TY - JOUR
T1 - A rare penetrant mutation in CFH confers high risk of age-related macular degeneration
AU - Raychaudhuri, Soumya
AU - Iartchouk, Oleg
AU - Chin, Kimberly
AU - Tan, Perciliz L.
AU - Tai, Albert K.
AU - Ripke, Stephan
AU - Gowrisankar, Sivakumar
AU - Vemuri, Soumya
AU - Montgomery, Kate
AU - Yu, Yi
AU - Reynolds, Robyn
AU - Zack, Donald J.
AU - Campochiaro, Betsy
AU - Campochiaro, Peter
AU - Katsanis, Elias Nicholas
AU - Daly, Mark J.
AU - Seddon, Johanna M.
N1 - Funding Information:
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.
PY - 2011/12
Y1 - 2011/12
N2 - 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.
AB - 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.
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U2 - 10.1038/ng.976
DO - 10.1038/ng.976
M3 - Article
C2 - 22019782
AN - SCOPUS:82255162545
VL - 43
SP - 1232
EP - 1236
JO - Nature Genetics
JF - Nature Genetics
SN - 1061-4036
IS - 12
ER -