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 Grassmann, Sebanti 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 ELee, 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, Gabri'lle 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-Sa'd, 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, Hél'ne Blanché, Jean Fran ois Deleuze, Robert P. Igo, 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, Anita Agarwal, Lebriz Ersoy, Albert Caramoy, Thomas Langmann, Nicole T.M. Saksens, Eiko Kde 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. 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, Gon'alo R. Abecasis*, Iris M. Heid

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

997 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 pages10
JournalNature Genetics
Early online date21 Dec 2015
Publication statusPublished - Feb 2016

Bibliographical note

We thank all participants of all the studies included for enabling this research by their participation in these studies. Computer resources for this project have been provided by the high-performance computing centers of the University of Michigan and the University of Regensburg. Group-specific acknowledgments can be found in the Supplementary Note. The Center for Inherited Diseases Research (CIDR) Program contract number is HHSN268201200008I. This and the main consortium work were predominantly funded by 1X01HG006934-01 to G.R.A. and R01 EY022310 to J.L.H.


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