Testosterone Pathway Genetic Polymorphisms in Relation to Primary Open-Angle Glaucoma:  An Analysis in Two Large Datasets

Jessica N. Cooke Bailey; Puya Gharahkhani; Jae H. Kang; Mariusz Butkiewicz; David A. Sullivan; Robert N. Weinreb; Hugues Aschard; R. Rand Allingham; Allison Ashley-Koch; Richard K. Lee; Sayoko E. Moroi; Murray H. Brilliant; Gadi Wollstein; Joel S. Schuman; John H. Fingert; Donald L. Budenz; Tony Realini; Terry Gaasterland; William K. Scott; Kuldev Singh; Arthur J. Sit; Robert P. Igo, Jr.; Yeunjoo E. Song; Lisa Hark; Robert Ritch; Douglas J. Rhee; Douglas Vollrath; Donald J. Zack; Felipe Medeiros; Thasarat S. Vajaranant; Daniel I. Chasman; William G. Christen; Margaret A. Pericak-Vance; Yutao Liu; Peter Kraft; Julia E. Richards; Bernard A. Rosner; Michael A. Hauser; Jamie E. Craig; Kathryn P. Burdon; Alex W. Hewitt; David A. Mackey; Jonathan L. Haines; Stuart MacGregor; Janey L. Wiggs; Louis R. Pasquale; Australian and New Zealand Registry of Advanced Glaucoma (ANZRAG) Consortium; Shiwani Sharma; Sarah Martin; Tiger Zhou; Emmanuelle Souzeau; John Landers; Jude T. Fitzgerald; Richard A. Mills; Rhys Fogarty; Sonja Klebe

doi:10.1167/iovs.17-22708

Testosterone Pathway Genetic Polymorphisms in Relation to Primary Open-Angle Glaucoma: An Analysis in Two Large Datasets

Jessica N. Cooke Bailey , Puya Gharahkhani, Jae H. Kang, Mariusz Butkiewicz, David A. Sullivan, Robert N. Weinreb, Hugues Aschard, R. Rand Allingham, Allison Ashley-Koch, Richard K. Lee, Sayoko E. Moroi, Murray H. Brilliant, Gadi Wollstein, Joel S. Schuman, John H. Fingert, Donald L. Budenz, Tony Realini, Terry Gaasterland, William K. Scott, Kuldev SinghArthur J. Sit, Robert P. Igo, Jr., Yeunjoo E. Song, Lisa Hark, Robert Ritch, Douglas J. Rhee, Douglas Vollrath, Donald J. Zack, Felipe Medeiros, Thasarat S. Vajaranant, Daniel I. Chasman, William G. Christen, Margaret A. Pericak-Vance, Yutao Liu, Peter Kraft, Julia E. Richards, Bernard A. Rosner, Michael A. Hauser, Jamie E. Craig, Kathryn P. Burdon, Alex W. Hewitt, David A. Mackey, Jonathan L. Haines, Stuart MacGregor, Janey L. Wiggs, Louis R. Pasquale, Australian and New Zealand Registry of Advanced Glaucoma (ANZRAG) Consortium, Shiwani Sharma, Sarah Martin, Tiger Zhou, Emmanuelle Souzeau, John Landers, Jude T. Fitzgerald, Richard A. Mills, Rhys Fogarty, Sonja Klebe

College of Medicine and Public Health

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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.

Original language	English
Pages (from-to)	629-636
Number of pages	8
Journal	Investigative Ophthalmology and Visual Science
Volume	59
Issue number	2
DOIs	https://doi.org/10.1167/iovs.17-22708
Publication status	Published - Feb 2018

Keywords

Glaucoma
slit lamp biomicroscopy
angle closure
cup-disc ratio
Pathway analysis
Testosterone
Primary open-angle glaucoma
Genetics

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Cooke Bailey , J. N., Gharahkhani, P., Kang, J. H., Butkiewicz, M., Sullivan, D. A., Weinreb, R. N., Aschard, H., Allingham, R. R., Ashley-Koch, A., Lee, R. K., Moroi, S. E., Brilliant, M. H., Wollstein, G., Schuman, J. S., Fingert, J. H., Budenz, D. L., Realini, T., Gaasterland, T., Scott, W. K., ... Klebe, S. (2018). Testosterone Pathway Genetic Polymorphisms in Relation to Primary Open-Angle Glaucoma: An Analysis in Two Large Datasets. Investigative Ophthalmology and Visual Science, 59(2), 629-636. https://doi.org/10.1167/iovs.17-22708

@article{ee8a77bd6ccc4acd9ab9f87a9be2e7cf,

title = "Testosterone Pathway Genetic Polymorphisms in Relation to Primary Open-Angle Glaucoma: An Analysis in Two Large Datasets",

