Testosterone pathway genetic polymorphisms in relation to primary open-angle glaucoma: An analysis in two large datasets

Australian and New Zealand Registry of Advanced Glaucoma (ANZRAG) Consortium

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Purpose: Sex hormones may be associated with primary open-angle glaucoma (POAG), although the mechanisms are unclear. We previously observed that gene variants involved with estrogen metabolism were collectively associated with POAG in women but not men; here we assessed gene variants related to testosterone metabolism collectively and POAG risk. Methods: We used two datasets: one from the United States (3853 cases and 33,480 controls) and another from Australia (1155 cases and 1992 controls). Both datasets contained densely called genotypes imputed to the 1000 Genomes reference panel. We used pathway- and gene-based approaches with Pathway Analysis by Randomization Incorporating Structure (PARIS) software to assess the overall association between a panel of single nucleotide polymorphisms (SNPs) in testosterone metabolism genes and POAG. In sex-stratified analyses, we evaluated POAG overall and POAG subtypes defined by maximum IOP (high-tension [HTG] or normal tension glaucoma [NTG]). Results: In the US dataset, the SNP panel was not associated with POAG (permuted P = 0.77), although there was an association in the Australian sample (permuted P = 0.018). In both datasets, the SNP panel was associated with POAG in men (permuted P ≤ 0.033) and not women (permuted P ≥ 0.42), but in gene-based analyses, there was no consistency on the main genes responsible for these findings. In both datasets, the testosterone pathway association with HTG was significant (permuted P ≤ 0.011), but again, gene-based analyses showed no consistent driver gene associations. Conclusions: Collectively, testosterone metabolism pathway SNPs were consistently associated with the high-tension subtype of POAG in two datasets.

Original languageEnglish (US)
Pages (from-to)629-636
Number of pages8
JournalInvestigative Ophthalmology and Visual Science
Volume59
Issue number2
DOIs
StatePublished - Feb 1 2018

Fingerprint

Genetic Polymorphisms
Testosterone
Genes
Single Nucleotide Polymorphism
Low Tension Glaucoma
Datasets
Primary Open Angle Glaucoma
Gonadal Steroid Hormones
Random Allocation
Estrogens
Software
Genotype
Genome

Keywords

  • Genetics
  • Pathway analysis
  • Primary open-angle glaucoma
  • Testosterone

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

Cite this

Testosterone pathway genetic polymorphisms in relation to primary open-angle glaucoma : An analysis in two large datasets. / Australian and New Zealand Registry of Advanced Glaucoma (ANZRAG) Consortium.

In: Investigative Ophthalmology and Visual Science, Vol. 59, No. 2, 01.02.2018, p. 629-636.

Research output: Contribution to journalArticle

Australian and New Zealand Registry of Advanced Glaucoma (ANZRAG) Consortium. / Testosterone pathway genetic polymorphisms in relation to primary open-angle glaucoma : An analysis in two large datasets. In: Investigative Ophthalmology and Visual Science. 2018 ; Vol. 59, No. 2. pp. 629-636.
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abstract = "Purpose: Sex hormones may be associated with primary open-angle glaucoma (POAG), although the mechanisms are unclear. We previously observed that gene variants involved with estrogen metabolism were collectively associated with POAG in women but not men; here we assessed gene variants related to testosterone metabolism collectively and POAG risk. Methods: We used two datasets: one from the United States (3853 cases and 33,480 controls) and another from Australia (1155 cases and 1992 controls). Both datasets contained densely called genotypes imputed to the 1000 Genomes reference panel. We used pathway- and gene-based approaches with Pathway Analysis by Randomization Incorporating Structure (PARIS) software to assess the overall association between a panel of single nucleotide polymorphisms (SNPs) in testosterone metabolism genes and POAG. In sex-stratified analyses, we evaluated POAG overall and POAG subtypes defined by maximum IOP (high-tension [HTG] or normal tension glaucoma [NTG]). Results: In the US dataset, the SNP panel was not associated with POAG (permuted P = 0.77), although there was an association in the Australian sample (permuted P = 0.018). In both datasets, the SNP panel was associated with POAG in men (permuted P ≤ 0.033) and not women (permuted P ≥ 0.42), but in gene-based analyses, there was no consistency on the main genes responsible for these findings. In both datasets, the testosterone pathway association with HTG was significant (permuted P ≤ 0.011), but again, gene-based analyses showed no consistent driver gene associations. Conclusions: Collectively, testosterone metabolism pathway SNPs were consistently associated with the high-tension subtype of POAG in two datasets.",
keywords = "Genetics, Pathway analysis, Primary open-angle glaucoma, Testosterone",
author = "{Australian and New Zealand Registry of Advanced Glaucoma (ANZRAG) Consortium} and {Cooke Bailey}, {Jessica N.} and Puya Gharahkhani and Kang, {Jae H.} and Mariusz Butkiewicz and Sullivan, {David A.} and Weinreb, {Robert N.} and Hugues Aschard and Allingham, {R. Rand} and Allison Ashley-Koch and Lee, {Richard K.} and Moroi, {Sayoko E.} and Brilliant, {Murray H.} and Gadi Wollstein and Schuman, {Joel S.} and Fingert, {John H.} and Budenz, {Donald L.} and Tony Realini and Terry Gaasterland and Scott, {William K.} and Kuldev Singh and Sit, {Arthur J.} and Igo, {Robert P.} and Song, {Yeunjoo E.} and Lisa Hark and Robert Ritch and Rhee, {Douglas J.} and Douglas Vollrath and Zack, {Donald J.} and Felipe Medeiros and Vajaranant, {Thasarat S.} and Chasman, {Daniel I.} and Christen, {William G.} and Pericak-Vance, {Margaret A.} and Yutao Liu and Peter Kraft and Richards, {Julia E.} and Rosner, {Bernard A.} and Hauser, {Michael A.} and Yutao Liu and Burdon, {Kathryn P.} and Hewitt, {Alex W.} and Mackey, {David A.} and Haines, {Jonathan L.} and Stuart Macgregor and Wiggs, {Janey L.} and Pasquale, {Louis R.}",
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T1 - Testosterone pathway genetic polymorphisms in relation to primary open-angle glaucoma

T2 - An analysis in two large datasets

AU - Australian and New Zealand Registry of Advanced Glaucoma (ANZRAG) Consortium

AU - Cooke Bailey, Jessica N.

