

AU - Haines, Jonathan L.

PY - 2012/4/1

Y1 - 2012/4/1

N2 - Optic nerve degeneration caused by glaucoma is a leading cause of blindness worldwide. Patients affected by the normal-pressure form of glaucoma are more likely to harbor risk alleles for glaucoma-related optic nerve disease. We have performed a meta-analysis of two independent genome-wide association studies for primary open angle glaucoma (POAG) followed by a normal-pressure glaucoma (NPG, defined by intraocular pressure (IOP) less than 22 mmHg) subgroup analysis. The single-nucleotide polymorphisms that showed the most significant associations were tested for association with a second form of glaucoma, exfoliation-syndrome glaucoma. The overall meta-analysis of the GLAUGEN and NEIGHBOR dataset results (3,146 cases and 3,487 controls) identified significant associations between two loci and POAG: the CDKN2BAS region on 9p21 (rs2157719 [G], OR = 0.69 [95%CI 0.63-0.75], p = 1.86×10-18), and the SIX1/SIX6 region on chromosome 14q23 (rs10483727 [A], OR = 1.32 [95%CI 1.21-1.43], p = 3.87×10-11). In sub-group analysis two loci were significantly associated with NPG: 9p21 containing the CDKN2BAS gene (rs2157719 [G], OR = 0.58 [95% CI 0.50-0.67], p = 1.17×10-12) and a probable regulatory region on 8q22 (rs284489 [G], OR = 0.62 [95% CI 0.53-0.72], p = 8.88×10-10). Both NPG loci were also nominally associated with a second type of glaucoma, exfoliation syndrome glaucoma (rs2157719 [G], OR = 0.59 [95% CI 0.41-0.87], p = 0.004 and rs284489 [G], OR = 0.76 [95% CI 0.54-1.06], p = 0.021), suggesting that these loci might contribute more generally to optic nerve degeneration in glaucoma. Because both loci influence transforming growth factor beta (TGF-beta) signaling, we performed a genomic pathway analysis that showed an association between the TGF-beta pathway and NPG (permuted p = 0.009). These results suggest that neuro-protective therapies targeting TGF-beta signaling could be effective for multiple forms of glaucoma.

AB - Optic nerve degeneration caused by glaucoma is a leading cause of blindness worldwide. Patients affected by the normal-pressure form of glaucoma are more likely to harbor risk alleles for glaucoma-related optic nerve disease. We have performed a meta-analysis of two independent genome-wide association studies for primary open angle glaucoma (POAG) followed by a normal-pressure glaucoma (NPG, defined by intraocular pressure (IOP) less than 22 mmHg) subgroup analysis. The single-nucleotide polymorphisms that showed the most significant associations were tested for association with a second form of glaucoma, exfoliation-syndrome glaucoma. The overall meta-analysis of the GLAUGEN and NEIGHBOR dataset results (3,146 cases and 3,487 controls) identified significant associations between two loci and POAG: the CDKN2BAS region on 9p21 (rs2157719 [G], OR = 0.69 [95%CI 0.63-0.75], p = 1.86×10-18), and the SIX1/SIX6 region on chromosome 14q23 (rs10483727 [A], OR = 1.32 [95%CI 1.21-1.43], p = 3.87×10-11). In sub-group analysis two loci were significantly associated with NPG: 9p21 containing the CDKN2BAS gene (rs2157719 [G], OR = 0.58 [95% CI 0.50-0.67], p = 1.17×10-12) and a probable regulatory region on 8q22 (rs284489 [G], OR = 0.62 [95% CI 0.53-0.72], p = 8.88×10-10). Both NPG loci were also nominally associated with a second type of glaucoma, exfoliation syndrome glaucoma (rs2157719 [G], OR = 0.59 [95% CI 0.41-0.87], p = 0.004 and rs284489 [G], OR = 0.76 [95% CI 0.54-1.06], p = 0.021), suggesting that these loci might contribute more generally to optic nerve degeneration in glaucoma. Because both loci influence transforming growth factor beta (TGF-beta) signaling, we performed a genomic pathway analysis that showed an association between the TGF-beta pathway and NPG (permuted p = 0.009). These results suggest that neuro-protective therapies targeting TGF-beta signaling could be effective for multiple forms of glaucoma.

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