Common variants at 9p21 and 8q22 are associated with increased susceptibility to optic nerve degeneration in glaucoma.
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 associati...
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2012
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oai:doaj.org-article:c0f601961fb1441ea4c7117937edd6512021-11-18T06:18:39ZCommon variants at 9p21 and 8q22 are associated with increased susceptibility to optic nerve degeneration in glaucoma.1553-73901553-740410.1371/journal.pgen.1002654https://doaj.org/article/c0f601961fb1441ea4c7117937edd6512012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22570617/pdf/?tool=EBIhttps://doaj.org/toc/1553-7390https://doaj.org/toc/1553-7404Optic 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.Janey L WiggsBrian L YaspanMichael A HauserJae H KangR Rand AllinghamLana M OlsonWael AbdrabouBao J FanDan Y WangWendy BrodeurDonald L BudenzJoseph CaprioliAndrew CrenshawKristy CrooksElizabeth DelbonoKimberly F DohenyDavid S FriedmanDouglas GaasterlandTerry GaasterlandCathy LaurieRichard K LeePaul R LichterStephanie LoomisYutao LiuFelipe A MedeirosCathy McCartyDaniel MirelSayoko E MoroiDavid C MuschAnthony RealiniFrank W RozsaJoel S SchumanKathleen ScottKuldev SinghJoshua D SteinEdward H TragerPaul VanveldhuisenDouglas VollrathGadi WollsteinSachiko YoneyamaKang ZhangRobert N WeinrebJason ErnstManolis KellisTomohiro MasudaDon ZackJulia E RichardsMargaret Pericak-VanceLouis R PasqualeJonathan L HainesPublic Library of Science (PLoS)articleGeneticsQH426-470ENPLoS Genetics, Vol 8, Iss 4, p e1002654 (2012) |
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DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
Genetics QH426-470 |
| spellingShingle |
Genetics QH426-470 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 Laurie Richard 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 Common variants at 9p21 and 8q22 are associated with increased susceptibility to optic nerve degeneration in glaucoma. |
| description |
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. |
| format |
article |
| author |
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 Laurie Richard 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 |
| author_facet |
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 Laurie Richard 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 |
| author_sort |
Janey L Wiggs |
| title |
Common variants at 9p21 and 8q22 are associated with increased susceptibility to optic nerve degeneration in glaucoma. |
| title_short |
Common variants at 9p21 and 8q22 are associated with increased susceptibility to optic nerve degeneration in glaucoma. |
| title_full |
Common variants at 9p21 and 8q22 are associated with increased susceptibility to optic nerve degeneration in glaucoma. |
| title_fullStr |
Common variants at 9p21 and 8q22 are associated with increased susceptibility to optic nerve degeneration in glaucoma. |
| title_full_unstemmed |
Common variants at 9p21 and 8q22 are associated with increased susceptibility to optic nerve degeneration in glaucoma. |
| title_sort |
common variants at 9p21 and 8q22 are associated with increased susceptibility to optic nerve degeneration in glaucoma. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2012 |
| url |
https://doaj.org/article/c0f601961fb1441ea4c7117937edd651 |
| work_keys_str_mv |
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