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

Lars G. Fritsche, Wilmar Igl, Jessica N. Cooke Bailey, Felix Grassman, Sebant Sengupta, Jennifer L. Bragg-Gresham, Kathryn P. Burdon, Scott J. Hebbring, Cindy Wen, Mathias Gorski, Ivana K. Kim, David Cho, Donald Zack, Eric Souied, Hendrik P. N. Scholl, Elisa Bala, Kristine E. Lee, David J. Hunter, Rebecca J. Sardell, Paul MitchellJoanna E. Merriam, Valentina Cipriani, Joshua D. Hoffman, Tina Schick, Yara T. E. Lechanteur, Robyn H. Guymer, Matthew P. Johnson, Yingda Jiang, Chloe M. Stanton, Gabriëlle H. S. Buitendijk, Xiaowei Zhan, Alan M. Kwong, Alexis Boleda, Matthew Brooks, Linn Gieser, Rinki Ratnapriya, Kari E. Branham, Johanna R. Foerster, John R. Heckenlively, Mohammad I. Othman, Brendan J. Vote, Helena Hai Liang, Emmanuelle Souzeau, Ian L. McAllister, Timothy Isaacs, Janette Hall, Stewart Lake, David A. Mackey, Ian J. Constable, Jamie E. Craig, Terrie E. 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 Brucker, Mingyao Li, Christine A. Curcio, Saddek Mohand-Saïd, José-Alain Sahel, Isabelle Audo, Mustapha Benchaboune, Angela J. Cree, Christina A. Rennie, Srinivas V. Goverdhan, Michelle Grunin, Shira Hagbi-Levi, Peter Campochiaro, Nicholas Katsanis, Frank G. Holz, Frédéric Blond, Hélène Blanché, Jean-François Deleuze, Robert P. Igo Jr, Barbara Truitt, Neal S. Peachey, Stacy M. Meuer, Chelsea E. Myers, Emily L. Moore, Ronald Klein, Michael A. Hauser, Eric A. Postel, Monique D. Courtenay, Stephen G. Schwartz, Jaclyn L. Kovach, William K. Scott, Gerald Liew, Ava G. 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 Jr, Anita Agarwal, Lebriz Ersoy, Albert Caramoy, Thomas Langmann, Nicole T. M. Saksens, Eiko K. de Jong, Carel B. Hoyng, Melinda S. 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 J. Lotery, Thierry Léveillard, Kang Zhang, Murray H. Brilliant, Alex W. Hewitt, Anand Swaroop, Emily Y. Chew, Margaret A. Pericak-Vance, Margaret DeAngelis, Dwight Stambolian, Jonathan L. Haines, Sudha K. Iyengar, Bernhard H. F. Weber, Gonçalo R. Abecasis, Iris M. Heid*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

932 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)134-143
Number of pages13
JournalNature Genetics
Issue number2
Publication statusPublished - Feb 2016
Externally publishedYes


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