Molecular Vision 2006; 12:1499-1505 <>
Received 25 August 2006 | Accepted 27 November 2006 | Published 4 December 2006

Genome-wide scan of additional Jewish families confirms linkage of a myopia susceptibility locus to chromosome 22q12

Dwight Stambolian,1 Grace Ibay,2 Lauren Reider,1 Debra Dana,1 Chris Moy,1 Melissa Schlifka,1 Taura N. Holmes,2 Elise Ciner,3 Joan E. Bailey-Wilson2

1Department of Ophthalmology, University of Pennsylvania, Philadelphia, PA; 2Inherited Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Baltimore, MD; 3Pennsylvania College of Optometry, Philadelphia, PA

Correspondence to: Dwight Stambolian M.D., Ph.D., Department of Ophthalmology, University of Pennsylvania, Room 313, Stellar Chance Laboratories, 422 Curie Blvd., Philadelphia, PA, 19104; Phone: (215) 898-0305; FAX: (215) 573-6728; email:


Purpose: A genome-wide scan was previously reported for myopia in Ashkenazi Jews. In order to confirm the previous linkage peaks, a collection of DNA samples from 19 new Ashkenazi Jewish families were tested for linkage in a genome wide scan.

Methods: Families were ascertained from an Orthodox Ashkenazi Jewish community through mailings. Myopia was defined as equal to or greater than -1 diopter in both meridians in both eyes. The genome wide scan used markers from a modified Cooperative Human Linkage Center version 9 (402 markers). Parametric two-point linkage was calculated with FASTLINK while multipoint linkage was calculated with GENEHUNTER.

Results: The results for the 19 families demonstrated several regions of suggestive linkage on chromosomes 7, 1, 17, and 22. A combined analysis of the 19 families and 44 previously reported families demonstrated an increase in the LOD score to 4.73 for the chromosome 22 locus.

Conclusions: Multiple chromosomal regions have exhibited some evidence of linkage to a myopia susceptibility gene in this Ashkenazi Jewish population. The strongest evidence of linkage to such a susceptibility gene in these data is on chromosome 22.


Myopia is an extremely common disorder in the modern world affecting up to 80-90% of young adults in some populations [1-6]. There is strong evidence to support the notion that myopia is a hereditary condition. Its concordant rate is higher between monozygotic than dizygotic twins [7,8]. Furthermore, the Framingham Offspring Eye Study found a significant correlation of myopia among siblings [9]. In addition, young children and adolescents with one myopic parent are more prone to develop myopia, and the risk is even higher when both parents are affected [10-13]. Premyopic school children with a positive parental history of myopia have also been shown to have ocular parameters predisposed to developing myopia [14]. All these findings indicate that the occurrence of myopia is genetically determined. The contrarian viewpoint, that myopia is solely environmental, is based on evidence demonstrating that the prevalence of myopia has escalated in the last few decades [1,5-7]. As a result, these two viewpoints have evolved with researchers now stressing the importance of gene-environment interaction in the predisposition to myopia [7,15,16].

Family based linkage studies focusing on highly penetrant, severe and rarer forms of myopia in a small number of families have implicated regions on chromosome 18p11.31 [17], 12q21-23 [18], 7q36 [19], and 17q21-22 [20]. The more common form of myopia, consisting of low to moderate grade, has received recent attention with some initial success. A large genome-wide scan (GWS) performed on Ashkenazi Jewish families found significant linkage for common myopia to chromosome 22q12 and weaker linkage on chromosome 14q32 [21]. Recently, Wojciechowski et al. [22] analyzed ocular refraction as a quantitative trait in an Ashkenazi Jewish population and found genome-wide significance for linkage on chromosome 1p36. One other previous study analyzed refraction in twins as a quantitative trait and found strong linkage to 11p13, 3q26, 8p23, and 4q12 [23]. We reported confirmatory evidence of a linked locus for myopia on 8p23 in a set of Amish families [24] as well as suggestive evidence on chromosome X.

Since our previous report on a GWS of myopia in 44 Ashkenazi Jewish families [21], we have been able to collect an additional 19 Jewish families. Here we report the results of a genome-wide scan on these additional 19 families as well as the combined linkage analyses on the full sample of 63 Jewish families.


We studied 256 individuals (137 males, 119 females) in 19 new Ashkenazi Jewish families as part of a genome screen in the Myopia Family Study. The study protocol adhered to the tenet of the Declaration of Helsinki and was approved by the University of Pennsylvania and the National Human Genome Research Institute, National Institutes of Health institutional review boards. Informed consent was obtained from the subjects after explanation of the nature and possible consequences of the study. A detailed ascertainment of families has been described elsewhere [21]. All Jewish individuals included in the study were of Ashkenazi heritage. Families were enrolled through an affected proband with a family history of myopia with a preference for one of the parents being myopic. These enrollment criteria were designed to preferentially select families that are consistent with a dominant mode of inheritance of a fairly high penetrance susceptibility allele [25]. Bilineal pedigrees were avoided due to the difficulty in determining the inherited risk allele transmitted to the affected offspring. Subjects younger than 50 years were given a cycloplegic refraction while those over 50 received a manifest refraction. Myopia was defined as having at least -1 diopter in both meridians in both eyes. After a potential family met the defined criteria, medical records were obtained for each member. Data collection included all eligible parents, cousins, grandparents, siblings, children, aunts, and uncles of probands.

Since myopia can develop during the school years, a child with a low to moderate degree of hyperopia could go on to develop myopia, depending on age. Age adjustments for refraction were followed according to previous studies evaluating the development of refractive error in children [26-33]. Subjects under the age of 21 were classified as unaffected according to the following criteria: 6- to 10-year olds with a refraction of greater than or equal to +2.00 diopters in each meridian, or 11- to 20-year olds with a refraction of greater than or equal to +1.50 diopters in each meridian. Subjects not meeting the criteria for either myopia or unaffected were classified as unknown for the trait. Excluded from the study were individuals with myopia resulting from premature birth, systemic or ocular diseases. Subjects with unilateral myopia were not included in the study unless the fellow eye was previously enucleated. Ancestry questions were completed for each proband to establish the country or region of origin of the proband's parents and grandparents. All families in this study originate from eastern and central Europe.

High molecular weight DNA was isolated from buffy coats with a kit (Puregene; Gentra Systems, Inc.; Minneapolis, MN). Following DNA extraction, samples were stored in a DNA repository under a unique code. DNA samples were sent to the Center for Inherited Disease Research (CIDR) for performing a genome wide scan (GWS). The GWS used markers from a modified Cooperative Human Linkage Center version 9 (402 markers, average spacing 9 cM, average heterozygosity 0.76). All genotyping was performed blind to clinical status.

Our genotyping data were subjected to several quality checks to ensure accuracy. Mendelian inconsistencies and potential relationship errors were evaluated and corrected prior to data analysis using SIPAIR [34] and GAS. The accuracy of putative relative pairs was checked using RelCheck [35,36]. Mendelian inconsistencies from individuals at multiple markers that could not be resolved by retyping were coded as missing for the purpose of the analysis.

Estimation of allele frequencies at marker loci was determined from the married-in unrelated founders in the families using SIPAIR and LINKMEND programs. The same methods of analysis were used in this follow-up study as in our original genome-wide scan in families from this same population [21] except that we only used one genetic model of disease susceptibility in the parametric analysis, i.e., the model that had resulted in the highest HLOD scores to chromosome 22 in the previous study. Two-point and multipoint LOD score analyses were performed assuming a dominant mode of inheritance of myopia risk, 0.0133 frequency of the susceptibility allele, penetrance of 0.90 for gene carriers and 0.10 for the non-gene carriers [21]. In order to ensure that the observed LOD scores were robust to variations in this model, we repeated the chromosome 22 analyses using several different values of genotypic penetrance. The Marshfield database was used to determine the inter-marker distances of the microsatellite markers. Parametric two-point linkage was calculated with the FASTLINK package [37,38] and heterogeneity was determined by the program HOMOG [39]. Multipoint parametric linkage assuming heterogeneity and nonparametric linkage analyses were performed with the GENEHUNTER and GENEHUNTER-PLUS X programs [40]. Multipoint analysis in Genehunter has program memory constraints that caused the splitting of large pedigrees into smaller ones for the purpose of analyses.

A combined analysis was performed on the total Jewish population using the 44 families from the original study and the 19 families from this current study. Multipoint parametric family LOD scores from both genome screens were combined to allow calculation of an overall heterogeneity LOD score.


Characteristics of study population

The study population included 19 families with an average age of 43 years. A total of 256 individuals (137 males; 119 females) were included in the analyses of which 81 were genotyped. About 75% of the individuals genotyped are myopes (Table 1). Most of the families are three generations (15 out of 21), fairly large (average of 13.5 members per family), and have large numbers of affected family members (average of 7.3 per family).

Genome-wide linkage analyses

The genome-wide screen for the 19 new families demonstrated several regions of suggestive linkage (Figure 1; Table 2). The highest multipoint heterogeneity LOD score was found at 7p13 (marker D7S817; HLOD=1.88; alpha=1.0); two other loci in this region were observed to have suggestive evidence for linkage to myopia: D7S1802 (HLOD= 1.3; alpha=0.79) and D7S1808 (HLOD=1.52; alpha=1.0). Linkage to chromosome 22 (marker D22S689, HLOD=1.33, alpha=0.38) was approximately 4 cM from the location of the peak significant linkage in our previously reported study in this population [21]. This was within the 1-LOD drop interval around this previously published linkage peak. Varying the penetrance models had virtually no effect on these HLOD scores (Figure 2). Two other regions have HLOD greater than 1.0 and included 1q21 (D1S1679; HLOD=1.3; alpha=0.9) and 17p12 (D17S974; HLOD=1.33; alpha=0.64). Except for chromosome 22, the other regions were not detected in our previously reported GWS. Two-point linkage results were quite similar to the multipoint analyses.

Combined multipoint HLOD scores in all families

Forty-four families from our previous GWS were combined with the 19 families from the current study to calculate a heterogeneity LOD score at each locus using the model of penetrance = 0.90 and phenocopy =0.10 (Table 3). The merged data increased the significance of linkage to D22S685 (HLOD=4.73; alpha=0.38) from the previous linkage scan (HLOD=3.54). The locus near D14S1426 (HLOD=1.53; alpha=0.31) was modestly increased with the additional families. A new locus at D15S642 (HLOD=1.65; alpha=0.4) showed suggestive linkage that was not present on the previous scan of 44 families. Interestingly, merging the data decreased the evidence for linkage at 8p23, 11q23 and 13q22 from the previous screen but did not affect the HLOD significantly for loci 1p21, 1q21, 7p13-15, 17p12.


The results of this second GWS linkage study of 19 independent families with mild to modest myopia provides evidence supporting our previous significant linkage result on chromosome 22 but did not reach the level required (p=0.01) [41] to definitively confirm this linkage. However, this much smaller set of families (less than half the number available for our original study) gave positive HLOD scores in the chromosome 22 candidate region, within the 1-LOD drop interval of the previously published significant linkage result. The marker yielding the peak multipoint HLOD score in the chromosome 22 region in these new 19 families is about 4 cM from the peak location in our previous study, at marker D22S685, and is the nearest flanking marker to D22S685 in this genome wide scan. The combined analyses of all 63 families resulted in an HLOD of 4.73 (alpha=0.38) in the region, a considerably more significant result than that obtained in the original 44 families alone (HLOD=3.54). This combined peak occurred at the same location (D22S685) as the previously published peak. The data suggest that additional loci for myopia exist in the Jewish population based on (1) the presence of heterogeneity showing that less than 50% of the families are linked to the chromosome 22 region; and (2) the small positive HLOD scores observed in other regions of the genome. Furthermore, there are currently listed in the Online Mendelian Inheritance in Man website (OMIM) about 150 genetic syndromes, defined by specific ocular and systemic disorders, that are associated with various levels of myopia. This wide spectrum of myopia-associated disorders strongly suggests that myopia has multiple etiologies.

The overall prevalence of myopia in the U.S. is estimated at 25% [42]. This prevalence changes when the population is stratified along ethnic and racial groups in the U.S. as well as among foreign countries [6,43]. The population for this study is a selected sample of Orthodox Ashkenazi Jews. While no published prevalence rates for myopia exist for Orthodox Ashkenazi Jews, there are studies that suggest the prevalence for this population may be higher than many other ethnic groups. For example, in a study of Orthodox Jewish students attending schools in Jerusalem a prevalence of 36% and 81% was found for females and males, respectively [44]. These prevalences included Ashkenazi and non-Ashkenazi Jewish backgrounds that have been shown not to be significantly different between both groups [45].

The Ashkenazi Jewish population is an excellent cohort for genetic studies. Its unique, well documented overall demography is consistent with several founding events, repeated bottlenecks, and dramatic expansions, from an estimated number of about 25,000 in 1300 A.D. to greater than 8,500,000 around the turn of the 20th century [46]. Recently, through studies of mtDNAs, it was determined that 40% of the current Ashkenazi population (8,000,000 people) can be traced back to four women [47]. The fact that the Ashkenazim come from a relatively genetically isolated population that has emerged from a small number of founders should reduce genetic heterogeneity and increase the likelihood of finding myopia genes. Furthermore, the orthodox population is particularly advantageous since the education is uniform throughout high school, decreasing the difference of near work between individuals. Thus, the Orthodox Ashkenazi sample collected for this study offers the advantage of a founder group, large families and relatively homogenous environment.

The concept that environmental factors influence ocular development has been well established in epidemiological and experimental animal studies. The frequent manifestation of myopia during school and college years, as well as in some occupations requiring intense and prolonged near work, has suggested the critical role of a near vision stimulus in the development of myopia. Despite the recognized importance of visual experience in the development of myopia there is still abundant evidence for genetic factors determining myopia development. For example, myopic parents are more likely to give rise to offspring with myopia than nonmyopic parents. Also, multiple twin studies have confirmed the higher similarity in identical twins compared to fraternal twins with regard to myopia. The overall conclusion of the aforedescribed evidence is that nonsyndromic myopia is most likely a heterogeneous disorder influenced by multiple genes and environment. Whether nonsyndromic myopia can be inherited through classical Mendelian inheritance is yet to be determined.

Therefore, there is a need to search for myopia susceptibility genes to identify possible allelic association of these genes with the expression of myopia. Common genetic polymorphisms, as opposed to rare mutations, will provide the most information with respect to elucidating the mechanism for myopia. Progress has recently been made in identifying two common polymorphisms associated with myopia in the Chinese. Two independent studies have found polymorphisms in transforming growth factor-beta and hepatocyte growth factor significantly associated with myopes compared to controls [48,49].

Our results from a sample of Ashkenazi Jews suggest the existence of a significant gene for myopia within 22q11.2. Future work will include dense mapping with single nucleotide polymorphisms to identify a common polymorphism that is more highly associated with Ashkenazi Jewish myopes compared to controls. Once this polymorphism is found, further analysis will be performed on affected and unaffected pairs from other ethnic and racial groups. Identification of this myopia susceptibility gene may provide a fundamental molecular understanding of myopia.


This research was supported in part by the Intramural Research Program of the NIH, NHGRI, and grant RO1 EY012226.


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