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New insights into the genetics of primary open-angle glaucoma based on meta-analyses of intraocular pressure and optic disc characteristics

New insights into the genetics of primary open-angle glaucoma based on meta-analyses of intraocular pressure and optic disc characteristics
New insights into the genetics of primary open-angle glaucoma based on meta-analyses of intraocular pressure and optic disc characteristics
Primary open-angle glaucoma (POAG), the most common optic neuropathy, is a highly heritable disease (h2 = 0.42 ± 0.09). Siblings of POAG cases have a ten-fold increase risk of developing the disease. Intraocular pressure (IOP) and optic nerve head characteristics are used clinically to predict POAG risk. We conducted a genome-wide association meta-analysis of IOP and optic disc parameters and validated our findings in multiple sets of POAG cases and controls. Using imputation to the 1000 genomes (1000G) reference set, we identified 9 new genomic regions associated with vertical cup disc ratio (VCDR) and 1 new region associated with IOP. Additionally, we found 5 novel loci for optic nerve cup area and 6 for disc area. Previously it was assumed that genetic variation influenced POAG either through IOP or via changes to the optic nerve head; here we present evidence that some genomic regions affect both IOP and the disc parameters. We characterized the effect of the novel loci through pathway analysis and found that pathways involved are not entirely distinct as assumed. Further, we identified a novel association between CDKN1A and POAG. Using a zebrafish model we show that six6b (associated with POAG and optic nerve head variation) alters the expression of cdkn1a. In summary, we have identified several novel genes influencing the major clinical risk predictors of POAG and showed that genetic variation in CDKN1A is important in POAG risk
438–453
Springelkamp, Henriët
ab8d297c-242a-43d7-a543-bd88b9b7eb50
Iglesias, Adriana I.
3ec0a9a9-d479-4887-a241-293eb32fa6e0
Mishra, Aniket
1f3a9964-30ea-41a4-8811-9f0180b6e3d4
Lotery, Andrew
5ecc2d2d-d0b4-468f-ad2c-df7156f8e514
Gibson, Jane
855033a6-38f3-4853-8f60-d7d4561226ae
Cree, Angela
6724b71b-8828-4abb-971f-0856c2af555e
et al.
NEIGHBORHOOD Consortium
Springelkamp, Henriët
ab8d297c-242a-43d7-a543-bd88b9b7eb50
Iglesias, Adriana I.
3ec0a9a9-d479-4887-a241-293eb32fa6e0
Mishra, Aniket
1f3a9964-30ea-41a4-8811-9f0180b6e3d4
Lotery, Andrew
5ecc2d2d-d0b4-468f-ad2c-df7156f8e514
Gibson, Jane
855033a6-38f3-4853-8f60-d7d4561226ae
Cree, Angela
6724b71b-8828-4abb-971f-0856c2af555e

Springelkamp, Henriët, Iglesias, Adriana I., Mishra, Aniket, Lotery, Andrew, Gibson, Jane and Cree, Angela , et al. and NEIGHBORHOOD Consortium (2017) New insights into the genetics of primary open-angle glaucoma based on meta-analyses of intraocular pressure and optic disc characteristics. Human Molecular Genetics, 26 (2), 438–453. (doi:10.1093/hmg/ddw399).

Record type: Article

Abstract

Primary open-angle glaucoma (POAG), the most common optic neuropathy, is a highly heritable disease (h2 = 0.42 ± 0.09). Siblings of POAG cases have a ten-fold increase risk of developing the disease. Intraocular pressure (IOP) and optic nerve head characteristics are used clinically to predict POAG risk. We conducted a genome-wide association meta-analysis of IOP and optic disc parameters and validated our findings in multiple sets of POAG cases and controls. Using imputation to the 1000 genomes (1000G) reference set, we identified 9 new genomic regions associated with vertical cup disc ratio (VCDR) and 1 new region associated with IOP. Additionally, we found 5 novel loci for optic nerve cup area and 6 for disc area. Previously it was assumed that genetic variation influenced POAG either through IOP or via changes to the optic nerve head; here we present evidence that some genomic regions affect both IOP and the disc parameters. We characterized the effect of the novel loci through pathway analysis and found that pathways involved are not entirely distinct as assumed. Further, we identified a novel association between CDKN1A and POAG. Using a zebrafish model we show that six6b (associated with POAG and optic nerve head variation) alters the expression of cdkn1a. In summary, we have identified several novel genes influencing the major clinical risk predictors of POAG and showed that genetic variation in CDKN1A is important in POAG risk

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HMG submission 1000G IGGC revised - Accepted Manuscript
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Accepted/In Press date: 28 September 2016
e-pub ahead of print date: 10 January 2017
Published date: 15 January 2017
Organisations: Clinical & Experimental Sciences

Identifiers

Local EPrints ID: 403548
URI: https://eprints.soton.ac.uk/id/eprint/403548
PURE UUID: 05cb38bf-5eb6-4406-bf98-1ae95a4b2642
ORCID for Andrew Lotery: ORCID iD orcid.org/0000-0001-5541-4305
ORCID for Jane Gibson: ORCID iD orcid.org/0000-0002-0973-8285

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Date deposited: 05 Dec 2016 10:06
Last modified: 03 Dec 2019 06:26

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Contributors

Author: Henriët Springelkamp
Author: Adriana I. Iglesias
Author: Aniket Mishra
Author: Andrew Lotery ORCID iD
Author: Jane Gibson ORCID iD
Author: Angela Cree

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