Myocilin Gene Gln368Ter Variant Penetrance and Association With Glaucoma in Population-Based and Registry-Based Studies

Xikun Han, Emmanuelle Souzeau, Jue-Sheng Ong, Jiyuan An, Owen M. Siggs, Kathryn P. Bunion, Stephen Best, Ivan Goldberg, Paul R. Healey, Stuart L. Graham, Jonathan B. Ruddle, Richard A. Mills, John Landers, Anna Galanopoulos, Andrew J. R. White, Robert Casson, David A. Mackey, Alex W. Hewitt, Puya Gharahkhani, Jamie E. Craig & 1 others Stuart MacGregor

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Abstract

IMPORTANCE The p.Gln368Ter (rs74315329) risk allele in themyocilin gene (MYOC) was initially reported to have high penetrance in glaucoma registry-based studies, but much lower estimates were recently obtained from population-based studies. We investigated this disparity using data from Australia and the United Kingdom.

OBJECTIVES To examine the penetrance and effect size of the MYOC p.Gln368Ter variant with glaucoma and ocular hypertension (OHT).

DESIGN, SETTING, AND PARTICIPANTS This cross-sectional study within the UK Biobank (UKBB) included participants of white British ancestry. Glaucoma cases were defined by International Classification of Diseases, Ninth Revision (ICD-9) and Tenth Revision (ICD-10) diagnoses and self-reported questionnaires. Carriers of the MYOC p.Gln368Ter variant were identified using genotype imputation from arrays. In contrast, 2 Australian registry-based studies, the Australian and New Zealand Registry of Advanced Glaucoma and the Glaucoma Inheritance Study in Tasmania, ascertained glaucoma cases referred by eye care clinicians, with historic control participants recruited from other Australian studies. Samples were either directly sequenced or had genotypes determined by imputation (for the Australian registry and historic control participants). Recruitment to the UKBB occurred between 2006 and 2010, and data analysis occurred from September 2017 to July 2018.

MAIN OUTCOMES AND MEASURES The penetrance and odds ratio (OR) were estimated for the MYOC p.Gln368Ter variants in participants with glaucoma and OHT.

RESULTS A total of 411 337 UKBB participants of white British ancestry (mean [SD] age, 56.6 [8.0] years) were included, plus 3071 Australian registry and 6750 historic control participants. In the UKBB, the minor allele frequency of the MYOC p.Gln368Ter variant was 1 in 786 individuals (0.13%). The odds ratio of p.Gln368Ter in patients with primary open-angle glaucoma (POAG) was 6.76 (95% CI, 4.05-11.29); glaucoma (POAG, self-reported glaucoma, and unspecified glaucoma), 4.40 (95% CI, 3.38-5.71); OHT, 3.56 (95% CI, 2.53-4.92); and OHT and glaucoma combined, 4.18 (95% CI, 3.05-5.67). The penetrance of the MYOC p.Gln368Ter variant was 7.6% in patients with glaucoma, 24.3% in patients with OHT, and 30.8% in patients with OHT and glaucoma combined. In the Australian registry studies, the odds of MYOC p.Gln368Ter variant were 12.16 (95% CI, 6.34-24.97) in patients with advanced glaucoma and 3.97 (95% CI, 1.55-9.75) in those with nonadvanced glaucoma; the penetrance of glaucoma was 56.1%, and penetrance in those considered to have glaucoma or be glaucoma suspects was 69.5%.

CONCLUSIONS AND RELEVANCE The MYOC p.Gln368Ter variant confers a very high-risk effect size for advanced glaucoma; the risk is lower in nonadvanced glaucoma and OHT. In the general population sample, approximately 50% of MYOC p.Gln368Ter carriers 65 years and older had glaucoma or OHT, with higher prevalence in the Australian registry studies.

Original languageEnglish
Pages (from-to)28-35
Number of pages8
JournalJAMA Ophthalmology
Volume137
Issue number1
DOIs
Publication statusPublished - Jan 2019

