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


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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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).

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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

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.

Correspondence to Michiaki Kubo.

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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).

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