Purchase this article with an account.
Yelena Bykhovskaya, Xiaohui Li, Kent D. Taylor, Jerome I. Rotter, Yaron S. Rabinowitz; Linkage Analysis Of High-density SNP Markers Confirms Location Of Keratoconus Locus At The 5q15-5q21.1 Chromosomal Region. Invest. Ophthalmol. Vis. Sci. 2012;53(14):1551.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
Previously we reported on a two-stage genome-wide linkage scan using microsatellite markers in a four-generation autosomal-dominant pedigree with keratoconus and identified a peak of 8.2 MB with LOD of 3.53 located at the 5q14.1-q21.3 chromosomal region (Tang et al. Genet Med 2005). To further confirm and potentially narrow down this linkage region we genotyped high density single nucleotide polymorphisms (SNPs) in the region and tested them for genetic linkage and association with keratoconus.
27 members of the four-generation family were genotyped using Illumina 1M beadchips. Merlin computer package (Abecasis et al. 2002) was used to perform parametric linkage analysis. Generalized estimation equation models accounting for familial correlations implemented in GWAF (Cheng et al. 2010) were used for association testing in families.
We performed linkage analysis under an autosomal dominant model with the same parameters (phenocopy rate of 0.01 and penetrance of 0.5) and pedigree-splitting method as was described in our original paper. Maximum Lod score of 2.49 was calculated at approximately 99 MB region of chromosome 5 confirming previously identified linkage using microsatellite markers. In addition, based on Lod scores greater than 2 we narrowed down linkage region to 5MB between 95MB to 100MB located at 5q15-5q21.1. Genetic association tests using the dominant model identified several SNPs with p values equal or less than 0.01 in this region, including SNP rs3853203 located approximately 35KB 5’ to the CAST gene, coding for calpain inhibitor Calpastatin.
Linkage analysis of high density SNPs confirms previously reported linkage at the 5q15-5q21.1 chromosomal region in an autosomal dominant family with keratoconus. Family based association provides evidence to suggest CAST as a candidate gene for keratoconus.
This PDF is available to Subscribers Only