Cite this

Han, Xikun ; Souzeau, Emmanuelle ; Ong, Jue-Sheng ; An, Jiyuan ; Siggs, Owen M. ; Bunion, Kathryn P. ; Best, Stephen ; Goldberg, Ivan ; Healey, Paul R. ; Graham, Stuart L. ; Ruddle, Jonathan B. ; Mills, Richard A. ; Landers, John ; Galanopoulos, Anna ; White, Andrew J. R. ; Casson, Robert ; Mackey, David A. ; Hewitt, Alex W. ; Gharahkhani, Puya ; Craig, Jamie E. ; MacGregor, Stuart. / Myocilin Gene Gln368Ter Variant Penetrance and Association With Glaucoma in Population-Based and Registry-Based Studies. In: JAMA Ophthalmology. 2019 ; Vol. 137, No. 1. pp. 28-35.
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title = "Myocilin Gene Gln368Ter Variant Penetrance and Association With Glaucoma in Population-Based and Registry-Based Studies",
abstract = "IMPORTANCE The p.Gln368Ter (rs74315329) risk allele in themyocilin gene (MYOC) was initially reported to have high penetrance in glaucoma registry-based studies, but much lower estimates were recently obtained from population-based studies. We investigated this disparity using data from Australia and the United Kingdom.OBJECTIVES To examine the penetrance and effect size of the MYOC p.Gln368Ter variant with glaucoma and ocular hypertension (OHT).DESIGN, SETTING, AND PARTICIPANTS This cross-sectional study within the UK Biobank (UKBB) included participants of white British ancestry. Glaucoma cases were defined by International Classification of Diseases, Ninth Revision (ICD-9) and Tenth Revision (ICD-10) diagnoses and self-reported questionnaires. Carriers of the MYOC p.Gln368Ter variant were identified using genotype imputation from arrays. In contrast, 2 Australian registry-based studies, the Australian and New Zealand Registry of Advanced Glaucoma and the Glaucoma Inheritance Study in Tasmania, ascertained glaucoma cases referred by eye care clinicians, with historic control participants recruited from other Australian studies. Samples were either directly sequenced or had genotypes determined by imputation (for the Australian registry and historic control participants). Recruitment to the UKBB occurred between 2006 and 2010, and data analysis occurred from September 2017 to July 2018.MAIN OUTCOMES AND MEASURES The penetrance and odds ratio (OR) were estimated for the MYOC p.Gln368Ter variants in participants with glaucoma and OHT.RESULTS A total of 411 337 UKBB participants of white British ancestry (mean [SD] age, 56.6 [8.0] years) were included, plus 3071 Australian registry and 6750 historic control participants. In the UKBB, the minor allele frequency of the MYOC p.Gln368Ter variant was 1 in 786 individuals (0.13{\%}). The odds ratio of p.Gln368Ter in patients with primary open-angle glaucoma (POAG) was 6.76 (95{\%} CI, 4.05-11.29); glaucoma (POAG, self-reported glaucoma, and unspecified glaucoma), 4.40 (95{\%} CI, 3.38-5.71); OHT, 3.56 (95{\%} CI, 2.53-4.92); and OHT and glaucoma combined, 4.18 (95{\%} CI, 3.05-5.67). The penetrance of the MYOC p.Gln368Ter variant was 7.6{\%} in patients with glaucoma, 24.3{\%} in patients with OHT, and 30.8{\%} in patients with OHT and glaucoma combined. In the Australian registry studies, the odds of MYOC p.Gln368Ter variant were 12.16 (95{\%} CI, 6.34-24.97) in patients with advanced glaucoma and 3.97 (95{\%} CI, 1.55-9.75) in those with nonadvanced glaucoma; the penetrance of glaucoma was 56.1{\%}, and penetrance in those considered to have glaucoma or be glaucoma suspects was 69.5{\%}.CONCLUSIONS AND RELEVANCE The MYOC p.Gln368Ter variant confers a very high-risk effect size for advanced glaucoma; the risk is lower in nonadvanced glaucoma and OHT. In the general population sample, approximately 50{\%} of MYOC p.Gln368Ter carriers 65 years and older had glaucoma or OHT, with higher prevalence in the Australian registry studies.",
keywords = "OPEN-ANGLE GLAUCOMA, GENOME-WIDE ASSOCIATION, INTRAOCULAR-PRESSURE, PREVALENCE, RISK, MUTATIONS, SUSCEPTIBILITY, IDENTIFICATION, METAANALYSIS, FAMILIES",
author = "Xikun Han and Emmanuelle Souzeau and Jue-Sheng Ong and Jiyuan An and Siggs, {Owen M.} and Bunion, {Kathryn P.} and Stephen Best and Ivan Goldberg and Healey, {Paul R.} and Graham, {Stuart L.} and Ruddle, {Jonathan B.} and Mills, {Richard A.} and John Landers and Anna Galanopoulos and White, {Andrew J. R.} and Robert Casson and Mackey, {David A.} and Hewitt, {Alex W.} and Puya Gharahkhani and Craig, {Jamie E.} and Stuart MacGregor",
year = "2019",
month = "1",
doi = "10.1001/jamaophthalmol.2018.4477",
language = "English",
volume = "137",
pages = "28--35",
journal = "Archives of Ophthalmology",
issn = "0003-9950",
publisher = "American Medical Association",
number = "1",

