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quinta-feira, 12 dezembro 2019 11:03

Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders

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Cross-Disorder Group of the Psychiatric Genomics Consortium1

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Phil H. Lee, Verneri Anttila, Hyejung Won, Yen-Chen A. Feng, Jacob Rosenthal, Zhaozhong Zhu, Elliot M. Tucker-Drob, Michel G. Nivard, Andrew D. Grotzinger, Danielle Posthuma, Meg M.-J. Wang, Dongmei Yu, Eli A. Stahl, Raymond K. Walters, Richard J.L. Anney, Laramie E. Duncan, Tian Ge, Rolf Adolfsson, Tobias Banaschewski, Sintia Belangero, Edwin H. Cook, Giovanni Coppola, Eske M. Derks, Pieter J. Hoekstra, Jaakko Kaprio, Anna Keski-Rahkonen, George Kirov, Henry R. Kranzler, Jurjen J. Luykx, Luis A. Rohde, Clement C. Zai, Esben Agerbo, M.J. Arranz, Philip Asherson, Marie Bækvad-Hansen, Gísli Baldursson, Mark Bellgrove, Richard A. Belliveau Jr., Jan Buitelaar, Christie L. Burton, Jonas Bybjerg-Grauholm, Miquel Casas, Felecia Cerrato, Kimberly Chambert, Claire Churchhouse, Bru Cormand, Jennifer Crosbie, Søren Dalsgaard, Ditte Demontis, Alysa E. Doyle, Ashley Dumont, Josephine Elia, Jakob Grove, Olafur O. Gudmundsson, Jan Haavik, Hakon Hakonarson, Christine S. Hansen, Catharina A. Hartman, Ziarih Hawi, Amaia Hervás, David M. Hougaard, Daniel P. Howrigan, Hailiang Huang, Jonna Kuntsi, Kate Langley, Klaus-Peter Lesch, Patrick W.L. Leung, Sandra K. Loo, Joanna Martin, Alicia R. Martin, James J., McGough, Sarah E. Medland, Jennifer L. Moran, Ole Mors, Preben B. Mortensen, Robert D. Oades, Duncan S. Palmer, Carsten B. Pedersen, Marianne G. Pedersen, Triinu Peters, Timothy Poterba, Jesper B. Poulsen, Josep Antoni Ramos-Quiroga, Andreas Reif, Marta Ribasés, Aribert Rothenberger, Paula Rovira, Cristina Sánchez-Mora, F. Kyle Satterstrom, Russell Schachar, Maria Soler Artigas, Stacy Steinberg, Hreinn Stefansson, Patrick Turley, G. Bragi Walters, Thomas Werge, Tetyana Zayats, Dan E. Arking, Francesco Bettella, Joseph D. Buxbaum, Jane H. Christensen, Ryan L. Collins, Hilary Coon, Silvia De Rubeis, Richard Delorme, Dorothy E. Grice, Thomas F. Hansen, Peter A. Holmans, Sigrun Hope, Christina M. Hultman, Lambertus Klei, Christine Ladd-Acosta, Pall Magnusson, Terje Nærland, Mette Nyegaard, Dalila Pinto, Per Qvist, Karola Rehnström, Abraham Reichenberg, Jennifer Reichert, Kathryn Roeder, Guy A. Rouleau, Evald Saemundsen, Stephan J. Sanders, Sven Sandin, Beate St Pourcain, Kari Stefansson, James S. Sutcliffe, Michael E. Talkowski, Lauren A. Weiss, A. Jeremy Willsey, Ingrid Agartz, Huda Akil, Diego Albani, Martin Alda, Thomas D. Als, Adebayo Anjorin, Lena Backlund, Nicholas Bass, Michael Bauer, Bernhard T. Baune, Frank Bellivier, Sarah E. Bergen, Wade H. Berrettini, Joanna M. Biernacka, Douglas H.R. Blackwood, Erlend Bøen, Monika Budde, William Bunney, Margit Burmeister, William Byerley, Enda M. Byrne, Sven Cichon, Toni-Kim Clarke, Jonathan R.I. Coleman, Nicholas Craddock, David Curtis, Piotr M. Czerski, Anders M. Dale, Nina Dalkner, Udo Dannlowski, Franziska Degenhardt, Arianna Di Florio, Torbjørn Elvsåshagen, Bruno Etain, Sascha B. Fischer, Andreas J. Forstner, Liz Forty, Josef Frank, Mark Frye, Janice M. Fullerton, Katrin Gade, Héléna A. Gaspar, Elliot S. Gershon, Michael Gill, Fernando S. Goes, Scott D. Gordon, Katherine Gordon-Smith, Melissa J. Green, Tiffany A. Greenwood, Maria Grigoroiu-Serbanescu, José