Fine-mapping of candidate region in Amish and Ashkenazi families confirms linkage of refractive error to a QTL on 1p34-p36

PURPOSE: A previous genome-wide study in Orthodox Ashkenazi Jewish pedigrees showed significant linkage of ocular refraction to a Quantitative Trait Locus (QTL) on 1p34-36.1. We carried out a fine-mapping study of this region in Orthodox Ashkenazi Jewish (ASHK) and Old Order Amish (OOA) families to confirm linkage and narrow the candidate region. METHODS: Families were recruited from ASHK and OOA American communities. The samples included: 402 individuals in 53 OOA families; and 596 members in 68 ASHK families. Families were ascertained to contain multiple myopic individuals. Genotyping of 1,367 SNPs was carried out within a 35cM (~23.9 Mb) candidate QTL region on 1p34-36. Multipoint variance components (VC) and regression-based (REG) linkage analyses were carried out separately in OOA and ASHK groups, and in a combined analysis that included all families. RESULTS: Evidence of linkage of refractive error was found in both OOA (VC LOD=3.45, REG LOD=3.38 at ~59 cM) and ASHK families (VC LOD=3.12, REG LOD=4.263 at ~66 cM). Combined analyses showed three highly significant linkage peaks, separated by ~11cM (or 10 Mb), within the candidate region. CONCLUSION: In a fine-mapping linkage study of OOA and ASHK families, we have confirmed linkage of refractive error to a QTL on 1p. The area of linkage has been narrowed down to a gene-rich region at 1p34.2-35.1 containing ~124 genes.