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Robert Wojciechowski, Claire L. Simpson, Joan E. Bailey-Wilson, Dwight Stambolian; Fine-mapping Of Linkage Region Shows A Novel Association Of Refractive Error To a Polymorphism In CSMD2. Invest. Ophthalmol. Vis. Sci. 2011;52(14):3295.
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© ARVO (1962-2015); The Authors (2016-present)
We previously demonstrated significant linkage of refractive error to a chromosomal region at 1p34-p36 in Orthodox Ashkenazi American (ASHK) Families. We conducted a fine-mapping association study in this candidate region among a subset of ASHK families to identify polymorphisms associated with ocular refraction.
Sixty ASHK families including 596 individuals were selected for the fine mapping study; 527 participants were genotyped at 1,365 common haplotype tagging SNPs. The markers spanned an area of ~25 Mb between 1p36.13 to 1p34.1. The mean spherical refractive error (MSE) and mean spherical component (SPH) in the sample were -3.56 (sd=3.31) and -3.31 (sd=3.27), respectively. Family-based association testing was performed on MSE and SPH using a linear mixed model implemented in the association subroutine of the program Merlin.
After quality control filtering, 1,240 SNPs were available for analysis. For association testing, a Bonferroni-corrected p-value of 4 x 10e-5 was adopted as a family-wise threshold for statistical significance. The most significant association signal was found for rs506546 (p=8.9x10e-6, q=0.023 for MSE; p=1.2x10e-5, q=0.015 for SPH), an intronic marker located between exons 67 and 68 of the large CUB and Sushi multiple domains 2 gene (CSMD2). The marker-specific heritability for rs506546 was estimated to be 4.5%.
We identified a common SNP within CSMD2 putatively associated with refractive variation in the ASHK population. CSMD2 spans 650 kb and contains 70 exons. It encodes a protein containing multiple CUB and Sushi domains, a single transmembrane domain and a short cytoplasmic tail. CSMD2 is expressed in human brain, retina and retinal pigment epithelium. Its functional role, however, is largely unknown and its effect on refractive regulation remains to be investigated.
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