The leading cause of vision loss in older adults in high-income countries. Two genes discovered in 2005 — CFH and ARMS2 — account for most of the known genetic risk; a run of later meta-analyses added ten smaller loci, mostly in the same complement and lipid-metabolism pathways.
Solid lines are connections this site curates. Dashed lines mean the two ends share a research paper — worth knowing, and not a claim that one explains the other.
Age-related macular degeneration (AMD) damages the macula, the part of the retina responsible for sharp, central vision — the vision used for reading, driving and recognising faces. It is the leading cause of vision loss in older adults in high-income countries. A 2014 systematic review and meta-analysis of 129,664 people across 39 population-based studies put the pooled prevalence at 8.69% of people aged 45–85, and projected 196 million people affected worldwide by 2020, rising to 288 million by 2040.
Before 2005, AMD's genetics were largely unknown. Two papers that year identified the two largest-effect loci still known: CFH (complement factor H) and ARMS2 (also called LOC387715), on different chromosomes and acting independently.
Zareparsi et al. 2005 found the Y402H variant (rs1061170) in CFH strongly associated with AMD in a single-center case-control study: the risk (C) allele was carried at 0.61 frequency in cases versus 0.34 in controls (P<10⁻²⁴), with a genotype relative risk of 2.44 (95% CI 2.08–2.83) for one copy and 5.93 (95% CI 4.33–8.02) for two. CFH is not a statistical curiosity here — it regulates the complement system, part of the innate immune response, and complement dysregulation is one of the field's leading mechanistic explanations for AMD.
Rivera et al. 2005, working in a German cohort (1,166 cases, 945 controls), found a second, independent locus: the Ala69Ser variant (rs10490924) in ARMS2, with a per-variant association of P=10⁻³⁴. Critically, the paper tested the two genes together and found their effects combine: people homozygous for both the CFH and ARMS2 risk alleles had a disease odds ratio of 57.6 (95% CI 37.2–89.0) compared with the baseline non-risk genotype — far higher than either gene alone.
Larger genome-wide association studies through the 2010s added ten more loci, most of them landing in the same two biological stories as CFH and ARMS2: complement regulation and lipid metabolism. Chen et al. 2010 (PNAS) reported signals near TIMP3 and several HDL-cholesterol-associated genes, including confirmation at the complement-adjacent CFB region (rs9380272, rs429608). Neale et al. 2010 (PNAS) implicated the hepatic lipase gene LIPC and, in the same discovery scan, a locus near ALDH1A2 (rs493258). Sobrin et al. 2012 (Ophthalmology), comparing AMD subtypes, added a variant near C1QTNF5/MFRP associated specifically with the choroidal-neovascularisation subtype (rs10033900). Fritsche et al. 2013 (Nature Genetics) — the largest of these studies — reported seven new genome-wide-significant loci at once, six of which are on this page: CETP, LIPC, SLC16A8, RAD51B, B3GALTL and FILIP1L.
Taken together, the twelve variants on this page span five separate studies published between 2005 and 2013. The two 2005 findings, CFH and ARMS2, remain by far the largest individual effects; everything found afterward has been smaller, and mostly reinforces the same two pathways rather than opening new ones.
2021-07-29 · Hospital Clínic de Barcelona & IDIBAPS (Dr. Blanca Molins, Ocular Inflammation research group)
Complement Factor H (CFH) may be involved in age-related macular degeneration (AMD)
Barcelona researchers described how the CFH Y402H risk variant (rs1061170, profiled on this site) changes how well complement factor H regulates inflammation and oxidative stress in the retina, and how a separate protein, FHR4 (made from the related CFHR4 gene), can compete with CFH and blunt its protective effect -- a mechanistic explanation for why this one variant carries such a large share of AMD risk. This is an older finding (2021), included here because the date is accurate and the mechanism it describes is still the current explanation, not because it is recent.
AMD is diagnosed with a dilated eye exam, retinal imaging (optical coherence tomography, fundus photography) and sometimes fluorescein angiography — not by genotype. Treatment depends on stage and subtype: regular monitoring and the AREDS2 antioxidant/mineral formula for intermediate disease, anti-VEGF injections for the neovascular ("wet") form. None of that is decided by the variants on this page — including a once-widely-discussed claim that CFH and ARMS2 genotype should change which AREDS2 ingredients someone takes, covered on the AREDS2 page, which did not hold up under independent re-analysis.
CFH and ARMS2 are marked as sensitive on this site because their individual effect sizes are unusually large for a common genetic variant, and the combined-genotype result from Rivera et al. 2005 — an OR of 57.6 for the highest-risk combination — is the kind of number that reads as far more deterministic than it should. Most people who carry a risk allele at either gene never develop advanced AMD; the studies behind these numbers report relative and combined risk in case-control cohorts, not absolute individual risk, and family history, smoking status and cardiovascular risk factors all still matter independently.
The other ten variants each come from one of four subsequent GWAS papers, all reporting genome-wide-significant but individually smaller associations. This page's honest reading of them is as five separate replications of the same underlying story — complement and lipid pathways drive AMD susceptibility — rather than ten new independent risks to track.
What a 23andMe/AncestryDNA export or raw VCF can and can't tell you about Age-Related Macular Degeneration comes down to these specific, well-studied positions — not a diagnosis.
CF1 · rs10033900
See detailed info →C2 · rs116503776
See detailed info →The studies behind these variants recruited participants from different ancestries — a result found in one population doesn't always transfer to another. Based on 11 of 13 linked studies with a resolved discovery ancestry.
Databases, guidelines and references
No. AMD is diagnosed with a dilated eye exam and retinal imaging. These variants come from genome-wide association and case-control studies and are not used diagnostically — carrying a risk allele, even at CFH and ARMS2, does not mean AMD will develop.
Their individual and combined effect sizes are unusually large for common genetic variants — a relative risk of 5.93 for CFH alone, and a combined odds ratio of 57.6 when both CFH and ARMS2 risk genotypes are present. That reads as more deterministic than any single genetic test result should.
Roughly two pathways. CFH and the CFB-region variants sit in the complement system, part of innate immunity; CETP, LIPC and the TIMP3/HDL-associated loci sit in lipid metabolism. ARMS2's mechanism is still not well understood, and it has no established function beyond its association with AMD.
A 2014 meta-analysis of 129,664 people found a pooled prevalence of 8.69% in people aged 45-85, and projected 196 million people affected worldwide by 2020, rising to 288 million by 2040.
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