Researchers in Boston have discovered a new common, noncoding variant in the Complement Factor H (CFH) gene that is associated with age-related macular degeneration (AMD), the leading cause of irreversible visual impairment and blindness among persons aged 60 and older.
Their analyses, for the first time, combine this new variant with all previously reported variants to estimate individual risk of advanced AMD. They observed additive accumulation of risk from alleles at these three genes, including CFH on chromosome 1, complement factor B (BF) and complement component 2 (C2) genes on chromosome 6, and the LOC gene on chromosome 10. They estimate that genotypes related to five variants in these three genes explain about half the sibling risk of AMD in the study population. Results are published online in Nature Genetics.
The principal investigator, Johanna M. Seddon, M.D., Director of the Epidemiology Unit and Macular Degeneration specialist at the Massachusetts Eye and Ear Infirmary, and Associate Professor at Harvard Medical School, collaborated with co-authors from the Center for Human Genetic Research at Massachusetts General Hospital and the Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology. They studied 2,172 unrelated European-descended individuals 60 years of age or older, who were diagnosed on the basis of ocular examination and ocular photography (1,238 affected individuals and 934 controls). Affected individuals were defined as those having advanced AMD related to visual loss with either geographic atrophy (dry) or neovascular (wet) disease. Controls were individuals without AMD. The mean age was 74 for controls (54% female) and 78 years for affected individuals (55% female). Both Illumina and Sequenom methods were used to genotype about 1540 single nucleotide polymorphisms (snp's).
AMD is a "common disease" meaning that it is complex, i.e., many genes and environmental factors contribute to the disease, similar to heart disease, schizophrenia and diabetes. The combinations of variation within a given gene and between genes, along with environmental factors, confers one's lifetime risk of a disease like AMD. Variations in the BF/C2 gene are protective for AMD, whereas the more common variations in the other two genes, CFH and LOC, increase risk of AMD. The authors provide new calculations that one's lifetime risk of AMD ranges from less than 1% to more than 50%, depending on the variations one has in these three genes. The research team also showed that the three genes do not interact, but confer risk independently.