Journal article

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 EM Lucas, Srujana Sahebjada, Nikolas Pontikos, Karla E Rojas Lopez, Anthony P Khawaja, Manir Ali, Lubica Dudakova, Pavlina Skalicka, Bart TH Van Dooren, Annette JM Geerards, Christoph W Haudum Show all

COMMUNICATIONS BIOLOGY | NATURE RESEARCH | Published : 2021

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..

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Grants

Awarded by HighThroughput Genomics Group at the Wellcome Trust Centre for Human Genetics - Wellcome Trust


Awarded by National Institute of Health Common Fund


Awarded by National Eye Institute (NEI)


Awarded by National Institute of Diabetes and Digestive and Kidney Diseases


Awarded by NEI


Awarded by National Institutes of Health


Awarded by National Heart, Lung, and Blood Institute


Awarded by National Institutes of Health, National Eye Institute


Awarded by National Center for Advancing Translational Sciences, CTSI


Awarded by National Health and Medical Research Council (NHMRC)


Awarded by Centre for Research Excellence


Awarded by AMD Genetics Consortium genotyped under The Center for Inherited Diseases Research (CIDR) Program


Awarded by NHMRC


Awarded by NHMRC Senior Research Fellowship


Awarded by KCL Department of Ophthalmology


Awarded by Leeds University and Leeds Teaching Hospitals NHS Trust


Awarded by MRC


Awarded by Australian National Health and Medical Research Council (NHMRC)


Awarded by Charles University and General University Hospital in Prague, Czech Republic


Awarded by Charles University


Funding Acknowledgements

The publication of this article has been enabled by a grant from Moorfields Eye Charity (GR001317). UK Biobank: This research has been conducted using the UK Biobank Resource under Application Number 17615. UK Biobank was established by the Wellcome Trust medical charity, Medical Research Council, Department of Health, Scottish Government, and Northwest Regional Development Agency. It also had funding from the Welsh Assembly Government, British Heart Foundation, and Diabetes UK. UCL and Moorfields, London, UK: We are grateful to all the patients at Moorfields Eye Hospital who participated in this study. This study was funded by Moorfields Eye Charity and the Rosetrees Trust. We were supported by infrastructure and funding from the National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital and UCL Institute of Ophthalmology. AED is supported by AED is supported by a UK Research and Innovation Future Leadership Fellowship, Moorfields Eye Charity, and Academy of Medical Sciences Springboard award. We thank Beverley Scott and Naushin Waseem for assistance with DNA extraction and DNA banking, and the HighThroughput Genomics Group at the Wellcome Trust Centre for Human Genetics (funded by Wellcome Trust grant reference 203141/Z/16/Z) for performing the genotyping on the discovery cohort. APK and NP are supported by Moorfields Eye Charity Career Development Fellowships. GERA, USA: We are grateful to the Kaiser Permanente Northern California members who have generously agreed to participate in the Kaiser Permanente Research Program on Genes, Environment, and Health. Support for participant enrollment, survey completion, and biospecimen collection for the RPGEH was provided by the Robert Wood Johnson Foundation, the Wayne and Gladys Valley Foundation, the Ellison Medical Foundation, and Kaiser Permanente Community Benefit Programs. Genotyping of the GERA cohort was funded by a grant from the National Institute on Aging, National Institute of Mental Health, and National Institute of Health Common Fund (RC2 AG036607). Data analyses were facilitated by National Eye Institute (NEI) grant R01 EY027004 (E.J.), National Institute of Diabetes and Digestive and Kidney Diseases grant R01 DK116738 (E.J.). The Los Angeles-affiliated cohort, USA: The authors gratefully acknowledge the support of The Eye Defects Research Foundation Inc. and NEI R01-09052. CAP study (control cohort) was supported by the National Institutes of Health grant U19 HL069757 from the National Heart, Lung, and Blood Institute; and grant UL1TR000124 from the National Center for Advancing Translational Sciences. In addition, this work was supported in part by the National Institutes of Health, National Eye Institute contract R01 EY009052, and by the National Center for Advancing Translational Sciences, CTSI grant UL1TR001881. Australia: The Australian replication case cohort was funded by a National Health and Medical Research Council (NHMRC) project grant 1104700 and Centre for Research Excellence 1023911. Control genotype data for this cohort were provided by the international AMD Genetics Consortium genotyped under The Center for Inherited Diseases Research (CIDR) Program contract number HHSN268201200008I. SM is supported by an NHMRC Fellowship and NHMRC grants 1150144, 1116360. Dr Burdon was supported by an NHMRC Senior Research Fellowship (1059954). King's College London and St. Thomas Hospital, UK: M.J. Simcoe is a recipient of a Fight for Sight PhD studentship. K. Patasova is a recipient of a Fight for Sight PhD studentship. P.G.Hysi the recipient of a Fight for Sight ECI fellowship. P.G. Hysi and C.J. Hammond acknowledge the TFC Frost Charitable Trust Support for the KCL Department of Ophthalmology. The statistical analyses were run in King's College London Rosalind HPC and Department of Twin Research and Genetic Epidemiology Linux clusters and server. The UK Biobank data was accessed as part of the UK Biobank projects 669 and 17615. Leeds University and Leeds Teaching Hospitals NHS Trust, UK: We thank the patients and relatives who participated in this project. This study was supported by grants SAC007 and SAC033 from the National Eye Research Centre, and LAF was supported by a PhD grant award from Fight For Sight. S.Siddiqui was supported by the MRC grant 408757. Thanks to Erica Di Martino for laboratory support. University of Melbourne, Royal Victorian Eye and Ear Hospital, Australia: This study was supported by the Australian National Health and Medical Research Council (NHMRC) project grant 1104700 and Senior Research Fellowship (1138585 to PNB), the Angior Family Foundation and a Lions Eye Foundation Fellowship (SS). The Centre for Eye Research Australia (CERA) receives Operational Infrastructure Support from the Victorian Government. The authors wish to thank all participants who took part in this Keratoconus study and made this work possible. The authors would also like to thank Eye Surgery Associates, Lindsay and Associates and Keratoconus Australia, as well as Mr Tony Ngo for assistance with subject recruitment. Charles University and General University Hospital in Prague, Czech Republic: PL, LD and PS were supported by UNCE/MED/007 and PROGRES1086, Q26/LF1 research programs of the Charles University and by grant GACR 20-19278S. We thank the participating patients and staff of the Cornea service from the Department of Ophthalmology, General University Hospital in Prague for assistance with recruitment. The Erasmus Medical Center: The authors are grateful to Barbara Obermayer-Pietsch, Arthur A Bergen, and Andre G. Uitterlinden for their tremendous help throughout this project. The study was supported by the Combined Ophthalmic Research Rotterdam (CORR) grant.