TY - JOUR
T1 - A 32 kb critical region excluding Y402H in CFH mediates risk for age-related macular degeneration
AU - Sivakumaran, Theru A.
AU - Igo, Robert P.
AU - Kidd, Jeffrey M.
AU - Itsara, Andy
AU - Kopplin, Laura J.
AU - Chen, Wei
AU - Hagstrom, Stephanie A.
AU - Peachey, Neal S.
AU - Francis, Peter J.
AU - Klein, Michael L.
AU - Chew, Emily Y.
AU - Ramprasad, Vedam L.
AU - Tay, Wan Ting
AU - Mitchell, Paul
AU - Seielstad, Mark
AU - Stambolian, Dwight E.
AU - Edwards, Albert O.
AU - Lee, Kristine E.
AU - Leontiev, Dmitry V.
AU - Jun, Gyungah
AU - Wang, Yang
AU - Tian, Liping
AU - Qiu, Feiyou
AU - Henning, Alice K.
AU - LaFramboise, Thomas
AU - Sen, Parveen
AU - Aarthi, Manoharan
AU - George, Ronnie
AU - Raman, Rajiv
AU - Das, Manmath Kumar
AU - Vijaya, Lingam
AU - Kumaramanickavel, Govindasamy
AU - Wong, Tien Y.
AU - Swaroop, Anand
AU - Abecasis, Goncalo R.
AU - Klein, Ronald
AU - Klein, Barbara E.K.
AU - Nickerson, Deborah A.
AU - Eichler, Evan E.
AU - Iyengar, Sudha K.
PY - 2011/10/12
Y1 - 2011/10/12
N2 - 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.
AB - 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.
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U2 - 10.1371/journal.pone.0025598
DO - 10.1371/journal.pone.0025598
M3 - Article
C2 - 22022419
AN - SCOPUS:80053938930
SN - 1932-6203
VL - 6
JO - PLoS One
JF - PLoS One
IS - 10
M1 - e25598
ER -