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 = "Glaucoma, slit lamp biomicroscopy, angle closure, cup-disc ratio, Pathway analysis, Testosterone, Primary open-angle glaucoma, Genetics",

author = "{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, Jr.}, {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 Craig, {Jamie E.} 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.} and {Australian and New Zealand Registry of Advanced Glaucoma (ANZRAG) Consortium} and Shiwani Sharma and Sarah Martin and Tiger Zhou and Emmanuelle Souzeau and John Landers and Fitzgerald, {Jude T.} and Mills, {Richard A.} and Rhys Fogarty and Sonja Klebe and Graham, {Stuart L.} and Casson, {Robert J.} and Mark Chehade and Ruddle, {Jonathan B.} and Ivan Goldberg and White, {Andrew J.} and Healey, {Paul R.} and Martin, {Nicholas G.} and Graham Radford-Smith and Whiteman, {David C.} and Law, {Matthew H.} and Brown, {Matthew A.} and Katie Cremin",

year = "2018",

month = feb,

doi = "10.1167/iovs.17-22708",

language = "English",

volume = "59",

pages = "629--636",

journal = "Investigative Ophthalmology and Visual Science",

issn = "0146-0404",

publisher = "Association for Research in Vision and Ophthalmology Inc.",

number = "2",

}

Cooke Bailey , JN, Gharahkhani, P, Kang, JH, Butkiewicz, M, Sullivan, DA, Weinreb, RN, Aschard, H, Allingham, RR, Ashley-Koch, A, Lee, RK, Moroi, SE, Brilliant, MH, Wollstein, G, Schuman, JS, Fingert, JH, Budenz, DL, Realini, T, Gaasterland, T, Scott, WK, Singh, K, Sit, AJ, Igo, Jr., RP, Song, YE, Hark, L, Ritch, R, Rhee, DJ, Vollrath, D, Zack, DJ, Medeiros, F, Vajaranant, TS, Chasman, DI, Christen, WG, Pericak-Vance, MA, Liu, Y, Kraft, P, Richards, JE, Rosner, BA, Hauser, MA, Craig, JE, Burdon, KP, Hewitt, AW, Mackey, DA, Haines, JL, MacGregor, S, Wiggs, JL, Pasquale, LR, Australian and New Zealand Registry of Advanced Glaucoma (ANZRAG) Consortium, Sharma, S, Martin, S, Zhou, T, Souzeau, E , Landers, J, Fitzgerald, JT, Mills, RA, Fogarty, R & Klebe, S 2018, 'Testosterone Pathway Genetic Polymorphisms in Relation to Primary Open-Angle Glaucoma: An Analysis in Two Large Datasets', Investigative Ophthalmology and Visual Science, vol. 59, no. 2, pp. 629-636. https://doi.org/10.1167/iovs.17-22708

TY - JOUR

T1 - Testosterone Pathway Genetic Polymorphisms in Relation to Primary Open-Angle Glaucoma

T2 - An Analysis in Two Large Datasets

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, Jr., 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 - Craig, Jamie E.

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.

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

AU - Sharma, Shiwani

AU - Martin, Sarah

AU - Zhou, Tiger

AU - Souzeau, Emmanuelle

AU - Landers, John

AU - Fitzgerald, Jude T.

AU - Mills, Richard A.

AU - Fogarty, Rhys

AU - Klebe, Sonja

AU - Graham, Stuart L.

AU - Casson, Robert J.

AU - Chehade, Mark

AU - Ruddle, Jonathan B.

AU - Goldberg, Ivan

AU - White, Andrew J.

AU - Healey, Paul R.

AU - Martin, Nicholas G.

AU - Radford-Smith, Graham

AU - Whiteman, David C.

AU - Law, Matthew H.

AU - Brown, Matthew A.

AU - Cremin, Katie

PY - 2018/2

Y1 - 2018/2

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 - Glaucoma

KW - slit lamp biomicroscopy

KW - angle closure

KW - cup-disc ratio

KW - Pathway analysis

KW - Testosterone

KW - Primary open-angle glaucoma

KW - Genetics

UR - http://purl.org/au-research/grants/NHMRC/535074

UR - http://purl.org/au-research/grants/NHMRC/1031362

UR - http://purl.org/au-research/grants/NHMRC/1023911

UR - http://purl.org/au-research/grants/NHMRC/1021105

UR - http://purl.org/au-research/grants/NHMRC/199600

UR - http://purl.org/au-research/grants/NHMRC/552429

UR - http://www.scopus.com/inward/record.url?scp=85041544064&partnerID=8YFLogxK

U2 - 10.1167/iovs.17-22708

DO - 10.1167/iovs.17-22708

M3 - Article

SN - 0146-0404

VL - 59

SP - 629

EP - 636

JO - Investigative Ophthalmology and Visual Science

JF - Investigative Ophthalmology and Visual Science

IS - 2

ER -

Testosterone Pathway Genetic Polymorphisms in Relation to Primary Open-Angle Glaucoma: An Analysis in Two Large Datasets

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