Genetic variants near TIMP3 and high-density lipoprotein-associated loci influence susceptibility to age-related macular degeneration

Wei Chen, Dwight Stambolian, Albert O. Edwards, Kari E. Branham, Mohammad Othman, Johanna Jakobsdottir, Nirubol Tosakulwong, Margaret A. Pericak-Vance, Peter A. Campochiaro, Michael L. Klein, Perciliz L. Tan, Yvette P. Conley, Atsuhiro Kanda, Laura Kopplin, Yanming Li, Katherine J. Augustaitis, Athanasios J. Karoukis, William K. Scott, Anita Agarwal, Jaclyn L. KovachStephen G. Schwartz, Eric A. Postel, Matthew Brooks, Keith H. Baratz, William L. Brown, Alexander J. Brucker, Anton Orlin, Gary Brown, Allen Ho, Carl Regillo, Larry Donoso, Lifeng Tian, Brian Kaderli, Dexter Hadley, Stephanie A. Hagstrom, Neal S. Peachey, Ronald Klein, Barbara E.K. Klein, Norimoto Gotoh, Kenji Yamashiro, Frederick Ferris, Jesen A. Fagerness, Robyn Reynolds, Lindsay A. Farrer, Ivana K. Kim, Joan W. Miller, Marta Cortón, Angel Carracedo, Manuel Sanchez-Salorio, Elizabeth W. Pugh, Kimberly F. Doheny, Maria Brion, Margaret M. DeAngelis, Daniel E. Weeks, Donald J. Zack, Emily Y. Chew, John R. Heckenlively, Nagahisa Yoshimura, Sudha K. Iyengar, Peter J. Francis, Nicholas Katsanis, Johanna M. Seddon, Jonathan L. Haines, Michael B. Gorin, Gonçalo R. Abecasis, Anand Swaroop

Research output: Contribution to journalArticlepeer-review

390 Scopus citations


We executed a genome-wide association scan for age-related macular degeneration (AMD) in 2,157 cases and 1,150 controls. Our results validate AMD susceptibility loci near CFH (P < 10-75), ARMS2 (P < 10 -59), C2/CFB (P < 10-20), C3 (P < 10-9), and CFI (P < 10-6). We compared our top findings with the Tufts/Massachusetts General Hospital genome-wide association study of advanced AMD (821 cases, 1,709 controls) and genotyped 30 promising markers in additional individuals (up to 7,749 cases and 4,625 controls). With these data, we identified a susceptibility locus near TIMP3 (overall P = 1.1 x 10 -11), a metalloproteinase involved in degradation of the extracellular matrix and previously implicated in early-onset maculopathy. In addition, our data revealed strong association signals with alleles at two loci (LIPC, P = 1.3 x 10-7; CETP, P = 7.4 x 10-7) that were previously associated with high-density lipoprotein cholesterol (HDL-c) levels in blood. Consistent with the hypothesis that HDL metabolism is associated with AMD pathogenesis, we also observed association with AMD of HDL-c - associated alleles near LPL (P = 3.0 x 10-3) and ABCA1 (P = 5.6 x 10 -4). Multilocus analysis including all susceptibility loci showed that 329 of 331 individuals (99%) with the highest-risk genotypes were cases, and 85% of these had advanced AMD. Our studies extend the catalog of AMD associated loci, help identify individuals at high risk of disease, and provide clues about underlying cellular pathways that should eventually lead to new therapies.

Original languageEnglish (US)
Pages (from-to)7401-7406
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number16
StatePublished - Apr 20 2010


  • Genome-wide association study
  • Single nucleotide polymorphism

ASJC Scopus subject areas

  • General


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