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

Soumya Raychaudhuri, Oleg Iartchouk, Kimberly Chin, Perciliz L. Tan, Albert K. Tai, Stephan Ripke, Sivakumar Gowrisankar, Soumya Vemuri, Kate Montgomery, Yi Yu, Robyn Reynolds, Donald J. Zack, Betsy Campochiaro, Peter Campochiaro, Nicholas Katsanis, Mark J. Daly, Johanna M. Seddon

Research output: Contribution to journalArticlepeer-review

217 Scopus citations


Two common variants in the gene encoding complement factor H (CFH), the Y402H substitution (rs1061170, c.1204C>T) and the intronic rs1410996 SNP, 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 binding. 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.

Original languageEnglish (US)
Pages (from-to)1232-1236
Number of pages5
JournalNature genetics
Issue number12
StatePublished - Dec 2011

ASJC Scopus subject areas

  • Genetics


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