Common variation in three genes, including a noncoding variant in CFH, strongly influences risk of age-related macular degeneration
Abstract
Age-related macular degeneration (AMD) is a common, late-onset disease with seemingly typical complexity: recurrence ratios for siblings of an affected individual are three- to sixfold higher than in the general population, and family-based analysis has resulted in only modestly significant evidence for linkage. In a case-control study drawn from a US-based population of European descent, we have identified a previously unrecognized common, noncoding variant in CFH, the gene encoding complement factor H, that substantially increases the influence of this locus on AMD, and we have strongly replicated the associations of four other previously reported common alleles in three genes (P values ranging from 10(-6) to 10(-70)). Despite excellent power to detect epistasis, we observed purely additive accumulation of risk from alleles at these genes. We found no differences in association of these loci with major phenotypic categories of advanced AMD. Genotypes at these five common SNPs define a broad spectrum of interindividual disease risk and explain about half of the classical sibling risk of AMD in our study population.
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Conditioning on the risk alleles and examining each of the 19 implicated loci for variants with independent association resulted in identification of previously well documented independently associated variants near CFH and C2/CFB and additional independent signals near C3, CETP, LIPC, FRK/COL10A1, IER3/DDR1, RAD51B.
“This analysis resulted in the identification of the previously well documented independently associated variants near CFH and C2/CFB8,10,31,32 and of additional independent signals near C3, CETP, LIPC, FRK/COL10A1, IER3/DDR1, RAD51B (Supplementary Table 6).”
From Seven new loci associated with age-related macular degeneration (2013) · cites this paper as [32]
This ARMS2/HTRA1 finding was later confirmed in several targeted studies and in a genome-wide association study.
“This finding was later confirmed in several targeted studies (107) and in a GWAS (37).”
From Unraveling a Multifactorial Late-Onset Disease: From Genetic Susceptibility to Disease Mechanisms for Age-Related Macular Degeneration (2009) · cites this paper as [107]
The genetic variants known to date are estimated to account for <50% of the heritability of AMD.
“The genetic variants known to date are estimated to account for <50% of the heritability of the disease (8,20).”
From Common variants near FRK/COL10A1 and VEGFA are associated with advanced age-related macular degeneration (2011) · cites this paper as [8]
Together with strongly associated variants in the ARMS2/HTRA1 region on chromosome 10, these multiple loci have been estimated to explain approximately one-half of the heritability of AMD.
“Together with strongly associated variants in the *ARMS2/HTRA1* region on chromosome 10 ([12](#r12), [13](#r13)), these multiple loci have been estimated to explain approximately one-half of the heritability of AMD ([6](#r6))”
From Genome-wide association study of advanced age-related macular degeneration identifies a role of the hepatic lipase gene ( <i>LIPC</i> ) (2010) · cites this paper as [6]
The role of the alternative complement pathway in AMD pathogenesis was documented by the discovery and replication of the CFH association and by reports of three additional risk loci in this pathway: CFB/C2 on chromosome 6, C3 on chromosome 19, and CFI on chromosome 4.
“The role of the alternative complement pathway in disease pathogenesis was documented by the discovery ([2](#r2)–[5](#r5)) and replication ([6](#r6), [7](#r7)) of the *CFH* association as well as reports of three additional risk loci in this pathway: *CFB/C2* on chromosome 6 ([6](#r6), [8](#r8)), *C3* on chromosome 19 ([9](#r9), [10](#r10)), and *CFI* on chromosome 4 ([11](#r11)).”
From Genome-wide association study of advanced age-related macular degeneration identifies a role of the hepatic lipase gene ( <i>LIPC</i> ) (2010) · cites this paper as [6]
A single locus can contain multiple independent common risk variants; for example, seven independent alleles at 8q24 for prostate cancer, three at CFH for AMD, three at IRF5 for SLE, and two at IL23R for Crohn's disease.
“5) A single locus can contain multiple independent common risk variants. Intensive study has already identified seven independent alleles at 8q24 for prostate cancer (92), three at complement factor H (CFH) for age-related macular degeneration (93, 94), three at IRF5 for systemic lupus erythematosus (95), and two at IL23R for Crohn’s disease (96).”
From Genetic Mapping in Human Disease (2008) · cites this paper as [93]
Searches have not yet found much evidence for epistasis.
“Although searches have not yet found much evidence for epistasis [e.g., (93, 94, 135)]”
From Genetic Mapping in Human Disease (2008) · cites this paper as [93]
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“In addition to the two novel loci, 10 previously reported loci in ARMS2/HTRA1 (rs10490924), CFH (rs1061170, and rs1410996), CFB (rs641153), C3 (rs2230199), C2 (rs9332739), CFI (rs10033900), LIPC (rs10468017), TIMP3 (rs9621532) and CETP (rs3764261) were confirmed with genomewide significant signals in this large study.”
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Self-citationGenotype-Specific Recurrence Risks as Indicators of the Genetic Architecture of Complex Diseases
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- Authors
- Maller, J., George, S., Purcell, S., Fagerness, J., Altshuler, D., Daly, M. J., & Seddon, J. M.
- Affiliations
- Massachusetts General Hospital (US)
- Massachusetts Eye and Ear Infirmary (US)
- Broad Institute (US)
- Corresponding author
- Daly, Mark J
- Seddon, Johanna M
- Venue
- Nature Genetics
- Published
- 2006-08-27
- Volume
- 38
- Issue
- 9
- Pages
- 1055-1059
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W1984944701
- Semantic Scholar
- a0aeaf39e1288bae3b546b3ee76dd65f595a8416
- Cited by
- 599
- References
- 29
- Citations by year
- 2026: 6 · 2025: 4 · 2024: 12 · 2023: 7 · 2022: 9 · 2021: 14 · 2020: 16 · 2019: 13 · 2018: 13 · 2017: 18 · 2016: 24 · 2015: 28 · 2014: 39 · 2013: 50 · 2012: 44
- FWCI
- 54.96
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Broad Institute
- National Institutes of Health (6u54rr020278-06)
- National Eye Institute (EY11309)
- National Center for Research Resources (U54-RR020278)
- Topics
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
- Keywords
- age-related macular degeneration, complement factor H, non-coding variants, single nucleotide polymorphisms, genetic susceptibility, additive hazards model, epistasis, familial recurrence risk
- MeSH terms
- Aged, Alleles, Humans, Macular Degeneration, Risk Factors, United States, Genetic Variation, Chi-Square Distribution, Logistic Models, Case-Control Studies, Complement Factor H, Polymorphism, Single Nucleotide, Siblings, White People
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