Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Seven new loci associated with age-related macular degeneration

Abstract

Age-related macular degeneration (AMD) is a common cause of blindness in older individuals. To accelerate the understanding of AMD biology and help design new therapies, we executed a collaborative genome-wide association study, including >17,100 advanced AMD cases and >60,000 controls of European and Asian ancestry. We identified 19 loci associated at P < 5 × 10−8. These loci show enrichment for genes involved in the regulation of complement activity, lipid metabolism, extracellular matrix remodeling and angiogenesis. Our results include seven loci with associations reaching P < 5 × 10−8 for the first time, near the genes COL8A1-FILIP1L, IER3-DDR1, SLC16A8, TGFBR1, RAD51B, ADAMTS9 and B3GALTL. A genetic risk score combining SNP genotypes from all loci showed similar ability to distinguish cases and controls in all samples examined. Our findings provide new directions for biological, genetic and therapeutic studies of AMD.

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Summary of GWAS results.
Figure 2: Sensitivity analysis.
Figure 3: Risk score analysis.

Accession codes

Accessions

Gene Expression Omnibus

NCBI Reference Sequence

References

  1. Swaroop, A., Chew, E.Y., Rickman, C.B. & Abecasis, G.R. Unravelling a late-onset multifactorial disease: from genetic susceptibility to disease mechanisms for age-related macular degeneration. Annu. Rev. Genomics Hum. Genet. 10, 19–43 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Seddon, J.M., Cote, J., Page, W.F., Aggen, S.H. & Neale, M.C. The US twin study of age-related macular degeneration: relative roles of genetic and environmental influences. Arch. Ophthalmol. 123, 321–327 (2005).

    Article  PubMed  Google Scholar 

  3. Friedman, D.S. et al. Prevalence of age-related macular degeneration in the United States. Arch. Ophthalmol. 122, 564–572 (2004).

    Article  PubMed  Google Scholar 

  4. Edwards, A.O. et al. Complement factor H polymorphism and age-related macular degeneration. Science 308, 421–424 (2005).

    Article  CAS  PubMed  Google Scholar 

  5. Haines, J.L. et al. Complement factor H variant increases the risk of age-related macular degeneration. Science 308, 419–421 (2005).

    Article  CAS  PubMed  Google Scholar 

  6. Klein, R.J. et al. Complement factor H polymorphism in age-related macular degeneration. Science 308, 385–389 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Yates, J.R. et al. Complement C3 variant and the risk of age-related macular degeneration. N. Engl. J. Med. 357, 553–561 (2007).

    Article  CAS  PubMed  Google Scholar 

  8. Gold, B. et al. Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration. Nat. Genet. 38, 458–462 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Fagerness, J.A. et al. Variation near complement factor I is associated with risk of advanced AMD. Eur. J. Hum. Genet. 17, 100–104 (2009).

    Article  CAS  PubMed  Google Scholar 

  10. Hageman, G.S. et al. A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proc. Natl. Acad. Sci. USA 102, 7227–7232 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Maller, J.B. et al. Variation in complement factor 3 is associated with risk of age-related macular degeneration. Nat. Genet. 39, 1200–1201 (2007).

    Article  CAS  PubMed  Google Scholar 

  12. Rivera, A. et al. Hypothetical LOC387715 is a second major susceptibility gene for age-related macular degeneration, contributing independently of complement factor H to disease risk. Hum. Mol. Genet. 14, 3227–3236 (2005).

    Article  CAS  PubMed  Google Scholar 

  13. Jakobsdottir, J. et al. Susceptibility genes for age-related maculopathy on chromosome 10q26. Am. J. Hum. Genet. 77, 389–407 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Klaver, C.C. et al. Genetic association of apolipoprotein E with age-related macular degeneration. Am. J. Hum. Genet. 63, 200–206 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Souied, E.H. et al. The ɛ4 allele of the apolipoprotein E gene as a potential protective factor for exudative age-related macular degeneration. Am. J. Ophthalmol. 125, 353–359 (1998).

