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.

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Item Type:	Article
Authors/Creators:	Hardcastle, AJ Liskova, P Bykhovskaya, Y McComish, BJ Davidson, AE Inglehearn, CF https://orcid.org/0000-0002-5143-2562 Li, X Choquet, H Habeeb, M Lucas, SEM Sahebjada, S Pontikos, N Lopez, KER Khawaja, AP Ali, M https://orcid.org/0000-0003-3204-3788 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 https://orcid.org/0000-0001-8373-9545 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
Copyright, Publisher and Additional Information:	© The Author(s) 2021. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Dates:	Published: 1 March 2021 Published (online): 1 March 2021 Accepted: 2 February 2021
Institution:	The University of Leeds
Funding Information:	Funder Grant number Fight for Sight Institute of Opthalmology REF 1835 National Eye Research Centre SCIAD 077
Depositing User:	Symplectic Publications
Date Deposited:	01 Feb 2023 14:35
Last Modified:	01 Feb 2023 14:35
Status:	Published
Publisher:	Springer Science and Business Media LLC
Identification Number:	10.1038/s42003-021-01784-0
Related URLs:	Author
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:195817

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

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