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C. J. Hammond, T. Andrew, N. Maniatis, T. D. Spector; Identification of Three Possible Myopia Susceptibility Genes on Chromosome 3q26 Using Linkage Disequilibrium Mapping. Invest. Ophthalmol. Vis. Sci. 2008;49(13):5425.
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Myopia has a strong heritable component. In a genome-wide linkage study, we observed evidence of linkage to chromosome 3q26 (LOD 3.7) (Hammond, Andrew et al 2004). In a replication study (unpublished) evidence of linkage to 3q26 was also observed (LOD 1.9) using 485 DZ pairs based upon spectacle prescription. Combined datasets showed evidence of linkage at LOD 2.63. We set out to examine this 3q26 locus for myopia susceptibility genes.
241 genetically "enriched" cases (individuals with < -1 diopters and a twin pair mean of =<-0.75 diopters) and 257 "super" controls (individuals with >+1 diopters and a twin pair mean of >+1 diopters) were selected. Based upon previous work (Maniatis et al 2002 and 2007), we defined a high resolution genetic Linkage Disequilibrium (LD) map using HapMap Phase II data. We used a cost effective and efficient study design, in which 3-6 SNPs per LDU for a range of common allele frequencies were placed evenly across the LD map, resulting in a total of ~2300 SNPs in 659 LDUs in the ~25MB 3q26 region. Each SNP was placed upon the LDU map and then tested for association with myopia using a multiple pair-wise composite likelihood (Maniatis 2004).
Preliminary analyses for the original 421 samples identified 6 potential regions of association. Additional SNPs were genotyped for the original and additional samples (n=443). The highest -logp values for SNPs in these 6 regions (29 SNPs) were tested for replication by cross-referencing SNP identifiers with Illumina Hap300 SNPs genotyped in an independent sample of twins (n=1430). SNPs in 2 LDU regions (regions 35 and 32) showed significant associations in original and replicate samples (eg SNP 1298, LDU region 35, association with case-control status at p=10E-4.85 for original and replicate combined datasets). The confidence intervals of LDU 35 was 150kb and contained 2 genes, 1 gene in LDU 32 was significantly associated.
The gene-rich SOX2 chromosomal region at 3q26 shows replicated evidence of linkage and association for at least two LDUs, and three possible candidate genes for common myopia have been identified. Further work is underway and the genes involved will be presented.
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