This incomplete knowledge of the genetic predisposition for keratoconus limits our understanding of the mechanisms that drive this disease. Therefore, alternative mechanisms, in addition to those influencing CCT, are likely to be involved. Previous studies have also implicated single nucleotide polymorphism (SNP) alleles upstream of the ZNF469 locus that is associated with a higher CCT but an increased risk for keratoconus 16, 20, 21. However, although CCT is highly heritable, it is a stable characteristic, in contrast to the acquired and progressive corneal thinning that is a feature of keratoconus. Several loci and variants for keratoconus have been identified through linkage studies and genome-wide association studies (GWASs) for central corneal thickness (CCT) 14, 15, 16, 17, 18, 19, 20. Keratoconus can also be a comorbidity of other genetically determined conditions such as Down syndrome 13. A high occurrence rate in first degree relatives, and concordance in twins, suggest that keratoconus has a strong genetic component 11, 12. The prevalence of keratoconus varies between ethnic groups, with figures as high as 1.2% reported in some predominantly European populations 8, to 2.3–3.3% in Maori or Iranian populations 9, 10. Keratoconus is a leading cause for visual impairment in adolescents and young adults which, untreated, can lead to legal blindness 1, 2, 3, 4, 5, 6, 7. 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. The results also suggest pleiotropy, with some disease mechanisms shared with other corneal diseases, such as Fuchs endothelial corneal dystrophy. 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. Here we report the first large scale genome-wide association study of keratoconus including 4,669 cases and 116,547 controls. It can lead to severe visual morbidity in children and young adults and is a common indication for corneal transplantation worldwide. Keratoconus is characterised by reduced rigidity of the cornea with distortion and focal thinning that causes blurred vision, however, the pathogenetic mechanisms are unknown. A multi-ethnic genome-wide association study implicates collagen matrix integrity and cell differentiation pathways in keratoconus
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