A multi-ethnic genome-wide association study implicates collagen matrix integrity and cell differentiation pathways in keratoconus

Alison J. Hardcastle; Petra Liskova; Yelena Bykhovskaya; Bennet J. McComish; Alice E. Davidson; Chris F. Inglehearn; Xiaohui Li; Hélène Choquet; Mahmoud Habeeb; Sionne E.M. Lucas; Srujana Sahebjada; Nikolas Pontikos; Karla E.Rojas Lopez; Anthony P. Khawaja; Manir Ali; Lubica Dudakova; Pavlina Skalicka; Bart T.H. Van Dooren; Annette J.M. Geerards; Christoph W. Haudum; Valeria Lo Faro; Abi Tenen; Mark J. Simcoe; Karina Patasova; Darioush Yarrand; Jie Yin; Salina Siddiqui; Aine Rice; Layal Abi Farraj; Yii Der Ida Chen; Jugnoo S. Rahi; Ronald M. Krauss; Elisabeth Theusch; Jac C. Charlesworth; Loretta Szczotka-Flynn; Carmel Toomes; Magda A. Meester-Smoor; Andrea J. Richardson; Paul A. Mitchell; Kent D. Taylor; Ronald B. Melles; Anthony J. Aldave; Richard A. Mills; Ke Cao; Elsie Chan; Mark D. Daniell; Jie Jin Wang; Jerome I. Rotter; Alex W. Hewitt; Stuart MacGregor; Caroline C.W. Klaver; Wishal D. Ramdas; Jamie E. Craig; Sudha K. Iyengar; David O’Brart; Eric Jorgenson; Paul N. Baird; Yaron S. Rabinowitz; Kathryn P. Burdon; Chris J. Hammond; Stephen J. Tuft; Pirro G. Hysi

doi:10.1038/s42003-021-01784-0

A multi-ethnic genome-wide association study implicates collagen matrix integrity and cell differentiation pathways in keratoconus

Alison J. Hardcastle, Petra Liskova, Yelena Bykhovskaya, Bennet J. McComish, Alice E. Davidson, Chris F. Inglehearn, Xiaohui Li, Hélène Choquet, Mahmoud Habeeb, Sionne E.M. Lucas, Srujana Sahebjada, Nikolas Pontikos, Karla E.Rojas Lopez, Anthony P. Khawaja, Manir Ali, Lubica Dudakova, Pavlina Skalicka, Bart T.H. Van Dooren, Annette J.M. Geerards, Christoph W. HaudumValeria Lo Faro, Abi Tenen, Mark J. Simcoe, Karina Patasova, Darioush Yarrand, Jie Yin, Salina Siddiqui, Aine Rice, Layal Abi Farraj, Yii Der Ida Chen, Jugnoo S. Rahi, Ronald M. Krauss, Elisabeth Theusch, Jac C. Charlesworth, Loretta Szczotka-Flynn, Carmel Toomes, Magda A. Meester-Smoor, Andrea J. Richardson, Paul A. Mitchell, Kent D. Taylor, Ronald B. Melles, Anthony J. Aldave, Richard A. Mills, Ke Cao, Elsie Chan, Mark D. Daniell, Jie Jin Wang, Jerome I. Rotter, Alex W. Hewitt, Stuart MacGregor, Caroline C.W. Klaver, Wishal D. Ramdas, Jamie E. Craig, Sudha K. Iyengar, David O’Brart, Eric Jorgenson, Paul N. Baird, Yaron S. Rabinowitz, Kathryn P. Burdon, Chris J. Hammond, Stephen J. Tuft, Pirro G. Hysi

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

22 Citations (Scopus)

3 Downloads (Pure)

Abstract

Keratoconus is characterised by reduced rigidity of the cornea with distortion and focal thinning that causes blurred vision, however, the pathogenetic mechanisms are unknown. It can lead to severe visual morbidity in children and young adults and is a common indication for corneal transplantation worldwide. Here we report the first large scale genome-wide association study of keratoconus including 4,669 cases and 116,547 controls. We have identified significant association with 36 genomic loci that, for the first time, implicate both dysregulation of corneal collagen matrix integrity and cell differentiation pathways as primary disease-causing mechanisms. The results also suggest pleiotropy, with some disease mechanisms shared with other corneal diseases, such as Fuchs endothelial corneal dystrophy. The common variants associated with keratoconus explain 12.5% of the genetic variance, which shows potential for the future development of a diagnostic test to detect susceptibility to disease.

