A 32 kb critical region excluding Y402H in CFH mediates risk for age-related macular degeneration.
Complement factor H shows very strong association with Age-related Macular Degeneration (AMD), and recent data suggest that multiple causal variants are associated with disease. To refine the location of the disease associated variants, we characterized in detail the structural variation at CFH and its paralogs, including two copy number polymorphisms (CNP), CNP147 and CNP148, and several rare deletions and duplications. Examination of 34 AMD-enriched extended families (N = 293) and AMD cases (White N = 4210 Indian = 134; Malay = 140) and controls (White N = 3229; Indian = 117; Malay = 2390) demonstrated that deletion CNP148 was protective against AMD, independent of SNPs at CFH. Regression analysis of seven common haplotypes showed three haplotypes, H1, H6 and H7, as conferring risk for AMD development. Being the most common haplotype H1 confers the greatest risk by increasing the odds of AMD by 2.75-fold (95% CI = [2.51, 3.01]; p = 8.31×10(-109)); Caucasian (H6) and Indian-specific (H7) recombinant haplotypes increase the odds of AMD by 1.85-fold (p = 3.52×10(-9)) and by 15.57-fold (P = 0.007), respectively. We identified a 32-kb region downstream of Y402H (rs1061170), shared by all three risk haplotypes, suggesting that this region may be critical for AMD development. Further analysis showed that two SNPs within the 32 kb block, rs1329428 and rs203687, optimally explain disease association. rs1329428 resides in 20 kb unique sequence block, but rs203687 resides in a 12 kb block that is 89% similar to a noncoding region contained in ΔCNP148. We conclude that causal variation in this region potentially encompasses both regulatory effects at single markers and copy number.
Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio, United States of America.
Theru A
TA
Sivakumaran
Robert P
RP
Igo
Jeffrey M
JM
Kidd
Andy
A
Itsara
Laura J
LJ
Kopplin
Wei
W
Chen
Stephanie A
SA
Hagstrom
Neal S
NS
Peachey
Peter J
PJ
Francis
Michael L
ML
Klein
Emily Y
EY
Chew
Vedam L
VL
Ramprasad
Wan-Ting
WT
Tay
Paul
P
Mitchell
Mark
M
Seielstad
Dwight E
DE
Stambolian
Albert O
AO
Edwards
Kristine E
KE
Lee
Dmitry V
DV
Leontiev
Gyungah
G
Jun
Yang
Y
Wang
Liping
L
Tian
Feiyou
F
Qiu
Alice K
AK
Henning
Thomas
T
LaFramboise
Parveen
P
Sen
Manoharan
M
Aarthi
Ronnie
R
George
Rajiv
R
Raman
Manmath Kumar
MK
Das
Lingam
L
Vijaya
Govindasamy
G
Kumaramanickavel
Tien Y
TY
Wong
Anand
A
Swaroop
Goncalo R
GR
Abecasis
Ronald
R
Klein
Barbara E K
BE
Klein
Deborah A
DA
Nickerson
Evan E
EE
Eichler
Sudha K
SK
Iyengar
D020029:Base Pairing / Q000235:genetics*; D001483:Base Sequence; D015331:Cohort Studies; D017242:Complement Factor H / Q000235:genetics*; D056915:DNA Copy Number Variations / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008268:Macular Degeneration / Q000235:genetics*; D008969:Molecular Sequence Data; D005810:Multigene Family / Q000235:genetics; D009154:Mutation / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012015:Reference Standards; D015203:Reproducibility of Results; D012307:Risk Factors
D017242:Complement Factor H