Bipolar multiplex families have an increased burden of common risk variants for psychiatric disorders

著者: Till F. M. Andlauer, José Guzmán‐Parra, Fabian Streit, Jana Strohmaier, Maria José González, Susana Gil Flores, Francisco J. Cabaleiro Fabeiro, Francisco del Río Noriega, Fermín Pérez, Jesus Haro González, Guillermo Orozco Díaz, Yolanda de Diego‐Otero, Berta Moreno‐Küstner, Georg Auburger, Franziska Degenhardt, Stefanie Heilmann‐Heimbach, Stefan Herms, Per Hoffmann, Josef Frank, Jerome C. Foo, Jens Treutlein, Stephanie H. Witt, Sven Cichon, Manolis Kogevinas, Eli A. Stahl, Gerome Breen, Andreas J. Forstner, Andrew McQuillin, Stephan Ripke, Vassily Trubetskoy, Manuel Mattheisen, Yunpeng Wang, Jonathan R. I. Coleman, Héléna A. Gaspar, Christiaan de Leeuw, Stacy Steinberg, Jennifer M. Whitehead Pavlides, Maciej Trzaskowski, Tune H. Pers, Peter Holmans, Liam Abbott, Esben Agerbo, Huda Akil, Diego Albani, Ney Alliey‐Rodriguez, Thomas D. Als, Adebayo Anjorin, Verneri Antilla, Swapnil Awasthi, Judith A. Badner, Marie Bækvad‐Hansen, Jack D. Barchas, Nicholas Bass, Michael Bauer, Richard A. Belliveau, Sarah E. Bergen, Carsten Bøcker Pedersen, Erlend Bøen, Marco P. Boks, James Boocock, Monika Budde, William E. Bunney, Margit Burmeister, Jonas Bybjerg‐Grauholm, William Byerley, Miguel Casas, Felecia Cerrato, Pablo Cervantes, Kimberly Chambert, Alexander W. Charney, Danfeng Chen, Claire Churchhouse, Toni‐Kim Clarke, William Coryell, David W. Craig, Cristiana Cruceanu, Piotr M. Czerski, Anders M. Dale, Simone de Jong, Franziska Degenhardt, Jurgen Del‐Favero, J. Raymond DePaulo, Srdjan Djurovic, Amanda Dobbyn, Ashley Dumont, Torbjørn Elvsåshagen, Valentina Escott‐Price, Chun Chieh Fan, Sascha B. Fischer, Matthew Flickinger, Tatiana Foroud, Liz Forty, Josef Frank, Christine Fraser, Nelson B Freimer, Louise Frisén, Katrin Gade, Diane Gage, Julie Garnham, Claudia Giambartolomei, Marianne Giørtz Pedersen, Jaqueline Goldstein, Scott D. Gordon, Katherine Gordon‐Smith, Elaine Green, Melissa J. Green, Tiffany A. Greenwood, Jakob Grove, Weihua Guan, José Guzmán‐Parra, Marian L. Hamshere, Martin Hautzinger, Urs Heilbronner, Stefan Herms, Maria Hipolito, Per Hoffmann, Dominic Holland, Laura M. Huckins, Stéphane Jamain, Jessica Johnson, Anders Juréus, Radhika Kandaswamy, Robert Karlsson, James L. Kennedy, Sarah Kittel‐Schneider, James A. Knowles, Manolis Kogevinas, Anna C. Koller, Ralph Kupka, Catharina Lavebratt, Jacob Lawrence, William Lawson, Markus Leber, Phil H. Lee, Shawn Levy, Jun Z. Li, Chunyu Liu, Susanne Lucae, Anna Maaser, Donald J. MacIntyre, Pamela B. Mahon, Wolfgang Maier, Lina Martinsson, Steve McCarroll, Peter McGuffin, Melvin G. McInnis, James McKay, Helena Medeiros, Sarah E. Medland, Fan Meng, Lili Milani, Grant W. Montgomery, Derek W. Morris, Thomas W. Mühleisen, Niamh Mullins, Hoang Nguyen, Caroline M. Nievergelt, Annelie Nordin Adolfsson, Evaristus Nwulia, Claire O’Donovan, Loes M. Olde Loohuis, Anil P. S. Ori, Lilijana Oruč, Urban Ösby, Roy H. Perlis, Amy Perry, Andrea Pfennig, James B. Potash, Shaun Purcell, Eline J. Regeer, Andreas Reif, Céline S. Reinbold, John P. Rice, Alexander Richards, Fabio Rivas, Margarita Rivera, Panos Roussos, Douglas M. Ruderfer, Euijung Ryu, Cristina Sánchez‐Mora, Alan F. Schatzberg, William A. Scheftner, Nicholas J. Schork, Cynthia Shannon Weickert, Tatyana Shehktman, Paul D. Shilling, Engilbert Sigurðsson, Claire Slaney, Olav B. Smeland, Janet L. Sobell, Christine Søholm Hansen, Anne T. Spijker, David St Clair, Michael Steffens, John S. Strauss, Fabian Streit, Jana Strohmaier, Szabolcs Szelinger, Robert