Original language	English
Article number	266
Number of pages	13
Journal	Communications Biology
Volume	4
DOIs	https://doi.org/10.1038/s42003-021-01784-0
Publication status	Published - 1 Mar 2021

Keywords

Keratoconus
collagen matrix integrity
rigidity of the cornea
severe visual morbidity
corneal transplantation
Fuchs endothelial corneal dystrophy

Access to Document

10.1038/s42003-021-01784-0Licence: CC BY

Published versionFinal published version, 1.65 MBLicence: CC BY

Cite this

Hardcastle, A. J., Liskova, P., Bykhovskaya, Y., McComish, B. J., Davidson, A. E., Inglehearn, C. F., Li, X., Choquet, H., Habeeb, M., Lucas, S. E. M., Sahebjada, S., Pontikos, N., Lopez, K. E. R., Khawaja, A. P., Ali, M., Dudakova, L., Skalicka, P., Van Dooren, B. T. H., Geerards, A. J. M., ... Hysi, P. G. (2021). A multi-ethnic genome-wide association study implicates collagen matrix integrity and cell differentiation pathways in keratoconus. Communications Biology, 4, [266]. https://doi.org/10.1038/s42003-021-01784-0

@article{a535e1771b584db69eb93fa2ffc1e70b,

title = "A multi-ethnic genome-wide association study implicates collagen matrix integrity and cell differentiation pathways in keratoconus",

abstract = "Keratoconus is characterised by reduced rigidity of the cornea with distortion and focal thinning that causes blurred vision, however, the pathogenetic mechanisms are unknown. It can lead to severe visual morbidity in children and young adults and is a common indication for corneal transplantation worldwide. Here we report the first large scale genome-wide association study of keratoconus including 4,669 cases and 116,547 controls. We have identified significant association with 36 genomic loci that, for the first time, implicate both dysregulation of corneal collagen matrix integrity and cell differentiation pathways as primary disease-causing mechanisms. The results also suggest pleiotropy, with some disease mechanisms shared with other corneal diseases, such as Fuchs endothelial corneal dystrophy. The common variants associated with keratoconus explain 12.5% of the genetic variance, which shows potential for the future development of a diagnostic test to detect susceptibility to disease.",

keywords = "Keratoconus, collagen matrix integrity, rigidity of the cornea, severe visual morbidity, corneal transplantation, Fuchs endothelial corneal dystrophy",

author = "Hardcastle, {Alison J.} and Petra Liskova and Yelena Bykhovskaya and McComish, {Bennet J.} and Davidson, {Alice E.} and Inglehearn, {Chris F.} and Xiaohui Li and H{\'e}l{\`e}ne Choquet and Mahmoud Habeeb and Lucas, {Sionne E.M.} and Srujana Sahebjada and Nikolas Pontikos and Lopez, {Karla E.Rojas} and Khawaja, {Anthony P.} and Manir Ali and Lubica Dudakova and Pavlina Skalicka and {Van Dooren}, {Bart T.H.} and Geerards, {Annette J.M.} and Haudum, {Christoph W.} and Faro, {Valeria Lo} and Abi Tenen and Simcoe, {Mark J.} and Karina Patasova and Darioush Yarrand and Jie Yin and Salina Siddiqui and Aine Rice and Farraj, {Layal Abi} and Chen, {Yii Der Ida} and Rahi, {Jugnoo S.} and Krauss, {Ronald M.} and Elisabeth Theusch and Charlesworth, {Jac C.} and Loretta Szczotka-Flynn and Carmel Toomes and Meester-Smoor, {Magda A.} and Richardson, {Andrea J.} and Mitchell, {Paul A.} and Taylor, {Kent D.} and Melles, {Ronald B.} and Aldave, {Anthony J.} and Mills, {Richard A.} and Ke Cao and Elsie Chan and Daniell, {Mark D.} and Wang, {Jie Jin} and Rotter, {Jerome I.} and Hewitt, {Alex W.} and Stuart MacGregor and Klaver, {Caroline C.W.} and Ramdas, {Wishal D.} and Craig, {Jamie E.} and Iyengar, {Sudha K.} and David O{\textquoteright}Brart and Eric Jorgenson and Baird, {Paul N.} and Rabinowitz, {Yaron S.} and Burdon, {Kathryn P.} and Hammond, {Chris J.} and Tuft, {Stephen J.} and Hysi, {Pirro G.}",

