Genetics of Age-Related Macular Degeneration
Anna Gabrielian, MD
Rama D. Jager, MD, FACS
Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss and blindness in older adults in the developed world.1 AMD has been implicated to be an inherited disease in a number of epidemiologic, functional, and genetic studies.
Familial aggregation studies have found the prevalence of AMD to be significantly higher among first-degree relatives of cases than in controls, in both siblings and offspring.2-4 Twin studies have provided an even stronger evidence of AMD heritability, explaining 46-71% of AMD variation.2
To date, a large number of both negative and positive candidate genes involved in the pathogenesis of AMD have been described. Negative candidate genes include TIMP3, VMD2, RDS, and several others examined recently in multi-candidate gene studies.5,6 Positive candidate genes include ABCA4, VEGF, MMP9, APOE, HLA, and several others.5,6 A number of linkage analysis studies have attempted to identify the genomic regions containing the susceptibility loci for AMD. An association with nearly every chromosome in the human genome has been implicated in the development AMD by linkage analysis.5 The most replicated linkage findings have been on chromosomes 1q25-31 and 10q26, with genetic variants at these loci conferring major disease risks, and together accounting for more than 50% of AMD pathology.7,8,9
Perhaps the most important discovery as a result of both linkage and association studies thus far is the consistent association of AMD pathogenesis and the complement factor H gene (CFH) located on chromosome 1q.8 CFH is a component of the immune system that helps to regulate inflammatory responses by preventing uncontrolled complement activation.10 Abnormal regulation of the complement cascade in AMD patients occurs at the level of Bruch's membrane and the adjacent retinal pigment epithelium, leading to drusen formation.11 Recent studies have shown the existence of a risk variant within the CFH gene - the Y402H variant - which puts patients expressing it at significantly higher risk of developing AMD.9 Several other factors involved in the complement cascade have also been studied (factor B [BF], complement component 2 [C2]) and appear to be protective of AMD.12
Most recently, investigations into the 10q26 locus have shown polymorphisms in the ARMS2 gene, localized to the ellipsoid region of the photoreceptors. Absence of this gene is a major risk factor for AMD, conferring disease through mitochondrial-related pathways.13 Polymorphisms in a promoter gene HTRA1, also localized to 10q26,13 have also shown a significant association with wet AMD in a co-dominant model of action. The genetic effect seemed to be stronger in older and Caucasians subjects versus younger and Asian subjects.14
Despite the many difficulties in deciphering the genetic code of AMD (the polygenic complexity of the disease, variable heritability and expression patterns, and the impact of lifestyle and environmental factors such as cigarette smoking and diet), recent research in AMD genetics has the potential of uncovering the genetic basis of this potentially devastating disease, in order to promote the development of newer and more effective therapies.
- Jager RD, Mieler WF, Miller JW. Age-related macular degeneration. N Engl J Med. 2008 Jun 12;358(24):2606-17
- Seddon JM, Ajani UA, Mitchell BD. Familial aggregation of age-related maculopathy. Am J Ophthalmol. 1997 Feb;123(2):199-206.
- Klaver CC, Wolfs RC, Assink JJ, van Duijn CM, Hofman A, de Jong PT. Genetic risk of age-related maculopathy. Population-based familial aggregation study. Arch Ophthalmol. 1998 Dec;116(12):1646-51.
- Klein BE, Klein R, Lee KE, Moore EL, Danforth L. Risk of incident age-related eye diseases in people with an affected sibling: The Beaver Dam Eye Study. Am J Epidemiol. 2001 Aug 1;154(3):207-11.
- Haddad S, Chen CA, Santangelo SL, Seddon JM. The genetics of age-related macular degeneration: a review of progress to date. Surv Ophthalmol. 2006 Jul-Aug;51(4):316-63.
- Patel N, Adewoyin T, Chong NV. Age-related macular degeneration: a perspective on genetic studies. Eye. 2008 Jun;22(6):768-76.
- Fisher SA, Abecasis GR, Yashar BM, Zareparsi S, Swaroop A, Iyengar SK, Klein BE, Klein R, Lee KE, Majewski J, Schultz DW, Klein ML, Seddon JM, Santangelo SL, Weeks DE, Conley YP, Mah TS, Schmidt S, Haines JL, Pericak-Vance MA, Gorin MB, Schulz HL, Pardi F, Lewis CM, Weber BH. Meta-analysis of genome scans of age-related macular degeneration. Hum Mol Genet. 2005 Aug 1;14(15):2257-64
- Hageman GS, Luthert PJ, Victor Chong NH, Johnson LV, Anderson DH, Mullins RF. An integrated hypothesis that considers drusen as biomarkers of immune-mediated processes at the RPE-Bruch's membrane interface in aging and age-related macular degeneration. Prog Retin Eye Res. 2001 Nov;20(6):705-32.
- Haines JL, Hauser MA, Schmidt S, Scott WK, Olson LM, Gallins P, Spencer KL, Kwan SY, Noureddine M, Gilbert JR, Schnetz-Boutaud N, Agarwal A, Postel EA, Pericak-Vance MA. Complement factor H variant increases the risk of age-related macular degeneration. Science. 2005 Apr 15;308(5720):419-21
- Rodríguez de Córdoba S, Esparza-Gordillo J, Goicoechea de Jorge E, Lopez-Trascasa M, Sánchez-Corral P. The human complement factor H: functional roles, genetic variations and disease associations. Mol Immunol. 2004 Jun;41(4):355-67
- Sivaprasad S, Chong NV. The complement system and age-related macular degeneration. Eye. 2006 Aug;20(8):867-72
- Gold B, Merriam JE, Zernant J, Hancox LS, Taiber AJ, Gehrs K, Cramer K, Neel J, Bergeron J, Barile GR, Smith RT; AMD Genetics Clinical Study Group, Hageman GS, Dean M, Allikmets R. Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration. Nat Genet. 2006 Apr;38(4):458-62
- Fritsche LG, Loenhardt T, Janssen A, Fisher SA, Rivera A, Keilhauer CN, Weber BH. Age-related macular degeneration is associated with an unstable ARMS2 (LOC387715) mRNA. Nat Genet. 2008 Jul;40(7):892-6
- Tang NP, Zhou B, Wang B, Yu RB. HTRA1 Promoter Polymorphism and Risk of Age-Related Macular Degeneration: A Meta-Analysis. Ann Epidemiol. 2009 Apr 16. [Epub ahead of print]
Ingrid U. Scott,
MD, MPH, Editor
Professor of Ophthalmology and
Public Health Sciences,
Penn State College of Medicine