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Rare variants in CFI, C3 and C9 are associated with high risk of advanced age-related macular degeneration


To define the role of rare variants in advanced age-related macular degeneration (AMD) risk, we sequenced the exons of 681 genes within all reported AMD loci and related pathways in 2,493 cases and controls. We first tested each gene for increased or decreased burden of rare variants in cases compared to controls. We found that 7.8% of AMD cases compared to 2.3% of controls are carriers of rare missense CFI variants (odds ratio (OR) = 3.6; P = 2 × 10−8). There was a predominance of dysfunctional variants in cases compared to controls. We then tested individual variants for association with disease. We observed significant association with rare missense alleles in genes other than CFI. Genotyping in 5,115 independent samples confirmed associations with AMD of an allele in C3 encoding p.Lys155Gln (replication P = 3.5 × 10−5, OR = 2.8; joint P = 5.2 × 10−9, OR = 3.8) and an allele in C9 encoding p.Pro167Ser (replication P = 2.4 × 10−5, OR = 2.2; joint P = 6.5 × 10−7, OR = 2.2). Finally, we show that the allele of C3 encoding Gln155 results in resistance to proteolytic inactivation by CFH and CFI. These results implicate loss of C3 protein regulation and excessive alternative complement activation in AMD pathogenesis, thus informing both the direction of effect and mechanistic underpinnings of this disorder.

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Figure 1: CFI burden of rare coding variants is greater in cases.
Figure 2: Burden of CFI rare variants.
Figure 3: C3 Gln155 confers resistance to cofactor activity.


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We thank the participants and numerous ophthalmologists throughout the country who took part in this study as well as the Age-Related Eye Disease Study Research Group. This research was supported in part by grants R01-EY11309 (J.M.S.), K08AR055688 (S.R.), U01HG0070033 (S.R.), F30HL103072 (M.T.) and R01-AI041592 (J.P.A. and E.C.M.) from the US National Institutes of Health (NIH); The Doris Duke Foundation (S.R.); the Edward N. & Della L. Thome Memorial Foundation (J.P.A.); the Massachusetts Lions Eye Research Fund, Inc. (J.M.S.); the Foundation Fighting Blindness (J.M.S.); the Macular Vision Research Foundation (J.M.S.); a Research to Prevent Blindness Challenge Grant to the New England Eye Center, Department of Ophthalmology, Tufts University School of Medicine; the American Macular Degeneration Foundation (J.M.S.); The Arnold and Mabel Beckman Initiative for Macular Research (J.M.S. and S.R.); and the Macular Degeneration Research Fund of the Ophthalmic Epidemiology and Genetics Service, New England Eye Center, Tufts Medical Center, Tufts University School of Medicine. N.K. is a Distinguished Brumley Professor. D.K. is a Wellcome Intermediate Clinical Fellow. We thank the French national Programme Hospitalier de Recherche Clinique (PHRC; E.S.).

Author information




J.M.S. and S.R. led the study. J.M.S., Y.Y., R.R., P.L.T., J.Z., E.S. and N.K. coordinated sequencing and genotyping. E.C.M., M.T., H.E.A., D.K. and J.P.A. conducted and interpreted complement functional studies. Y.Y., J.I.G., S.G., M.J.D. and S.R. conducted all statistical analyses.

Corresponding authors

Correspondence to Johanna M Seddon or Soumya Raychaudhuri.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–14 and Supplementary Tables 1 and 3–7 (PDF 2650 kb)

Supplementary Table 2

(a) Results of burden tests for 681 genes targeted for sequencing. (b) Results of testing 1,824 single variants for association. (XLSX 387 kb)

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Seddon, J., Yu, Y., Miller, E. et al. Rare variants in CFI, C3 and C9 are associated with high risk of advanced age-related macular degeneration. Nat Genet 45, 1366–1370 (2013).

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