Guzman-Parra, Joanna Hauser, Martin Hautzinger, Urs Heilbronner, Stefan Herms, Per Hoffmann, Dominic Holland, Stéphane Jamain, Ian Jones, Lisa A. Jones, Radhika Kandaswamy, John R. Kelsoe, James L. Kennedy, Oedegaard Ketil Joachim, Sarah Kittel-Schneider, Manolis Kogevinas, Anna C. Koller, Catharina Lavebratt, Cathryn M. Lewis, Qingqin S. Li, Jolanta Lissowska, Loes M.O. Loohuis, Susanne Lucae, Anna Maaser, Ulrik F. Malt, Nicholas G. Martin, Lina Martinsson, Susan L. McElroy, Francis J. McMahon, Andrew McQuillin, Ingrid Melle, Andres Metspalu, Vincent Millischer, Philip B. Mitchell, Grant W. Montgomery, Gunnar Morken, Derek W. Morris, Bertram Müller-Myhsok, Niamh Mullins, Richard M. Myers, Caroline M. Nievergelt, Merete Nordentoft, Annelie Nordin Adolfsson, Markus M. Nöthen, Roel A. Ophoff, Michael J. Owen, Sara A. Paciga, Carlos N. Pato, Michele T. Pato, Roy H. Perlis, Amy Perry, James B. Potash, Céline S. Reinbold, Marcella Rietschel, Margarita Rivera, Mary Roberson, Martin Schalling, Peter R. Schofield, Thomas G. Schulze, Laura J. Scott, Alessandro Serretti, Engilbert Sigurdsson, Olav B. Smeland, Eystein Stordal, Fabian Streit, Jana Strohmaier, Thorgeir E. Thorgeirsson, Jens Treutlein, Gustavo Turecki, Arne E. Vaaler, Eduard Vieta, John B. Vincent, Yunpeng Wang, Stephanie H. Witt, Peter Zandi, Roger A.H. Adan, Lars Alfredsson, Tetsuya Ando, Harald Aschauer, Jessica H. Baker, Vladimir Bencko, Andrew W. Bergen, Andreas Birgegård, Vesna Boraska Perica, Harry Brandt, Roland Burghardt, Laura Carlberg, Matteo Cassina, Maurizio Clementi, Philippe Courtet, Steven Crawford, Scott Crow, James J. Crowley, Unna N. Danner, Oliver S.P. Davis, Daniela Degortes, Janiece E. DeSocio, Danielle M. Dick, Christian Dina, Elisa Docampo, Karin Egberts, Stefan Ehrlich, Thomas Espeseth, Fernando Fernández-Aranda, Manfred M. Fichter, Lenka Foretova, Monica Forzan, Giovanni Gambaro, Ina Giegling, Fragiskos Gonidakis, Philip Gorwood, Monica Gratacos Mayora, Yiran Guo, Katherine A. Halmi, Konstantinos Hatzikotoulas, Johannes Hebebrand, Sietske G. Helder, Beate Herpertz-Dahlmann, Wolfgang Herzog, Anke Hinney, Hartmut Imgart, Susana Jiménez-Murcia, Craig Johnson, Jennifer Jordan, Antonio Julià, Deborah Kaminská, Leila Karhunen, Andreas Karwautz, Martien J.H. Kas, Walter H. Kaye, Martin A. Kennedy, Youl-Ri Kim, Lars Klareskog, Kelly L. Klump, Gun Peggy S. Knudsen, Mikael Landén, Stephanie Le Hellard, Robert D. Levitan, Dong Li, Paul Lichtenstein, Mario Maj, Sara Marsal, Sara McDevitt, James Mitchell, Palmiero Monteleone, Alessio Maria Monteleone, Melissa A. Munn-Chernoff, Benedetta Nacmias, Marie Navratilova, Julie K. O’Toole, Leonid Padyukov, Jacques Pantel, Hana Papezova, Raquel Rabionet, Anu Raevuori, Nicolas Ramoz, Ted Reichborn-Kjennerud, Valdo Ricca, Marion Roberts, Dan Rujescu, Filip Rybakowski, André Scherag, Ulrike Schmidt, Jochen Seitz, Lenka Slachtova, Margarita C.T. Slof-Op‘t Landt, Agnieszka Slopien, Sandro Sorbi, Lorraine Southam, Michael Strober, Alfonso Tortorella, Federica Tozzi, Janet Treasure, Konstantinos Tziouvas, Annemarie A. van Elburg, Tracey D. Wade, Gudrun Wagner, Esther Walton, Hunna J. Watson, H-Erich Wichmann, D. Blake Woodside, Eleftheria Zeggini, Stephanie Zerwas, Stephan Zipfel, Mark J. Adams, Till F.M. Andlauer, Klaus Berger, Elisabeth B. Binder, Dorret I. Boomsma, Enrique Castelao, Lucía Colodro-Conde, Nese Direk, Anna R. Docherty, Enrico Domenici, Katharina Domschke, Erin