    Article  CAS  PubMed  Google Scholar 

  16. McKay, G.J. et al. Evidence of association of APOE with age-related macular degeneration: a pooled analysis of 15 studies. Hum. Mutat. 32, 1407–1416 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. 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 107, 7401–7406 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  18. Neale, B.M. et al. Genome-wide association study of advanced age-related macular degeneration identifies a role of the hepatic lipase gene (LIPC). Proc. Natl. Acad. Sci. USA 107, 7395–7400 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Yu, Y. et al. Common variants near FRK/COL10A1 and VEGFA are associated with advanced age-related macular degeneration. Hum. Mol. Genet. 20, 3699–3709 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Arakawa, S. et al. Genome-wide association study identifies two susceptibility loci for exudative age-related macular degeneration in the Japanese population. Nat. Genet. 43, 1001–1004 (2011).

    Article  CAS  PubMed  Google Scholar 

  21. McCarthy, M.I. et al. Genome-wide association studies for complex traits: consensus, uncertainty and challenges. Nat. Rev. Genet. 9, 356–369 (2008).

    Article  CAS  PubMed  Google Scholar 

  22. Li, Y., Willer, C.J., Sanna, S. & Abecasis, G.R. Genotype imputation. Annu. Rev. Genomics Hum. Genet. 10, 387–406 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Marchini, J., Howie, B., Myers, S., McVean, G. & Donnelly, P. A new multipoint method for genome-wide association studies by imputation of genotypes. Nat. Genet. 39, 906–913 (2007).

    CAS  PubMed  Google Scholar 

  24. Browning, B.L. & Browning, S.R. A unified approach to genotype imputation and haplotype-phase inference for large data sets of trios and unrelated individuals. Am. J. Hum. Genet. 84, 210–223 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Li, Y., Willer, C.J., Ding, J., Scheet, P. & Abecasis, G.R. MaCH: using sequence and genotype data to estimate haplotypes and unobserved genotypes. Genet. Epidemiol. 34, 816–834 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  26. Willer, C.J., Li, Y. & Abecasis, G.R. METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics 26, 2190–2191 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Skol, A.D., Scott, L.J., Abecasis, G.R. & Boehnke, M. Joint analysis is more efficient than replication-based analysis for two-stage genome-wide association studies. Nat. Genet. 38, 209–213 (2006).

    Article  CAS  PubMed  Google Scholar 

  28. Higgins, J.P., Thompson, S.G., Deeks, J.J. & Altman, D.G. Measuring inconsistency in meta-analyses. Br. Med. J. 327, 557–560 (2003).

    Article  Google Scholar 

  29. Sobrin, L. et al. ARMS2/HTRA1 locus can confer differential susceptibility to the advanced subtypes of age-related macular degeneration. Am. J. Ophthalmol. 151, 345–352 (2011).

    Article  CAS  PubMed  Google Scholar 

  30. Seddon, J.M. et al. Association of CFH Y402H and LOC387715 A69S with progression of age-related macular degeneration. J. Am. Med. Assoc. 297, 1793–1800 (2007).

    Article  CAS  Google Scholar 

  31. Li, M. et al. CFH haplotypes without the Y402H coding variant show strong association with susceptibility to age-related macular degeneration. Nat. Genet. 38, 1049–1054 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Maller, J. et al. Common variation in three genes, including a noncoding variant in CFH, strongly influences risk of age-related macular degeneration. Nat. Genet. 38, 1055–1059 (2006).

    Article  CAS  PubMed  Google Scholar 

  33. Nejentsev, S., Walker, N., Riches, D., Egholm, M. & Todd, J.A. Rare variants of IFIH1, a gene implicated in antiviral responses, protect against type 1 diabetes. Science 324, 387–389 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Raychaudhuri, S. et al. A rare penetrant mutation in CFH confers high risk of age-related macular degeneration. Nat. Genet. 43, 1232–1236 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Pruim, R.J. et al. LocusZoom: regional visualization of genome-wide association scan results. Bioinformatics 26, 2336–2337 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Adzhubei, I.A. et al. A method and server for predicting damaging missense mutations. Nat. Methods 7, 248–249 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Sivakumaran, T.A. et al. A 32 kb critical region excluding Y402H in CFH mediates risk for age-related macular degeneration. PLoS ONE 6, e25598 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Wellcome Trust Case Control Consortium.. Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls. Nature 464, 713–720 (2010).

