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.

Amphia Hospital Breda The Netherlands

Centre for Eye Research Australia Royal Victorian Eye and Ear Hospital East Melbourne VIC Australia

Centre for Vision Research Department of Ophthalmology Westmead Institute for Medical Research University of Sydney Westmead NSW Australia

Department of Epidemiology Erasmus Medical Center GD Rotterdam The Netherlands

Department of Ophthalmology 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czech Republic

Department of Ophthalmology Academic Medical Center Amsterdam The Netherlands

Department of Ophthalmology Case Western Reserve University Cleveland OH USA

Department of Ophthalmology Erasmus Medical Center GD Rotterdam The Netherlands

Department of Ophthalmology Flinders University Adelaide SA Australia

Department of Ophthalmology St James's University Hospital Leeds UK

Department of Ophthalmology University Medical Center Groningen Groningen the Netherlands

Department of Paediatrics and Inherited Metabolic Disorders 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czech Republic

Department of Surgery and Board of Governors Regenerative Medicine Institute Cedars Sinai Medical Center Los Angeles CA USA

Department of Surgery Ophthalmology University of Melbourne Royal Victorian Eye and Ear Hospital East Melbourne VIC Australia

Department of Twin Research and Genetic Epidemiology King's College London London UK

Division of Endocrinology and Diabetology Endocrinology Lab Platform Department of Internal Medicine Medical University of Graz Graz Austria

Division of Molecular Medicine Leeds Institute of Medical Research University of Leeds Leeds UK

Division of Research Kaiser Permanente Northern California Oakland CA USA

Health Services and Systems Research Duke NUS Medical School Singapore Singapore

Institute for Translational Genomics and Population Sciences The Lundquist Institute for Biomedical Innovation at Harbor UCLA Medical Center; Department of Pediatrics Harbor UCLA Medical Center Torrance CA USA

Melbourne Stem Cell Centre Melbourne VIC 3800 Australia

Menzies Institute for Medical Research University of Tasmania Hobart TAS Australia

Moorfields Eye Hospital NHS Foundation Trust London UK

NIHR Biomedical Research Centre Moorfields Eye Hospital London UK

Oakland Research Institute Oakland CA USA

QIMR Berghofer Medical Research Institute Brisbane QLD Australia

School of Primary and Allied Health Care Monash University Melbourne VIC Australia

Section of Ophthalmology School of Life Course Sciences King's College London London UK

St Thomas Hospital Guy's and St Thomas NHS Trust London London UK

The Cornea Eye Institute Beverly Hills CA USA

The Jules Stein Institute University of California Los Angeles Los Angeles CA USA

The Rotterdam Eye Hospital Rotterdam The Netherlands

UCL Great Ormond Street Hospital Institute of Child Health London UK

UCL Institute of Ophthalmology London UK

Vision Eye Institute Melbourne VIC Australia

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