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A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common 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, most rare, protein-altering variant. Analyzing 16,144 patients and 17,832 con...
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4745342/ https://www.ncbi.nlm.nih.gov/pubmed/26691988 http://dx.doi.org/10.1038/ng.3448 |
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author | Fritsche, Lars G. Igl, Wilmar Cooke Bailey, Jessica N. Grassmann, Felix Sengupta, Sebanti Bragg-Gresham, Jennifer L. Burdon, Kathryn P. Hebbring, Scott J. Wen, Cindy Gorski, Mathias Kim, Ivana K. Cho, David Zack, Donald Souied, Eric Scholl, Hendrik P. N. Bala, Elisa Lee, Kristine E. Hunter, David J. Sardell, Rebecca J. Mitchell, Paul Merriam, Joanna E. Cipriani, Valentina Hoffman, Joshua D. Schick, Tina Lechanteur, Yara T. E. Guymer, Robyn H. Johnson, Matthew P. Jiang, Yingda Stanton, Chloe M. Buitendijk, Gabriëlle H. S. Zhan, Xiaowei Kwong, Alan M. Boleda, Alexis Brooks, Matthew Gieser, Linn Ratnapriya, Rinki Branham, Kari E. Foerster, Johanna R. Heckenlively, John R. Othman, Mohammad I. Vote, Brendan J. Liang, Helena Hai Souzeau, Emmanuelle McAllister, Ian L. Isaacs, Timothy Hall, Janette Lake, Stewart Mackey, David A. Constable, Ian J. Craig, Jamie E. Kitchner, Terrie E. Yang, Zhenglin Su, Zhiguang Luo, Hongrong Chen, Daniel Ouyang, Hong Flagg, Ken Lin, Danni Mao, Guanping Ferreyra, Henry Stark, Klaus von Strachwitz, Claudia N. Wolf, Armin Brandl, Caroline Rudolph, Guenther Olden, Matthias Morrison, Margaux A. Morgan, Denise J. Schu, Matthew Ahn, Jeeyun Silvestri, Giuliana Tsironi, Evangelia E. Park, Kyu Hyung Farrer, Lindsay A. Orlin, Anton Brucker, Alexander Li, Mingyao Curcio, Christine Mohand-Saïd, Saddek Sahel, José-Alain Audo, Isabelle Benchaboune, Mustapha Cree, Angela J. Rennie, Christina A. Goverdhan, Srinivas V. Grunin, Michelle Hagbi-Levi, Shira Campochiaro, Peter Katsanis, Nicholas Holz, Frank G. Blond, Frédéric Blanché, Hélène Deleuze, Jean-François Igo, Robert P. Truitt, Barbara Peachey, Neal S. Meuer, Stacy M. Myers, Chelsea E. Moore, Emily L. Klein, Ronald Hauser, Michael A. Postel, Eric A. Courtenay, Monique D. Schwartz, Stephen G. Kovach, Jaclyn L. Scott, William K. Liew, Gerald Tƒan, Ava G. Gopinath, Bamini Merriam, John C. Smith, R. Theodore Khan, Jane C. Shahid, Humma Moore, Anthony T. McGrath, J. Allie Laux, Reneé Brantley, Milam A. Agarwal, Anita Ersoy, Lebriz Caramoy, Albert Langmann, Thomas Saksens, Nicole T. M. de Jong, Eiko K. Hoyng, Carel B. Cain, Melinda S. Richardson, Andrea J. Martin, Tammy M. Blangero, John Weeks, Daniel E. Dhillon, Bal van Duijn, Cornelia M. Doheny, Kimberly F. Romm, Jane Klaver, Caroline C. W. Hayward, Caroline Gorin, Michael B. Klein, Michael L. Baird, Paul N. den Hollander, Anneke I. Fauser, Sascha Yates, John R. W. Allikmets, Rando Wang, Jie Jin Schaumberg, Debra A. Klein, Barbara E. K. Hagstrom, Stephanie A. Chowers, Itay Lotery, Andrew J. Léveillard, Thierry Zhang, Kang Brilliant, Murray H. Hewitt, Alex W. Swaroop, Anand Chew, Emily Y. Pericak-Vance, Margaret A. DeAngelis, Margaret Stambolian, Dwight Haines, Jonathan L. Iyengar, Sudha K. Weber, Bernhard H. F. Abecasis, Gonçalo R. Heid, Iris M. |