  39. 1000 Genomes Project Consortium. A map of human genome variation from population scale sequencing. Nature 467, 1061–1073 (2010).

  40. Fritsche, L.G. et al. Age-related macular degeneration is associated with an unstable ARMS2 (LOC387715) mRNA. Nat. Genet. 40, 892–896 (2008).

    Article  CAS  PubMed  Google Scholar 

  41. Dewan, A. et al. HTRA1 promoter polymorphism in wet age-related macular degeneration. Science 314, 989–992 (2006).

    Article  CAS  PubMed  Google Scholar 

  42. Hughes, A.E. et al. A common CFH haplotype, with deletion of CFHR1 and CFHR3, is associated with lower risk of age-related macular degeneration. Nat. Genet. 38, 1173–1177 (2006).

    Article  CAS  PubMed  Google Scholar 

  43. Fritsche, L.G. et al. An imbalance of human complement regulatory proteins CFHR1, CFHR3 and factor H influences risk for age-related macular degeneration (AMD). Hum. Mol. Genet. 19, 4694–4704 (2010).

    Article  CAS  PubMed  Google Scholar 

  44. Brooks, M.J., Rajasimha, H.K., Roger, J.E. & Swaroop, A. Next-generation sequencing facilitates quantitative analysis of wild-type and Nrl−/− retinal transcriptomes. Mol. Vis. 17, 3034–3054 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Strunnikova, N.V. et al. Transcriptome analysis and molecular signature of human retinal pigment epithelium. Hum. Mol. Genet. 19, 2468–2486 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Hindorff, L.A. et al. Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. Proc. Natl. Acad. Sci. USA 106, 9362–9367 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  47. Subramanian, A. et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl. Acad. Sci. USA 102, 15545–15550 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Manolio, T.A. et al. Finding the missing heritability of complex diseases. Nature 461, 747–753 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. So, H.C., Gui, A.H., Cherny, S.S. & Sham, P.C. Evaluating the heritability explained by known susceptibility variants: a survey of ten complex diseases. Genet. Epidemiol. 35, 310–317 (2011).

    Article  PubMed  Google Scholar 

  50. Seddon, J.M., Reynolds, R., Yu, Y., Daly, M.J. & Rosner, B. Risk models for progression to advanced age-related macular degeneration using demographic, environmental, genetic, and ocular factors. Ophthalmology 118, 2203–2211 (2011).

    Article  PubMed  Google Scholar 

  51. Devlin, B. & Roeder, K. Genomic control for association studies. Biometrics 55, 997–1004 (1999).

    Article  CAS  PubMed  Google Scholar 

  52. Wallace, C. et al. The imprinted DLK1-MEG3 gene region on chromosome 14q32.2 alters susceptibility to type 1 diabetes. Nat. Genet. 42, 68–71 (2010).

    Article  CAS  PubMed  Google Scholar 

  53. Huang, L. et al. Genotype-imputation accuracy across worldwide human populations. Am. J. Hum. Genet. 84, 235–250 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Purcell, S. et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559–575 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Aulchenko, Y.S., Struchalin, M.V. & van Duijn, C.M. ProbABEL package for genome-wide association analysis of imputed data. BMC Bioinformatics 11, 134 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Zeger, S.L. & Liang, K.Y. Longitudinal data analysis for discrete and continuous outcomes. Biometrics 42, 121–130 (1986).

    Article  CAS  PubMed  Google Scholar 

  57. R Core Team. R: A Language and Environment for Statistical Computing (R Foundation for Statistical Computing, Vienna, 2012).

  58. International HapMap Consortium. Integrating common and rare genetic variation in diverse human populations. Nature 467, 52–58 (2010).

  59. Nyholt, D.R. A simple correction for multiple testing for single-nucleotide polymorphisms in linkage disequilibrium with each other. Am. J. Hum. Genet. 74, 765–769 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. 1000 Genomes Project Consortium. An integrated map of genetic variation from 1,092 human genomes. Nature 491, 56–65 (2012).

