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)(1-4) and the intronic rs1410996 SNP(5,6), 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 binding(7,8). 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.
Division of Genetics, Brigham and Women's Hospital, Boston, Massachusetts, USA. soumya@broadinstitute.org
Soumya
S
Raychaudhuri
Oleg
O
Iartchouk
Kimberly
K
Chin
Perciliz L
PL
Tan
Albert K
AK
Tai
Stephan
S
Ripke
Sivakumar
S
Gowrisankar
Soumya
S
Vemuri
Kate
K
Montgomery
Yi
Y
Yu
Robyn
R
Reynolds
Donald J
DJ
Zack
Betsy
B
Campochiaro
Peter
P
Campochiaro
Nicholas
N
Katsanis
Mark J
MJ
Daly
Johanna M
JM
Seddon
D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D017242:Complement Factor H / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006579:Heterozygote; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D015810:Linkage Disequilibrium; D008268:Macular Degeneration / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D019683:Penetrance; D020641:Polymorphism, Single Nucleotide; D025341:Principal Component Analysis; D012307:Risk Factors; D017422:Sequence Analysis, DNA
C493495:CFH protein, human; D017242:Complement Factor H