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A rare penetrant mutation in CFH confers high risk of age-related macular degeneration


Two common variants in the gene encoding complement factor H (CFH), the Y402H substitution (rs1061170, c.1204C>T)1,2,3,4 and the intronic rs1410996 SNP5,6, explain 17% of age-related macular degeneration (AMD) liability. However, proof for the involvement of CFH, as opposed to a neighboring transcript, and knowledge of the potential mechanism of susceptibility alleles are lacking. Assuming that rare functional variants might provide mechanistic insights, we used genotype data and high-throughput sequencing to discover a rare, high-risk CFH haplotype with a c.3628C>T mutation that resulted in an R1210C substitution. This allele has been implicated previously in atypical hemolytic uremic syndrome, and it abrogates C-terminal ligand binding7,8. Genotyping R1210C in 2,423 AMD cases and 1,122 controls demonstrated high penetrance (present in 40 cases versus 1 control, P = 7.0 × 10−6) and an association with a 6-year-earlier onset of disease (P = 2.3 × 10−6). This result suggests that loss-of-function alleles at CFH are likely to drive AMD risk. This finding represents one of the first instances in which a common complex disease variant has led to the discovery of a rare penetrant mutation.

Figure 1: A rare CFH haplotype is associated with AMD risk.
Figure 2: Sequencing the H5 haplotype identifies an R1210C-encoding mutation.
Figure 3: The phenotype of the R1210C-encoding mutation.


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We appreciate the contribution to the research of J.M.S. of an anonymous donor. This research was supported in part by grants RO1-EY11309 (J.M.S.), K08AR055688-01A1 (S. Raychaudhuri) and U01 MH085520-01 (S. Ripke) from the US National Institutes of Health (NIH), and by the Massachusetts Lions Eye Research Fund, Inc., the American Macular Degeneration Research Fund, the Foundation Fighting Blindness, the Macular Vision Research Foundation, a Research to Prevent Blindness Challenge Grant to the New England Eye Center, Department of Ophthalmology, Tufts University School of Medicine, 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. The MIGen study was funded by grants from the NIH National Heart, Lung, and Blood Institute (NLBI) (R01HL087676) and the NIH National Center for Research Resources (NCRR). We acknowledge informal and helpful discussions from our colleagues B. Neale, R. Plenge, P. de Bakker, D. Reich, E. Stahl, B. Stranger and B. Voight.

Author information




S. Raychaudhuri, J.M.S., N.K. and M.J.D. conceptualized this study, wrote the initial manuscript and interpreted all results. S. Raychaudhuri oversaw the statistical analyses and coordinated collaborative experimental efforts. J.M.S. and M.J.D. oversaw genome-wide genotyping of the Boston-phased data. S. Ripke analyzed the genome-wide Boston-phased genotype data to assess population stratification and recent ancestry. J.M.S., K.C., R.R. and Y.Y. organized the Boston clinical cohort. B.C., P.C. and D.J.Z. organized the Baltimore clinical cohort. P.L.T. and N.K. genotyped the Baltimore samples. A.T. genotyped the Boston samples. O.I., S.G., S.V. and K.M. sequenced the CFH gene.

Corresponding authors

Correspondence to Soumya Raychaudhuri or Johanna M Seddon.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–5 and Supplementary Tables 1–3 and 5–8 (PDF 1266 kb)

Supplementary Table 4

Polymorphic variants from high throughput sequencing of CFH in 33 cases and 27 controls (XLSX 96 kb)

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Raychaudhuri, S., Iartchouk, O., Chin, K. et al. A rare penetrant mutation in CFH confers high risk of age-related macular degeneration. Nat Genet 43, 1232–1236 (2011).

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