  61. Wang, K., Li, M. & Hakonarson, H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res. 38, e164 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Lee, P.H., O'Dushlaine, C., Thomas, B. & Purcell, S.M. INRICH: interval-based enrichment analysis for genome-wide association studies. Bioinformatics 28, 1797–1799 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We are indebted to all the participants who volunteered their time, DNA and information to make this research study possible. We are also in great debt to the clinicians, nurses and research staff who participated in patient recruitment and phenotyping. We thank H. Chin for constant support and encouragement, which helped us bring this project to completion. We thank S. Miller and J. Barb for access to RPE expression data and the MIGEN study group for use of their genotype data. We thank C. Pappas, N. Miller, J. Hageman, W. Hubbard, L. Lucci, A. Vitale, P. Bernstein and N. Amin for technical and clinical assistance. We thank E. Rochtchina, A.C. Viswanathan, J. Xie, M. Inouye, E.G. Holliday, J. Attia and R.J. Scott for contributions to the Blue Mountains Eye Study GWAS. We thank members of the Genetic Factors in AMD Study Group, the Scottish Macula Society Study Group and the Wellcome Trust Clinical Research facility at Southampton General Hospital. We thank T. Peto and colleagues at the Reading Centre, Moorfields Eye Hospital and C. Brussee and A. Hooghart for help in patient recruitment and phenotyping. Full details of funding sources can be found in the Supplementary Note.

