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.

Genome-wide association study identifies two susceptibility loci for exudative age-related macular degeneration in the Japanese population

Abstract

Age-related macular degeneration (AMD), the leading cause of irreversible blindness in the world, is a complex disease caused by multiple environmental and genetic risk factors. To identify genetic factors that modify the risk of exudative AMD in the Japanese population, we conducted a genome-wide association study and a replication study using a total of 1,536 individuals with exudative AMD and 18,894 controls. In addition to CFH (rs800292, P = 4.23 × 10−15) and ARMS2 (rs3750847, P = 8.67 × 10−29) loci, we identified two new susceptibility loci for exudative AMD: TNFRSF10A-LOC389641 on chromosome 8p21 (rs13278062, combined P = 1.03 × 10−12, odds ratio = 0.73) and REST-C4orf14-POLR2B-IGFBP7 on chromosome 4q12 (rs1713985, combined P = 2.34 × 10−8, odds ratio = 1.30). Fine mapping revealed that rs13278062, which is known to alter TNFRSF10A transcriptional activity, had the most significant association in 8p21 region. Our results provide new insights into the pathophysiology of exudative 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: Case-control association plots, LD map and genomic structure of the TNFRSF10A- LOC389641 region in chromosome 8p21 (a) and the REST-C4orf14-POLR2B-IGFBP7 region in chromosome 4q12 (b).

Accession codes

Accessions

Gene Expression Omnibus

References

  1. Wong, T.Y. et al. The natural history and prognosis of neovascular age-related macular degeneration. Ophthalmology 115, 116–126 (2008).

    Article  PubMed Central  Google Scholar 

  2. Yuzawa, M. et al. Report on the nationwide epidemiological survey of exudative age-related macular degeneration in Japan. Int. Ophthalmol. 21, 1–3 (1997).

    CAS  Article  PubMed Central  Google Scholar 

  3. Laude, A. et al. Polypoidal choroidal vasculopathy and neovascular age-related macular degeneration: same or different disease? Prog. Retin. Eye Res. 29, 19–29 (2010).

    Article  PubMed Central  Google Scholar 

  4. Kawasaki, R. et al. The prevalence of age-related macular degeneration in Asians. A systematic review and meta-analysis. Ophthalmology 117, 921–927 (2010).

    Article  PubMed Central  Google Scholar 

  5. Dunaief, J.L., Dentchev, T., Ying, G.S. & Milam, A.H. The role of apoptosis in age-related macular degeneration. Arch. Ophthalmol. 120, 1435–1442 (2002).

    Article  PubMed Central  Google Scholar 

  6. Ding, X., Patel, M. & Chan, C.C. Molecular pathology of the age-related macular degeneration. Prog. Retin. Eye Res. 28, 1–18 (2009).

    CAS  Article  PubMed Central  Google Scholar 

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

    CAS  Article  PubMed Central  Google Scholar 

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

    CAS  Article  PubMed Central  Google Scholar 

  9. 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).

    CAS  Article  Google Scholar 

  10. 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).

    CAS  Article  PubMed Central  Google Scholar 

  11. Goto, A. et al. Genetic analysis of typical wet-type age-related macular degeneration and polypoidal choroidal vasculopathy in Japanese population. J. Ocul. Biol. Dis. Infor. 2, 164–175 (2009).

    Article  PubMed Central  Google Scholar 

  12. Kopplin, L.J. et al. Genome-wide association identifies SKIV2L and MYRIP as protective factors for age-related macular degeneration. Genes Immun. 11, 609–621 (2010).

    CAS  Article  PubMed Central  Google Scholar 

  13. 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).

    CAS  Article  PubMed Central  Google Scholar 

  14. 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).

    CAS  Article  PubMed Central  Google Scholar 

  15. Montes, T., Tortajada, A., Morgan, B.P., Rodriguez de Cordoba, S. & Harris, C.L. Functional basis of protection against age-related macular degeneration conferred by a common polymorphism in complement factor B. Proc. Natl. Acad. Sci. USA 106, 4366–4371 (2009).

    CAS  Article  PubMed Central  Google Scholar 

  16. Spencer, K.L. et al. C3 R102G polymorphism increases risk of age-related macular degeneration. Hum. Mol. Genet. 17, 1821–1824 (2008).

    CAS  Article  PubMed Central  Google Scholar 

  17. 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).

    CAS  Article  PubMed Central  Google Scholar 

  18. Seddon, J.M., Santangelo, S.L., Book, K., Chong, S. & Cote, J. A genome-wide scan age-related macular degeneration provides evidence for linkage to several chromosomal regions. Am. J. Hum. Genet. 73, 780–790 (2003).

    CAS  Article  PubMed Central  Google Scholar 

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

    CAS  Article  PubMed Central  Google Scholar 

  20. Parapuram, S.K. et al. Distinct signature of altered homeostasis in aging rod photoreceptors: implications for retinal diseases. PLoS ONE 5, e13885 (2010).

    Article  PubMed Central  Google Scholar 

  21. Johnstone, R.W., Frew, A.J. & Smyth, M.J. The TRAIL apoptotic pathway in cancer onset, progression and therapy. Nat. Rev. Cancer 8, 782–798 (2008).