C. Thompson, Thorgeir EThorgeirsson, Jens Treutlein, Helmut Vedde, Weiqing Wang, Stanley J. Watson, Thomas W. Weickert, Stephanie H. Witt, Simon Xi, Wei Xu, Allan H. Young, Peter P. Zandi, Peng Zhang, Sebastian Zöllner, Rolf Adolfsson, Ingrid Agartz, Martin Alda, Lena Backlund, Bernhard T. Baune, Frank Bellivier, Wade H. Berrettini, Joanna M. Biernacka, Douglas Blackwood, Michael Boehnke, Anders D. Børglum, Aiden Corvin, Nicholas Craddock, Mark J. Daly, Udo Dannlowski, Tõnu Esko, Bruno Étain, Mark A. Frye, Janice M. Fullerton, Elliot S. Gershon, Michael Gill, Fernando S. Goes, Maria Grigoroiu‐Serbânescu, Joanna Hauser, David M. Hougaard, Christina M. Hultman, Ian Jones, Lisa Jones, René S. Kahn, George Kirov, Mikael Landén, Marion Leboyer, Cathryn M. Lewis, Qingqin S. Li, Jolanta Lissowska, Nicholas G. Martin, Fermín Mayoral, Susan L. McElroy, Andrew M. McIntosh, Francis J. McMahon, Ingrid Melle, Andres Metspalu, Philip B. Mitchell, Gunnar Morken, Ole Mors, Preben Bo Mortensen, Bertram Müller-Myhsok, R Myers, Benjamin M. Neale, Vishwajit L. Nimgaonkar, Merete Nordentoft, Markus M. Nöthen, Michael O‘Donovan, Ketil J. Øedegaard, Michael J. Owen, Sara A. Paciga, Carlos N. Pato, Michele T. Pato, Daniëlle Posthuma, Josep Antoni Ramos‐Quiroga, Marta Ribasés, Marcella Rietschel, Guy A. Rouleau, Martin Schalling, Peter R. Schofield, Thomas G. Schulze, Alessandro Serretti, Jordan W. Smoller, Hreinn Stefánsson, Kari Stefansson, Eystein Stordal, Patrick F. Sullivan, Gustavo Turecki, Arne E Vaaler, Eduard Vieta, John B. Vincent, Thomas Werge, John I. Nürnberger, Naomi R. Wray, Arianna Di Florio, Howard J. Edenberg, Sven Cichon, Roel A. Ophoff, Laura J. Scott, Ole A. Andreassen, John R. Kelsoe, Pamela Sklar, Naomi R. Wray, Stephan Ripke, Manuel Mattheisen, Maciej Trzaskowski, Enda M. Byrne, Abdel Abdellaoui, Mark J. Adams, Esben Agerbo, Tracy Air, Till F. M. Andlauer, Silviu‐Alin Bacanu, Marie Bækvad‐Hansen, Aartjan T.F. Beekman, Tim B. Bigdeli, Elisabeth B. Binder, Julien Bryois, Henriette N. Buttenschøn, Jonas Bybjerg‐Grauholm, Na Cai, Enrique Castelao, Jane Christensen, Toni‐Kim Clarke, Jonathan R. I. Coleman, Lucía Colodro‐Conde, Baptiste Couvy‐Duchesne, Nick Craddock, Gregory E. Crawford, Gail Davies, Ian J. Deary, Franziska Degenhardt, Eske M. Derks, Neşe Direk, Conor V. Dolan, Erin C. Dunn, Thalia C. Eley, Valentina Escott‐Price, Farnush Farhadi Hassan Kiadeh, Hilary K. Finucane, Jerome C. Foo, Andreas J. Forstner, Josef Frank, Héléna A. Gaspar, Michael Gill, Fernando S. Goes, Scott D. Gordon, Jakob Grove, Lynsey S. Hall, Christine Søholm Hansen, Thomas Folkmann Hansen, Stefan Herms, Ian B. Hickie, Per Hoffmann, Georg Homuth, Carsten Horn, Jouke‐Jan Hottenga, David M. Hougaard, David M. Howard, Marcus Ising, Rick Jansen, Ian Jones, Lisa Jones, Eric Jorgenson, James A. Knowles, Isaac S. Kohane, Julia Kraft, Warren W. Kretzschmar, Zoltán Kutalik, Yihan Li, Penelope A. Lind, Donald J. MacIntyre, Dean F. MacKinnon, Robert Maier, Wolfgang Maier, Jonathan Marchini, Hamdi Mbarek, Patrick J. McGrath, Peter McGuffin, Sarah E. Medland, Divya Mehta, Christel M. Middeldorp, Evelin Mihailov, Yuri Milaneschi, Lili Milani, Francis M. Mondimore, Grant W. Montgomery, Sara Mostafavi, Niamh Mullins, Matthias Nauck, Bernard Ng, Michel G. Nivard, Dale R. Nyholt, Paul F. O’Reilly, Högni Óskarsson, Michael J. Owen, Jodie N. Painter, Carsten Bøcker Pedersen, Marianne Giørtz Pedersen, Roseann E. Peterson, Erik Pettersson, Wouter J. Peyrot, Giorgio Pistis, Daniëlle Posthuma, Jorge A. Quiroz, Per Qvist, John P. Rice, Brien P. Riley, Margarita Rivera, Saira Saeed