author_facet | Fritsche, Lars G. Igl, Wilmar Cooke Bailey, Jessica N. Grassmann, Felix Sengupta, Sebanti Bragg-Gresham, Jennifer L. Burdon, Kathryn P. Hebbring, Scott J. Wen, Cindy Gorski, Mathias Kim, Ivana K. Cho, David Zack, Donald Souied, Eric Scholl, Hendrik P. N. Bala, Elisa Lee, Kristine E. Hunter, David J. Sardell, Rebecca J. Mitchell, Paul Merriam, Joanna E. Cipriani, Valentina Hoffman, Joshua D. Schick, Tina Lechanteur, Yara T. E. Guymer, Robyn H. Johnson, Matthew P. Jiang, Yingda Stanton, Chloe M. Buitendijk, Gabriëlle H. S. Zhan, Xiaowei Kwong, Alan M. Boleda, Alexis Brooks, Matthew Gieser, Linn Ratnapriya, Rinki Branham, Kari E. Foerster, Johanna R. Heckenlively, John R. Othman, Mohammad I. Vote, Brendan J. Liang, Helena Hai Souzeau, Emmanuelle McAllister, Ian L. Isaacs, Timothy Hall, Janette Lake, Stewart Mackey, David A. Constable, Ian J. Craig, Jamie E. Kitchner, Terrie E. Yang, Zhenglin Su, Zhiguang Luo, Hongrong Chen, Daniel Ouyang, Hong Flagg, Ken Lin, Danni Mao, Guanping Ferreyra, Henry Stark, Klaus von Strachwitz, Claudia N. Wolf, Armin Brandl, Caroline Rudolph, Guenther Olden, Matthias Morrison, Margaux A. Morgan, Denise J. Schu, Matthew Ahn, Jeeyun Silvestri, Giuliana Tsironi, Evangelia E. Park, Kyu Hyung Farrer, Lindsay A. Orlin, Anton Brucker, Alexander Li, Mingyao Curcio, Christine Mohand-Saïd, Saddek Sahel, José-Alain Audo, Isabelle Benchaboune, Mustapha Cree, Angela J. Rennie, Christina A. Goverdhan, Srinivas V. Grunin, Michelle Hagbi-Levi, Shira Campochiaro, Peter Katsanis, Nicholas Holz, Frank G. Blond, Frédéric Blanché, Hélène Deleuze, Jean-François Igo, Robert P. Truitt, Barbara Peachey, Neal S. Meuer, Stacy M. Myers, Chelsea E. Moore, Emily L. Klein, Ronald Hauser, Michael A. Postel, Eric A. Courtenay, Monique D. Schwartz, Stephen G. Kovach, Jaclyn L. Scott, William K. Liew, Gerald Tƒan, Ava G. Gopinath, Bamini Merriam, John C. Smith, R. Theodore Khan, Jane C. Shahid, Humma Moore, Anthony T. McGrath, J. Allie Laux, Reneé Brantley, Milam A. Agarwal, Anita Ersoy, Lebriz Caramoy, Albert Langmann, Thomas Saksens, Nicole T. M. de Jong, Eiko K. Hoyng, Carel B. Cain, Melinda S. Richardson, Andrea J. Martin, Tammy M. Blangero, John Weeks, Daniel E. Dhillon, Bal van Duijn, Cornelia M. Doheny, Kimberly F. Romm, Jane Klaver, Caroline C. W. Hayward, Caroline Gorin, Michael B. Klein, Michael L. Baird, Paul N. den Hollander, Anneke I. Fauser, Sascha Yates, John R. W. Allikmets, Rando Wang, Jie Jin Schaumberg, Debra A. Klein, Barbara E. K. Hagstrom, Stephanie A. Chowers, Itay Lotery, Andrew J. Léveillard, Thierry Zhang, Kang Brilliant, Murray H. Hewitt, Alex W. Swaroop, Anand Chew, Emily Y. Pericak-Vance, Margaret A. DeAngelis, Margaret Stambolian, Dwight Haines, Jonathan L. Iyengar, Sudha K. Weber, Bernhard H. F. Abecasis, Gonçalo R. Heid, Iris M. |
author_sort | Fritsche, Lars G. |
collection | PubMed |
description | 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, most rare, protein-altering variant. 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. While wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first signal specific to wet AMD, near MMP9 (difference-P = 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. |
format | Online Article Text |
id | pubmed-4745342 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
record_format | MEDLINE/PubMed |
spelling | pubmed-47453422016-06-21 A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants Fritsche, Lars G. Igl, Wilmar Cooke Bailey, Jessica N. Grassmann, Felix Sengupta, Sebanti Bragg-Gresham, Jennifer L. Burdon, Kathryn P. Hebbring, Scott J. Wen, Cindy Gorski, Mathias Kim, Ivana K. Cho, David Zack, Donald Souied, Eric Scholl, Hendrik P. N. Bala, Elisa Lee, Kristine E. Hunter, David J. Sardell, Rebecca J. Mitchell, Paul Merriam, Joanna E. Cipriani, Valentina Hoffman, Joshua D. Schick, Tina Lechanteur, Yara T. E. Guymer, Robyn H. Johnson, Matthew P. Jiang, Yingda Stanton, Chloe M. Buitendijk, Gabriëlle H. S. Zhan, Xiaowei Kwong, Alan