Molecular genetics of age-related macular degeneration: current status

Age-related macular degeneration (AMD), a multifactorial human disorder, is the most common cause of acquired visual impairment in people over the age 60. It is estimated to affect millions of individuals worldwide. Prevalence increases with age; among persons 75 years and older, mild, or early forms occur in nearly 30% and advanced forms in about 7% of the population. AMD has been associated both with environmental and genetic factors. However, the clinical heterogeneity, late age at onset, and complex etiology have confounded genetic studies of the disorder. Methods applicable to the study of single-gene and some complex disorders (i.e., linkage analysis, sib-pair analysis, transmission disequilibrium test, etc.) have had limited utility in elucidating the genetic components of the complex AMD trait. Recently, substantial progress has been made in determining the genetic basis of monogenic eye disorders. On a monthly basis mutations are identified in new genes responsible for some form of retinal degeneration. Most, if not all, of these genes become candidates for potential involvement in multifactorial disorders especially if the phenotypes of the early-onset Mendelian diseases they cause resemble later onset complex traits. Unfortunately, to date mutational analyses of the candidate genes in AMD patients to date have not yielded the highly anticipated information: statistically significant association of sequence variants with AMD. Whether this is due to the unsuccessful selection of the right candidate genes for the analysis, or the methods employed, or both, has to be elucidated. This review summarizes current knowledge of genetic research aimed at delineating the molecular genetic basis of age-related macular degeneration. Moreover, it attempts to offer some approaches for the future studies directed towards understanding the genetic components of this complex disorder.