University Of Tasmania

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A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants

journal contribution
posted on 2023-05-18, 16:05 authored by Fritsche, LG, Igl, W, Bailey, JN, Grassmann, F, Sengupta, S, Bragg-Gresham, JL, Kathryn BurdonKathryn Burdon, Hebbring, SJ, Wen, C, Gorski, M, Kim, IK, Cho, D, Zack, D, Souied, E, Scholl, HPN, Bala, E, Lee, KE, Hunter, DJ, Sardell, RJ, Mitchell, P, Merriam, JE, Cipriani, V, Hoffman, JD, Schick, T, Lechanteur, YTE, Guymer, RH, Johnson, MP, Jiang, Y, Stanton, CM, Buitendijk, GH, Zhan, X, Kwong, AM, Boleda, A, Brooks, M, Gieser, L, Ratnapriya, R, Branham, KE, Foerster, JR, Heckenlively, JR, Othman, MI, Brendan VoteBrendan Vote, Liang, HH, Souzeau, E, McAllister, IL, Isaacs, T, Hall, J, Lake, S, David MackeyDavid Mackey, Constable, IJ, Craig, JE, Kitchner, TE, Yang, Z, Su, Z, Luo, H, Chen, D, Ouyang, H, Flagg, K, Lin, D, Mao, G, Ferreyra, H, Stark, K, von Strachwitz, CN, Wolf, A, Brandl, C, Rudolph, G, Olden, M, Morrison, MA, Morgan, DJ, Schu, M, Ahn, J, Silvestri, G, Tsironi, EE, Park, KH, Farrer, LA, Orlin, A, Brucker, A, Li, M, Curcio, CA, Mohand-Said, S, Sahel, J-A, Audo, I, Benchaboune, M, Cree, AJ, Rennie, CA, Goverdhan, SV, Grunin, M, Hagbi-Levi, S, Campochiaro, P, Katsanis, N, Holz, FG, Blond, F, Blanche, H, Deleuze, J-F, Igo Jr, RP, Truitt, B, Peachey, NS, Meuer, SM, Myers, CE, Moore, EL, Klein, R, Hauser, MA, Postel, EA, Courtenay, MD, Schwartz, SG, Kovach, JL, Scott, WK, Liew, G, Tan, AG, Gopinath, B, Merriam, JC, Smith, RT, Khan, JC, Shahid, H, Moore, AT, McGrath, JA, Laux, R, Brantley Jr, MA, Agarwal, A, Ersoy, L, Caramoy, A, Langmann, T, Saksens, NTM, de Jong, EK, Hoyng, CB, Cain, MS, Richardson, AJ, Martin, TM, Blangero, J, Weeks, DE, Dhillon, B, van Duijn, CM, Doheny, KF, Romm, J, Klaver, CC, Hayward, C, Gorin, MB, Klein, ML, Baird, PN, den Hollander, AI, Fauser, S, Yates, JRW, Allikmets, R, Wang, JJ, Schaumberg, DA, Klein, BEK, Hagstrom, SA, Chowers, I, Lotery, AJ, Leveillard, T, Zhang, K, Brilliant, MH, Alexander HewittAlexander Hewitt, Swaroop, A, Chew, EY, Pericak-Vance, MA, DeAngelis, M, Stambolian, D, Haines, JL, Iyengar, SK, Weber, BH, Abecasis, GR, Heid, IM
Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with limited therapeutic options. Here we report on a study of >12 million variants, including 163,714 directly genotyped, mostly rare, protein-altering variants. Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants (P < 5 × 10−8) distributed across 34 loci. Although wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first genetic association signal specific to wet AMD, near MMP9 (difference P value = 4.1 × 10−10). Very rare coding variants (frequency <0.1%) in CFH, CFI and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.


Publication title

Nature Genetics








Menzies Institute for Medical Research


Nature Publishing Group

Place of publication

United States

Rights statement

© 2016 Nature America

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  • Restricted

Socio-economic Objectives

Clinical health not elsewhere classified

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