M. Boleda, Alexis Brooks, Matthew Gieser, Linn Ratnapriya, Rinki Branham, Kari E. Foerster, Johanna R. Heckenlively, John R. Othman, Mohammad I. Vote, Brendan J. Liang, Helena Hai Souzeau, Emmanuelle McAllister, Ian L. Isaacs, Timothy Hall, Janette Lake, Stewart Mackey, David A. Constable, Ian J. Craig, Jamie E. Kitchner, Terrie E. Yang, Zhenglin Su, Zhiguang Luo, Hongrong Chen, Daniel Ouyang, Hong Flagg, Ken Lin, Danni Mao, Guanping Ferreyra, Henry Stark, Klaus von Strachwitz, Claudia N. Wolf, Armin Brandl, Caroline Rudolph, Guenther Olden, Matthias Morrison, Margaux A. Morgan, Denise J. Schu, Matthew Ahn, Jeeyun Silvestri, Giuliana Tsironi, Evangelia E. Park, Kyu Hyung Farrer, Lindsay A. Orlin, Anton Brucker, Alexander Li, Mingyao Curcio, Christine Mohand-Saïd, Saddek Sahel, José-Alain Audo, Isabelle Benchaboune, Mustapha Cree, Angela J. Rennie, Christina A. Goverdhan, Srinivas V. Grunin, Michelle Hagbi-Levi, Shira Campochiaro, Peter Katsanis, Nicholas Holz, Frank G. Blond, Frédéric Blanché, Hélène Deleuze, Jean-François Igo, Robert P. Truitt, Barbara Peachey, Neal S. Meuer, Stacy M. Myers, Chelsea E. Moore, Emily L. Klein, Ronald Hauser, Michael A. Postel, Eric A. Courtenay, Monique D. Schwartz, Stephen G. Kovach, Jaclyn L. Scott, William K. Liew, Gerald Tƒan, Ava G. Gopinath, Bamini Merriam, John C. Smith, R. Theodore Khan, Jane C. Shahid, Humma Moore, Anthony T. McGrath, J. Allie Laux, Reneé Brantley, Milam A. Agarwal, Anita Ersoy, Lebriz Caramoy, Albert Langmann, Thomas Saksens, Nicole T. M. de Jong, Eiko K. Hoyng, Carel B. Cain, Melinda S. Richardson, Andrea J. Martin, Tammy M. Blangero, John Weeks, Daniel E. Dhillon, Bal van Duijn, Cornelia M. Doheny, Kimberly F. Romm, Jane Klaver, Caroline C. W. Hayward, Caroline Gorin, Michael B. Klein, Michael L. Baird, Paul N. den Hollander, Anneke I. Fauser, Sascha Yates, John R. W. Allikmets, Rando Wang, Jie Jin Schaumberg, Debra A. Klein, Barbara E. K. Hagstrom, Stephanie A. Chowers, Itay Lotery, Andrew J. Léveillard, Thierry Zhang, Kang Brilliant, Murray H. Hewitt, Alex W. Swaroop, Anand Chew, Emily Y. Pericak-Vance, Margaret A. DeAngelis, Margaret Stambolian, Dwight Haines, Jonathan L. Iyengar, Sudha K. Weber, Bernhard H. F. Abecasis, Gonçalo R. Heid, Iris M. Nat Genet Article 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, most rare, protein-altering variant. 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. While wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first signal specific to wet AMD, near MMP9 (difference-P = 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. 2015-12-21 2016-02 /pmc/articles/PMC4745342/ /pubmed/26691988 http://dx.doi.org/10.1038/ng.3448 Text en http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms |
spellingShingle | Article Fritsche, Lars G. Igl, Wilmar Cooke Bailey, Jessica N. Grassmann, Felix Sengupta, Sebanti Bragg-Gresham, Jennifer L. Burdon, Kathryn P. Hebbring, Scott J. Wen, Cindy Gorski, Mathias Kim, Ivana K. Cho, David Zack, Donald Souied, Eric Scholl, Hendrik P. N. Bala, Elisa Lee, Kristine E. Hunter, David J. Sardell, Rebecca J. Mitchell, Paul Merriam, Joanna E. Cipriani, Valentina Hoffman, Joshua D. Schick, Tina Lechanteur, Yara T. E. Guymer, Robyn H. Johnson, Matthew P. Jiang, Yingda Stanton, Chloe M. Buitendijk, Gabriëlle H. S. Zhan, Xiaowei Kwong, Alan M. Boleda, Alexis Brooks, Matthew Gieser, Linn Ratnapriya, Rinki Branham, Kari E. Foerster, Johanna R. Heckenlively, John R. Othman, Mohammad I. Vote, Brendan J. Liang, Helena Hai Souzeau, Emmanuelle McAllister, Ian L. Isaacs, Timothy Hall, Janette Lake, Stewart Mackey, David A. Constable, Ian