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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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Hardcastle, AJ, Liskova, P, Bykhovskaya, Y, McComish, BJ ORCID: 0000-0003-1940-0007, Davidson, AE, Inglehearn, CF, Li, X, Choquet, H, Habeeb, M, Lucas, SEM ORCID: 0000-0003-0104-5406, 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 ORCID: 0000-0001-6201-3518, 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 ORCID: 0000-0002-5123-5999, MacGregor, S, Klaver, CCW, Ramdas, WD, Craig, JE, Iyengar, SK, O'Brart, D, Jorgenson, E, Baird, PN, Rabinowitz, YS, Burdon, KP ORCID: 0000-0001-8217-1249, Hammond, CJ, Tuft, SJ and 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. 1-13 , doi: 10.1038/s42003-021-01784-0.

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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.

Item Type: Article
Authors/Creators:Hardcastle, AJ and Liskova, P and Bykhovskaya, Y and McComish, BJ and Davidson, AE and Inglehearn, CF and Li, X and Choquet, H and Habeeb, M and Lucas, SEM and Sahebjada, S and Pontikos, N and Lopez, KER and Khawaja, AP and Ali, M and Dudakova, L and Skalicka, P and Van Dooren, BTH and Geerards, AJM and Haudum, CW and Faro, VL and Tenen, A and Simcoe, MJ and Patasova, K and Yarrand, D and Yin, J and Siddiqui, S and Rice, A and Farraj, LA and Chen, YDI and Rahi, JS and Krauss, RM and Theusch, E and Charlesworth, JC and Szczotka-Flynn, L and Toomes, C and Meester-Smoor, MA and Richardson, AJ and Mitchell, PA and Taylor, KD and Melles, RB and Aldave, AJ and Mills, RA and Cao, K and Chan, E and Daniell, MD and Wang, JJ and Rotter, JI and Hewitt, AW and MacGregor, S and Klaver, CCW and Ramdas, WD and Craig, JE and Iyengar, SK and O'Brart, D and Jorgenson, E and Baird, PN and Rabinowitz, YS and Burdon, KP and Hammond, CJ and Tuft, SJ and Hysi, PG
Keywords: keratoconus, genome-wide association studies, genetics
Journal or Publication Title: Communications Biology
Publisher: Nature Publishing Group UK
ISSN: 2399-3642
DOI / ID Number: 10.1038/s42003-021-01784-0
Copyright Information:

© The Author(s) 2021. This article is licensed under a Creative Commons Attribution 4.0 International License, (http://creativecommons.org/ licenses/by/4.0/.) 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.

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