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.

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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


  1. Division of Genetics, Brigham and Women's Hospital, Boston, Massachusetts, USA.

    • Soumya Raychaudhuri
  2. Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Boston, Massachusetts, USA.

    • Soumya Raychaudhuri
  3. Partners HealthCare Center for Personalized Genetic Medicine, Boston, Massachusetts, USA.

    • Soumya Raychaudhuri
    • , Oleg Iartchouk
    • , Sivakumar Gowrisankar
    • , Soumya Vemuri
    •  & Kate Montgomery
  4. Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.

    • Soumya Raychaudhuri
    • , Stephan Ripke
    •  & Mark J Daly
  5. Ophthalmic Epidemiology and Genetics Service, New England Eye Center, Tufts Medical Center, Boston, Massachusetts, USA.

    • Kimberly Chin
    • , Yi Yu
    • , Robyn Reynolds
    •  & Johanna M Seddon
  6. Center for Human Disease Modeling, Department of Cell Biology, Duke University, Durham, North Carolina, USA.

    • Perciliz L Tan
    •  & Nicholas Katsanis
  7. Department of Pediatrics, Duke University, Durham, North Carolina, USA.

    • Perciliz L Tan
    •  & Nicholas Katsanis
  8. Study Center on the Immunogenetics of Infectious Disease, Department of Pathology, Tufts University School of Medicine, Boston, Massachusetts, USA.

    • Albert K Tai
  9. Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Stephan Ripke
    •  & Mark J Daly
  10. McKusick-Nathans Institute of Genetic Medicine, Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

    • Donald J Zack
    • , Betsy Campochiaro
    •  & Peter Campochiaro
  11. Department of Ophthalmology, Tufts University School of Medicine, Boston, Massachusetts, USA.

    • Johanna M Seddon


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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.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Soumya Raychaudhuri or Johanna M Seddon.

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    Polymorphic variants from high throughput sequencing of CFH in 33 cases and 27 controls

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