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

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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.

Original language	English
Pages (from-to)	266
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., ... Hysi, P. G. (2021). A multi-ethnic genome-wide association study implicates collagen matrix integrity and cell differentiation pathways in keratoconus. Communications Biology, 4(1), 266. https://doi.org/10.1038/s42003-021-01784-0

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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.",

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'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",

pages = "266",

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, Faro, VL, 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, 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, no. 1, pp. 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.

UR - https://www.mendeley.com/catalogue/ac89c195-c3ef-3855-9a36-ce0c5479b956/

U2 - 10.1038/s42003-021-01784-0

DO - 10.1038/s42003-021-01784-0

M3 - Article

C2 - 33649486

SN - 2399-3642

VL - 4

SP - 266

JO - Communications Biology

JF - Communications Biology

IS - 1

ER -

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

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