Association of LOC339766 With High Myopia in Caucasian Family Cohorts

Abstract

Purpose: : We previously reported a non-syndromic, high-grade myopia locus on chromosome 2q37 which has been independently replicated in other studies. To identify causative variants, we employed a multi-pronged approach comprised of intra-locus densely spaced SNP family-based association analyses to refine the interval, contracted interval candidate gene identification, SNP variant discovery by case/control cohort candidate gene sequencing, and subsequent genotyping and association analyses in a high-grade myopia family dataset for assessing myopia susceptibility.

Methods: : Illumina GoldenGate genotyping was performed on the original 4.56 Mb interval using 145 SNPs with an average spacing of 31.5 kb in a cohort of 146 multiplex high-grade myopia families. The family-based pedigree disequilibrium test (PDT) and the association in the presence of linkage (APL) test were used for determining association of markers with myopia phenotype stratified by severity. The region incorporating the LOC339766 gene showed significant association. To identify potential risk-associated sequence variants, coding exon sequencing of this gene was performed in independent select case (≤ -6.00 diopters (D) spherical equivalent (SE) and control (≥ +0.50 D SE) datasets. Genotyping and association analyses were performed on LOC339766 identified SNP variants and tagging SNPs using Taqman^TM allelic discrimination assays in Caucasian Duke and International cohorts in a total of 265 myopia families.

Results: : PDT analyses from the GoldenGate assay data revealed significant association of several SNPs with high-grade myopia status involving the LOC339766 gene (p<0.01). Genotyping results (with identified variants and tagging SNPs) revealed significant association of the LOC339766 gene polymorphisms with myopia. The Duke cohort showed association with SNPs rs10203853 and rs17868346 (p <0.01, min p=0.004) and the International cohort showed association with SNPs rs17863814 and rs28900694 (p<0.01, min p=1x10^-4). The results were consistent after correcting for multiple testing.

Conclusions: : LOC339766 gene variants are associated with high-grade myopia in Caucasians. The 2q37 locus may play an important role in autosomal dominant early-onset myopic development. Expression and functional studies to further characterize this hypothetical gene are underway.

Keywords: refractive error development • candidate gene analysis • gene mapping