Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases

Blue Mountains Eye Study—GWAS group; Adriana I Iglesias; Aniket Mishra; Veronique Vitart; Yelena Bykhovskaya; René Höhn; Henriët Springelkamp; Gabriel Cuellar-Partida; Puya Gharahkhani; Jessica N Cooke Bailey; Colin E Willoughby; Xiaohui Li; Seyhan Yazar; Abhishek Nag; Anthony P Khawaja; Ozren Polašek; David Siscovick; Paul Mitchell; Yih Chung Tham; Jonathan L Haines; Lisa S Kearns; Caroline Hayward; Yuan Shi; Elisabeth M van Leeuwen; Kent D Taylor; Pieter Bonnemaijer; Jerome I Rotter; Nicholas G Martin; Tanja Zeller; Richard A Mills; Sandra E Staffieri; Jost B Jonas; Irene Schmidtmann; Thibaud Boutin; Jae H Kang; Sionne E M Lucas; Tien Yin Wong; Manfred E Beutel; James F Wilson; André G Uitterlinden; Eranga N Vithana; Paul J Foster; Pirro G Hysi; Alex W Hewitt; Chiea Chuen Khor; Louis R Pasquale; Grant W Montgomery; Caroline C W Klaver; Tin Aung; Norbert Pfeiffer; Christopher J Hammond

doi:10.1038/s41467-018-03646-6

Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases

Blue Mountains Eye Study—GWAS group, Adriana I Iglesias, Aniket Mishra, Veronique Vitart, Yelena Bykhovskaya, René Höhn, Henriët Springelkamp, Gabriel Cuellar-Partida, Puya Gharahkhani, Jessica N Cooke Bailey, Colin E Willoughby, Xiaohui Li, Seyhan Yazar, Abhishek Nag, Anthony P Khawaja, Ozren Polašek, David Siscovick, Paul Mitchell, Yih Chung Tham, Jonathan L HainesLisa S Kearns, Caroline Hayward, Yuan Shi, Elisabeth M van Leeuwen, Kent D Taylor, Pieter Bonnemaijer, Jerome I Rotter, Nicholas G Martin, Tanja Zeller, Richard A Mills, Sandra E Staffieri, Jost B Jonas, Irene Schmidtmann, Thibaud Boutin, Jae H Kang, Sionne E M Lucas, Tien Yin Wong, Manfred E Beutel, James F Wilson, André G Uitterlinden, Eranga N Vithana, Paul J Foster, Pirro G Hysi, Alex W Hewitt, Chiea Chuen Khor, Louis R Pasquale, Grant W Montgomery, Caroline C W Klaver, Tin Aung, Norbert Pfeiffer, Christopher J Hammond

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

60 Citations (Scopus)

Abstract

Central corneal thickness (CCT) is a highly heritable trait associated with complex eye diseases such as keratoconus and glaucoma. We perform a genome-wide association meta-analysis of CCT and identify 19 novel regions. In addition to adding support for known connective tissue-related pathways, pathway analyses uncover previously unreported gene sets. Remarkably, >20% of the CCT-loci are near or within Mendelian disorder genes. These included FBN1, ADAMTS2 and TGFB2 which associate with connective tissue disorders (Marfan, Ehlers-Danlos and Loeys-Dietz syndromes), and the LUM-DCN-KERA gene complex involved in myopia, corneal dystrophies and cornea plana. Using index CCT-increasing variants, we find a significant inverse correlation in effect sizes between CCT and keratoconus (r = -0.62, P = 5.30 × 10-5) but not between CCT and primary open-angle glaucoma (r = -0.17, P = 0.2). Our findings provide evidence for shared genetic influences between CCT and keratoconus, and implicate candidate genes acting in collagen and extracellular matrix regulation.

