What is the role of genetics in the etiology of age-related macular degeneration (AMD)?

Updated: Nov 11, 2019
  • Author: Lucia Sobrin, MD, MPH; Chief Editor: Karl S Roth, MD  more...
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Age-related macular degeneration (AMD) is a common polygenic disease in which multiple genetic variants, as well as environmental and lifestyle factors, contribute to disease risk, each adding a small to moderate amount of increased risk. The risk of developing the disease is at least three-fold higher in people who have a family member with AMD than in those without a first-degree relative with AMD. This risk is amplified when immediate family members have the disease, with one study estimating a 27.8 times increased risk with an affected parent and 12 times increased risk for those with an affected sibling. [1, 2, 3, 4, 5, 6, 7]

Several genetic variants have been consistently associated with AMD. The common coding variant Y402H in the complement factor H (CFH) gene was the first identified. The odds ratio associated with being homozygous for the risk variant for all categories of AMD is estimated to be between 2.45 and 3.33; the odds ratios are higher, between 3.5 and 7.4, for advanced dry and wet forms of AMD. [8, 9, 10] Several other genetic loci in the alternative complement cascade have also been consistently shown to affect AMD risk. These include other variants in CFH, [11] as well as other genes: factor B (BF)/complement component 2 (C2), [11, 12] complement component 3 (C3), [13, 14] and complement factor I (CFI). [15, 16, 17, 18]

Several genes not involved in the complement cascade have also been implicated. Variation in the HTRA1/ARMS2 locus on chromosome 10 has been convincingly associated with AMD, with an effect size similar to or greater than that seen with CFH. [19] The function of this gene is not completely understood, but there is evidence that it confers greater risk for wet AMD than for geographic atrophy. [20]

Rare genetic variants in the complement system have also been found to play an important role in AMD. [21] Such rare variants have been described in the complement factor H (CFH), complement factor I (CFI), complement factor 9 (C9), and complement factor 3 (C3) genes. [22]

Hepatic lipase C (LIPC) and tissue inhibitor of metalloproteinase 3 (TIMP3) have been reported to be associated with AMD in large genome-wide association studies. [23, 24] LIPC, a novel AMD gene, is involved in high-density lipoprotein cholesterol (HDL) metabolism, [23, 25] and TIMP3 is implicated in a mendelian, early-onset form of macular degeneration known as Sorsby's fundus dystrophy. [3]

The International AMD Genomics Consortium discovered a total of 52 genetic variants that are associated with AMD. These variants are located among 34 loci. A genetic variant near MMP9 specific to the neovascular form of AMD was also identified. [21]

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