Two–Stage Genome–Wide Linkage Scan in Keratoconus Sib–Pair Families

Abstract

Abstract: : To identify the susceptibility gene loci for keratoconus (KC), we performed a genome–wide linkage analysis using data from 67 KC sib–pair families with 107 affected–sib pairs. A total of 356 subjects were genotyped for 408 microsatellite markers along the genome at ∼10cM density. In order to further delineate the linkage, additional 58 microsatellite markers at ∼2cM density in the identified linkage regions on chromosomes 4, 5, 9, 12 and 14 were genotyped. Multipoint linkage analysis was performed using all pedigrees and Caucasians only (40 families, 217 individuals) by non–parametric methods and maximum likelihood estimates of identity by descent sharing as implemented in GeneHunter. Most linkage peaks were consistent between Caucasian and all pedigrees. The strongest evidence of linkage was observed at the telomere (159 cM) of chromosome 9 (LOD=4.5) for all pedigrees. Other suggestive linkages were identified at 176 cM of chromosome 4 (LOD=2.7), 143 cM of chromosome 5 (LOD=2.0), 7 cM of chromosome 9 (LOD=2.8), 12 cM of chromosome 11 (LOD=2.3), 27 cM of chromosome 12 (LOD=2.3) and 14 cM of chromosome 14 (LOD=2.9). After fine mapping these regions (except chromosome 11), most linkage peaks remained similar (LOD=2.4 at 176 cM on chromosome 4, LOD=2.3 at 144 cM on chromosome 5, LOD=4.1 at 159 cM on chromosome 9, LOD=2.1 at 7 cM on chromosome 12, and LOD=2.5 at 18 cM on chromosome 14). These results indicate that several loci may contribute to KC susceptibility. In addition, it is intriguing that we have observed evidence of linkage at 103 cM on chromosome 5 in a four–generation pedigree (published) as well as a maximum LOD of 2.0 from sib–pair families at 143 cM on chromosome 5. Although these two peaks do not perfectly overlap, their close proximity raises the possibility that these genomic regions might be the same KC susceptibility locus.

Keywords: linkage analysis • gene mapping