Original language	English
Pages (from-to)	1864
Journal	Nature Communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-03646-6
Publication status	Published - 14 May 2018

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Blue Mountains Eye Study—GWAS group, Iglesias, A. I., Mishra, A., Vitart, V., Bykhovskaya, Y., Höhn, R., Springelkamp, H., Cuellar-Partida, G., Gharahkhani, P., Bailey, J. N. C., Willoughby, C. E., Li, X., Yazar, S., Nag, A., Khawaja, A. P., Polašek, O., Siscovick, D., Mitchell, P., Tham, Y. C., ... Hammond, C. J. (2018). Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases. Nature Communications, 9(1), 1864. https://doi.org/10.1038/s41467-018-03646-6

@article{cec2ade87f634ad4b990c412c8b4d084,

title = "Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases",

abstract = "Central corneal thickness (CCT) is a highly heritable trait associated with complex eye diseases such as keratoconus and glaucoma. We perform a genome-wide association meta-analysis of CCT and identify 19 novel regions. In addition to adding support for known connective tissue-related pathways, pathway analyses uncover previously unreported gene sets. Remarkably, >20% of the CCT-loci are near or within Mendelian disorder genes. These included FBN1, ADAMTS2 and TGFB2 which associate with connective tissue disorders (Marfan, Ehlers-Danlos and Loeys-Dietz syndromes), and the LUM-DCN-KERA gene complex involved in myopia, corneal dystrophies and cornea plana. Using index CCT-increasing variants, we find a significant inverse correlation in effect sizes between CCT and keratoconus (r = -0.62, P = 5.30 × 10-5) but not between CCT and primary open-angle glaucoma (r = -0.17, P = 0.2). Our findings provide evidence for shared genetic influences between CCT and keratoconus, and implicate candidate genes acting in collagen and extracellular matrix regulation.",

author = "{Blue Mountains Eye Study—GWAS group} and Iglesias, {Adriana I} and Aniket Mishra and Veronique Vitart and Yelena Bykhovskaya and Ren{\'e} H{\"o}hn and Henri{\"e}t Springelkamp and Gabriel Cuellar-Partida and Puya Gharahkhani and Bailey, {Jessica N Cooke} and Willoughby, {Colin E} and Xiaohui Li and Seyhan Yazar and Abhishek Nag and Khawaja, {Anthony P} and Ozren Pola{\v s}ek and David Siscovick and Paul Mitchell and Tham, {Yih Chung} and Haines, {Jonathan L} and Kearns, {Lisa S} and Caroline Hayward and Yuan Shi and {van Leeuwen}, {Elisabeth M} and Taylor, {Kent D} and Pieter Bonnemaijer and Rotter, {Jerome I} and Martin, {Nicholas G} and Tanja Zeller and Mills, {Richard A} and Staffieri, {Sandra E} and Jonas, {Jost B} and Irene Schmidtmann and Thibaud Boutin and Kang, {Jae H} and Lucas, {Sionne E M} and Wong, {Tien Yin} and Beutel, {Manfred E} and Wilson, {James F} and Uitterlinden, {Andr{\'e} G} and Vithana, {Eranga N} and Foster, {Paul J} and Hysi, {Pirro G} and Hewitt, {Alex W} and Khor, {Chiea Chuen} and Pasquale, {Louis R} and Montgomery, {Grant W} and Klaver, {Caroline C W} and Tin Aung and Norbert Pfeiffer and Hammond, {Christopher J}",

year = "2018",

month = may,

day = "14",

doi = "10.1038/s41467-018-03646-6",

language = "English",

volume = "9",

pages = "1864",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

number = "1",

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Blue Mountains Eye Study—GWAS group, Iglesias, AI, Mishra, A, Vitart, V, Bykhovskaya, Y, Höhn, R, Springelkamp, H, Cuellar-Partida, G, Gharahkhani, P, Bailey, JNC, Willoughby, CE, Li, X, Yazar, S, Nag, A, Khawaja, AP, Polašek, O, Siscovick, D, Mitchell, P, Tham, YC, Haines, JL, Kearns, LS, Hayward, C, Shi, Y, van Leeuwen, EM, Taylor, KD, Bonnemaijer, P, Rotter, JI, Martin, NG, Zeller, T, Mills, RA, Staffieri, SE, Jonas, JB, Schmidtmann, I, Boutin, T, Kang, JH, Lucas, SEM, Wong, TY, Beutel, ME, Wilson, JF, Uitterlinden, AG, Vithana, EN, Foster, PJ, Hysi, PG, Hewitt, AW, Khor, CC, Pasquale, LR, Montgomery, GW, Klaver, CCW, Aung, T, Pfeiffer, N & Hammond, CJ 2018, 'Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases', Nature Communications, vol. 9, no. 1, pp. 1864. https://doi.org/10.1038/s41467-018-03646-6

