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March 2011, Issue 49

Genetics of AMD

Jaclyn L. Kovach, MD
Assistant Professor of Clinical Ophthalmology
Bascom Palmer Eye Institute
University of Miami Miller School of Medicine


Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss in older adults in the western hemisphere.1 It is estimated that 30% of Americans ≥ 75 years of age have AMD2 and that by the year 2020, approximately 3 million Americans will be affected by advanced AMD.3 The etiology of the disease is multifactorial, involving a complex interaction of inflammatory, oxidative, degenerative, and genetic components. Recent developments in the field of human genomics have fostered advancements in our knowledge of the genetic basis of AMD.

Prior to 2005, understanding of the heritability of AMD was limited and based largely on familial aggregation studies. These studies confirmed that a family history of AMD increases one’s risk for the development of the disease, and first degree relatives of affected patients have a four-fold increased risk of developing the condition. In addition, monozygotic twins are known to have a high level of concordance for AMD compared to dizygotic twins.4-7 Underlying genes of multiple heritable dystrophies including TIMP3, EFEMP1, ABCA4, RDS,  ELVOL4, and VMD28 have been investigated as possible candidate genes associated with AMD, but to date, a pathogenic role has only been proven for TIMP39and ABCA4.8

In 2005, a new era dawned with the completion of the International Haplotype Map Project which compiled a collection of millions of single nucleotide polymorphisms (SNP), which are normal variations in gene structure that may protect against or predispose to various conditions. Genome-wide association studies in large cohorts have identified several susceptibility loci associated with increased AMD risk.

Complement factor H (CFH), complement factor B (CFB)/complement component 2 (C2), LOC387715/ARMS2 and HTRA1 are believed to be responsible for the majority of heritable AMD risk, with other genes playing a significant but smaller role.10-12 Complement factor H SNP Y402H (rs1061170) on chromosome 1q32 was the first major susceptibility gene discovered for AMD and could be responsible for 50% of AMD risk. The CFH gene codes for a glycoprotein that regulates the alternative complement pathway and binds to Bruch’s membrane. The Y402H SNP can result in abnormal complement activation and host cell destruction secondary to ineffective binding to Bruch’s membrane. CFH Y402H promotes the development of early AMD (drusen formation) and progression to advanced AMD, and can act synergistically with smoking history to increase one’s risk of wet AMD.13,14

Various SNPs in the complement factor I (CFI),15 CFB/C2,11 and complement component 3 (C3) genes also promote complement activation and increase AMD risk. Complement component 3, the convergence point of the complement pathways, plays a critical role in the formation of the membrane attack complex (MAC) and consequential cell lysis. Nine SNPs in the C3 gene are associated with AMD, with SNP R102G being specifically related to wet AMD.16  

Affecting every step in AMD pathogenesis, the consequences of uncontrolled complement include promoting leukocyte accumulation, reactive oxygen species, drusen formation, retinal pigment epithelial cell damage (MAC-induced cell lysis), and elevation of vascular endothelial growth factor (VEGF) which leads to development of choroidal neovascularization (CNV).15 

LOC387715/ARMS2 A69S and HTRA1 was the second major susceptibility locus identified for AMD. These genes occupy several kilobases on a segment of chromosome 10q26. ARMS2 is thought to mediate oxidative stress, and HTRA1 is a serine protease found in drusen. Homozygosity for the high risk polymorphism confers increased risk for AMD progression and earlier onset of wet AMD.12

AMD susceptibility is also associated with polymorphisms in the LIPC, CETP, LPL, ABCA1 and APOE genes that are involved with cholesterol metabolism.9 Other genetic variants with weak or questionable AMD association include HMCN1, VEGF, TLR3, TLR4, and Serping1.17,18
During the past few years we have made great strides to elevate our level of understanding of the complex and polygenic basis of AMD. This knowledge has provided the foundation for genetic testing, and the potential for gene-guided treatment and gene therapy.


1. Jager RD, Meiler WF, Miller JW. Age-related macular degeneration. N Engl J Med. 2008 Jun 12;358(24):2606-17.
2. Klein R, Klein BE, Linton KL. Prevalence of age-related maculopathy. The Beaver Dam Eye Study. Ophthalmology. 1992;99(6):933-43.
3. Freidman DS, O’Colmain BJ, Munoz B et al. Prevalence of age-related macular degeneration in the United States. Arch Ophthalmol. 2004;122(4):564-72.
4. Seddon JM, Ajani UA, Mitchell BD. Familial aggregation of age-related maculopathy. Am J Ophthalmol. 1997 Feb;123(2):199-206.
5. Klaver CC, Wolfs RC, Assink JJ et al. Genetic risk of age-related maculopathy. Population-based familial aggregation study. Arch Ophthalmol. 1998 Dec;116(12):1646-51.
6. Klein BE, Klein R, Lee ME et al. 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.
7. Meyers SM. A twin study on age-related macular degeneration. Trans Am Ophthalmol Soc. 1994;92:775-843.
8. Klaver CC, Allikmets R. Genetics of macular dystrophies and implications for age-related macular degeneration. Dev Ophthalmol. 2003;37:155-69.
9. Chen W et al.  Genetic variants near TIMP3 and high-density lipoprotein-associated loci influence susceptibility to age-related macular degeneration. Proc Natl Acad Sci USA. 2010 Apr 20; 107(16):7401-6.
10. Hageman GS, Anderson DH, Johnson LV et al. A common haplotype in the complement regulatory gene factor H (CFH) predisposes individuals to age-related macular degeneration. Proc Natl Acad Sci USA. 2005;102:7227-32.
11. Gold B, Merriam JE, Zernant J et al. Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration. Nat Gen. 2006;38:458-62.
12. Rivera A, Fisher SA, Fritsche LG et al. Hypothetical LOC387715 is a second major susceptibility gene for age-related macular degeneration, contributing independently to complement factor H to risk. Hum Mol Genet. 2005;14:3227-36.
13. Clark SJ, Bishop PN, Day AJ. Complement factor H and age-related macular degeneration: the role of glycosaminoglycan recognition in disease pathology. Biochem Soc Trans. 2010 Oct;38(5):1342-8.
14. Cotlier E,Weinreb R. The role of complement factor H in age-related macular degeneration: a review. Surv Ophthalmol. May-June;55(3);227-46.
15.Zipfel PH, Lauer N, Skerka C. The role of complement in AMD. Adv Exp Med Biol. 2010;703:9-24  
16. Gehrs KM, Jackson JR, Brown EN et al. Complement, age-related macular degeneration and a vision of the future. Arch Ophthalmol. 2010 Mar;128(3):349-58.
17. Katta S, Kaur I, Chakrabarti S. The molecular genetic basis of age-related macular degeneration: an overview. J Genet. 2009 Dec;88(4):425-49.
18. Lee AY, Kulkarni M, Fang AM et al. The effect of genetic variants in SERPING1 on the risk of neovascular age-related macular degeneration. Br J Ophthalmol. 2010 Jul;94(7):915-7.


Ingrid U. Scott, MD, MPH,  Editor

Professor of Ophthalmology and
Public Health Sciences,
Penn State College of Medicine


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