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A rare nonsynonymous sequence variant in C3 is associated with high risk of age-related macular degeneration


Through whole-genome sequencing of 2,230 Icelanders, we detected a rare nonsynonymous SNP (minor allele frequency = 0.55%) in the C3 gene encoding a p.Lys155Gln substitution in complement factor 3, which, following imputation into a set of Icelandic cases with age-related macular degeneration (AMD) and controls, associated with disease (odds ratio (OR) = 3.45; P = 1.1 × 10−7). This signal is independent of the previously reported common SNPs in C3 encoding p.Pro314Leu and p.Arg102Gly that associate with AMD. The association of p.Lys155Gln was replicated in AMD case-control samples of European ancestry with OR = 4.22 and P = 1.6 × 10−10, resulting in OR = 3.65 and P = 8.8 × 10−16 for all studies combined. In vitro studies have suggested that the p.Lys155Gln substitution reduces C3b binding to complement factor H, potentially creating resistance to inhibition by this factor. This resistance to inhibition in turn is predicted to result in enhanced complement activation.

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Figure 1: Overview of the association in the C3 gene region.

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The authors would like to thank the individuals who participated in the study and whose contributions made this work possible. We thank our valued colleagues who contributed to data collection, sample handling, genotyping and data analysis. H.L., Y.D. and K.Z. are supported in part by 973 program grant 2013CB967504, National Science Foundation of China grant 81130017, the NEI/US National Institutes of Health and a Veterans Affairs Merit Award. The Dutch replication study was supported by the Netherlands Organization for Scientific Research (Vidi Innovational Research Award 016.096.309 to A.I.d.H.) and the Foundation Fighting Blindness (grant C-GE-0811-0548-RAD04 to A.I.d.H.).

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The study was designed and results interpreted by H.H., P.S., H. Stefansson, G.T., U.T. and K.S. H.H., P.S. and U.T. wrote the first draft and, together with I.J., D.F.G. and K.S. wrote the final version of the manuscript. Statistical analysis was carried out by H.H., P.S., G.T., D.F.G. and A.K. O.T.M. oversaw sequencing for the Icelandic cohort, and G.M. processed the raw sequencing data. Subject recruitment, phenotyping, biological material collection and handling, and genotyping were supervised and carried out by H. Stefansson, G.T., G.B.W., T. Rafnar, A.G., G.H., E.S., F.J., H. Sigurdsson, A.I.d.H., M.R.D., F.E.S.-K., C.J.F.B., S.F., T. Ristau, S.L., J.P.H.v.d.V., C.B.H., K.Z., H.L., L.Z., Y.S., M.P., S.P., H.F., Y.D. and P.S.B. Principal investigators and corresponding authors for the replication study populations are A.I.d.H. (the EUGENDA cohort), K.Z. (the US cohort) and L.A.K. (population controls from Nijmegen).

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Correspondence to Patrick Sulem or Kari Stefansson.

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The authors declare competing financial interests. H.H., P.S., G.T., H. Stefansson, I.J., G.M., D.F.G., G.B.W., O.T.M., A.K., T.R., U.T. and K.S. are employees of deCODE Genetics/Amgen.

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Helgason, H., Sulem, P., Duvvari, M. et al. A rare nonsynonymous sequence variant in C3 is associated with high risk of age-related macular degeneration. Nat Genet 45, 1371–1374 (2013).

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