}

Han, X, Souzeau, E, Ong, J-S, An, J, Siggs, OM, Bunion, KP, Best, S, Goldberg, I, Healey, PR, Graham, SL, Ruddle, JB, Mills, RA, Landers, J, Galanopoulos, A, White, AJR, Casson, R, Mackey, DA, Hewitt, AW, Gharahkhani, P, Craig, JE & MacGregor, S 2019, 'Myocilin Gene Gln368Ter Variant Penetrance and Association With Glaucoma in Population-Based and Registry-Based Studies' JAMA Ophthalmology, vol. 137, no. 1, pp. 28-35. https://doi.org/10.1001/jamaophthalmol.2018.4477

Myocilin Gene Gln368Ter Variant Penetrance and Association With Glaucoma in Population-Based and Registry-Based Studies. / Han, Xikun; Souzeau, Emmanuelle; Ong, Jue-Sheng; An, Jiyuan; Siggs, Owen M.; Bunion, Kathryn P.; Best, Stephen; Goldberg, Ivan; Healey, Paul R.; Graham, Stuart L.; Ruddle, Jonathan B.; Mills, Richard A.; Landers, John; Galanopoulos, Anna; White, Andrew J. R.; Casson, Robert; Mackey, David A.; Hewitt, Alex W.; Gharahkhani, Puya; Craig, Jamie E.; MacGregor, Stuart.

In: JAMA Ophthalmology, Vol. 137, No. 1, 01.2019, p. 28-35.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Myocilin Gene Gln368Ter Variant Penetrance and Association With Glaucoma in Population-Based and Registry-Based Studies

AU - Han, Xikun

AU - Souzeau, Emmanuelle

AU - Ong, Jue-Sheng

AU - An, Jiyuan

AU - Siggs, Owen M.

AU - Bunion, Kathryn P.

AU - Best, Stephen

AU - Goldberg, Ivan

AU - Healey, Paul R.

AU - Graham, Stuart L.

AU - Ruddle, Jonathan B.

AU - Mills, Richard A.

AU - Landers, John

AU - Galanopoulos, Anna

AU - White, Andrew J. R.

AU - Casson, Robert

AU - Mackey, David A.

AU - Hewitt, Alex W.

AU - Gharahkhani, Puya

AU - Craig, Jamie E.

AU - MacGregor, Stuart

PY - 2019/1

Y1 - 2019/1

N2 - IMPORTANCE The p.Gln368Ter (rs74315329) risk allele in themyocilin gene (MYOC) was initially reported to have high penetrance in glaucoma registry-based studies, but much lower estimates were recently obtained from population-based studies. We investigated this disparity using data from Australia and the United Kingdom.OBJECTIVES To examine the penetrance and effect size of the MYOC p.Gln368Ter variant with glaucoma and ocular hypertension (OHT).DESIGN, SETTING, AND PARTICIPANTS This cross-sectional study within the UK Biobank (UKBB) included participants of white British ancestry. Glaucoma cases were defined by International Classification of Diseases, Ninth Revision (ICD-9) and Tenth Revision (ICD-10) diagnoses and self-reported questionnaires. Carriers of the MYOC p.Gln368Ter variant were identified using genotype imputation from arrays. In contrast, 2 Australian registry-based studies, the Australian and New Zealand Registry of Advanced Glaucoma and the Glaucoma Inheritance Study in Tasmania, ascertained glaucoma cases referred by eye care clinicians, with historic control participants recruited from other Australian studies. Samples were either directly sequenced or had genotypes determined by imputation (for the Australian registry and historic control participants). Recruitment to the UKBB occurred between 2006 and 2010, and data analysis occurred from September 2017 to July 2018.MAIN OUTCOMES AND MEASURES The penetrance and odds ratio (OR) were estimated for the MYOC p.Gln368Ter variants in participants with glaucoma and OHT.RESULTS A total of 411 337 UKBB participants of white British ancestry (mean [SD] age, 56.6 [8.0] years) were included, plus 3071 Australian registry and 6750 historic control participants. In the UKBB, the minor allele frequency of the MYOC p.Gln368Ter variant was 1 in 786 individuals (0.13%). The odds ratio of p.Gln368Ter in patients with primary open-angle glaucoma (POAG) was 6.76 (95% CI, 4.05-11.29); glaucoma (POAG, self-reported glaucoma, and unspecified glaucoma), 4.40 (95% CI, 3.38-5.71); OHT, 3.56 (95% CI, 2.53-4.92); and OHT and glaucoma combined, 4.18 (95% CI, 3.05-5.67). The penetrance of the MYOC p.Gln368Ter variant was 7.6% in patients with glaucoma, 24.3% in patients with OHT, and 30.8% in patients with OHT and glaucoma combined. In the Australian registry studies, the odds of MYOC p.Gln368Ter variant were 12.16 (95% CI, 6.34-24.97) in patients with advanced glaucoma and 3.97 (95% CI, 1.55-9.75) in those with nonadvanced glaucoma; the penetrance of glaucoma was 56.1%, and penetrance in those considered to have glaucoma or be glaucoma suspects was 69.5%.CONCLUSIONS AND RELEVANCE The MYOC p.Gln368Ter variant confers a very high-risk effect size for advanced glaucoma; the risk is lower in nonadvanced glaucoma and OHT. In the general population sample, approximately 50% of MYOC p.Gln368Ter carriers 65 years and older had glaucoma or OHT, with higher prevalence in the Australian registry studies.

