Rare variants in optic disc area gene CARD10 enriched in primary open-angle glaucoma

Tiger Zhou; Emmanuelle Souzeau; Shiwani Sharma; Owen M. Siggs; Ivan Goldberg; Paul R. Healey; Stuart Graham; Alex W. Hewitt; David A. Mackey; Robert J. Casson; John Landers; Richard Mills; Jonathan J. Ellis; Paul J. Leo; Matthew A. Brown; Stuart MacGregor; Kathryn P. Burdon; Jamie E. Craig

doi:10.1002/mgg3.248

Rare variants in optic disc area gene CARD10 enriched in primary open-angle glaucoma

Tiger Zhou, Emmanuelle Souzeau, Shiwani Sharma, Owen M. Siggs, Ivan Goldberg, Paul R. Healey, Stuart Graham, Alex W. Hewitt, David A. Mackey, Robert J. Casson, John Landers, Richard Mills, Jonathan J. Ellis, Paul J. Leo, Matthew A. Brown, Stuart MacGregor, Kathryn P. Burdon, Jamie E. Craig

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Abstract

Background: Genome-wide association studies (GWAS) have identified association of common alleles with primary open-angle glaucoma (POAG) and its quantitative endophenotypes near numerous genes. This study aims to determine whether rare pathogenic variants in these disease-associated genes contribute to POAG.

Methods: Participants fulfilled strict inclusion criteria of advanced POAG at a young age of diagnosis. Myocilin mutation carriers were excluded using direct sequencing. Whole exome sequencing was performed on 187 glaucoma cases and 103 local screened nonglaucoma controls then joint-called with exomes of 993 previously sequenced Australian controls. GWAS-associated genes were assessed for enrichment of rare predicted pathogenic variants in POAG. Significantly enriched genes were compared against Exome Aggregation Consortium (ExAC) public control.

Results: Eighty-six GWAS disease or trait-associated glaucoma genes were captured and sequenced. CARD10 showed enrichment after Bonferroni correction for rare variants in glaucoma cases (OR = 13.2, P = 6.94 × 10(⁵) with mutations identified in 4.28% of our POAG cohort compared to 0.27% in controls. CARD10 was significantly associated with optic disc parameters in previous GWAS. The whole GWAS gene set showed no enrichment in POAG overall (OR = 1.12, P = 0.51).

Conclusion: We report here an enrichment of rare predicted pathogenic coding variants within a GWAS-associated locus in POAG (CARD10). These findings indicate that both common and rare pathogenic coding variants in CARD10 may contribute to POAG pathogenesis.

Original language	English
Pages (from-to)	624-633
Number of pages	10
Journal	Molecular Genetics and Genomic Medicine
Volume	4
Issue number	6
DOIs	https://doi.org/10.1002/mgg3.248
Publication status	Published - Nov 2016
Externally published	Yes

Bibliographical note

Copyright the Author(s) 2016. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

Keywords

CARD10
Genome-wide association study
Rare variants
Whole exome sequencing

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Zhou, Tiger ; Souzeau, Emmanuelle ; Sharma, Shiwani ; Siggs, Owen M. ; Goldberg, Ivan ; Healey, Paul R. ; Graham, Stuart ; Hewitt, Alex W. ; Mackey, David A. ; Casson, Robert J. ; Landers, John ; Mills, Richard ; Ellis, Jonathan J. ; Leo, Paul J. ; Brown, Matthew A. ; MacGregor, Stuart ; Burdon, Kathryn P. ; Craig, Jamie E. / Rare variants in optic disc area gene CARD10 enriched in primary open-angle glaucoma. In: Molecular Genetics and Genomic Medicine. 2016 ; Vol. 4, No. 6. pp. 624-633.

@article{41d737752e8348b4ac7abe30d28266e8,

title = "Rare variants in optic disc area gene CARD10 enriched in primary open-angle glaucoma",

abstract = "Background: Genome-wide association studies (GWAS) have identified association of common alleles with primary open-angle glaucoma (POAG) and its quantitative endophenotypes near numerous genes. This study aims to determine whether rare pathogenic variants in these disease-associated genes contribute to POAG.Methods: Participants fulfilled strict inclusion criteria of advanced POAG at a young age of diagnosis. Myocilin mutation carriers were excluded using direct sequencing. Whole exome sequencing was performed on 187 glaucoma cases and 103 local screened nonglaucoma controls then joint-called with exomes of 993 previously sequenced Australian controls. GWAS-associated genes were assessed for enrichment of rare predicted pathogenic variants in POAG. Significantly enriched genes were compared against Exome Aggregation Consortium (ExAC) public control.Results: Eighty-six GWAS disease or trait-associated glaucoma genes were captured and sequenced. CARD10 showed enrichment after Bonferroni correction for rare variants in glaucoma cases (OR = 13.2, P = 6.94 × 10(5) with mutations identified in 4.28{\%} of our POAG cohort compared to 0.27{\%} in controls. CARD10 was significantly associated with optic disc parameters in previous GWAS. The whole GWAS gene set showed no enrichment in POAG overall (OR = 1.12, P = 0.51).Conclusion: We report here an enrichment of rare predicted pathogenic coding variants within a GWAS-associated locus in POAG (CARD10). These findings indicate that both common and rare pathogenic coding variants in CARD10 may contribute to POAG pathogenesis.",

keywords = "CARD10, Genome-wide association study, Rare variants, Whole exome sequencing",

author = "Tiger Zhou and Emmanuelle Souzeau and Shiwani Sharma and Siggs, {Owen M.} and Ivan Goldberg and Healey, {Paul R.} and Stuart Graham and Hewitt, {Alex W.} and Mackey, {David A.} and Casson, {Robert J.} and John Landers and Richard Mills and Ellis, {Jonathan J.} and Leo, {Paul J.} and Brown, {Matthew A.} and Stuart MacGregor and Burdon, {Kathryn P.} and Craig, {Jamie E.}",

