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

2015; Nature Portfolio; Volume: 48; Issue: 2 Linguagem: Inglês

10.1038/ng.3448

1546-1718

Lars G. Fritsche, Wilmar Igl, Jessica N. Cooke Bailey, Felix Graßmann, Sebanti Sengupta, Jennifer L. Bragg‐Gresham, Kathryn P. Burdon, Scott J. Hebbring, Cindy Wen, Mathias Gorski, Ivana K. Kim, David Cho, Donald J. Zack, Eric H. Souied, Hendrik P. N. Scholl, Elisa Bala, Kristine E Lee, David J. Hunter, Rebecca J. Sardell, Paul Mitchell, Joanna E. Merriam, Valentina Cipriani, Joshua Hoffman, Tina Schick, Yara T. E. Lechanteur, Robyn H. Guymer, Matthew P. Johnson, Yingda Jiang, Chloë M. Stanton, Gabriëlle H.S. Buitendijk, Xiaowei Zhan, Alan Kwong, Alexis Boleda, Matthew Brooks, Linn Gieser, Rinki Ratnapriya, Kari Branham, Johanna R. Foerster, John R. Heckenlively, Mohammad Othman, Brendan J. Vote, Helena Liang, Emmanuelle Souzeau, Ian L. McAllister, Timothy Isaacs, Janette M. Hall, Stewart Lake, David A. Mackey, Ian J. Constable, Jamie E. Craig, Terrie Kitchner, Zhenglin Yang, Zhiguang Su, Hongrong Luo, Daniel Chen, Hong Ouyang, Ken Flagg, Danni Lin, Guanping Mao, Henry Ferreyra, Klaus Stark, Claudia N. von Strachwitz, Armin Wolf, Caroline Brandl, Guenther Rudolph, Matthias Olden, Margaux A. Morrison, Denise J. Morgan, Matthew Schu, Jeeyun Ahn, Giuliana Silvestri, Evangelia E. Tsironi, Kyu Hyung Park, Lindsay A. Farrer, Anton Orlin, Alexander J. Brucker, Mingyao Li, Christine A. Curcio, Saddek Mohand‐Saïd, José‐Alain Sahel, Isabelle Audo, Mustapha Benchaboune, Angela J. Cree, Christina Rennie, Srinivas Goverdhan, Michelle Grunin, Shira Hagbi-Levi, Peter A. Campochiaro, Nicholas Katsanis, Frank G. Holz, Frédéric Blond, Hélène Blanché, Jean‐François Deleuze, Robert P. Igo, Barbara Truitt, Neal S. Peachey, Stacy M. Meuer, Chelsea E. Myers, Emily Moore, Ronald Klein, Michael A. Hauser, Eric A. Postel, Monique D. Courtenay, Stephen G. Schwartz, Jaclyn L. Kovach, William K. Scott, Gerald Liew, Ava Grace Tan, Bamini Gopinath, John C. Merriam, R. Theodore Smith, Jane C. Khan, Humma Shahid, Anthony T. Moore, J. Allie McGrath, Reneé Laux, Milam A. Brantley, Anita Agarwal, Lebriz Ersoy, Albert Caramoy, Thomas Langmann, Nicole T.M. Saksens, Eiko K. de Jong, Carel B. Hoyng, Melinda Cain, Andrea J. Richardson, Tammy M. Martin, John Blangero, Daniel E. Weeks, Bal Dhillon, Cornelia M. van Duijn, Kimberly F. Doheny, Jane Romm, Caroline C. W. Klaver, Caroline Hayward, Michael B. Gorin, Michael L. Klein, Paul N. Baird, Anneke I. den Hollander, Sascha Fauser, John R W Yates, Rando Allikmets, Jie Jin Wang, Debra A. Schaumberg, Barbara E.K. Klein, Stephanie A. Hagstrom, Itay Chowers, Andrew Lotery, Thierry Léveillard, Kang Zhang, Murray H. Brilliant, Alex W. Hewitt, Anand Swaroop, Emily Y. Chew, Margaret A. Pericak‐Vance, Margaret M. DeAngelis, Dwight Stambolian, Jonathan L. Haines, Sudha K. Iyengar, Bernhard H. F. Weber, Gonçalo R. Abecasis, Iris M. Heid,

Genetic Associations and Epidemiology

Iris Heid, Gonçalo Abecasis, Sudha Iyengar and colleagues report the results of a large genome-wide association meta-analysis of macular degeneration based on over 43,000 subjects. They identify 16 new risk loci, including some very rare coding variants. 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.