The Genetics of the Mood Disorder Spectrum: Genome-wide Association Analyses of More Than 185,000 Cases and 439,000 Controls.

Citation metadata

From: Biological Psychiatry(Vol. 88, Issue 2)
Publisher: Elsevier B.V.
Document Type: Report
Length: 2,360 words

Document controls

Main content

Abstract :

Keywords Affective disorders; Bipolar disorder; Genetic correlation; Genome-wide association study; Major depressive disorder; Mood disorders Abstract Background Mood disorders (including major depressive disorder and bipolar disorder) affect 10% to 20% of the population. They range from brief, mild episodes to severe, incapacitating conditions that markedly impact lives. Multiple approaches have shown considerable sharing of risk factors across mood disorders despite their diagnostic distinction. Methods To clarify the shared molecular genetic basis of major depressive disorder and bipolar disorder and to highlight disorder-specific associations, we meta-analyzed data from the latest Psychiatric Genomics Consortium genome-wide association studies of major depression (including data from 23andMe) and bipolar disorder, and an additional major depressive disorder cohort from UK Biobank (total: 185,285 cases, 439,741 controls; nonoverlapping N = 609,424). Results Seventy-three loci reached genome-wide significance in the meta-analysis, including 15 that are novel for mood disorders. More loci from the Psychiatric Genomics Consortium analysis of major depression than from that for bipolar disorder reached genome-wide significance. Genetic correlations revealed that type 2 bipolar disorder correlates strongly with recurrent and single-episode major depressive disorder. Systems biology analyses highlight both similarities and differences between the mood disorders, particularly in the mouse brain cell types implicated by the expression patterns of associated genes. The mood disorders also differ in their genetic correlation with educational attainment--the relationship is positive in bipolar disorder but negative in major depressive disorder. Conclusions The mood disorders share several genetic associations, and genetic studies of major depressive disorder and bipolar disorder can be combined effectively to enable the discovery of variants not identified by studying either disorder alone. However, we demonstrate several differences between these disorders. Analyzing subtypes of major depressive disorder and bipolar disorder provides evidence for a genetic mood disorders spectrum. Author Affiliation: (a) Social, Genetic, and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London, United Kingdom (b) National Institute for Health Research Maudsley Biomedical Research Centre, King's College London, London, United Kingdom (c) Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden * Address correspondence to Gerome Breen, Ph.D., Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology, and Neuroscience, London, SE5 8AF, United Kingdom. Article History: Received 2 May 2019; Revised 27 September 2019; Accepted 15 October 2019 (footnote) The Bipolar Disorder and Major Depressive Disorder Working Groups of the Psychiatric Genomics Consortium are collaborative coauthors for this article. The individual authors are (numbers refer to affiliations listed in ): Enda M. Byrne4, Andreas J. Forstner5,6,7,8,9, Peter A. Holmans10, Christiaan A. de Leeuw11, Manuel Mattheisen12,13,14,15,16, Andrew McQuillin17, Jennifer M. Whitehead Pavlides18, Tune H. Pers19,20, Stephan Ripke21,22,23, Eli A. Stahl19,24,25, Stacy Steinberg26, Vassily Trubetskoy22, Maciej Trzaskowski4, Yunpeng Wang27,28, Liam Abbott21, Abdel Abdellaoui29, Mark J. Adams30, Annelie Nordin Adolfsson31, Esben Agerbo16,32,33, Huda Akil34, Diego Albani35, Ney Alliey-Rodriguez36, Thomas D. Als12,13,16, Till F. M. Andlauer37,38, Adebayo Anjorin39, Verneri Anttila23, Sandra Van der Auwera40, Swapnil Awasthi22, Silviu-Alin Bacanu41, Judith A Badner42, Marie Bækvad-Hansen16,43, Jack D. Barchas44, Nicholas