note = "Copyright the Author(s) 2016. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.",

year = "2016",

month = "11",

doi = "10.1002/mgg3.248",

language = "English",

volume = "4",

pages = "624--633",

journal = "Molecular Genetics and Genomic Medicine",

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Zhou, T, Souzeau, E, Sharma, S, Siggs, OM, Goldberg, I, Healey, PR, Graham, S, Hewitt, AW, Mackey, DA, Casson, RJ, Landers, J, Mills, R, Ellis, JJ, Leo, PJ, Brown, MA, MacGregor, S, Burdon, KP & Craig, JE 2016, 'Rare variants in optic disc area gene CARD10 enriched in primary open-angle glaucoma', Molecular Genetics and Genomic Medicine, vol. 4, no. 6, pp. 624-633. https://doi.org/10.1002/mgg3.248

Rare variants in optic disc area gene CARD10 enriched in primary open-angle glaucoma. / Zhou, Tiger; Souzeau, Emmanuelle; Sharma, Shiwani; Siggs, Owen M.; Goldberg, Ivan; Healey, Paul R.; Graham, Stuart; Hewitt, Alex W.; Mackey, David A.; Casson, Robert J.; Landers, John; Mills, Richard; Ellis, Jonathan J.; Leo, Paul J.; Brown, Matthew A.; MacGregor, Stuart; Burdon, Kathryn P.; Craig, Jamie E.

In: Molecular Genetics and Genomic Medicine, Vol. 4, No. 6, 11.2016, p. 624-633.

Research output: Contribution to journal › Article

TY - JOUR

T1 - Rare variants in optic disc area gene CARD10 enriched in primary open-angle glaucoma

AU - Zhou, Tiger

AU - Souzeau, Emmanuelle

AU - Sharma, Shiwani

AU - Siggs, Owen M.

AU - Goldberg, Ivan

AU - Healey, Paul R.

AU - Graham, Stuart

AU - Hewitt, Alex W.

AU - Mackey, David A.

AU - Casson, Robert J.

AU - Landers, John

AU - Mills, Richard

AU - Ellis, Jonathan J.

AU - Leo, Paul J.

AU - Brown, Matthew A.

AU - MacGregor, Stuart

AU - Burdon, Kathryn P.

AU - Craig, Jamie E.

N1 - Copyright the Author(s) 2016. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

PY - 2016/11

Y1 - 2016/11

N2 - Background: Genome-wide association studies (GWAS) have identified association of common alleles with primary open-angle glaucoma (POAG) and its quantitative endophenotypes near numerous genes. This study aims to determine whether rare pathogenic variants in these disease-associated genes contribute to POAG.Methods: Participants fulfilled strict inclusion criteria of advanced POAG at a young age of diagnosis. Myocilin mutation carriers were excluded using direct sequencing. Whole exome sequencing was performed on 187 glaucoma cases and 103 local screened nonglaucoma controls then joint-called with exomes of 993 previously sequenced Australian controls. GWAS-associated genes were assessed for enrichment of rare predicted pathogenic variants in POAG. Significantly enriched genes were compared against Exome Aggregation Consortium (ExAC) public control.Results: Eighty-six GWAS disease or trait-associated glaucoma genes were captured and sequenced. CARD10 showed enrichment after Bonferroni correction for rare variants in glaucoma cases (OR = 13.2, P = 6.94 × 10(5) with mutations identified in 4.28% of our POAG cohort compared to 0.27% in controls. CARD10 was significantly associated with optic disc parameters in previous GWAS. The whole GWAS gene set showed no enrichment in POAG overall (OR = 1.12, P = 0.51).Conclusion: We report here an enrichment of rare predicted pathogenic coding variants within a GWAS-associated locus in POAG (CARD10). These findings indicate that both common and rare pathogenic coding variants in CARD10 may contribute to POAG pathogenesis.

AB - Background: Genome-wide association studies (GWAS) have identified association of common alleles with primary open-angle glaucoma (POAG) and its quantitative endophenotypes near numerous genes. This study aims to determine whether rare pathogenic variants in these disease-associated genes contribute to POAG.Methods: Participants fulfilled strict inclusion criteria of advanced POAG at a young age of diagnosis. Myocilin mutation carriers were excluded using direct sequencing. Whole exome sequencing was performed on 187 glaucoma cases and 103 local screened nonglaucoma controls then joint-called with exomes of 993 previously sequenced Australian controls. GWAS-associated genes were assessed for enrichment of rare predicted pathogenic variants in POAG. Significantly enriched genes were compared against Exome Aggregation Consortium (ExAC) public control.Results: Eighty-six GWAS disease or trait-associated glaucoma genes were captured and sequenced. CARD10 showed enrichment after Bonferroni correction for rare variants in glaucoma cases (OR = 13.2, P = 6.94 × 10(5) with mutations identified in 4.28% of our POAG cohort compared to 0.27% in controls. CARD10 was significantly associated with optic disc parameters in previous GWAS. The whole GWAS gene set showed no enrichment in POAG overall (OR = 1.12, P = 0.51).Conclusion: We report here an enrichment of rare predicted pathogenic coding variants within a GWAS-associated locus in POAG (CARD10). These findings indicate that both common and rare pathogenic coding variants in CARD10 may contribute to POAG pathogenesis.

KW - CARD10

KW - Genome-wide association study

KW - Rare variants

KW - Whole exome sequencing

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U2 - 10.1002/mgg3.248

DO - 10.1002/mgg3.248

M3 - Article

VL - 4

SP - 624

EP - 633

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JF - Molecular Genetics and Genomic Medicine

SN - 2324-9269

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