Genomic strategies to understand causes of keratoconus

Abstract

Keratoconus (KTCN) is a degenerative disorder of the eye characterized by the conical shape and thinning of the cornea. The abnormal structure of KTCN-affected cornea results in loss of visual acuity. While many studies examine how environmental factors influence disease development, finding the genetic triggers has been a major emphasis of KTCN research. This paper focuses on genomic strategies that were implemented for finding candidate genes, including linkage and association studies, and presents different approaches of mutation screening. The advantages and limitations of particular tools are discussed based on literature and personal experience. Since etiology underlying KTCN is complex, numerous findings indicating heterogeneity of genetic factors involved KTCN etiology are presented.

Multiple Differentially Methylated Regions Specific to Keratoconus Explain Known Keratoconus Linkage Loci

“…2) overlapped known KTCN linkage loci, namely, 3p14.3, 23 5q35.2, 24 13q32.3, 25 15q24.1, 26 and 20p13, 27 whereas 15 DMRs were located on six chromosome arms, namely, 2q, 4q, 5p, 9p, 14q, and 17q, that have been linked to KTCN. 5,28 The detailed information regarding each region is presented in the Table. None of the identified DMR regions overlapped known genome-wide association study loci. [29][30][31][32][33][34][35] The majority of DMRs (65%, 73 regions) overlapped known genes (the detailed overlap status between DMRs and different categories of genomic annotations is presented in Supplementary Fig.…”

“…A number of genomic regions and sequence variants have been associated with KTCN but turned out to be specific to particular families or populations and failed to explain the cause of the disease in the general population. 5 A potential solution to this problem of missing heritability has been recently suggested, as epigenetic modifications, including DNA methylation and histone modifications, were shown to affect phenotype in heritable manner. 6,7 To verify if this is the case for KTCN, we performed the comprehensive analysis of DNA methylation in human KTCN and non-KTCN corneas using the RRBS approach.…”

“…4 Multiple loci and gene variants have been linked to KTCN, but they tend to be specific to particular families or populations. 5 Epigenetic modifications, such as DNA methylation and histone marks, have been suggested to play vital role in shaping complex phenotypes, including disease etiology. 6 These modifications have been shown to be both highly plastic, responding to environmental conditions, and able to alter gene expression in heritable manner.…”

“…11 We also found that many of detected DMRs overlap previously described KTCN susceptibility regions. 5…”

Keratoconus at a Molecular Level: A Review

“…Clinically, keratoconus is defined as an ectatic disease presenting abnormal posterior ectasia, abnormal corneal thickness distribution and clinical non‐inflammatory corneal thinning (Gomes et al, ). The exact cause of keratoconus is not certain, although strong correlations have been made with genetic and environmental factors (Karolak and Gajecka, ). Keratoconus normally affects both eyes, in some rare cases the disease can be unilateral (Holland et al, ).…”