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