C. Dunn, Jerome C. Foo, E.J.C. de. Geus, Hans J. Grabe, Steven P. Hamilton, Carsten Horn, Jouke-Jan Hottenga, David Howard, Marcus Ising, Stefan Kloiber, Douglas F., Levinson, Glyn Lewis, Patrik K.E. Magnusson, Hamdi Mbarek, Christel M. Middeldorp, Sara Mostafavi, Dale R. Nyholt, Brenda WJH. Penninx, Roseann E. Peterson, Giorgio Pistis, David J. Porteous, Martin Preisig, Jorge A. Quiroz, Catherine Schaefer, Eva C. Schulte, Jianxin Shi, Daniel J. Smith, Pippa A. Thomson, Henning Tiemeier, Rudolf Uher, Sandra van der Auwera, Myrna M. Weissman, Madeline Alexander, Martin Begemann, Elvira Bramon, Nancy G. Buccola, Murray J. Cairns, Dominique Campion, Vaughan J. Carr, C. Robert Cloninger, David Cohen, David A. Collier, Aiden Corvin, Lynn E. DeLisi, Gary Donohoe, Frank Dudbridge, Jubao Duan, Robert Freedman, Pablo V. Gejman, Vera Golimbet, Stephanie Godard, Hannelore Ehrenreich, Annette M. Hartmann, Frans A. Henskens, Masashi Ikeda, Nakao Iwata, Assen V. Jablensky, Inge Joa, Erik G. Jönsson, Brian J. 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Fernandez, Blanca Garcia-Delgar, Daniel A. Geller, Donald L. Gilbert, Marco A. Grados, Erica Greenberg, Edna Grünblatt, Julie Hagstrøm, Gregory L. Hanna, Andreas Hartmann, Tammy Hedderly, Gary A. Heiman, Isobel Heyman, Hyun Ju Hong, Alden Huang, Chaim Huyser, Laura Ibanez-Gomez, Ekaterina A. Khramtsova, Young Key Kim, Young-Shin Kim, Robert A. King, Yun-Joo Koh, Anastasios Konstantinidis, Sodahm Kook, Samuel Kuperman, Bennett L. Leventhal, Christine Lochner, Andrea G. Ludolph, Marcos Madruga-Garrido, Irene Malaty, Athanasios Maras, James T. McCracken, Inge A. Meijer, Pablo Mir, Astrid Morer, Kirsten R. Müller-Vahl, Alexander Münchau, Tara L. Murphy, Allan Naarden, Peter Nagy, Gerald Nestadt, Paul S. Nestadt, Humberto Nicolini, Erika L. Nurmi, Michael S. Okun, Peristera Paschou, Fabrizio Piras, Federica Piras, Christopher Pittenger, Kerstin J. Plessen, Margaret A. Richter, Renata Rizzo, Mary Robertson, Veit Roessner, Stephan Ruhrmann, Jack F. Samuels, Paul Sandor, Monika Schlögelhofer, Eun-Young Shin, Harvey Singer, Dong-Ho Song, Jungeun Song, Gianfranco Spalletta, Dan J. Stein, S Evelyn Stewart, Eric A. Storch, Barbara Stranger, Manfred Stuhrmann, Zsanett Tarnok, Jay A. Tischfield, Jennifer Tübing, Frank Visscher, Nienke Vulink, Michael Wagner, Susanne Walitza, Sina Wanderer, Martin Woods, Yulia Worbe, Gwyneth Zai, Samuel H. Zinner, Patrick F. Sullivan, Barbara Franke, Mark J. Daly, Cynthia M. Bulik, Cathryn M. Lewis, Andrew M. McIntosh, Michael C. O’Donovan, Amanda Zheutlin, Ole A. Andreassen, Anders D. Børglum, Gerome Breen, Howard J. Edenberg, Ayman H. Fanous, Stephen V. Faraone, Joel Gelernter, Carol A. Mathews, Manuel Mattheisen, Karen S. Mitchell, Michael C. Neale, John I. Nurnberger, Stephan Ripke, Susan L. Santangelo, Jeremiah M. Scharf, Murray B. Stein, Laura M. Thornton, James T.R. Walters, Naomi R. Wray, Daniel H. Geschwind, Benjamin M. Neale, Kenneth S. Kendler, Jordan W. Smoller

Cell

December 12, 2019


Highlights

  • Three groups of highly genetically-related disorders among 8 psychiatric disorders
  • Identified 109 pleiotropic loci affecting more than one disorder
  • Pleiotropic genes show heightened expression beginning in 2nd prenatal trimester
  • Pleiotropic genes play prominent roles in neurodevelopmental processes

Summary: Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.


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