Family aggregation of high myopia: estimation of the sibling recurrence risk ratio.

PURPOSE: To estimate the sibling recurrence risk (KS) and the sibling recurrence risk ratio (lambda(S)) for high myopia in a cohort in the United Kingdom. METHOD: The recurrence risks for myopia and high myopia were estimated in the siblings of 296 randomly selected high myopes ascertained from an optometric practice population. A model using an age of onset of spectacle wear for myopia of 9.1 +/- 0.7 years or younger was developed as a surrogate for high myopia. The influence of parental myopia on the sibling recurrence risk for high myopia was also evaluated. RESULTS: KS was estimated (95% confidence limits) to be 10.0% (5.9, 14.8) and lambdaS to be 4.9 (2.8, 7.6). High myopes without myopic parents were surprisingly common ( approximately 40%) and were less likely to have highly myopic siblings (KS approximately 6%) than those with at least one myopic parent (KS approximately 14%). CONCLUSIONS: The sibling recurrence risk ratio reported herein (lambdaS approximately 4.9) implies that the high penetrance autosomal dominant loci for high myopia identified to date account for only a minority of cases of high myopia in the United Kingdom. Furthermore, high-penetrance autosomal dominant inheritance or even high-penetrance recessive inheritance, per se, cannot account for most cases of high myopia. Instead, it may be necessary to consider high myopia as a "complex disease" resulting from the influence of either alleles of reduced penetrance ("susceptibility genes"), environmental factors, or both.

Linkage analysis of the genetic loci for high myopia on 18p, 12q, and 17q in 51 U.K. families.

PURPOSE: To determine the extent to which high myopia in a cohort of 51 U.K. families can be attributed to currently identified genetic loci. METHODS: The families comprised 245 subjects with phenotypic information and DNA available, of whom 170 were classified as affected. Subjects were genotyped for microsatellite markers spanning approximately 40cM regions on 18p (MYP2), 12q (MYP3) and 17q, together with markers flanking COL2A1, COL11A1, and FBN1. Two-point linkage analyses were performed using the same disease gene segregation model as was used in the original publications, followed by nonparametric and multipoint analyses using Genehunter (http://linkage.rockefeller.edu/soft/gh/ provided in the public domain by Rockefeller University, New York, NY), with additional maximization over the parameter alpha, the proportion of linked families. RESULTS: Evidence of linkage was found for the MYP3 locus on 12q (two-point Zmax = 2.54, P = 0.0003 and multipoint hLOD = 1.08 at alpha = 0.24, P = 0.023 for marker D12S332; nonparametric linkage [NPL] = 1.49, P = 0.07 for marker D12S1607). For the 17q locus there was weak evidence of excess allele sharing and linkage under a recessive model (NPL = 1.34, P = 0.09 for marker D17S956; two-point hLOD = 1.24 at alpha = 0.30 for marker D17S1795; multipoint hLOD = 1.24 at alpha = 0.17, P = 0.014 for marker at 77.68 cM, between markers D17S956 and D17S1853). No significant linkage was found to the MYP2 locus on 18p, or to the COL2A1, COL11A1, and FBN1 genes. CONCLUSIONS: These results suggest that the MYP3 locus on 12q could be responsible for high myopia in approximately 25% of the U.K. families showing apparent autosomal dominant transmission, but that the loci on 18p and 17q are less common causes. Thus, additional loci for high myopia are likely to be the cause of the majority of cases of high myopia in the United Kingdom.

Astigmatic axis is related to the level of spherical ametropia.

PURPOSE: Against-the-rule (ATR) astigmatism has been shown to be a risk factor for subsequent myopia development. In this study, we evaluated the relationship between astigmatic axis and the level of spherical ametropia in both myopes and hypermetropes. METHODS: Astigmatic axes were analyzed in two distinct cohorts. First, 53 high myopes from families that were recruited for linkage analysis were compared with an age-matched control group derived from family members. Second, cross-sectional data were analyzed for 90,884 subjects attending 19 optometric practices in the north of England. Initially, the relationship between astigmatic axis and cylinder power and between axis and sphere power were analyzed in 21- to 40-year olds and 21- to 30-year olds, respectively, to control for the effects of age. Multivariate logistic regression analysis was then performed using data for all compound astigmats in the cohort to examine the effect of sphere power, cylinder power, age, and sex on the odds of subjects having either ATR or with-the-rule (WTR) astigmatism. RESULTS: In the genetic study cohort, there was an excess of WTR astigmats in the high myopes compared with controls, but this only reached significance for the right eye. In the much larger optometric practice sample, the association of WTR astigmatism with high myopia was highly significant. A parallel increase in WTR astigmatism was also found for high hypermetropes. In addition, the odds of having WTR astigmatism were increased if subjects were young or had a high cylinder power. ATR astigmatism occurred more often with increasing age and in subjects with lower spherical ametropia. Indeed, for 21- to 30-year-old subjects with low myopia (> or =-2.00 DS in the least minus meridian), ATR occurred more often than WTR astigmatism. CONCLUSION: Astigmatic axis was found to be related to the level of ametropia, with both a higher spherical component or higher cylinder power increasing the odds of astigmatism being WTR. Low ametropes, particularly myopes, were more likely to have axes ATR.