Bass17, Michael Bauer45, Aartjan T. F. Beekman46, Richard Belliveau21, Sarah E. Bergen3, Tim B. Bigdeli41,47, Elisabeth B. Binder37,48, Erlend Bøen49, Marco Boks50, James Boocock51, Monika Budde52, William Bunney53, Margit Burmeister54, Henriette N. Buttenschøn3,12,55, Jonas Bybjerg-Grauholm16,43, William Byerley56, Na Cai57,58, Miquel Casas59,60,61,62, Enrique Castelao63, Felecia Cerrato21, Pablo Cervantes64, Kimberly Chambert21, Alexander W. Charney25, Danfeng Chen21, Jane Hvarregaard Christensen12,13,55, Claire Churchhouse21,23, David St Clair65, Toni-Kim Clarke30, Lucía Colodro-Conde66, William Coryell67, Baptiste Couvy-Duchesne18,68, David W. Craig69, Gregory E. Crawford70,71, Cristiana Cruceanu37,64, Piotr M. Czerski72, Anders M. Dale73,74,75,76, Gail Davies77, Ian J. Deary77, Franziska Degenhardt7,8, Jurgen Del-Favero78, J Raymond DePaulo79, Eske M. Derks66, Nese Direk80,81, Srdjan Djurovic82,83, Amanda L. Dobbyn24,25, Conor V. Dolan29, Ashley Dumont21, Erin C. Dunn21,84,85, Thalia C. Eley1, Torbjørn Elvsåshagen86,87, Valentina Escott-Price10, Chun Chieh Fan76, Hilary K. Finucane88,89, Sascha B. Fischer5,9, Matthew Flickinger90, Jerome C. Foo91, Tatiana M. Foroud92, Liz Forty10, Josef Frank91, Christine Fraser10, Nelson B. Freimer93, Louise Frisén94,95,96, Katrin Gade52,97, Diane Gage21, Julie Garnham98, Claudia Giambartolomei51, Fernando S. Goes99, Jaqueline Goldstein21, Scott D. Gordon66, Katherine Gordon-Smith100, Elaine K. Green101, Melissa J. Green102, Tiffany A. Greenwood75, Jakob Grove12,13,16,103, Weihua Guan104, Lynsey S. Hall30,105, Marian L. Hamshere1, Christine Søholm Hansen16,43, Thomas F. Hansen16,106,107, Martin Hautzinger108, Urs Heilbronner52, Albert M. van Hemert109, Stefan Herms5,7,8,9, Ian B. Hickie110, Maria Hipolito111, Per Hoffmann5,7,8,9, Dominic Holland73,112, Georg Homuth113, Carsten Horn114, Jouke-Jan Hottenga29, Laura Huckins24,25, Marcus Ising15, Stéphane Jamain116,117, Rick Jansen46, Jessica S. Johnson24,25, Simone de Jong1,2, Eric Jorgenson118, Anders Juréus3, Radhika Kandaswamy1, Robert Karlsson3, James L. Kennedy119,120,121,122, Farnush Farhadi Hassan Kiadeh123, Sarah Kittel-Schneider124, James A. Knowles125,126, Manolis Kogevinas127, Isaac S. Kohane128,129,130, Anna C. Koller7,8, Julia Kraft22, Warren W. Kretzschmar131, Jesper Krogh132, Ralph Kupka46,133, Zoltán Kutalik134,135, Catharina Lavebratt94, Jacob Lawrence136, William B. Lawson111, Markus Leber137, Phil H. Lee21,23,138, Shawn E. Levy139, Jun Z. Li140, Yihan Li131, Penelope A. Lind66, Chunyu Liu141, Loes M. Olde Loohuis93, Anna Maaser7,8, Donald J. MacIntyre142,143, Dean F. MacKinnon99, Pamela B. Mahon79,144, Wolfgang Maier145, Robert M. Maier18, Jonathan Marchini146, Lina Martinsson95, Hamdi Mbarek29, Steve McCarroll21,147, Patrick McGrath148, Peter McGuffin1, Melvin G. McInnis149, James D. McKay150, Helena Medeiros126, Sarah E. Medland66, Divya Mehta18,151, Fan Meng34,149, Christel M. Middeldorp29,152,153, Evelin Mihailov154, Yuri Milaneschi46, Lili Milani154, Saira Saeed Mirza80, Francis M. Mondimore99, Grant W. Montgomery4, Derek W. Morris155,156, Sara Mostafavi157,158, Thomas W Mühleisen5,159, Niamh Mullins1, Matthias Nauck160,161, Bernard Ng158, Hoang Nguyen24,25, Caroline M. Nievergelt75,162, Michel G. Nivard29, Evaristus A. Nwulia111, Dale R. Nyholt163, Claire O'Donovan98, Paul F. O'Reilly1, Anil P. S. Ori93, Lilijana Oruc164, Urban Ösby165, Hogni Oskarsson166, Jodie N. Painter66, José Guzman Parra167, Carsten Bøcker Pedersen16,32,33, Marianne Giørtz Pedersen16,32,33, Amy Perry100, Roseann E. Peterson41,168, Erik Pettersson3, Wouter J. Peyrot46, Andrea Pfennig45, Giorgio Pistis63, Shaun M. Purcell25,144, Jorge A. Quiroz169, Per Qvist12,13,55, Eline J. Regeer170, Andreas Reif124, Céline S. Reinbold5,9, John P. Rice171, Brien P. Riley41, Fabio Rivas167, Margarita Rivera1,172, Panos Roussos24,25,173, Douglas M. Ruderfer174, Euijung Ryu175, Cristina Sánchez-Mora59,60,62, Alan F. Schatzberg176, William A. Scheftner177, Robert