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.
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Wong, T.Y. et al. The natural history and prognosis of neovascular age-related macular degeneration. Ophthalmology 115, 116–126 (2008).
Yuzawa, M. et al. Report on the nationwide epidemiological survey of exudative age-related macular degeneration in Japan. Int. Ophthalmol. 21, 1–3 (1997).
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).
Kawasaki, R. et al. The prevalence of age-related macular degeneration in Asians. A systematic review and meta-analysis. Ophthalmology 117, 921–927 (2010).
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).
Ding, X., Patel, M. & Chan, C.C. Molecular pathology of the age-related macular degeneration. Prog. Retin. Eye Res. 28, 1–18 (2009).
Klein, R.J. et al. Complement factor H polymorphism in age-related macular degeneration. Science 308, 385–389 (2005).
Dewan, A. et al. HTRA1 promoter polymorphism in wet age-related macular degeneration. Science 314, 989–992 (2006).
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).
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).
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).
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).
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).
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).
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).
Spencer, K.L. et al. C3 R102G polymorphism increases risk of age-related macular degeneration. Hum. Mol. Genet. 17, 1821–1824 (2008).
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).
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).
Strunnikova, N.V. et al. Transcriptome analysis and molecular signature of human retinal pigment epithelium. Hum. Mol. Genet. 19, 2468–2486 (2010).
Parapuram, S.K. et al. Distinct signature of altered homeostasis in aging rod photoreceptors: implications for retinal diseases. PLoS ONE 5, e13885 (2010).
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).
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).
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).
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).
Wang, M. et al. Genetic variants in the death receptor 4 gene contribute to susceptibility to bladder cancer. Mutat. Res. 661, 85–92 (2009).
Parihar, A., Parihar, M.S., Chen, Z. & Ghafourifar, P. mAtNOS1 induces apoptosis of human mammary adenocarcinoma cells. Life Sci. 82, 1077–1082 (2008).
Yannuzzi, L.A. et al. Polypoidal choroidal vasculopathy and neovascularized age-related macular degeneration. Arch. Ophthalmol. 117, 1503–1510 (1999).
Yannuzzi, L.A. et al. Retinal angiomatous proliferation in age-related macular degeneration. Retina 21, 416–434 (2001).
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).
Matsumoto, H., Sato, T. & Kishi, S. Tomographic features of intraretinal neovascularization in retinal angiomatous proliferation. Retina 30, 425–430 (2010).
Nakamura, Y. The BioBank Japan Project. Clin. Adv. Hematol. Oncol. 5, 696–697 (2007).
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).
Ohnishi, Y. et al. A high-throughput SNP typing system for genome-wide association studies. J. Hum. Genet. 46, 471–477 (2001).
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).
Barrett, J.C., Fry, B., Maller, J. & Daly, M.J. Haploview: analysis and visualization of LD and haplotype maps. Bioinfomatics 21, 263–265 (2005).
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.
The authors declare no competing financial interests.
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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
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