WNT10A exonic variant increases the risk of keratoconus by decreasing corneal thickness

Gabriel Cuellar-Partida; Henriet Springelkamp; Sionne E. M. Lucas; Seyhan Yazar; Alex W. Hewitt; Adriana I. Iglesias; Grant W. Montgomery; Nicholas G. Martin; Craig E. Pennell; Elisabeth M. van Leeuwen; Virginie J. M. Verhoeven; Albert Hofman; Andre G. Uitterlinden; Wishal D. Ramdas; Roger. C. W. Wolfs; Johannes R. Vingerling; Matthew A. Brown; Richard A. Mills; Jamie E. Craig; Caroline C. W. Klaver; Cornelia M. van Duijn; Kathryn P. Burdon; Stuart MacGregor; David A. Mackey

doi:10.1093/hmg/ddv211

WNT10A exonic variant increases the risk of keratoconus by decreasing corneal thickness

Gabriel Cuellar-Partida, Henriet Springelkamp, Sionne E. M. Lucas, Seyhan Yazar, Alex W. Hewitt, Adriana I. Iglesias, Grant W. Montgomery, Nicholas G. Martin, Craig E. Pennell, Elisabeth M. van Leeuwen, Virginie J. M. Verhoeven, Albert Hofman, Andre G. Uitterlinden, Wishal D. Ramdas, Roger. C. W. Wolfs, Johannes R. Vingerling, Matthew A. Brown, Richard A. Mills, Jamie E. Craig, Caroline C. W. KlaverCornelia M. van Duijn, Kathryn P. Burdon, Stuart MacGregor^*, David A. Mackey

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Keratoconus is a degenerative eye condition which results from thinning of the cornea and causes vision distortion. Treatments such as ultraviolet (UV) cross-linking have proved effective for management of keratoconus when performed in early stages of the disease. The central corneal thickness (CCT) is a highly heritable endophenotype of keratoconus, and it is estimated that up to 95% of its phenotypic variance is due to genetics. Genome-wide association efforts of CCT have identified common variants (i.e. minor allele frequency (MAF) >5%). However, these studies typically ignore the large set of exonic variants whose MAF is usually low. In this study, we performed a CCT exome-wide association analysis in a sample of 1029 individuals from a population-based study in Western Australia. We identified a genome-wide significant exonic variant rs121908120 (P = 6.63 ? 10(-10)) in WNT10A. This gene is 437 kb from a gene previously associated with CCT (USP37). We showed in a conditional analysis that the WNT10A variant completely accounts for the signal previously seen at USP37. We replicated our finding in independent samples from the Brisbane Adolescent Twin Study, Twin Eye Study in Tasmania and the Rotterdam Study. Further, we genotyped rs121908120 in 621 keratoconus cases and compared the frequency to a sample of 1680 unscreened controls from the Queensland Twin Registry. We found that rs121908120 increases the risk of keratoconus two times (odds ratio 2.03, P = 5.41 ? 10(-5)). ? The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Original language	English
Pages (from-to)	5060-5068
Journal	Human Molecular Genetics
Volume	24
Issue number	17
DOIs	https://doi.org/10.1093/hmg/ddv211
Publication status	Published - 1 Sept 2015

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10.1093/hmg/ddv211

Cite this

Cuellar-Partida, G., Springelkamp, H., Lucas, S. E. M., Yazar, S., Hewitt, A. W., Iglesias, A. I., Montgomery, G. W., Martin, N. G., Pennell, C. E., van Leeuwen, E. M., Verhoeven, V. J. M., Hofman, A., Uitterlinden, A. G., Ramdas, W. D., Wolfs, R. C. W., Vingerling, J. R., Brown, M. A., Mills, R. A., Craig, J. E., ... Mackey, D. A. (2015). WNT10A exonic variant increases the risk of keratoconus by decreasing corneal thickness. Human Molecular Genetics, 24(17), 5060-5068. https://doi.org/10.1093/hmg/ddv211

@article{ea52b4ea3ea742d7a54dcc4e505f28ca,

title = "WNT10A exonic variant increases the risk of keratoconus by decreasing corneal thickness",

abstract = "Keratoconus is a degenerative eye condition which results from thinning of the cornea and causes vision distortion. Treatments such as ultraviolet (UV) cross-linking have proved effective for management of keratoconus when performed in early stages of the disease. The central corneal thickness (CCT) is a highly heritable endophenotype of keratoconus, and it is estimated that up to 95% of its phenotypic variance is due to genetics. Genome-wide association efforts of CCT have identified common variants (i.e. minor allele frequency (MAF) >5%). However, these studies typically ignore the large set of exonic variants whose MAF is usually low. In this study, we performed a CCT exome-wide association analysis in a sample of 1029 individuals from a population-based study in Western Australia. We identified a genome-wide significant exonic variant rs121908120 (P = 6.63 ? 10(-10)) in WNT10A. This gene is 437 kb from a gene previously associated with CCT (USP37). We showed in a conditional analysis that the WNT10A variant completely accounts for the signal previously seen at USP37. We replicated our finding in independent samples from the Brisbane Adolescent Twin Study, Twin Eye Study in Tasmania and the Rotterdam Study. Further, we genotyped rs121908120 in 621 keratoconus cases and compared the frequency to a sample of 1680 unscreened controls from the Queensland Twin Registry. We found that rs121908120 increases the risk of keratoconus two times (odds ratio 2.03, P = 5.41 ? 10(-5)). ? The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.",

