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.

The development of refractive error is mediated by both environmental and genetic factors. We performed regression-based quantitative trait locus (QTL) linkage analysis on Ashkenazi Jewish families to identify regions in the genome responsible for ocular refraction. We measured refractive error on individuals in 49 multi-generational American families of Ashkenazi Jewish descent. The average family size was 11.1 individuals and was composed of 2.7 generations. Recruitment criteria specified that each family contain at least two myopic members. The mean spherical equivalent refractive error in the sample was −3.46D (SD=3.29) and 87% of individuals were myopic. Microsatellite genotyping with 387 markers was performed on 411 individuals. We performed multipoint regression-based linkage analysis for ocular refraction and a log transformation of the trait using the statistical package Merlin-Regress. Empirical genomewide significance levels were estimated through gene-dropping simulations by generating random genotypes at each of the 387 markers in 200 replicates of our pedigrees. Maximum LOD scores of 9.5 for ocular refraction and 8.7 for log-transformed refraction (LTR) were observed at 49.1 cM on chromosome 1p36 between markers D1S552 and D1S1622. The empirical genomewide significance levels were P=0.065 for ocular refraction and P<0.005 for LTR, providing strong evidence for linkage of refraction to this locus. The inter-marker region containing the peak spans 11 Mb and contains approximately 189 genes. Conclusion: We found genomewide significant NIH Public Access

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