AU - Gharahkhani, Puya

AU - Kang, Jae H.

AU - Butkiewicz, Mariusz

AU - Sullivan, David A.

AU - Weinreb, Robert N.

AU - Aschard, Hugues

AU - Allingham, R. Rand

AU - Ashley-Koch, Allison

AU - Lee, Richard K.

AU - Moroi, Sayoko E.

AU - Brilliant, Murray H.

AU - Wollstein, Gadi

AU - Schuman, Joel S.

AU - Fingert, John H.

AU - Budenz, Donald L.

AU - Realini, Tony

AU - Gaasterland, Terry

AU - Scott, William K.

AU - Singh, Kuldev

AU - Sit, Arthur J.

AU - Igo, Robert P.

AU - Song, Yeunjoo E.

AU - Hark, Lisa

AU - Ritch, Robert

AU - Rhee, Douglas J.

AU - Vollrath, Douglas

AU - Zack, Donald J.

AU - Medeiros, Felipe

AU - Vajaranant, Thasarat S.

AU - Chasman, Daniel I.

AU - Christen, William G.

AU - Pericak-Vance, Margaret A.

AU - Liu, Yutao

AU - Kraft, Peter

AU - Richards, Julia E.

AU - Rosner, Bernard A.

AU - Hauser, Michael A.

AU - Liu, Yutao

AU - Burdon, Kathryn P.

AU - Hewitt, Alex W.

AU - Mackey, David A.

AU - Haines, Jonathan L.

AU - Macgregor, Stuart

AU - Wiggs, Janey L.

AU - Pasquale, Louis R.

PY - 2018/2/1

Y1 - 2018/2/1

N2 - Purpose: Sex hormones may be associated with primary open-angle glaucoma (POAG), although the mechanisms are unclear. We previously observed that gene variants involved with estrogen metabolism were collectively associated with POAG in women but not men; here we assessed gene variants related to testosterone metabolism collectively and POAG risk. Methods: We used two datasets: one from the United States (3853 cases and 33,480 controls) and another from Australia (1155 cases and 1992 controls). Both datasets contained densely called genotypes imputed to the 1000 Genomes reference panel. We used pathway- and gene-based approaches with Pathway Analysis by Randomization Incorporating Structure (PARIS) software to assess the overall association between a panel of single nucleotide polymorphisms (SNPs) in testosterone metabolism genes and POAG. In sex-stratified analyses, we evaluated POAG overall and POAG subtypes defined by maximum IOP (high-tension [HTG] or normal tension glaucoma [NTG]). Results: In the US dataset, the SNP panel was not associated with POAG (permuted P = 0.77), although there was an association in the Australian sample (permuted P = 0.018). In both datasets, the SNP panel was associated with POAG in men (permuted P ≤ 0.033) and not women (permuted P ≥ 0.42), but in gene-based analyses, there was no consistency on the main genes responsible for these findings. In both datasets, the testosterone pathway association with HTG was significant (permuted P ≤ 0.011), but again, gene-based analyses showed no consistent driver gene associations. Conclusions: Collectively, testosterone metabolism pathway SNPs were consistently associated with the high-tension subtype of POAG in two datasets.

AB - Purpose: Sex hormones may be associated with primary open-angle glaucoma (POAG), although the mechanisms are unclear. We previously observed that gene variants involved with estrogen metabolism were collectively associated with POAG in women but not men; here we assessed gene variants related to testosterone metabolism collectively and POAG risk. Methods: We used two datasets: one from the United States (3853 cases and 33,480 controls) and another from Australia (1155 cases and 1992 controls). Both datasets contained densely called genotypes imputed to the 1000 Genomes reference panel. We used pathway- and gene-based approaches with Pathway Analysis by Randomization Incorporating Structure (PARIS) software to assess the overall association between a panel of single nucleotide polymorphisms (SNPs) in testosterone metabolism genes and POAG. In sex-stratified analyses, we evaluated POAG overall and POAG subtypes defined by maximum IOP (high-tension [HTG] or normal tension glaucoma [NTG]). Results: In the US dataset, the SNP panel was not associated with POAG (permuted P = 0.77), although there was an association in the Australian sample (permuted P = 0.018). In both datasets, the SNP panel was associated with POAG in men (permuted P ≤ 0.033) and not women (permuted P ≥ 0.42), but in gene-based analyses, there was no consistency on the main genes responsible for these findings. In both datasets, the testosterone pathway association with HTG was significant (permuted P ≤ 0.011), but again, gene-based analyses showed no consistent driver gene associations. Conclusions: Collectively, testosterone metabolism pathway SNPs were consistently associated with the high-tension subtype of POAG in two datasets.

KW - Genetics

KW - Pathway analysis

KW - Primary open-angle glaucoma

KW - Testosterone

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