author = "Gabriel Cuellar-Partida and Henriet Springelkamp and Lucas, {Sionne E. M.} and Seyhan Yazar and Hewitt, {Alex W.} and Iglesias, {Adriana I.} and Montgomery, {Grant W.} and Martin, {Nicholas G.} and Pennell, {Craig E.} and {van Leeuwen}, {Elisabeth M.} and Verhoeven, {Virginie J. M.} and Albert Hofman and Uitterlinden, {Andre G.} and Ramdas, {Wishal D.} and Wolfs, {Roger. C. W.} and Vingerling, {Johannes R.} and Brown, {Matthew A.} and Mills, {Richard A.} and Craig, {Jamie E.} and Klaver, {Caroline C. W.} and {van Duijn}, {Cornelia M.} and Burdon, {Kathryn P.} and Stuart MacGregor and Mackey, {David A.}",

year = "2015",

month = sep,

day = "1",

doi = "10.1093/hmg/ddv211",

language = "English",

volume = "24",

pages = "5060--5068",

journal = "Human Molecular Genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

number = "17",

}

Cuellar-Partida, G, Springelkamp, H, Lucas, SEM, Yazar, S, Hewitt, AW, Iglesias, AI, Montgomery, GW, Martin, NG, Pennell, CE, van Leeuwen, EM, Verhoeven, VJM, Hofman, A, Uitterlinden, AG, Ramdas, WD, Wolfs, RCW, Vingerling, JR, Brown, MA, Mills, RA, Craig, JE, Klaver, CCW, van Duijn, CM, Burdon, KP, MacGregor, S & Mackey, DA 2015, 'WNT10A exonic variant increases the risk of keratoconus by decreasing corneal thickness', Human Molecular Genetics, vol. 24, no. 17, pp. 5060-5068. https://doi.org/10.1093/hmg/ddv211

TY - JOUR

T1 - WNT10A exonic variant increases the risk of keratoconus by decreasing corneal thickness

AU - Cuellar-Partida, Gabriel

AU - Springelkamp, Henriet

AU - Lucas, Sionne E. M.

AU - Yazar, Seyhan

AU - Hewitt, Alex W.

AU - Iglesias, Adriana I.

AU - Montgomery, Grant W.

AU - Martin, Nicholas G.

AU - Pennell, Craig E.

AU - van Leeuwen, Elisabeth M.

AU - Verhoeven, Virginie J. M.

AU - Hofman, Albert

AU - Uitterlinden, Andre G.

AU - Ramdas, Wishal D.

AU - Wolfs, Roger. C. W.

AU - Vingerling, Johannes R.

AU - Brown, Matthew A.

AU - Mills, Richard A.

AU - Craig, Jamie E.

AU - Klaver, Caroline C. W.

AU - van Duijn, Cornelia M.

AU - Burdon, Kathryn P.

AU - MacGregor, Stuart

AU - Mackey, David A.

PY - 2015/9/1

Y1 - 2015/9/1

N2 - Keratoconus is a degenerative eye condition which results from thinning of the cornea and causes vision distortion. Treatments such as ultraviolet (UV) cross-linking have proved effective for management of keratoconus when performed in early stages of the disease. The central corneal thickness (CCT) is a highly heritable endophenotype of keratoconus, and it is estimated that up to 95% of its phenotypic variance is due to genetics. Genome-wide association efforts of CCT have identified common variants (i.e. minor allele frequency (MAF) >5%). However, these studies typically ignore the large set of exonic variants whose MAF is usually low. In this study, we performed a CCT exome-wide association analysis in a sample of 1029 individuals from a population-based study in Western Australia. We identified a genome-wide significant exonic variant rs121908120 (P = 6.63 ? 10(-10)) in WNT10A. This gene is 437 kb from a gene previously associated with CCT (USP37). We showed in a conditional analysis that the WNT10A variant completely accounts for the signal previously seen at USP37. We replicated our finding in independent samples from the Brisbane Adolescent Twin Study, Twin Eye Study in Tasmania and the Rotterdam Study. Further, we genotyped rs121908120 in 621 keratoconus cases and compared the frequency to a sample of 1680 unscreened controls from the Queensland Twin Registry. We found that rs121908120 increases the risk of keratoconus two times (odds ratio 2.03, P = 5.41 ? 10(-5)). ? The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

AB - Keratoconus is a degenerative eye condition which results from thinning of the cornea and causes vision distortion. Treatments such as ultraviolet (UV) cross-linking have proved effective for management of keratoconus when performed in early stages of the disease. The central corneal thickness (CCT) is a highly heritable endophenotype of keratoconus, and it is estimated that up to 95% of its phenotypic variance is due to genetics. Genome-wide association efforts of CCT have identified common variants (i.e. minor allele frequency (MAF) >5%). However, these studies typically ignore the large set of exonic variants whose MAF is usually low. In this study, we performed a CCT exome-wide association analysis in a sample of 1029 individuals from a population-based study in Western Australia. We identified a genome-wide significant exonic variant rs121908120 (P = 6.63 ? 10(-10)) in WNT10A. This gene is 437 kb from a gene previously associated with CCT (USP37). We showed in a conditional analysis that the WNT10A variant completely accounts for the signal previously seen at USP37. We replicated our finding in independent samples from the Brisbane Adolescent Twin Study, Twin Eye Study in Tasmania and the Rotterdam Study. Further, we genotyped rs121908120 in 621 keratoconus cases and compared the frequency to a sample of 1680 unscreened controls from the Queensland Twin Registry. We found that rs121908120 increases the risk of keratoconus two times (odds ratio 2.03, P = 5.41 ? 10(-5)). ? The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

U2 - 10.1093/hmg/ddv211

DO - 10.1093/hmg/ddv211

M3 - Article

C2 - 26049155

SN - 0964-6906

VL - 24

SP - 5060

EP - 5068

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 17

ER -