Debra Dana

Genomewide Linkage Scan for Myopia Susceptibility Loci among Ashkenazi Jewish Families Shows Evidence of Linkage on Chromosome 22q12

Mild/moderate (common) myopia is a very common disorder, with both genetic and environmental influences. The environmental factors are related to near work and can be measured. There are no known genetic loci for common myopia. Our goal is to find evidence for a myopia susceptibility gene causing common myopia. Cycloplegic and manifest refraction were performed on 44 large American families of Ashkenazi Jewish descent, each with at least two affected siblings. Individuals with at least -1.00 diopter or lower in each meridian of both eyes were classified as myopic. Microsatellite genotyping with 387 markers was performed by the Center for Inherited Disease Research. Linkage analyses were conducted with parametric and nonparametric methods by use of 12 different penetrance models. The family-based association test was used for an association scan. A maximum multipoint parametric heterogeneity LOD (HLOD) score of 3.54 was observed at marker D22S685, and nonparametric linkage analyses gave consistent results, with a P value of.0002 at this marker. The parametric multipoint HLOD scores exceeded 3.0 for a 4-cM interval, and significant evidence of genetic heterogeneity was observed. This genomewide scan is the first step toward identifying a gene on chromosome 22 with an influence on common myopia. At present, we are following up our linkage results on chromosome 22 with a dense map of >1,500 single-nucleotide-polymorphism markers for fine mapping and association analyses. Identification of a susceptibility locus in this region may eventually lead to a better understanding of gene-environment interactions in the causation of this complex trait.

A Novel Approach to Search for Identity by Descent in Small Samples of Patients and Controls from the Same Mendelian Breeding Unit: A Pilot Study on Myopia

Autosomal dominant high myopia, a genetic disorder already mapped to region 18p11.31, is common in Carloforte (Sardinia, Italy), an isolated village of 8,000 inhabitants descending from a founder group of 300 in the early 1700s. Fifteen myopic propositi and 36 normal controls were selected for not having ancestors in common at least up to the grandparental generation, although still descendants of the original founders. All subjects were genotyped for 14 markers located on autosome 18 at a resolution of about 10 cM. Allelic distributions were found to be similar at all tested loci in propositi and controls, except for the candidate marker D18S63 known to segregate in close linkage association with high myopia. In particular, the frequency of allele 85 among the propositi was almost double that of the controls (Fisher’s exact test, p = 0.037). The association is more striking when the frequency of the genotype 85/85 in the two groups is compared (Fisher’s exact test, p = 0.005). This conclusion was further evaluated through a bootstrap analysis by computing the overall probability of the observed data under the null hypothesis (i.e. no difference between the two groups in frequency distributions for the chromosome 18 markers). Again, marker D18S63 was found to have a sample probability lower than 0.004, which is significant at the 0.05 level after correcting for simultaneous testing of multiple loci. The study demonstrates the efficiency of our novel strategy to detect identity by descent (IBD) in small numbers of patients and controls when they are both part of well-defined Mendelian breeding units (MBUs). The iterative application of our strategy in separate MBUs is expected to become the method of choice to evaluate the ever-growing number of reported associations between candidate genes and multifactorial traits and diseases.

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

BackgroundTo 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.MethodsCycloplegic 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.ResultsThere 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 p-values 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.ConclusionsSignificant 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.

Genome-wide scan of African-American and white families for linkage to myopia.

PURPOSE To identify myopia susceptibility genes influencing common myopia in 94 African-American and 36 White families. DESIGN A prospective study of families with myopia consisting of a minimum of two individuals affected with myopia. METHODS Extended families consisting of at least two siblings affected with myopia were ascertained. A genome-wide linkage scan using 387 markers was conducted by the Center for Inherited Disease Research. Linkage analyses were conducted with parametric and nonparametric methods. Model-free linkage analysis was performed maximizing over penetrance and over dominance (that is, fitting a wide range of both dominant and recessive models). RESULTS Under the model-free analysis, the maximum two point heterogeneity logarithm of the odds score (MALOD) was 2.87 at D6S1009 in the White cohort and the maximum multipoint MALOD was 2.42 at D12S373-D12S1042 in the same cohort. The nonparametric linkage (NPL) maximum multipoint at D6S1035 had a P value of .005. An overall multipoint NPL score was obtained by combining NPL scores from both populations. The highest combined NPL score was observed at D20S478 with a significant P value of .008. Suggestive evidence of linkage in the White cohort mapped to a previously mapped locus on chromosome 11 at D11S1981 (NPL = 2.14; P = .02). CONCLUSIONS Suggestive evidence of linkage to myopia in both African Americans and Whites was seen on chromosome 20 and became more significant when the scores were combined for both groups. The locus on chromosome 11 independently confirms a report by Hammond and associates mapping a myopia quantitative trait locus to this region.