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Relative Roles of Genetic and Environmental Influences

Johanna M. Seddon, MD, ScM; Jennifer Cote, MPH; William F. Page, PhD; Steven H. Aggen, PhD; Michael C. Neale, PhD

Arch Ophthalmol. 2005;123:321-327.

Context  Age-related macular degeneration (AMD) is the leading cause of irreversible blindness among older individuals in many parts of the world. The relative importance of genes and environment in the etiology of this major public health problem is not well understood.

Objective  To investigate the impact of genetic and environmental factors.

Participants  Living twins in the National Academy of Sciences–National Research Council World War II Veteran Twin Registry born between 1917 and 1927.

Methods  Twins were surveyed for the known presence of macular degeneration. Enrolled twins underwent a standardized examination and fundus photography. Age-related macular degeneration evaluation was completed for 840 elderly male twins, 210 monozygotic and 181 dizygotic complete twin pairs, both concordant and discordant for presence or absence of AMD, and 58 singletons. A bivariate twin model incorporating initial screening ascertainment and age effects was employed to partition variation in liability to AMD and signs of maculopathy into additive genetic, common environment, and unique environment components.

Main Outcome Measure  Heritability of AMD grade and signs of maculopathy based on clinical examination and fundus photographs.

Results  Of the 840 twins, 331 had no signs of maculopathy and 241 had early signs, while 162 had intermediate AMD and 106 had advanced AMD. Heritability (additive genetic) estimates were significant for overall AMD grade (0.46) and for intermediate (0.67) and advanced (0.71) AMD. Significant unique environmental proportions of variance were also observed for these AMD variables (0.37, 0.19, and 0.24, respectively). Shared or common environmental contributions were not significant (0.05-0.17). For specific macular drusen and retinal pigment epithelial characteristics, significant genetic (0.26-0.71) and unique environmental (0.28-0.64) proportions of variance were detected.

Conclusions  Genetic factors play a substantial role in the etiology of AMD and associated macular characteristics, explaining 46% to 71% of the variation in the overall severity of the disease. Environmental factors unique to each twin also contribute to the occurrence of this disease. This quantification of relative genetic and environmental contributions to the development of AMD should guide future research on this important cause of blindness.

Author Affiliations: Epidemiology Unit, Massachusetts Eye and Ear Infirmary (Dr Seddon and Ms Cote), Department of Ophthalmology, Harvard Medical School (Dr Seddon), and Department of Epidemiology, Harvard School of Public Health (Dr Seddon), Boston, Mass; National Academy of Sciences–National Research Council World War II Veteran Twin Registry, Washington, DC (Dr Page); and Departments of Psychiatry (Drs Aggen and Neale) and Human Genetics (Dr Neale) and Virginia Institute for Psychiatric and Behavioral Genetics (Drs Aggen and Neale), Virginia Commonwealth University, Richmond.

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