year = "2021",

month = mar,

day = "1",

doi = "10.1038/s42003-021-01784-0",

language = "English",

volume = "4",

journal = "Communications Biology",

issn = "2399-3642",

}

Hardcastle, AJ, Liskova, P, Bykhovskaya, Y, McComish, BJ, Davidson, AE, Inglehearn, CF, Li, X, Choquet, H, Habeeb, M, Lucas, SEM, Sahebjada, S, Pontikos, N, Lopez, KER, Khawaja, AP, Ali, M, Dudakova, L, Skalicka, P, Van Dooren, BTH, Geerards, AJM, Haudum, CW, Faro, VL, Tenen, A, Simcoe, MJ, Patasova, K, Yarrand, D, Yin, J, Siddiqui, S, Rice, A, Farraj, LA, Chen, YDI, Rahi, JS, Krauss, RM, Theusch, E, Charlesworth, JC, Szczotka-Flynn, L, Toomes, C, Meester-Smoor, MA, Richardson, AJ, Mitchell, PA, Taylor, KD, Melles, RB, Aldave, AJ, Mills, RA, Cao, K, Chan, E, Daniell, MD, Wang, JJ, Rotter, JI, Hewitt, AW, MacGregor, S, Klaver, CCW, Ramdas, WD, Craig, JE, Iyengar, SK, O’Brart, D, Jorgenson, E, Baird, PN, Rabinowitz, YS, Burdon, KP, Hammond, CJ, Tuft, SJ & Hysi, PG 2021, 'A multi-ethnic genome-wide association study implicates collagen matrix integrity and cell differentiation pathways in keratoconus', Communications Biology, vol. 4, 266. https://doi.org/10.1038/s42003-021-01784-0

TY - JOUR

T1 - A multi-ethnic genome-wide association study implicates collagen matrix integrity and cell differentiation pathways in keratoconus

AU - Hardcastle, Alison J.

AU - Liskova, Petra

AU - Bykhovskaya, Yelena

AU - McComish, Bennet J.

AU - Davidson, Alice E.

AU - Inglehearn, Chris F.

AU - Li, Xiaohui

AU - Choquet, Hélène

AU - Habeeb, Mahmoud

AU - Lucas, Sionne E.M.

AU - Sahebjada, Srujana

AU - Pontikos, Nikolas

AU - Lopez, Karla E.Rojas

AU - Khawaja, Anthony P.

AU - Ali, Manir

AU - Dudakova, Lubica

AU - Skalicka, Pavlina

AU - Van Dooren, Bart T.H.

AU - Geerards, Annette J.M.

AU - Haudum, Christoph W.

AU - Faro, Valeria Lo

AU - Tenen, Abi

AU - Simcoe, Mark J.

AU - Patasova, Karina

AU - Yarrand, Darioush

AU - Yin, Jie

AU - Siddiqui, Salina

AU - Rice, Aine

AU - Farraj, Layal Abi

AU - Chen, Yii Der Ida

AU - Rahi, Jugnoo S.

