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Felicia Hawthorne, Dianna Abbott, Khanh-Nhat Tran Viet, Ravikanth Metlapally, Janeen Morgan, Yi-Ju Li, Terri L. Young; Heritable High-grade Myopia: Fine-mapping Of The High-grade Myopia 3 Locus. Invest. Ophthalmol. Vis. Sci. 2011;52(14):3294.
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To perform a high-density single nucleotide polymorphism (SNP) fine-mapping association study of the replicated, qualitatively assessed autosomal dominant high-grade myopia locus, MYP3 at chromosome 12q21-23 in a large family-based cohort
Illumina Custom Goldengate genotyping of 768 selected interval SNPs was performed in 644 samples from 82 families with heritable high-grade myopia. Association analyses were performed for the qualitative trait of high myopia (SE < -6.00D) using the Pedigree Disequilibrium Test (PDT), and the Association in the Presence of Linkage (APL) test. In addition, the Quantitative Transmission Disequilibrium Test (QTDT) was conducted by treating refractive errors as quantitative traits. Quantitative tests were run for both dioptric sphere (SPH) and spherical equivalent (SE) phenotypes using both the average (avg) and the least (best) myopic of the two eyes.
Two contracted, strong association signals within MYP3 were found in all three tests; one at 78 Mb and the other at 96 Mb. The most significant markers did not overlap, however, clusters of significant markers were found in proximity. Significant results at 78 Mb were noted by PDT for RS10861796 (p = 0.0086) and APL for RS12301103 (p = 0.0057). At 96 Mb, the most significant p-value for PDT and APL was at RS7137537 (PDT p = 0.0111; APL p = 0.0016).For QTDT, the most significantly associated marker for all four traits at 78 Mb was RS4439580 (avg SPH p = 0.0014; avg SE p = 0.0002; best SPH p = 0.0038; best SE p = 0.0109). At 96 Mb, the most significantly associated marker was RS7953575 (avg SPH p = 0.0068; avg SE p = 0.0026; best SPH p = 0.0108; best SE p = 0.0018). The best p-value in this region was for avg SE at RS1971036 (p = 2X10-5).
Significant SNP association signals were found in two distinct, contracted intervals within the MYP3 locus, supported by both qualitative and quantitative trait analyses. Chromosome 12 at 78 Mb and at 96 Mb may each contain causative or susceptibility genes for high myopia. Additional studies are underway to refine the association results and screen candidate genes within the intervals.
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