Myopia, or nearsightedness, is the most common human eye disorder. Its diagnosis is based on refractive error biometrics, either negative sphere (SPH) or spherical equivalent (SE) (SE=SPH+
1/2 cylinder) and is measured in diopters (D). Worldwide, individuals do not share the same myopic development risk, as the prevalence of myopia varies in different countries. Studies, primarily in adults but in some schoolchildren cohorts, have reported approximate prevalence rates of 17% in Australia, 26%–35% in the United States, and 27% in Western Europe [1
]. Higher prevalence rates of 71%–96% have been reported in Asian countries such as Japan, Taiwan, Hong Kong, and Singapore [5
]. Having myopia can significantly impact one’s daily life. High-grade levels of myopic refractive error (e.g., SEM or SPH less than −5.00 D) have associated ocular comorbidities of increased risk of premature cataracts, glaucoma, retinal detachment, and macular chorioretinal degeneration [1
]. Myopia clearly is a significant global public health problem.
The genetic basis of myopia is supported by familial aggregation, segregation, and twin studies. High heritability estimates have been reported for SEM (0.5–0.96) [14
] and axial length (AL) (0.40–0.94) [14
]. The relative risk of myopia in siblings of a person with myopia has been estimated to be 5–20 for high myopia (SEM ≤ −6.00 D), and 1.5–3 for lower degrees of myopia (SE: −1.00 to −3.00 D) [19
]. To date, more than 18 myopia (MYP) genetic chromosomal loci (MYP1–MYP18 and other implicated chromosomal regions) have been reported by genome-wide linkage studies in families. Most regions (11 MYP loci) were mapped for high-grade myopia in limited pedigree linkage studies. Although quantitative refractive data are generally available on ascertained samples, very few studies have used these continuous traits to map quantitative trait loci (QTLs) for myopia.
Of the 18 MYP chromosomal loci identified, five (MYP7 [11p13], MYP8 [3q26], MYP9 [4q12], MYP10 [8p23], and MYP14 [1p34–36]) [21
] were initially identified through quantitative trait linkage analysis using refractive error measurements (SPH and SE) as the traits. For example, the MYP7–MYP10 loci were identified using 221 dizygotic (DZ) twins from a classical twin study designed to investigate the heritability of refractive error. The strongest linkage signal was at chromosome 11p13, which contained the biologically relevant candidate gene paired box gene 6 (PAX6
). In contrast to the twin study design, the MYP14 locus was a QTL found after 49 multigenerational Ashkenazi Jewish families ascertained for common myopia using SEM as the trait were analyzed [22
]. No evidence of linkage to this region was found in the authors’ efforts to replicate this finding in a meta-analysis consisting of Old Order Amish, African American, and Caucasian subjects [23
]. However, in a later effort to fine-map the MYP14 locus in a combined cohort of Old Order Amish and Ashkenazi Jewish families, replication of this locus was accomplished, and the QTL was narrowed to a 10 Mb area extending from chromosome 1p34.2 to chromosome 1p35.2 [24
As was the case with localizing MYP14, successful efforts to find QTLs for refractive error have often used homogenous populations in genome-wide linkage studies. These homogenous populations have included Ashkenazi Jews [22
], Caucasians [23
], African Americans [23
], and Old Order Amish [23
], and different loci have been identified. For instance, MYP14 was not found in Caucasians, and 4q21 and 12q24 were found in Caucasians but not Ashkenazi Jews and Old Order Amish [21
]. Overall, the QTL studies to date used either a small number of multigenerational pedigrees or twins. A more comprehensive and large-scale approach will help verify the existing regions.
This study is an international collaborative effort combining high-grade myopia pedigrees from five sites, leading to the largest family data set for myopia to date. We performed a genome-wide quantitative trait linkage scan using SPH and SEM directly and compared the results to known myopia loci. The outcomes of this study provide us with additional information regarding known genetic loci, and we have identified new myopia loci.