Heritability of Refractive Error and Familial Aggregation of Myopia in an Elderly American Population

Myopia is the leading cause of visual impairment in nearly all population-based studies of ocular disease, and correction of refractive error consumed over $12 billion per year in the United States 10 years ago, even before the recent surge in refractive surgery.1 In some populations of east Asia, studies suggest that the prevalence of myopia may exceed 80% among young persons,2 and there is some evidence that rates may be increasing rapidly.3 There is also evidence for a recent increase in the prevalence of myopia in populations such as Eskimos, in whom myopia was rare only a few generations ago.4 Such apparent rapid changes in the prevalence of myopia within defined populations argue for strong environmental influences in the development of myopia. For example, much evidence exists that implicates near work as an important determinant of myopia.5–10 Nevertheless, there is also considerable evidence that myopia is under genetic control. Studies have consistently shown strong correlations between the refractive errors of first-degree relatives.11–13 Twin studies by Hammond et al.,14 Teikari et al.,15,16 and Lyhne et al.17 have suggested that the heritability—that is, the proportion of the population variance under genetic control—for refraction may exceed 80%. It is therefore likely that the development of myopia is mediated by both environmental and genetic risk factors. At least four chromosomal locations18–22 have been linked to high (that is, in excess of 5 D) myopia. No such loci had been identified for moderate myopia (1–5 D), which comprises some 80% of myopia among American adults,23 until a recent report by Stambolian et al.24 who found significant genetic linkage of myopia to a region on chromosome 22 in an Ashkenazi Jewish population. Moreover, in a genome-wide scan of 221 dizygotic twin pairs, Hammond et al.25 reported significant linkage signals to multiple genetic loci when analyzing refractive error as a quantitative trait. Their highest linkage peak was observed at chromosomal location 11p13 while evidence for linkage was also noted at regions 3q26, 8p23, and 4q12. The relative paucity of evidence for linkage in lower levels of refractive error, compared with high myopia, is partly because high myopia may be more likely to present in an autosomal dominant fashion,22 whereas the genetics of lower refractive errors may be more complex and multifactorial. Nevertheless, Farbrother et al.26 argue that even high myopia phenotypes are unlikely to be inherited in an autosomal dominant fashion and that a multifactorial etiology is more likely. In view of the high prevalence (some 20 million American adults23) and the resultant significant impact on the health economy in the cost of spectacles, contact lenses, and refractive surgery, it certainly seems that moderate myopia is deserving of genetic study to elucidate its fundamental mechanisms, which may or may not be the same as those of high myopia. Using linear regression models and generalized estimating equations (GEEs), we estimated the heritability of refractive error in a population-based sample of elderly sibships in eastern Maryland. We also used logistic regression models to calculate the odds of myopia in siblings of myopic individuals compared with siblings of nonmyopes, using four thresholds to define myopia.