Expanded Genome-wide Linkage Scan for Fuchs Endothelial Corneal Dystrophy

Abstract

Purpose: : To map genetic determinants of Fuchs endothelial corneal dystrophy (FECD) by using an expanded family dataset and high-density single nucleotide polymorphisms (SNPs) for genome-wide linkage analysis.

Methods: : Genome-wide SNP genotyping with the Illumina GoldenGate linkage panel IVB (5759 SNPs) on 92 individuals from 22 multiplex FECD families established evidence of linkage to 5 chromosomes. We sought to expand our initial findings by increasing our linkage sample to include 186 individuals from 46 multiplex FECD families by adding 94 individuals collected through a collaboration between Duke and Johns Hopkins Universities. Genotyping of these new samples was conducted on Illumina’s Infinium HumanLinkage-12 platform containing 6090 SNPs, of which 4811 overlap with the GoldenGate IVB platform. As a prelude to comprehensive two-point and multipoint genome-wide linkage analyses, which are currently underway, we have performed preliminary two-point parametric analyses for both dominant (DOM) and recessive (REC) genetic models using FASTLINK/HOMOG for chromosomes 15 and 17, which had two of the strongest linkage peaks in our previous report.

Results: : Initial data cleaning identified 3/94 non-performing samples and 61/6090 non-performing SNPs. The chromosome 15 peak marker from our previous report, rs352476, showed a decrease in two-point HLOD score from 2.48 to 1.48 (DOM) and from 3.25 to 0.40 (REC) in the new analysis. No SNPs on chromosome 15 produced HLOD scores > 1.5. However, two SNPs on chromosome 17, rs1564296 and rs938350, did produce HLOD scores >1.5 in at least one genetic model. Notably, rs938350, the peak marker from our previous report, showed a decrease in HLOD score under the DOM model (from 2.10 to 1.33) but an increase in the REC model (from 1.09 to 2.63). Two SNPs located within 10 cM of rs938350, rs1530348 and rs454138, had HLOD scores > 1.5 in our previous scan but were not included on the Infinium linkage panel; genotype imputation will determine replication of HLOD scores.

Conclusions: : Between our two linkage scans, we have observed HLOD scores > 1.5 for 3 SNPs in the same locus on chromosome 17 (rs938350, rs1530348, and rs454138). We anticipate replicating our initial chromosome 17 peak once multipoint analyses are completed, although non-overlapping SNPs between the two Illumina platforms may suffer from a reduction in sample size. Genotype imputation is underway and may improve our linkage results.

Keywords: gene mapping • cornea: endothelium • genetics