et al. 1998; Swaroop et al. 2007). This was most striking when cases with more severe disease were analysed, for example Klaver and colleagues found an associated lifetime risk of 50% for relatives of patients compared to 12% for relatives of controls (Klaver et al. 1998). Twin studies provide further support for a role for inherited factors with comparisons of monozygotic and dizygotic-twins, concordant and discordant for the disease, allowing estimation of heritability (Hammond et al. 2002; Seddon et al. 2005). A large study of 840 twins estimated
Box 9.3 Age-related macular degeneration (OMIM 603075)
This progressive disease can lead to profound visual loss but spares peripheral vision (Fig. 9.16). This is because the disease affects the macula, a central region of the retina responsible for highest visual acuity through a very dense collection of specialized photoreceptors (cones). Initially extracellular deposits of debris, 'drusen', are seen behind the retina, specifically between the retinal pigment epithelium and a membrane in front of a vascular region called the choroid. Early disease is mild but through damage and chronic inflammatory change, regions of atrophy ('geographic atrophy') can develop which may include the centre of the macula, leading to advanced (sometimes called 'dry') disease (de Jong
2006; Jager et al. 2008). The development of new blood vessels (choroidal neovascularization, seen in 'wet' exudative disease) related to vascular endothelial growth factor and other cytokines is responsible for the majority of cases of severe visual loss through complications such as haemorrhage, retinal detachment, or fluid accumulation (de Jong 2006; Jager et al. 2008). Age-related macular degeneration is common and rises in incidence with age. In the United States, the estimated prevalence of advanced disease involving geographic atrophy and/or neovascularization is 1.5% among people over the age of 40 years, rising to 15% of white women over 80 years (Friedman et al. 2004).
heritability at 46% for age-related macular degeneration, rising to 71% for advanced disease (Seddon et al. 2005).
To investigate further the genetic contribution to a common multifactorial disease like age-related macular degeneration, some insight may be gained by looking at similar but distinct rare traits inherited in a mendelian fashion. For example, Stargardt's disease (OMIM 248200) leads to severe macular degeneration in childhood with very impaired visual acuity but normal peripheral vision. This recessive disorder was mapped to chromosome 1p22 by linkage analysis (Hoyng et al. 1996) and diverse mutations identified involving the causative gene ABCR, which encodes an ATP binding transporter expressed in the retina (Allikmets et al. 1997). Screening of patients with age-related macular degeneration showed 26 out of 167 had mutations in the same gene with various deletions and nonsynonymous changes found (Allikmets et al. 1997). However further work suggested that while these may be rare variants causing age-related macular degeneration, they are not major genetic contributors to the disease, with a number of studies failing to find this association (Stone et al. 1998; Swaroop et al. 2007).
Linkage analysis has been used with considerable success in studying genetic factors underlying age-related macular degeneration, despite the apparent difficulties of studying a multifactorial disease that is also late onset. The latter means that generally only a single generation is available to study within a family, as parents may have died and children are too young for the disease to be apparent, precluding the analysis of large multigener-ational families. Studies of affected sibling pairs have been extensively and successfully employed with linkage to several loci, notably chromosome 1q31-q32 and 10q26 (Fig. 9.17) (Swaroop et al. 2007).
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