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Genetic Variants Near TIMP3 and High-Density Lipoprotein–Associated Loci Influence Susceptibility to Age-Related Macular Degeneration

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Genetic Variants Near TIMP3 and High-Density Lipoprotein–Associated Loci Influence Susceptibility to Age-Related Macular Degeneration Genetic variants near TIMP3 and high-density lipoprotein–associated loci influence susceptibility to age-related macular degeneration Wei Chena,1, Dwight Stambolianb,1, Albert O. Edwardsc,1, Kari E. Branhamd, Mohammad Othmand, Johanna Jakobsdottire, Nirubol Tosakulwongc, Margaret A. Pericak-Vancef, Peter A. Campochiarog, Michael L. Kleinh, Perciliz L. Tang, Yvette P. Conleye, Atsuhiro Kandai, Laura Kopplinj, Yanming Lia, Katherine J. Augustaitisd, Athanasios J. Karoukisd, William K. Scottf, Anita Agarwalk, Jaclyn L. Kovachf, Stephen G. Schwartzf, Eric A. Postell, Matthew Brooksi, Keith H. Baratzc, William L. Brownc, Complications of Age-Related Macular Degeneration Prevention Trial (CAPT) Research Groupm, Alexander J. Bruckern, Anton Orlinn, Gary Browno,p, Allen Hoo,p, Carl Regilloo,p, Larry Donosoq, Lifeng Tiann, Brian Kaderlin, Dexter Hadleyn, Stephanie A. Hagstromj,r, Neal S. Peacheyj,r,s, Ronald Kleint, Barbara E. K. Kleint, Norimoto Gotohu, Kenji Yamashirou, Frederick Ferris IIIv, Jesen A. Fagernessw, Robyn Reynoldsx, Lindsay A. Farrery, Ivana K. Kimz, Joan W. Millerz, Marta Cortónaa,bb, Angel Carracedobb, Manuel Sanchez-Saloriocc, Elizabeth W. Pughdd, Kimberly F. Dohenydd, Maria Brionaa,bb, Margaret M. DeAngelisz, Daniel E. Weekse, Donald J. Zackg, Emily Y. Chewv, John R. Heckenlivelyd, Nagahisa Yoshimurau, Sudha K. Iyengarj, Peter J. Francish, Nicholas Katsanisg, Johanna M. Seddonx,ee, Jonathan L. Hainesk, Michael B. Gorinff, Gonçalo R. Abecasisa,2, and Anand Swaroopd,i,2 aCenter for Statistical Genetics, Biostatistics, University of Michigan, Ann Arbor, MI 48109; bOphthalmology and Human Genetics, University of Pennsylvania, Philadelphia, PA 19104; cOphthalmology, Mayo Clinic, Rochester, MN 55906; dOphthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI 48105; eUniversity of Pittsburgh, Pittsburgh, PA 15260; fUniversity of Miami Miller School of Medicine, Miami, FL 31136; gJohns Hopkins University School of Medicine, Baltimore, MD 21205; hOregon Health and Science University, Portland, OR 97239; iNeurobiology-Neurodegeneration and Repair Laboratory, National Eye Institute, Bethesda, MD 20892; jCase Western Reserve University, Cleveland, OH 44106; kVanderbilt University Medical Center, Nashville, TN 37232; lDuke University Medical Center, Durham, NC 27705; mCAPT Coordinating Center, University of Pennsylvania, Philadelphia, PA 19104; nUniversity of Pennsylvania, Philadelphia, PA 19104; oMid-Atlantic Retina, Cherry Hill, NJ 08002; pThomas Jefferson University, Philadelphia, PA 19107; qPhiladelphia Retina Endowment Fund, Philadelphia, PA 19107; rCleveland Clinical Foundation, Cleveland, OH 44195; sLouis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, OH 44106; tUniversity of Wisconsin School of Medicine and Public Health, Madison, WI 53705; uKyoto University Graduate School of Medicine, Kyoto, 606-8501 Japan; vNational Eye Institute, Bethesda, MD 20892; wMassachusetts General Hospital and Broad Institute, Cambridge, MA 02114; xTufts Medical Center, Boston, MA 02111; yBoston University, Boston, MA 02215; zMassachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA 02114; aaComplexo Hospitalario Universitario de Santiago, 15706 Santiago de Compostela, Spain; bbUniversity of Santiago de Compostela, 15705 Santiago de Compostela, Spain; ccInstituto Gallego de Oftalmología, 15706 Santiago de Compostela, Spain; ddCenter for Inherited Disease Research, Johns Hopkins School of Medicine, Baltimore, MD 21287; eeTufts University School of Medicine, Boston, MA 02111; and ffUniversity of California, Los Angeles, CA 90095 Edited by Mark T. Keating, Novartis Institute for Biomedical Research, Cambridge, MA, and approved March 4, 2010 (received for review November 11, 2009) We executed a genome-wide association scan for age-related which is necessary for sharp central vision. An early hallmark of macular degeneration (AMD) in 2,157 cases and 1,150 controls. AMD is the appearance of drusen, which are extracellular Our results validate AMD susceptibility loci near CFH (P < 10−75), deposits of proteins and lipids under the retinal pigment epi- − − − ARMS2 (P < 10 59), C2/CFB (P < 10 20), C3 (P < 10 9), and CFI (P < thelium (RPE). As the disease progresses, drusen grow in size and − 10 6). We compared our top findings with the Tufts/Massachusetts number. In advanced stages of AMD, atrophy of the RPE (geo- General Hospital genome-wide association study of advanced AMD graphic atrophy) and/or development of new blood vessels GENETICS (821 cases, 1,709 controls) and genotyped 30 promising markers in (neovascularization) result in