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, Nicholas
AU - Daly, Mark J.
AU - Seddon, Johanna M.
N1 - K08 AR055688-01A1S1, NIAMS NIH HHS, United StatesK08 AR055688-04, NIAMS NIH HHS, United StatesK08AR055688-01A1, NIAMS NIH HHS, United StatesR01-EY11309, NEI NIH HHS, United StatesR01HL087676, NHLBI NIH HHS, United StatesU01 MH085520-01, NIMH NIH HHS, United States
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. © 2011 Nature America, Inc. All rights reserved.
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. © 2011 Nature America, Inc. All rights reserved.
U2 - 10.1038/ng.976
DO - 10.1038/ng.976
M3 - Article
C2 - 22019782
SN - 1061-4036
VL - 43
SP - 1232
EP - 1236
JO - Nature Genetics
JF - Nature Genetics
IS - 12
ER -