AB - IMPORTANCE The p.Gln368Ter (rs74315329) risk allele in themyocilin gene (MYOC) was initially reported to have high penetrance in glaucoma registry-based studies, but much lower estimates were recently obtained from population-based studies. We investigated this disparity using data from Australia and the United Kingdom.OBJECTIVES To examine the penetrance and effect size of the MYOC p.Gln368Ter variant with glaucoma and ocular hypertension (OHT).DESIGN, SETTING, AND PARTICIPANTS This cross-sectional study within the UK Biobank (UKBB) included participants of white British ancestry. Glaucoma cases were defined by International Classification of Diseases, Ninth Revision (ICD-9) and Tenth Revision (ICD-10) diagnoses and self-reported questionnaires. Carriers of the MYOC p.Gln368Ter variant were identified using genotype imputation from arrays. In contrast, 2 Australian registry-based studies, the Australian and New Zealand Registry of Advanced Glaucoma and the Glaucoma Inheritance Study in Tasmania, ascertained glaucoma cases referred by eye care clinicians, with historic control participants recruited from other Australian studies. Samples were either directly sequenced or had genotypes determined by imputation (for the Australian registry and historic control participants). Recruitment to the UKBB occurred between 2006 and 2010, and data analysis occurred from September 2017 to July 2018.MAIN OUTCOMES AND MEASURES The penetrance and odds ratio (OR) were estimated for the MYOC p.Gln368Ter variants in participants with glaucoma and OHT.RESULTS A total of 411 337 UKBB participants of white British ancestry (mean [SD] age, 56.6 [8.0] years) were included, plus 3071 Australian registry and 6750 historic control participants. In the UKBB, the minor allele frequency of the MYOC p.Gln368Ter variant was 1 in 786 individuals (0.13%). The odds ratio of p.Gln368Ter in patients with primary open-angle glaucoma (POAG) was 6.76 (95% CI, 4.05-11.29); glaucoma (POAG, self-reported glaucoma, and unspecified glaucoma), 4.40 (95% CI, 3.38-5.71); OHT, 3.56 (95% CI, 2.53-4.92); and OHT and glaucoma combined, 4.18 (95% CI, 3.05-5.67). The penetrance of the MYOC p.Gln368Ter variant was 7.6% in patients with glaucoma, 24.3% in patients with OHT, and 30.8% in patients with OHT and glaucoma combined. In the Australian registry studies, the odds of MYOC p.Gln368Ter variant were 12.16 (95% CI, 6.34-24.97) in patients with advanced glaucoma and 3.97 (95% CI, 1.55-9.75) in those with nonadvanced glaucoma; the penetrance of glaucoma was 56.1%, and penetrance in those considered to have glaucoma or be glaucoma suspects was 69.5%.CONCLUSIONS AND RELEVANCE The MYOC p.Gln368Ter variant confers a very high-risk effect size for advanced glaucoma; the risk is lower in nonadvanced glaucoma and OHT. In the general population sample, approximately 50% of MYOC p.Gln368Ter carriers 65 years and older had glaucoma or OHT, with higher prevalence in the Australian registry studies.

KW - OPEN-ANGLE GLAUCOMA

KW - GENOME-WIDE ASSOCIATION

KW - INTRAOCULAR-PRESSURE

KW - PREVALENCE

KW - RISK

KW - MUTATIONS

KW - SUSCEPTIBILITY

KW - IDENTIFICATION

KW - METAANALYSIS

KW - FAMILIES

U2 - 10.1001/jamaophthalmol.2018.4477

DO - 10.1001/jamaophthalmol.2018.4477

M3 - Article

VL - 137

SP - 28

EP - 35

JO - Archives of Ophthalmology

JF - Archives of Ophthalmology

SN - 0003-9950

IS - 1

ER -