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

AJ Hardcastle; P Liskova; Y Bykhovskaya; BJ McComish; AE Davidson; CF Inglehearn; X Li; H Choquet; Mahmoud Habeeb; SEM Lucas; S Sahebjada; N Pontikos; KER Lopez; AP Khawaja; M (Mehabat) Ali; L Dudakova; P Skalicka; Bart van Dooren; AJM Geerards; CW Haudum; V Lo Faro; A Tenen; MJ Simcoe; K Patasova; D Yarrand; J Yin; S Siddiqui; A Rice; LA Farraj; YDI Chen; JS Rahi; RM Krauss; E Theusch; JC Charlesworth; L Szczotka-Flynn; C Toomes; Magda Meester - Smoor; AJ Richardson; PA Mitchell; KD Taylor; RB Melles; AJ Aldave; RA Mills; K Cao; E Chan; MD Daniell; JJ Wang; JI Rotter; AW Hewitt; S Macgregor; Caroline Klaver; Wishal Ramdas; JE Craig; SK Iyengar; D O'Brart; E Jorgenson; PN Baird; YS Rabinowitz; KP Burdon; CJ Hammond; SJ Tuft; PG 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

AJ Hardcastle, P Liskova, Y Bykhovskaya, BJ McComish, AE Davidson, CF Inglehearn, X Li, H Choquet, Mahmoud Habeeb, SEM Lucas, S Sahebjada, N Pontikos, KER Lopez, AP Khawaja, M (Mehabat) Ali, L Dudakova, P Skalicka, Bart van Dooren, AJM Geerards, CW HaudumV Lo Faro, A Tenen, MJ Simcoe, K Patasova, D Yarrand, J Yin, S Siddiqui, A Rice, LA Farraj, YDI Chen, JS Rahi, RM Krauss, E Theusch, JC Charlesworth, L Szczotka-Flynn, C Toomes, Magda Meester - Smoor, AJ Richardson, PA Mitchell, KD Taylor, RB Melles, AJ Aldave, RA Mills, K Cao, E Chan, MD Daniell, JJ Wang, JI Rotter, AW Hewitt, S Macgregor, Caroline Klaver, Wishal Ramdas, JE Craig, SK Iyengar, D O'Brart, E Jorgenson, PN Baird, YS Rabinowitz, KP Burdon, CJ Hammond, SJ Tuft, PG 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
Article number	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, 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, B., Geerards, AJM., ... Hysi, PG. (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

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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 = "AJ Hardcastle and P Liskova and Y Bykhovskaya and BJ McComish and AE Davidson and CF Inglehearn and X Li and H Choquet and Mahmoud Habeeb and SEM Lucas and S Sahebjada and N Pontikos and KER Lopez and AP Khawaja and Ali, {M (Mehabat)} and L Dudakova and P Skalicka and {van Dooren}, Bart and AJM Geerards and CW Haudum and {Lo Faro}, V and A Tenen and MJ Simcoe and K Patasova and D Yarrand and J Yin and S Siddiqui and A Rice and LA Farraj and YDI Chen and JS Rahi and RM Krauss and E Theusch and JC Charlesworth and L Szczotka-Flynn and C Toomes and {Meester - Smoor}, Magda and AJ Richardson and PA Mitchell and KD Taylor and RB Melles and AJ Aldave and RA Mills and K Cao and E Chan and MD Daniell and JJ Wang and JI Rotter and AW Hewitt and S Macgregor and Caroline Klaver and Wishal Ramdas and JE Craig and SK Iyengar and D O'Brart and E Jorgenson and PN Baird and YS Rabinowitz and KP Burdon and CJ Hammond and SJ Tuft and PG Hysi",

year = "2021",

month = mar,

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

language = "English",

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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, B, Geerards, AJM, Haudum, CW, Lo Faro, V, 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, M, 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, C , Ramdas, W, 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, 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, AJ

AU - Liskova, P

AU - Bykhovskaya, Y

AU - McComish, BJ

AU - Davidson, AE

AU - Inglehearn, CF

AU - Li, X

AU - Choquet, H

AU - Habeeb, Mahmoud

AU - Lucas, SEM

AU - Sahebjada, S

AU - Pontikos, N

AU - Lopez, KER

AU - Khawaja, AP

AU - Ali, M (Mehabat)

AU - Dudakova, L

AU - Skalicka, P

AU - van Dooren, Bart

AU - Geerards, AJM

AU - Haudum, CW

AU - Lo Faro, V

AU - Tenen, A

AU - Simcoe, MJ

AU - Patasova, K

AU - Yarrand, D

AU - Yin, J

AU - Siddiqui, S

AU - Rice, A

AU - Farraj, LA

AU - Chen, YDI

AU - Rahi, JS

AU - Krauss, RM

AU - Theusch, E

AU - Charlesworth, JC

AU - Szczotka-Flynn, L

AU - Toomes, C

AU - Meester - Smoor, Magda

AU - Richardson, AJ

AU - Mitchell, PA

AU - Taylor, KD

AU - Melles, RB

AU - Aldave, AJ

AU - Mills, RA

AU - Cao, K

AU - Chan, E

AU - Daniell, MD

AU - Wang, JJ

AU - Rotter, JI

AU - Hewitt, AW

AU - Macgregor, S

AU - Klaver, Caroline

AU - Ramdas, Wishal

AU - Craig, JE

AU - Iyengar, SK

AU - O'Brart, D

AU - Jorgenson, E

AU - Baird, PN

AU - Rabinowitz, YS

AU - Burdon, KP

AU - Hammond, CJ

AU - Tuft, SJ

AU - Hysi, PG

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

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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