Association mapping of the high-grade myopia MYP3 locus reveals novel candidates UHRF1BP1L, PTPRR and PPFIA2.

Myopia, or nearsightedness, is a common ocular genetic disease for which over 20 candidate genomic loci have been identified. The high-grademyopia locus, MYP3, has been reported on chromosome 12q21-23 by four independent linkage studies.We performed a genetic associationstudy of the MYP3 locus in a family-based high-grademyopia cohort (n = 82) by genotyping 768 single-nucleotide polymorphisms (SNPs) within the linkage region. Qualitative testing for high-grademyopia (sphere ≤ -5 D affected, > -0.5 D unaffected) and quantitative testing on the average dioptricsphere were performed.Several genetic markers were nominally significantly associated with high-grademyopia in qualitative testing, including rs3803036, a missense mutation in PTPRR (P = 9.1 × 10(-4)) and rs4764971, an intronic SNP in UHRF1BP1L (P = 6.1 × 10(-4)). Quantitative testing determined statistically significant SNPs rs4764971, also found by qualitative testing (P = 3.1 × 10(-6)); rs7134216, in the 3' untranslated region (UTR) of DEPDC4 (P = 5.4 × 10(-7)); and rs17306116, an intronic SNP within PPFIA2 (P < 9 × 10(-4)). Independently conducted whole genome expression array analyses identified protein tyrosine phosphatasegenes PTPRR and PPFIA2, which are in the same gene family, as differentially expressed in normal rapidly growing fetal relative to normal adult ocular tissue (confirmed by RT-qPCR).In an independent high-grademyopia cohort, an intronic SNP in UHRF1BP1L, rs4764971, was validated for quantitative association, and SNPs within PTPRR (quantitative) and PPFIA2 (qualitative and quantitative) approached significance. Three genes identified by our association study and supported by ocular expression and/or replication, UHRF1BP1L, PTPRR, and PPFIA2, are novel candidates for myopic development within the MYP3 locus that should be further studied.