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.

Genome-Wide Association Study Identifies Two Common Loci Associated with Pigment Dispersion Syndrome/Pigmentary Glaucoma and Implicates Myopia in its Development

“…Genotypes were then called together to prevent artefacts from batch effects and were then imputed to the Haplotype Reference Consortium panel 16 using the Michigan Imputation Server 17 as previously described 25 .…”

Cohort profile: ‘Biomarkers of Personalised Medicine’ (BioPersMed): a single-centre prospective observational cohort study in Graz/Austria to evaluate novel biomarkers in cardiovascular and metabolic diseases

“…40 These observations were in line with previous findings of another research group. 41 Furthermore, genetic data from the genome-wide association study and optometric phenotyping of the BioPersMed cohort were already used as control data for a large keratoconus genomic study in cooperation with researchers from the UK and the Netherlands, 42 for the analysis of allelic determinants with a reported association to 25(OH)D levels and their influence on vitamin D, 43 and to identify novel biomarkers for non-alcoholic fatty liver disease 44 in cooperation with local researchers. Data on bone morphology from the BioPersMed cohort were used to link Sarcopenia with increased risk of falls, osteoporosis and mortality.…”

Cloud-based genomics pipelines for ophthalmology: reviewed from research to clinical practice

“…Large GWAS have been applied to ophthalmology for glaucoma, diabetic retinopathy, keratoconus, and other conditions. 91 Once a GWAS is complete, a number of SNPs are identified as being significantly associated with a disease. These can then be taken forward to build a polygenic risk score (PRS), which is a tailored measure of genetic risk for an individual to develop a condition such as glaucoma.…”