WNT10A exonic variant increases the risk of keratoconus by decreasing corneal thickness

Abstract

Keratoconus is a degenerative eye condition which results from thinning of the cornea and causes vision distortion. Treatments such as ultraviolet (UV) cross-linking have proved effective for management of keratoconus when performed in early stages of the disease. The central corneal thickness (CCT) is a highly heritable endophenotype of keratoconus, and it is estimated that up to 95% of its phenotypic variance is due to genetics. Genome-wide association efforts of CCT have identified common variants (i.e. minor allele frequency (MAF) >5%). However, these studies typically ignore the large set of exonic variants whose MAF is usually low. In this study, we performed a CCT exome-wide association analysis in a sample of 1029 individuals from a population-based study in Western Australia. We identified a genome-wide significant exonic variant rs121908120 (P = 6.63 × 10(-10)) in WNT10A. This gene is 437 kb from a gene previously associated with CCT (USP37). We showed in a conditional analysis that the WNT10A variant completely accounts for the signal previously seen at USP37. We replicated our finding in independent samples from the Brisbane Adolescent Twin Study, Twin Eye Study in Tasmania and the Rotterdam Study. Further, we genotyped rs121908120 in 621 keratoconus cases and compared the frequency to a sample of 1680 unscreened controls from the Queensland Twin Registry. We found that rs121908120 increases the risk of keratoconus two times (odds ratio 2.03, P = 5.41 × 10(-5)).

Analysis of multiple genetic loci reveals MPDZ-NF1B rs1324183 as a putative genetic marker for keratoconus

“…Previous studies have identified the association of CCT with a polymorphic variant in WNT10A in patients with keratoconus 21. However, the genotype-phenotype correlation of MPDZ-NF1B was first discovered in this study, with association of MPDZ-NF1B rs1324183 with corneal thickness and curvature.…”

Genetic associations for keratoconus: a systematic review and meta-analysis

“…1). In the meta-analysis, we excluded 12 of the 36 articles because 7 of them were about gene variants that were not tested in additional independent studies 27–33 , 2 reported insufficient genotype data for meta-analysis 34, 35 , 2 were reviews 25, 26 , and 1 was an animal study 36 . We did not receive genotype data after contacting some of the authors 34, 35 .…”

Differential Expression of Coding and Long Noncoding RNAs in Keratoconus-affected Corneas

“…WNT signaling pathway is essential for normal corneal development and a missense coding variant (rs121908120, c.1145T>A, p.228Phe>Ile) in the WNT10A gene has been associated with KC risk 72 . Moreover, using RNA-Seq, a recent study showed dysregulation in WNT signaling in the KC-affected corneal epithelium.…”