    CAS  Article  PubMed Central  Google Scholar 

  22. Chaudhary, P.M. et al. Death receptor 5, a new member of the TNFR family, and DR4 induce FADD-dependent apoptosis and activate the NF-B pathway. Immunity 7, 821–830 (1997).

    CAS  Article  Google Scholar 

  23. Li, J.H., Kirkiles-Smith, N.C., McNiff, J.M. & Pober, J.S. TRAIL induces apoptosis and inflammatory gene expression in human endothelial cells. J. Immunol. 171, 1526–1533 (2003).

    CAS  Article  PubMed Central  Google Scholar 

  24. Guan, B., Yue, P., Lotan, R. & Sun, S.Y. Evidence that the human death receptor 4 is regulated by activator protein 1. Oncogene 21, 3121–3129 (2002).

    CAS  Article  Google Scholar 

  25. Wang, M. et al. Genetic variants in the death receptor 4 gene contribute to susceptibility to bladder cancer. Mutat. Res. 661, 85–92 (2009).

    CAS  Article  PubMed Central  Google Scholar 

  26. Parihar, A., Parihar, M.S., Chen, Z. & Ghafourifar, P. mAtNOS1 induces apoptosis of human mammary adenocarcinoma cells. Life Sci. 82, 1077–1082 (2008).

    CAS  Article  PubMed Central  Google Scholar 

  27. Yannuzzi, L.A. et al. Polypoidal choroidal vasculopathy and neovascularized age-related macular degeneration. Arch. Ophthalmol. 117, 1503–1510 (1999).

    CAS  Article  PubMed Central  Google Scholar 

  28. Yannuzzi, L.A. et al. Retinal angiomatous proliferation in age-related macular degeneration. Retina 21, 416–434 (2001).

    CAS  Article  PubMed Central  Google Scholar 

  29. Sato, T., Kishi, S., Watanabe, G., Matsumoto, H. & Mukai, R. Tomographic features of branching vascular networks in polypoidal choroidal vasculopathy. Retina 27, 589–594 (2007).

    Article  PubMed Central  Google Scholar 

  30. Matsumoto, H., Sato, T. & Kishi, S. Tomographic features of intraretinal neovascularization in retinal angiomatous proliferation. Retina 30, 425–430 (2010).

    Article  PubMed Central  Google Scholar 

  31. Nakamura, Y. The BioBank Japan Project. Clin. Adv. Hematol. Oncol. 5, 696–697 (2007).

    Google Scholar 

  32. Yasuda, M. et al. Nine-year incidence and risk factors for age-related macular degeneration in a defined Japanese population: the Hisayama Study. Ophthalmology 116, 2135–2140 (2009).

    Article  PubMed Central  Google Scholar 

  33. Ohnishi, Y. et al. A high-throughput SNP typing system for genome-wide association studies. J. Hum. Genet. 46, 471–477 (2001).

    CAS  Article  Google Scholar 

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

    CAS  Article  PubMed Central  Google Scholar 

  35. Barrett, J.C., Fry, B., Maller, J. & Daly, M.J. Haploview: analysis and visualization of LD and haplotype maps. Bioinfomatics 21, 263–265 (2005).

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We thank all of the subjects who participated in this study. We are grateful to A. Yoshida, K. Kano, S. Kawahara, R. Arita, K. Ishikawa, E. Hasegawa, R. Asato, S. Notomi, T. Asakuma and A. Kuni of the Kyushu University, K. Horie-Inoue, S. Inoue and T. Awata of the Saitama Medical University, H. Bessho, N. Kondo and W. Matsumiya of the Kobe university and M. Inoue of the Yokohama City University Medical Center for collecting samples. We thank the staff of the Laboratory for Genotyping Development, Center for Genomic Medicine, RIKEN, the staffs of the BioBank Japan project and the members of the Rotary Club of Osaka-Midosuji District 2660 Rotary International in Japan. We want to express special thanks to F. Miya for the support of gene expression data. This work was conducted as a part of the BioBank Japan Project and supported by the Ministry of Education, Culture, Sports, Sciences and Technology of the Japanese government.

Author information

Authors and Affiliations

Authors

Contributions

S.A., T.I., Y.N. and M.K. designed the study. S.A., N.H., K.A., T.A. and M.K. performed genotyping. S.A. and M.K. wrote the manuscript. A.T. performed statistical analysis at the genome-wide phase. Y.N. and M.K. managed DNA samples belonging to BioBank Japan. T.I. and Y.N. obtained funding for the study. M.Y., Y.O., S.Y. and H.E. collected GWAS samples. T.T., K.M., S.H., A.N., A.A. and K.K. collected case samples for the replication study. Y.K., N.K., Y.N. and M.K. supervised the study.

Corresponding author

Correspondence to Michiaki Kubo.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–3 and Supplementary Tables 1–7. (PDF 1591 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Arakawa, S., Takahashi, A., Ashikawa, K. 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). https://doi.org/10.1038/ng.938

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng.938

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