Genetic influence on early age-related maculopathy: A twin study

Abstract

ObjectiveAge-related macular degeneration (AMD) is the most common cause of blindness in industrialized countries. There has been considerable interest in the genetics of early age-related maculopathy (ARM) and AMD, because they have phenotypes similar to inherited diseases where mutations have been identified, but the heritability of ARM and AMD is unknown. DesignA classical twin study was performed to compare the concordance in monozygotic (MZ) and dizygotic (DZ) twins in an unselected sample of female volunteer twins. ParticipantsFive hundred six twin pairs, 226 MZ and 280 DZ, with a mean age of 62 years, were examined. MethodsARM was graded from stereoscopic macular photographs of 501 of the twin pairs (99%) according to the International ARM Epidemiologic Study Group grading system. The casewise concordance was calculated for twin pairs from 2 × 2 contingency tables of affected/unaffected twins, and these tables were used in maximum likelihood genetic modeling to estimate the heritabilities of phenotypes graded. Main outcome measuresPrevalence of ARM; concordance in MZ and DZ twins of the phenotypes of ARM, soft drusen >63 μm and ≥125 μm diameter, pigmentary changes and hard drusen (<20 and ≥20 in number); heritability of ARM and subphenotypes. ResultsThe overall prevalence of ARM was 14.6% (95% confidence interval [CI], 12.4%–16.8%). The concordance for ARM in MZ twins was 0.37 compared with 0.19 in DZ twins, suggesting a role for genes. Modeling confirmed a genetic effect for phenotypes of ARM, soft drusen, pigmentary changes, and ≥20 hard drusen, although there was little genetic effect for scattered (<20) hard drusen. The heritability of ARM was estimated as 45% (95% CI, 35%–53%). The most heritable phenotypes were soft drusen ≥125 μm (57%) and ≥20 hard drusen (81%), with the latter being dominantly inherited. ConclusionsThis study confirms a significant genetic influence in ARM and suggests that future genetic studies should examine phenotypes of large (≥125 μm) soft drusen and ≥20 hard drusen, because these seem to be the most heritable components.