by Theru A. Sivakumaran, Robert P. Igo, Jeffrey M. Kidd, Andy Itsara, Laura J. Kopplin, Wei Chen, Stephanie A. Hagstrom, Neal S. Peachey, Peter J. Francis, Michael L. Klein, Emily Y. Chew, Vedam L. Ramprasad, Wan-Ting Tay, Paul Mitchell, Mark Seielstad, Dwight E. Stambolian, Albert O. Edwards, Kristine E. Lee, Dmitry V. Leontiev, Gyungah Jun, Yang Wang, Liping Tian, Feiyou Qiu, Alice K. Henning, Thomas LaFramboise, Parveen Sen, Manoharan Aarthi, Ronnie George, Rajiv Raman, Manmath Kumar Das, Lingam Vijaya, Govindasamy Kumaramanickavel, Tien Y. Wong, Anand Swaroop, Goncalo R. Abecasis, Ronald Klein, Barbara E. K. Klein, Deborah A. Nickerson, Evan E. Eichler, Sudha K. Iyengar
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 ?CNP148. We conclude that causal variation in this region potentially encompasses both regulatory effects at single markers and copy number.