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; Helene 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

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, Helene 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

^*Corresponding author for this work

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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. Alison Hardcastle et al. report a genome-wide meta-analysis of keratoconus, a condition affecting the cornea that causes blurred vision and often leads to blindness. They identify 36 genomic regions associated with keratoconus, 31 of which are novel, and show that the genes in these regions implicate genetic pathways involved in collagen matrix integrity and cell differentiation.

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

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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., ... MacGregor, S. (2021). A multi-ethnic genome-wide association study implicates collagen matrix integrity and cell differentiation pathways in keratoconus. Communications biology, 4(1), Article 266. https://doi.org/10.1038/s42003-021-01784-0

@article{049b0a0cf018466cbec9ba6a332063d2,

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. Alison Hardcastle et al. report a genome-wide meta-analysis of keratoconus, a condition affecting the cornea that causes blurred vision and often leads to blindness. They identify 36 genomic regions associated with keratoconus, 31 of which are novel, and show that the genes in these regions implicate genetic pathways involved in collagen matrix integrity and cell differentiation.",

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 Helene 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 {Lo Faro}, Valeria 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",

year = "2021",

month = mar,

day = "1",

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

language = "English",

volume = "4",

journal = "Communications biology",

issn = "2399-3642",

publisher = "Nature Publishing Group",

number = "1",

}

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, Lo Faro, V, Tenen, A, Simcoe, MJ, Patasova, K, Yarrand, D, Yin, J, Siddiqui, S, Rice, A, Farraj, LA, Chen, Y-DI, 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 2021, 'A multi-ethnic genome-wide association study implicates collagen matrix integrity and cell differentiation pathways in keratoconus', Communications biology, vol. 4, no. 1, 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, Helene

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 - Lo Faro, Valeria

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

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. Alison Hardcastle et al. report a genome-wide meta-analysis of keratoconus, a condition affecting the cornea that causes blurred vision and often leads to blindness. They identify 36 genomic regions associated with keratoconus, 31 of which are novel, and show that the genes in these regions implicate genetic pathways involved in collagen matrix integrity and cell differentiation.

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. Alison Hardcastle et al. report a genome-wide meta-analysis of keratoconus, a condition affecting the cornea that causes blurred vision and often leads to blindness. They identify 36 genomic regions associated with keratoconus, 31 of which are novel, and show that the genes in these regions implicate genetic pathways involved in collagen matrix integrity and cell differentiation.

U2 - 10.1038/s42003-021-01784-0

DO - 10.1038/s42003-021-01784-0

M3 - Article

SN - 2399-3642

VL - 4

JO - Communications biology

JF - Communications biology

IS - 1

M1 - 266

ER -

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

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