Author information

Authors and Affiliations

Consortia

Contributions

AMD Gene Analysis Committee: L.G.F., W.C., M.S., B.L.Y., Y.Y., L.A.F., I.M.H. (co-lead) and G.R.A. (co-lead). AMD Gene Phenotype Committee: R.K., C.C.W.K., T.L., J.M.S. (lead) and J.J.W. (co-lead). AMD Gene Steering Committee: B.H.F.W. (chair, senior executive committee), G.R.A. (senior executive committee), M.M.D. (senior executive committee), J.L.H. (senior executive committee), S.K.I. (senior executive committee), M.A.P.-V. (senior executive committee), R.A., P.N. Baird, C.C.W.K., B.E.K.K., M.L.K., M.K., T.L., J.M.S., U.T., D.E.W., J.R.W.Y. and K.Z. AMD-EU-JHU: D.J.Z., I.A., M. Benchaboune, A.C.B., P.A.C., I.C., F.G.H., Y. Kamatani, N.K., A.J.L., S.M.-S., O.P., R. Ripp, J.-A.S., H.P.N.S., E.H.S., A.R.W., D.Z., G.M.L. and T.L. contributed phenotypes, genotypes and analyses for the AMD-EU-JHU study. BDES: R.P.I., B.E.K.K., R.K., K.E.L., C.E.M., T.A.S., B.J.T. and S.K.I. contributed phenotypes, genotypes and analyses for the BDES study. Blue Mountains Eye Study: X.S., P.M., T.Y.W. and J.J.W. contributed phenotypes, genotypes and analyses for BMES. BU/Utah: M.S., G.S.H., G.J., I.K.K., D.J.M., M.A.M., C.P., K.H.P., D.A.S., G.S., E.E.T., M.M.D. and L.A.F. contributed phenotypes, genotypes and analyses for the BU/Utah study. CCF/VAMC: S.A.H., P.J., G.J.T.P., N.S.P., G.M.S.-S., R.P.I. and S.K.I. contributed phenotypes, genotypes and analyses for the CCF/VAMC study. CEI: P.J.F. and M.L.K. contributed phenotypes, genotypes and analyses for the CEI study. Columbia: J.E.M., G.R.B., R.T.S. and R.A. contributed phenotypes, genotypes and analyses for the Columbia study. deCODE: A.G., G.T., H. Sigurdsson, H. Stefansson, K.S. and U.T. contributed phenotypes, genotypes and analyses for the deCODE study. Japan Age-Related Eye Diseases Study: S.A., T.I., Y. Kiyohara, Y.N., Y.O., A.T. and M.K. contributed phenotypes, genotypes and analyses for JAREDS. Melbourne: R.H.G., M.S.C., A.J.R. and P.N. Baird contributed phenotypes, genotypes and analyses for the Melbourne study. Miami/Vanderbilt: B.L.Y., A.A., W.H.C., J.L.K., A.C.N., S.G.S., W.K.S., M.A.P.-V. and J.L.H. contributed phenotypes, genotypes and analyses for the Miami/Vanderbilt study. MMAP/NEI: W.C., K.E.B., M. Brooks, A.J.B., C.-C.C., E.Y.C., R.C., A.O.E., J.S.F., N.G., J.R.H., A.O., M.I.O., R.R.P., E.R., D.E.S., N.T., A.S. and G.R.A. contributed phenotypes, genotypes and analyses for the MMAP/NEI study. Rotterdam: G.H.S.B., A.G.U., C.M.v.D., J.R.V. and C.C.W.K. contributed phenotypes, genotypes and analyses for the Rotterdam study. SAGE: T.A., C.-Y.C., B.K.C. and E.N.V. contributed phenotypes, genotypes and analyses for the SAGE study. Southern German AMD Study: L.G.F., C.G., C.H., C.N.K., P.L., T.M., G.R., H.-E.W., T.W.W., B.H.F.W. and I.M.H. contributed phenotypes, genotypes and analyses for the Southern German AMD Study. Tufts/Massachusetts General Hospital: Y.Y., S.R., K.A.C., M.J.D., E.E., J.F., J.P.A.I., R. Reynolds, L.S. and J.M.S. contributed phenotypes, genotypes and analyses for the Tufts/MGH study. UK Cambridge/Edinburgh: V.C., A.M.A., P.N. Bishop, D.G.C., B.D., S.P.H., J.C.K., A.T.M., H. Shahid, A.F.W. and J.R.W.Y. contributed phenotypes, genotypes and analyses for the UK Cambridge/Edinburgh study. University of Pittsburgh/UCLA: D.E.W., Y.P.C., M.C.O. and M.B.G. contributed phenotypes, genotypes and analyses for the University of Pittsburgh/UCLA study. UCSD: G. Hannum, H.A.F., G. Hughes, I.K., C.J.L., M.Z., L.Z. and K.Z. contributed phenotypes, genotypes and analyses for the USCD study. VRF: R.J.G., L.V., R.P.I. and S.K.I. contributed phenotypes, genotypes and analyses for the VRF study. Gene expression and RNA sequencing data: data were contributed and analyzed by M. Brooks, J.S.F., N.G., R.R.P. and A.S.

Corresponding authors

Correspondence to Jonathan L Haines, Lindsay A Farrer, Iris M Heid or Gonçalo R Abecasis.

Ethics declarations

Competing interests

A.A., G.R.A., K.E.B., V.C., Y.P.C., M.J.D., A.O.E., L.G.F., M.B.G., J.L.H., A.T.M., D.A.S., W.K.S., J.M.S., A.S., B.H.F.W., D.E.W. and J.R.W.Y. are coinventors or beneficiaries of patents related to genetic discoveries in AMD. J.L.H. and M.M.D. are shareholders in ArcticDX. S.G.S. is a consultant for Alimera, Bausch + Lomb, Eyetech and ThromboGenics and receives royalties from IC Labs. U.T., K.S., G.T. and H. Stefansson are affiliated and/or employed by deCODE Genetics and own stock and/or stock options in the company. H.P.N.S. is on advisory boards for Sanofi-Fovea and AMD Therapy Fund and on the safety monitoring board of StemCells Inc. P.M. is on advisory boards for Allergan, Bayer, Novartis, Pfizer and Solvay and has received travel, honorarium and research support from these companies; he has no stock, equity, contract of employment or named position on company boards.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–4, Supplementary Tables 1–11 and Supplemetnary Note (PDF 2644 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

The AMD Gene Consortium. Seven new loci associated with age-related macular degeneration. Nat Genet 45, 433–439 (2013). https://doi.org/10.1038/ng.2578

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng.2578

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing