Candidate high myopia loci on chromosomes 18p and 12q do not play a major role in susceptibility to common myopia

Grace Ibay 2 Betty Doan 2 Lauren Reider 1 Debra Dana 1 Melissa Schlifka 1 Heping Hu 2 Taura Holmes 2 Jennifer O'Neill 2 Robert Owens 0 Elise Ciner 3 Joan E Bailey-Wilson 2 Dwight Stambolian 1 0 Owens Optometrics , 654 E. Main St., New Holland, PA 17557 , USA 1 Dept. of Ophthalmology, University of Pennsylvania , 3535 Market St., Suite 701, Philadelphia, PA 19104 , USA 2 Inherited Disease Research Branch, National Human Genome Research Institute, National Institutes of Health , 333 Cassell Dr., Suite 2000, Baltimore, MD 21224 , USA 3 Pennsylvania College of Optometry , 8360 Old York Rd., Elkins Park, PA 19027 , USA Background: To determine whether previously reported loci predisposing to nonsyndromic high myopia show linkage to common myopia in pedigrees from two ethnic groups: Ashkenazi Jewish and Amish. We hypothesized that these high myopia loci might exhibit allelic heterogeneity and be responsible for moderate /mild or common myopia. Methods: Cycloplegic and manifest refraction were performed on 38 Jewish and 40 Amish families. Individuals with at least -1.00 D in each meridian of both eyes were classified as myopic. Genomic DNA was genotyped with 12 markers on chromosomes 12q21-23 and 18p11.3. Parametric and nonparametric linkage analyses were conducted to determine whether susceptibility alleles at these loci are important in families with less severe, clinical forms of myopia. Results: There was no strong evidence of linkage of common myopia to these candidate regions: all two-point and multipoint heterogeneity LOD scores were < 1.0 and non-parametric linkage pvalues were > 0.01. However, one Amish family showed slight evidence of linkage (LOD>1.0) on 12q; another 3 Amish families each gave LOD >1.0 on 18p; and 3 Jewish families each gave LOD >1.0 on 12q. Conclusions: Significant evidence of linkage (LOD> 3) of myopia was not found on chromosome 18p or 12q loci in these families. These results suggest that these loci do not play a major role in the causation of common myopia in our families studied. - appears to distinguish different groups with regard to prevalence. Caucasians have a higher prevalence than African Americans[3]. Asian populations have the highest prevalence rates with reports ranging from 50 90%[1,4,5]. Jewish Caucasians, one of the target populations of the present study, have consistently demonstrated a higher myopia prevalence than the general Caucasian population in both U.S. and European population surveys; Orthodox Jewish males in particular show increased susceptibility[6,7]. Despite many decades of research, little is known about the precise molecular defects and abnormal biochemical pathways that result in myopia. Compelling data from familial aggregation and twin studies indicate that susceptibility to myopia is inherited. Several familial aggregation studies have reported a greater prevalence of myopia in children of myopic parents compared to children of nonmyopic parents [8-12]. Several twin studies have demonstrated a very high heritability (estimates ranging from 60 to 90%) for myopia [13-15]. Other recent genetic studies of families with -6.00 D or more of myopia (termed high or pathological myopia) have reported significant linkage to regions on chromosome 18p11.31, 12q21-23, 17q2122 and 7q36 [16-19]. The 18p candidate region has been confirmed in an independent study of high myopia [20]. Mutti et al.[21] examined the hypothesis that families with milder, juvenile onset myopia might show linkage to these same candidate regions. They found no evidence to support such a role in this more common form of myopia but their study was not highly powered in the presence of heterogeneity. Evidence also exists that myopia may be under environmental influences. The rapid increase in the prevalence of myopia over the last several decades suggests that environmental factors are important [22,23]. Furthermore, studies have shown a positive correlation of specific environmental factors, such as nearwork, with myopia [24,25]. It has been postulated that myopia develops in a person who engages in significant periods of sustained nearwork as an adaptive response to achieve better focus for near images[26]. Interestingly, Cordain et al.[27] suggest a positive correlation for myopia with increased consumption of carbohydrates, hyperinsulinemia and type II diabetes. Finally, experimental findings from animal studies show that the refractive state of young chicks will adapt to compensate for refractive errors induced by spectacle lenses[28]. The combination of genetic and environmental influences on the development of myopia suggests that myopia is a complex disorder and should not be classified as a simple Mendelian trait. Further evidence is shown by studies that have reported correlation coefficients for myopia between offspring and parents and between pairs of siblings to lie between 0.070.36 [29-32]. Due to the possible complexity of myopia, population isolates offer many advantages for genome-wide mapping studies[33]. First, they have reduced genetic complexity. Second, the people in most isolates share a common environment and culture. Differences in diet, exercise, sanitary conditions, and exposure to infectious diseases are minimized. A common language and religion usually promote social cohesion. Therefore, some of the environmental noise surrounding complex diseases that are determined by a combination of nature and nurture may be avoided. To avoid some of the complexity in mapping genes for myopia we have collected refractive measurements and DNA samples from Amish and orthodox Jewish families with myopia. The Old Order Amish are mostly rural farmers and craftsmen. They lead a culturally and technologically distinct lifestyle. They are a genetically well-defined founder population with large families and well-documented genealogies [34,35]. Family history records of the Amish in Lancaster County, Pennsylvania, beginning from 1727 are highly preserved[36]. Other features of this population include a relatively high standard of living, low migratory tendencies, and no practice of birth control, which facilitate the recruitment of large and extended families. The orthodox Jewish families in this study are all of Ashkenazi descent, a population with known founder effects in other common diseases[37]. This population also has somewhat larger family sizes than average in the US. In this initial report, we describe the design of our study and show that two regions (18p and 12q) previously reported to be linked to high myopia cannot explain the familial aggregation in these families with mostly moderate to milder forms of myopia. We had hypothesized that allelic heterogeneity might exist at these candidate loci such that in addition to highly penetrant alleles for extreme high myopia, there might also exist other susceptibility alleles of (possibly) lower penetrance that produce milder phenotypic forms of myopia. However, we found n (...truncated)