Identification of novel suggestive loci for high-grade myopia in Polish families

Abstract

Purpose: Myopia is the most common human eye disorder with complex genetic and environmental causes. To date, several myopia loci have been identified in families of different geographic origin. However, no causative gene(s) have yet been identified. The aim of this study was the characterization of Polish families with high-grade myopia, including genetic analysis.

Methods: Forty-two multiplex Polish families with non-syndromic high-grade myopia participated in the study. All family members underwent detailed ophthalmic examination and high-grade myopia was defined as ≤-6.0 diopters (D) based on the spherical refractive error. A genome-wide single nucleotide polymorphism (SNP)-based high-density linkage scan was performed using Affymetrix Human SNP Array 6.0 on a selected family (HM-32) with multiple affected individuals.

Results: Nonparametric linkage analysis identified three novel loci in family HM-32 at chromosome 7p22.1-7p21.1 ([NPL] 8.26; p=0.006), chromosome 7p12.3-7p11.2 ([NPL] 8.23; p=0.006), and chromosome 12p12.3-12p12.1 ([NPL] 8.02; p=0.006), respectively. The effect of linkage disequilibrium on linkage due to dense SNP map was addressed by systematically pruning SNPs from the linkage panel.

Conclusions: Haplotype analysis with informative crossovers in affected individuals defined a 12.2; 10.9; and 9.5 Mb genomic regions for high-grade myopia spanned between SNP markers rs11977885/rs10950639, rs11770622/rs9719399, and rs4763417/rs10842388 on chromosomes 7p22.1-7p21.1, 7p12.3-7p11.2, and 12p12.3-12p12.1, respectively.

Figure 1

Pedigree of family HM-32 with high myopia. Blackened symbols: individuals with high myopia; unblackened symbols: unaffected individuals; symbols with question mark: individuals with unknown disease status. Individuals used in the linkage analysis are numbered under their symbols in the pedigree.

Figure 2

Pedigrees of 14 of 42 Polish families, with familial high myopia. Filled symbols: individuals with high myopia; open symbols: unaffected individuals; symbols with question mark: individuals with unknown disease status.

Figure 3

Results of the multipoint nonparametric linkage analysis for family HM-32. The x-axis represents the chromosomal location for each of the 22 autosomes, and the y-axis represents the Z mean/LOD. The highest peak are at chromosome 7p22.1–7p21.1 (nonparametric linkage [NPL] 8.26; p=0.006), 7p12.3–7p11.2 ([NPL] 8.23; p=0.006), and 12p12.3–12p12.1 ([NPL] 8.02; p=0.006).

Figure 4

Genotypes and haplotypes of chromosomes 7p22.1–7p21.1, 7p12.3–7p11.2, and 12p12.3–12p12.1. Haplotypes associated with affected status are shown in red. Haplotype analysis showed that the cosegregating segment of the MYP loci in family HM-32 was between markers rs11977885/rs10950639, rs11770622/rs9719399 and rs4763417/rs10842388 on chromosomes A: 7p22.1–7p21.1, B: 7p12.3–7p11.2, and C: 12p12.3–12p12.1, respectively.