Mirza, Robert A. Schoevers, Eva C. Schulte, Ling Shen, Jianxin Shi, Stanley I. Shyn, Engilbert Sigurðsson, Grant Sinnamon, Johannes H. Smit, Daniel J. Smıth, Hreinn Stefánsson, Stacy Steinberg, Fabian Streit, Jana Strohmaier, Katherine E. Tansey, Henning Teismann, Alexander Teumer, Wesley K. Thompson, Pippa A. Thomson, Thorgeir E. Thorgeirsson, Matthew Traylor, Jens Treutlein, Vassily Trubetskoy, André G. Uitterlinden, Daniel Umbricht, Sandra Van der Auwera, Albert M. van Hemert, Alexander Viktorin, Peter M. Visscher, Yunpeng Wang, Bradley T. Webb, Shantel Weinsheimer, Jürgen Wellmann, Gonneke Willemsen, Stephanie H. Witt, Yang Wu, Hualin Simon Xi, Jian Yang, Futao Zhang, Volker Arolt, Bernhard T. Baune, Klaus Peter Berger, Dorret I. Boomsma, Sven Cichon, Udo Dannlowski, Eco J. C. de Geus, J. Raymond DePaulo, Enrico Domenici, Katharina Domschke, Tõnu Esko, Hans J. Grabe, Steven P. Hamilton, Caroline Hayward, Andrew C. Heath, Kenneth S. Kendler, Stefan Kloiber, Glyn Lewis, Qingqin S. Li, Susanne Lucae, Pamela A. F. Madden, Patrik K. E. Magnusson, Nicholas G. Martin, Andrew M. McIntosh, Andres Metspalu, Ole Mors, Preben Bo Mortensen, Bertram Müller-Myhsok, Merete Nordentoft, Markus M. Nöthen, Michael O‘Donovan, Sara A. Paciga, Nancy L. Pedersen, Brenda W.J.H. Penninx, Roy H. Perlis, David J. Porteous, James B. Potash, Martin Preisig, Marcella Rietschel, Catherine Schaefer, Thomas G. Schulze, Jordan W. Smoller, Kari Stefansson, Henning Tiemeier, Rudolf Uher, Henry Völzke, Myrna M. Weissman, Thomas Werge, Cathryn M. Lewis, Douglas F. Levinson, Gerome Breen, Anders D. Børglum, Patrick F. Sullivan, Fabio Rivas, Fermín Mayoral, Bertram Müller-Myhsok, Andreas J. Forstner, Markus M. Nöthen, Marcella Rietschel - Molecular Psychiatry 2019 被引用: 47

Multiplex families with a high prevalence of a psychiatric disorder are often examined to identify rare genetic variants with large effect sizes. In the present study, we analysed whether the risk for bipolar disorder (BD) in BD multiplex families is influenced by common genetic variants. Furthermore, we investigated whether this risk is conferred mainly by BD-specific risk variants or by variants also associated with the susceptibility to schizophrenia or major depression. In total, 395 individuals from 33 Andalusian BD multiplex families (166 BD, 78 major depressive disorder, 151 unaffected) as well as 438 subjects from an independent, BD case/control cohort (161 unrelated BD, 277 unrelated controls) were analysed. Polygenic risk scores (PRS) for BD, schizophrenia (SCZ), and major depression were calculated and compared between the cohorts. Both the familial BD cases and unaffected family members had higher PRS for all three psychiatric disorders than the independent controls, with BD and SCZ being significant after correction for multiple testing, suggesting a high baseline risk for several psychiatric disorders in the families. Moreover, familial BD cases showed significantly higher BD PRS than unaffected family members and unrelated BD cases. A plausible hypothesis is that, in multiplex families with a general increase in risk for psychiatric disease, BD development is attributable to a high burden of common variants that confer a specific risk for BD. The present analyses demonstrated that common genetic risk variants for psychiatric disorders are likely to contribute to the high incidence of affective psychiatric disorders in the multiplex families. However, the PRS explained only part of the observed phenotypic variance, and rare variants might have also contributed to disease development.