death of photoreceptors and central additional individuals (up to 7,749 cases and 4,625 controls). With vision loss. these data, we identified a susceptibility locus near TIMP3 (overall P = 1.1 × 10−11), a metalloproteinase involved in degradation of the extracellular matrix and previously implicated in early-onset Author contributions:W.C.,D.S.,A.O.E.,K.E.B.,M.O.,J.J.,N.T.,P.L.T., Y.P.C.,A.K.,L.K.,Y.L.,K.J.A., maculopathy. In addition, our data revealed strong association sig- A.J.K., W.K.S., A.A., J.L.K., S.G.S., E.A.P., M. Brooks, K.H.B., W.L.B., A.J.B., A.O., G.B., A.H., C.R., LIPC P × −7 CETP P × −7 L.D., L.T., B.K., D.H., B.E.K.K., F.F., J.A.F., E.W.P., K.F.D., M.M.D., D.E.W., D.J.Z., E.Y.C., J.R.H., S.K.I., nals with alleles at two loci ( , = 1.3 10 ; , = 7.4 10 ) P.J.F., N.K., J.M.S., J.L.H., M.B.G., G.R.A., and A.S. performed research; D.S., A.O.E., K.E.B., M.O., that were previously associated with high-density lipoprotein cho- G.R.A., and A.S. designed research; D.S., M.A.P.-V., P.A.C., M.L.K., A.K., L.K., CAPT Research lesterol (HDL-c) levels in blood. Consistent with the hypothesis that Group, S.A.H., N.S.P., R.K., N.G., K.Y., J.A.F., R.R., L.A.F., I.K.K., J.W.M., M.C., A.C., M.S.-S., HDL metabolism is associated with AMD pathogenesis, we also M. Brion, M.M.D., D.E.W., D.J.Z., N.Y., S.K.I., P.J.F., N.K., J.M.S., J.L.H., M.B.G., and A.S. contrib- — uted new reagents/analytic tools; W.C., J.J., N.T., L.K., Y.L., M. Brion, S.K.I., G.R.A., and A.S. observed association with AMD of HDL-c associated alleles near analyzed data; and W.C., D.S., A.O.E., G.R.A., and A.S. wrote the paper. LPL (P = 3.0 × 10−3) and ABCA1 (P = 5.6 × 10−4). Multilocus analysis Conflict of interest statement: A.O.E., J.J., M.A.P.-V., Y.P.C., A.K., W.K.S., A.A., E.A.P., M.M.D., including all susceptibility loci showed that 329 of 331 individuals D.E.W., J.M.S., J.L.H., M.B.G., G.R.A. and A.S. are listed as inventors on patents relating to (99%) with the highest-risk genotypes were cases, and 85% of these the use of genetic data in age-related macular degeneration. S.G.S. has previously received had advanced AMD. Our studies extend the catalog of AMD asso- research funding from Genentech and owns equity in Pfizer. ciated loci, help identify individuals at high risk of disease, and A complete listing of The CAPT Investigative Group is available at http://amd.nei.nih.gov/ provide clues about underlying cellular pathways that should even- gwas/CAPTAuthorList.pdf. tually lead to new therapies. This article is a PNAS Direct Submission. Freely available online through the PNAS open access option. genome-wide association study | single nucleotide polymorphism Data deposition: Genotype and phenotype data described in this article have been de- posited in the Database of Genotypes and Phenotypes (accession no. phs000182.v1.p1). 1 ge-related macular degeneration (AMD) is a progressive W.C., D.S, and A.O.E. contributed equally to this work. 2 Aneurodegenerative disease and a common cause of blindness To whom correspondence may be addressed. E-mail: [email protected] or goncalo@ umich.edu. in the elderly population, particularly in developed countries (1). This article contains supporting information online at www.pnas.org/cgi/content/full/ The disease affects primarily the macular region of the retina, 0912702107/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.0912702107 PNAS | April 20, 2010 | vol. 107 | no. 16 | 7401–7406 Downloaded by guest on October 2, 2021 Multiple genetic linkage studies provided strong evidence of susceptibility loci, notably on chromosomes 1q31 and 10q36 (2). Disease-associated variants near CFH (1q31) and in a cluster of genes near ARMS2 (10q26) were first identified both through genome-wide association studies (GWASs) (3, 4) and fine map- ping of linkage signals (5—8). Discovery of association between AMD and the CFH locus led researchers to discovery of associa- tion signals near other complement genes, including C2/CFB, C3, and CFI (9—12). Results and Discussion The execution of progressively larger GWAS typically results in the gradual discovery of new susceptibility loci [see the examples of Crohn’s disease (13), type 2 diabetes (14), obesity (15), and lipids (16, 17)]. To identify additional susceptibility loci and biochemical pathways contributing to AMD, we performed GWAS in a large collection of cases and controls (Table S1) using a genotyping platform that captures >90% of common variants in European ancestry samples. We genotyped study samples, including 75 blind duplicates, together with HapMap controls at the Center for Inherited Dis- ease Research (Johns Hopkins) with Illumina Human370 chips. Fig. 1. Summary of genome-wide association scan results. (Upper) Summary of the significance of the association signal at each examined SNP in the After genotyping, we excluded 18 individuals with an unexpected fi fi discovery samples.
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