TY - JOUR

T1 - Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases

AU - Blue Mountains Eye Study—GWAS group

AU - Iglesias, Adriana I

AU - Mishra, Aniket

AU - Vitart, Veronique

AU - Bykhovskaya, Yelena

AU - Höhn, René

AU - Springelkamp, Henriët

AU - Cuellar-Partida, Gabriel

AU - Gharahkhani, Puya

AU - Bailey, Jessica N Cooke

AU - Willoughby, Colin E

AU - Li, Xiaohui

AU - Yazar, Seyhan

AU - Nag, Abhishek

AU - Khawaja, Anthony P

AU - Polašek, Ozren

AU - Siscovick, David

AU - Mitchell, Paul

AU - Tham, Yih Chung

AU - Haines, Jonathan L

AU - Kearns, Lisa S

AU - Hayward, Caroline

AU - Shi, Yuan

AU - van Leeuwen, Elisabeth M

AU - Taylor, Kent D

AU - Bonnemaijer, Pieter

AU - Rotter, Jerome I

AU - Martin, Nicholas G

AU - Zeller, Tanja

AU - Mills, Richard A

AU - Staffieri, Sandra E

AU - Jonas, Jost B

AU - Schmidtmann, Irene

AU - Boutin, Thibaud

AU - Kang, Jae H

AU - Lucas, Sionne E M

AU - Wong, Tien Yin

AU - Beutel, Manfred E

AU - Wilson, James F

AU - Uitterlinden, André G

AU - Vithana, Eranga N

AU - Foster, Paul J

AU - Hysi, Pirro G

AU - Hewitt, Alex W

AU - Khor, Chiea Chuen

AU - Pasquale, Louis R

AU - Montgomery, Grant W

AU - Klaver, Caroline C W

AU - Aung, Tin

AU - Pfeiffer, Norbert

AU - Hammond, Christopher J

PY - 2018/5/14

Y1 - 2018/5/14

N2 - Central corneal thickness (CCT) is a highly heritable trait associated with complex eye diseases such as keratoconus and glaucoma. We perform a genome-wide association meta-analysis of CCT and identify 19 novel regions. In addition to adding support for known connective tissue-related pathways, pathway analyses uncover previously unreported gene sets. Remarkably, >20% of the CCT-loci are near or within Mendelian disorder genes. These included FBN1, ADAMTS2 and TGFB2 which associate with connective tissue disorders (Marfan, Ehlers-Danlos and Loeys-Dietz syndromes), and the LUM-DCN-KERA gene complex involved in myopia, corneal dystrophies and cornea plana. Using index CCT-increasing variants, we find a significant inverse correlation in effect sizes between CCT and keratoconus (r = -0.62, P = 5.30 × 10-5) but not between CCT and primary open-angle glaucoma (r = -0.17, P = 0.2). Our findings provide evidence for shared genetic influences between CCT and keratoconus, and implicate candidate genes acting in collagen and extracellular matrix regulation.

AB - Central corneal thickness (CCT) is a highly heritable trait associated with complex eye diseases such as keratoconus and glaucoma. We perform a genome-wide association meta-analysis of CCT and identify 19 novel regions. In addition to adding support for known connective tissue-related pathways, pathway analyses uncover previously unreported gene sets. Remarkably, >20% of the CCT-loci are near or within Mendelian disorder genes. These included FBN1, ADAMTS2 and TGFB2 which associate with connective tissue disorders (Marfan, Ehlers-Danlos and Loeys-Dietz syndromes), and the LUM-DCN-KERA gene complex involved in myopia, corneal dystrophies and cornea plana. Using index CCT-increasing variants, we find a significant inverse correlation in effect sizes between CCT and keratoconus (r = -0.62, P = 5.30 × 10-5) but not between CCT and primary open-angle glaucoma (r = -0.17, P = 0.2). Our findings provide evidence for shared genetic influences between CCT and keratoconus, and implicate candidate genes acting in collagen and extracellular matrix regulation.

U2 - 10.1038/s41467-018-03646-6

DO - 10.1038/s41467-018-03646-6

M3 - Article

C2 - 29760442

SN - 2041-1723

VL - 9

SP - 1864

JO - Nature Communications

JF - Nature Communications

IS - 1

ER -

Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases

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