AU - Krauss, Ronald M.

AU - Theusch, Elisabeth

AU - Charlesworth, Jac C.

AU - Szczotka-Flynn, Loretta

AU - Toomes, Carmel

AU - Meester-Smoor, Magda A.

AU - Richardson, Andrea J.

AU - Mitchell, Paul A.

AU - Taylor, Kent D.

AU - Melles, Ronald B.

AU - Aldave, Anthony J.

AU - Mills, Richard A.

AU - Cao, Ke

AU - Chan, Elsie

AU - Daniell, Mark D.

AU - Wang, Jie Jin

AU - Rotter, Jerome I.

AU - Hewitt, Alex W.

AU - MacGregor, Stuart

AU - Klaver, Caroline C.W.

AU - Ramdas, Wishal D.

AU - Craig, Jamie E.

AU - Iyengar, Sudha K.

AU - O’Brart, David

AU - Jorgenson, Eric

AU - Baird, Paul N.

AU - Rabinowitz, Yaron S.

AU - Burdon, Kathryn P.

AU - Hammond, Chris J.

AU - Tuft, Stephen J.

AU - Hysi, Pirro G.

PY - 2021/3/1

Y1 - 2021/3/1

N2 - Keratoconus is characterised by reduced rigidity of the cornea with distortion and focal thinning that causes blurred vision, however, the pathogenetic mechanisms are unknown. It can lead to severe visual morbidity in children and young adults and is a common indication for corneal transplantation worldwide. Here we report the first large scale genome-wide association study of keratoconus including 4,669 cases and 116,547 controls. We have identified significant association with 36 genomic loci that, for the first time, implicate both dysregulation of corneal collagen matrix integrity and cell differentiation pathways as primary disease-causing mechanisms. The results also suggest pleiotropy, with some disease mechanisms shared with other corneal diseases, such as Fuchs endothelial corneal dystrophy. The common variants associated with keratoconus explain 12.5% of the genetic variance, which shows potential for the future development of a diagnostic test to detect susceptibility to disease.

AB - Keratoconus is characterised by reduced rigidity of the cornea with distortion and focal thinning that causes blurred vision, however, the pathogenetic mechanisms are unknown. It can lead to severe visual morbidity in children and young adults and is a common indication for corneal transplantation worldwide. Here we report the first large scale genome-wide association study of keratoconus including 4,669 cases and 116,547 controls. We have identified significant association with 36 genomic loci that, for the first time, implicate both dysregulation of corneal collagen matrix integrity and cell differentiation pathways as primary disease-causing mechanisms. The results also suggest pleiotropy, with some disease mechanisms shared with other corneal diseases, such as Fuchs endothelial corneal dystrophy. The common variants associated with keratoconus explain 12.5% of the genetic variance, which shows potential for the future development of a diagnostic test to detect susceptibility to disease.

KW - Keratoconus

KW - collagen matrix integrity

KW - rigidity of the cornea

KW - severe visual morbidity

KW - corneal transplantation

KW - Fuchs endothelial corneal dystrophy

UR - http://www.scopus.com/inward/record.url?scp=85101817565&partnerID=8YFLogxK

UR - http://purl.org/au-research/grants/NHMRC/1104700

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

UR - http://purl.org/au-research/grants/NHMRC/1150144

UR - http://purl.org/au-research/grants/NHMRC/1116360

UR - http://purl.org/au-research/grants/NHMRC/1059954

UR - http://purl.org/au-research/grants/NHMRC/1138585

U2 - 10.1038/s42003-021-01784-0

DO - 10.1038/s42003-021-01784-0

M3 - Article

AN - SCOPUS:85101817565

SN - 2399-3642

VL - 4

JO - Communications Biology

JF - Communications Biology

M1 - 266

ER -

A multi-ethnic genome-wide association study implicates collagen matrix integrity and cell differentiation pathways in keratoconus

Abstract

Keywords

Access to Document

Other files and links

Fingerprint

Cite this