J. Craig, Jamie E. Kitchner, Terrie E. Yang, Zhenglin Su, Zhiguang Luo, Hongrong Chen, Daniel Ouyang, Hong Flagg, Ken Lin, Danni Mao, Guanping Ferreyra, Henry Stark, Klaus von Strachwitz, Claudia N. Wolf, Armin Brandl, Caroline Rudolph, Guenther Olden, Matthias Morrison, Margaux A. Morgan, Denise J. Schu, Matthew Ahn, Jeeyun Silvestri, Giuliana Tsironi, Evangelia E. Park, Kyu Hyung Farrer, Lindsay A. Orlin, Anton Brucker, Alexander Li, Mingyao Curcio, Christine Mohand-Saïd, Saddek Sahel, José-Alain Audo, Isabelle Benchaboune, Mustapha Cree, Angela J. Rennie, Christina A. Goverdhan, Srinivas V. Grunin, Michelle Hagbi-Levi, Shira Campochiaro, Peter Katsanis, Nicholas Holz, Frank G. Blond, Frédéric Blanché, Hélène Deleuze, Jean-François Igo, Robert P. Truitt, Barbara Peachey, Neal S. Meuer, Stacy M. Myers, Chelsea E. Moore, Emily L. Klein, Ronald Hauser, Michael A. Postel, Eric A. Courtenay, Monique D. Schwartz, Stephen G. Kovach, Jaclyn L. Scott, William K. Liew, Gerald Tƒan, Ava G. Gopinath, Bamini Merriam, John C. Smith, R. Theodore Khan, Jane C. Shahid, Humma Moore, Anthony T. McGrath, J. Allie Laux, Reneé Brantley, Milam A. Agarwal, Anita Ersoy, Lebriz Caramoy, Albert Langmann, Thomas Saksens, Nicole T. M. de Jong, Eiko K. Hoyng, Carel B. Cain, Melinda S. Richardson, Andrea J. Martin, Tammy M. Blangero, John Weeks, Daniel E. Dhillon, Bal van Duijn, Cornelia M. Doheny, Kimberly F. Romm, Jane Klaver, Caroline C. W. Hayward, Caroline Gorin, Michael B. Klein, Michael L. Baird, Paul N. den Hollander, Anneke I. Fauser, Sascha Yates, John R. W. Allikmets, Rando Wang, Jie Jin Schaumberg, Debra A. Klein, Barbara E. K. Hagstrom, Stephanie A. Chowers, Itay Lotery, Andrew J. Léveillard, Thierry Zhang, Kang Brilliant, Murray H. Hewitt, Alex W. Swaroop, Anand Chew, Emily Y. Pericak-Vance, Margaret A. DeAngelis, Margaret Stambolian, Dwight Haines, Jonathan L. Iyengar, Sudha K. Weber, Bernhard H. F. Abecasis, Gonçalo R. Heid, Iris M. A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants |
title | A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants |
title_full | A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants |
title_fullStr | A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants |
title_full_unstemmed | A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants |
title_short | A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants |
title_sort | large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4745342/ https://www.ncbi.nlm.nih.gov/pubmed/26691988 http://dx.doi.org/10.1038/ng.3448 |
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pericakvancemargareta largegenomewideassociationstudyofagerelatedmaculardegenerationhighlightscontributionsofrareandcommonvariants AT deangelismargaret largegenomewideassociationstudyofagerelatedmaculardegenerationhighlightscontributionsofrareandcommonvariants AT stamboliandwight largegenomewideassociationstudyofagerelatedmaculardegenerationhighlightscontributionsofrareandcommonvariants AT hainesjonathanl largegenomewideassociationstudyofagerelatedmaculardegenerationhighlightscontributionsofrareandcommonvariants AT iyengarsudhak largegenomewideassociationstudyofagerelatedmaculardegenerationhighlightscontributionsofrareandcommonvariants AT weberbernhardhf largegenomewideassociationstudyofagerelatedmaculardegenerationhighlightscontributionsofrareandcommonvariants AT abecasisgoncalor largegenomewideassociationstudyofagerelatedmaculardegenerationhighlightscontributionsofrareandcommonvariants AT heidirism largegenomewideassociationstudyofagerelatedmaculardegenerationhighlightscontributionsofrareandcommonvariants |