Myopia in Chinese families shows linkage to 10q26.13

Abstract

Purpose: To determine genetic linkage between myopia and Han Chinese patients with a family history of the disease.

Methods: One hundred seventy-six Han Chinese patients from 34 extended families were given eye examinations, and mean spherical equivalent (MSE) in diopters (D) was calculated by adding the spherical component of the refraction to one-half the cylindrical component and taking the average of both eyes. The MSE was converted to a binary phenotype, where all patients with an MSE of -1.00 D or less were coded as affected. Unaffected individuals had an MSE greater than 0.00 D (ages 21 years and up), +1.50 (ages 11-20), or +2.00 D (ages 6-10 years). Individuals between the given upper threshold and -1.00 were coded as unknown. Patients were genotyped on an exome chip. Three types of linkage analyses were performed: single-variant two-point, multipoint, and collapsed haplotype pattern (CHP) variant two-point.

Results: The CHP variant two-point results identified a significant peak (heterogeneity logarithm of the odds [HLOD] = 3.73) at 10q26.13 in TACC2. The single-variant two-point and multipoint analyses showed highly suggestive linkage to the same region. The single-variant two-point results identified 25 suggestive variants at HTRA1, also at 10q26.13.

Conclusions: We report a significant genetic linkage between myopia and Han Chinese patients at 10q26.13. 10q26.13 contains several good candidate genes, such as TACC2 and the known age-related macular degeneration gene HTRA1. Targeted sequencing of the region is planned to identify the causal variant(s).

Figure 1

Example of linked disease markers with no association. The diagram illustrates the scenario where common variants can be linked along a haplotype within families but will not be identified by an association study. Here, we place theoretical disease variants Z1, Z2, and Z3 in families 1, 2, and 3, respectively. We assume that the disease-causing variants Z are rare and are not genotyped. Markers A, B, C, and D are assumed to have a common minor allele frequency (MAF) and have been genotyped. All four markers are also located on the same haplotype close to each other, so that it is unlikely any crossing over will occur within families. Looking within each family, it is clear that all markers are linked to the disease marker because in each family the black haplotype cosegregates with the disease phenotype. However, looking across each family, A, B, C, and D are not associated with the disease phenotype, because both alleles of each marker are present in affected and unaffected individuals.

Figure 2

Genome-wide collapsed haplotype pattern variant two-point HLOD scores. Plot showing the genome-wide collapsed haplotype pattern (CHP) variant two-point heterogeneity logarithm of the odds (HLOD) scores produced by SEQLinkage and MERLIN. The lines at 1.9 and 3.3 represent the suggestive and significant thresholds, respectively, recommended by Lander and Kruglyak.

Figure 3

Genome-wide multipoint HLOD scores. Plot of the genome-wide multipoint heterogeneity logarithm of the odds (HLOD) scores produced by SimWalk2. The lines at 1.9 and 3.3 represent the suggestive and significant thresholds, respectively, recommended by Lander and Kruglyak.

Figure 4

Genome-wide single-variant two-point HLOD scores. Plot showing the single-variant two-point heterogeneity logarithm of the odds (HLOD) scores produced by TwoPointLods. The lines at 1.9 and 3.3 represent the suggestive and significant thresholds, respectively, recommended by Lander and Kruglyak.

Figure 5

Chromosome 10 two-point single-variant LOD scores. Plot of the single-variant two-point heterogeneity logarithm of the odds (HLOD) scores produced by TwoPointLods for chromosome 10, which contains single nucleotide polymorphisms (SNPs) that exhibit suggestive evidence of linkage to myopia. The lines at 1.9 and 3.3 represent the respective suggestive and significant thresholds, respectively, recommended by Lander and Kruglyak. The SNPs in the age-related macular degeneration (AMD) risk locus HTRA1 are marked in blue.

Figure 6

Chromosome 9 two-point single-variant LOD scores. Plot of the single-variant two-point heterogeneity logarithm of the odds (HLOD) scores produced by TwoPointLods for chromosome 9, which contains single nucleotide polymorphisms (SNPs) that exhibit suggestive evidence of linkage to myopia. The lines at 1.9 and 3.3 represent the respective suggestive and significant thresholds, respectively, recommended by Lander and Kruglyak.