Genetic variants near <i>TIMP3</i> and high-density lipoprotein–associated loci influence susceptibility to age-related macular degeneration

Wei Chen(University of Michigan), Dwight Stambolian(University of Pennsylvania), Albert O. Edwards(Mayo Clinic in Arizona), Kari Branham(University of Michigan), Mohammad Othman(University of Michigan), Jóhanna Jakobsdóttir(University of Pittsburgh), Nirubol Tosakulwong(Mayo Clinic in Arizona), Margaret A. Pericak‐Vance(University of Miami), Peter A. Campochiaro(Johns Hopkins University), Michael L. Klein(Oregon Health & Science University), Perciliz L. Tan(Johns Hopkins University), Yvette P. Conley(University of Pittsburgh), Atsuhiro Kanda(National Eye Institute), Laura J. Kopplin(Case Western Reserve University), Yanming Li(University of Michigan), Katherine J. Augustaitis(University of Michigan), Athanasios J. Karoukis(University of Michigan), William K. Scott(University of Miami), Anita Agarwal(Vanderbilt University Medical Center), Jaclyn L. Kovach(University of Miami), Stephen G. Schwartz(University of Miami), Eric A. Postel(Duke Medical Center), Matthew Brooks(National Eye Institute), Keith H. Baratz(Mayo Clinic in Arizona), William L. Brown(Mayo Clinic in Arizona), Alexander J. Brucker(University of Pennsylvania), Anton Orlin(University of Pennsylvania), Gary C. Brown(Thomas Jefferson University), Allen C. Ho(Thomas Jefferson University), Carl D. Regillo(Thomas Jefferson University), Larry A. Donoso, Lifeng Tian(University of Pennsylvania), Brian Kaderli(University of Pennsylvania), Dexter Hadley(University of Pennsylvania), Stephanie A. Hagstrom(Cleveland Clinic), Neal S. Peachey(Cleveland Clinic), Ronald Klein(University of Wisconsin–Madison), Barbara E.K. Klein(University of Wisconsin–Madison), Norimoto Gotoh(Kyoto University), Kenji Yamashiro(Kyoto University), Frederick L. Ferris(National Institutes of Health), Jesen Fagerness(Broad Institute), Robyn Reynolds(Tufts University), Lindsay A. Farrer(Boston University), Ivana K. Kim(Massachusetts Eye and Ear Infirmary), Joan W. Miller(Massachusetts Eye and Ear Infirmary), Marta Cortón(Universidade de Santiago de Compostela), Ángel Carracedo(Universidade de Santiago de Compostela), Manuel Sánchez‐Salorio, Elizabeth Pugh(Johns Hopkins University), Kimberly F. Doheny(Johns Hopkins University), Marı́a Brión(Universidade de Santiago de Compostela), Margaret M. DeAngelis(Massachusetts Eye and Ear Infirmary), Daniel E. Weeks(University of Pittsburgh), Donald J. Zack(Johns Hopkins University), Emily Y. Chew(National Institutes of Health), John R. Heckenlively(University of Michigan), Nagahisa Yoshimura(Kyoto University), Sudha K. Iyengar(Case Western Reserve University), Peter J. Francis(Oregon Health & Science University), Nicholas Katsanis(Johns Hopkins University), Johanna M. Seddon(Tufts University), Jonathan L. Haines(Vanderbilt University Medical Center), Michael B. Gorin(University of California, Los Angeles), Gonçalo R. Abecasis(University of Michigan), Anand Swaroop(University of Michigan), Robert N. Johnson, Everett Ai(Vanderbilt University), H. Richard McDonald, Margaret Stolarczuk(Harvard University Press), Peter R. Pavan, Karina K. Billiris, Mohan Iyer, Matthew M. Menosky, Scott E. Pautler, Sharon M. Millard, G. Baker Hubbard, Thomas Aaberg, Lindy DuBois, Alice T. Lyon, Susan Anderson-Nelson, Lee M. Jampol, David V. Weinberg, Annie Muñana, Zuzanna Rozenbajgier, David H. Orth, Jack Cohen, Matthew MacCumber(National Institutes of Health), Matthew MacCumber(National Institutes of Health), Celeste Figliulo, Liz Porcz(Johns Hopkins University), James C. Folk, H. Culver Boldt, Stephen R. Russell, Rachel Ivins, Connie J. Hinz, Charles C. Barr, Steve Bloom, Ken Jaegers(University of Michigan), Brian Kritchman(University of Pennsylvania), Greg K. Whittington, Jeffrey S. Heier, Albert R. Frederick(National Institutes of Health), Michael G. Morley(University of California, Los Angeles), Trexler M. Topping, Heather L. Davis, Susan B. Bressler, Neil M. Bressler, W T Jr Doll, Michael T. Trese(University of California, Los Angeles), A. Capone, Bruce R. Garretson, T. Hassan, Alan Ruby, Tammy Osentoski, Colin A. McCannel, Margaret Ruszczyk, G. Grand, Kevin J. Blinder, Nancy M. Holekamp, Daniel P. Joseph, Gaurav K. Shah, Ginny Nobel, Andrew N. Antoszyk, David J. Browning, Alison H Stallings, Lawrence J. Singerman, David T. Miller(Harvard University Press), Michael Novák(University of California, Los Angeles), Scott Pendergast(University of Miami), Hernando Zegarra, Stephanie A. Schura(Cleveland Clinic), Sheila Smith-Brewer, Frederick H. Davidorf, Robert Chambers, Louis J. Chorich, Jill Salerno, Richard F. Dreyer, Colin Ma(Harvard University Press), Marcia Kopfer, Michael L. Klein(Oregon Health & Science University), David J. Wilson, Susan K. Nolte, Juan E. Grunwald, Alexander J. Brucker(University of Pennsylvania), Josh Dunaief, Stuart L. Fine, Albert M. Maguire, Robert A. Stoltz, Monique McRay, Gary E. Fish, Rajiv Anand(National Institutes of Health), Rand Spencer, Jean Arnwine, Suresh R. Chandra, Michael M. Altaweel(University of California, Los Angeles), Barbara Blodi(University of Wisconsin–Madison), Justin L. Gottlieb, Michael S. Ip(University of California, Los Angeles), T. Michael Nork, Jennie Perry-Raymond, Stuart L. Fine, Maureen G. Maguire, Mary Brightwell-Arnold, Sandra Harkins, Ellen Peskin, Gui‐Shuang Ying, Natalie Kurinij
Proceedings of the National Academy of Sciences
April 12, 2010
10.1073/pnas.0912702107
Cited by 514Open Access
Full Text

Abstract

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.

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