Schoevers178, Nicholas J. Schork179, Eva C. Schulte52,180, Tatyana Shehktman75, Ling Shen118, Jianxin Shi181, Paul D. Shilling75, Stanley I. Shyn182, Engilbert Sigurdsson183, Claire Slaney98, Olav B. Smeland73,184,185, Johannes H. Smit46, Daniel J. Smith186, Janet L. Sobell187, Anne T. Spijker188, Michael Steffens189, John S. Strauss121,190, Fabian Streit91, Jana Strohmaier91, Szabolcs Szelinger191, Katherine E. Tansey192, Henning Teismann193, Alexander Teumer194, Robert C Thompson149, Wesley Thompson55,75,87,107, Pippa A. Thomson195, Thorgeir E. Thorgeirsson26, Matthew Traylor196, Jens Treutlein91, André G. Uitterlinden197, Daniel Umbricht198, Helmut Vedder199, Alexander Viktorin3, Peter M. Visscher4,18, Weiqing Wang24,25, Stanley J. Watson149, Bradley T. Webb168, Cynthia Shannon Weickert102,200, Thomas W. Weickert102,200, Shantel Marie Weinsheimer55,107, Jürgen Wellmann193, Gonneke Willemsen29, Stephanie H. Witt91, Yang Wu4, Hualin S. Xi201, Wei Xu202,203, Jian Yang4,18, Allan H. Young204, Peter Zandi205, Peng Zhang206, Futao Zhang4, Sebastian Zollner149, Rolf Adolfsson31, Ingrid Agartz14,49,207, Martin Alda98,208, Volker Arolt209, Lena Backlund95, Bernhard T. Baune210, Frank Bellivier211,212,213,214, Klaus Berger193, Wade H. Berrettini215, Joanna M. Biernacka175, Douglas H. R. Blackwood30, Michael Boehnke90, Dorret I. Boomsma29, Aiden Corvin156, Nicholas Craddock10, Mark J. Daly21,23, Udo Dannlowski209, Enrico Domenici216, Katharina Domschke217, Tõnu Esko19,147,154,218, Bruno Etain211,213,214,219, Mark Frye220, Janice M. Fullerton200,221, Elliot S. Gershon36,222, EJC de Geus29,223, Michael Gill156, Fernando Goes79, Hans J. Grabe40, Maria Grigoroiu-Serbanescu224, Steven P. Hamilton225, Joanna Hauser72, Caroline Hayward226, Andrew C. Heath171, David M. Hougaard16,43, Christina M. Hultman3, Ian Jones10, Lisa A. Jones100, René S. Kahn25,50, Kenneth S. Kendler41, George Kirov10, Stefan Kloiber115,121,190, Mikael Landén3,227, Marion Leboyer117,211,228, Glyn Lewis17, Qingqin S. Li229, Jolanta Lissowska230, Susanne Lucae115, Pamela A. F. Madden119, Patrik K. Magnusson3, Nicholas G. Martin66,231, Fermin Mayoral167, Susan L. McElroy232, Andrew M. McIntosh30,77, Francis J. McMahon233, Ingrid Melle234,235, Andres Metspalu154,236, Philip B. Mitchell102, Gunnar Morken237,238, Ole Mors16,239, Preben Bo Mortensen12,16,32,33, Bertram Müller-Myhsok37,240,241, Richard M. Myers139, Benjamin M. Neale19,21,23, Vishwajit Nimgaonkar242, Merete Nordentoft16,243, Markus M. Nöthen7,8, Michael C. O'Donovan10, Ketil J. Oedegaard244,245, Michael J. Owen10, Sara A. Paciga246, Carlos Pato126,247, Michele T. Pato126, Nancy L. Pedersen3, Brenda W. J. H. Penninx46, Roy H. Perlis248,249, David J. Porteous195, Danielle Posthuma11,250, James B. Potash79, Martin Preisig63, Josep Antoni Ramos-Quiroga59,60,61,62, Marta Ribasés59,60,62, Marcella Rietschel91, Guy A. Rouleau251,252, Catherine Schaefer118, Martin Schalling94, Peter R. Schofield200,221, Thomas G. Schulze52,79,91,97,233, Alessandro Serretti253, Jordan W. Smoller21,84,85, Hreinn Stefansson26, Kari Stefansson26,254, Eystein Stordal255,256, Henning Tiemeier80,257,258, Gustavo Turecki259, Rudolf Uher98, Arne E. Vaaler260, Eduard Vieta261, John B. Vincent190, Henry Völzke194, Myrna M. Weissman148,262, Thomas Werge16,107,263, Ole A. Andreassen184,185, Anders D. Børglum12,13,16, Sven Cichon5,7,9,159, Howard J. Edenberg264, Arianna Di Florio10,265, John Kelsoe75, Douglas F. Levinson176, Cathryn M. Lewis1,2,266, John I. Nurnberger92,267, Roel A. Ophoff50,51,93, Laura J. Scott90, Pamela Sklar24,25[Dagger], Patrick F. Sullivan3,265,268, and Naomi R. Wray4,18. Byline: Jonathan R.I. Coleman (a,b), Héléna A. Gaspar (a,b), Julien Bryois (c), Enda M. Byrne, Andreas J. Forstner, Peter A. Holmans, Christiaan A. de Leeuw, Manuel Mattheisen, Andrew McQuillin, Jennifer M. Whitehead Pavlides, Tune H. Pers, Stephan Ripke, Eli A. Stahl, Stacy Steinberg, Vassily Trubetskoy, Maciej Trzaskowski, Yunpeng Wang, Liam Abbott, Abdel Abdellaoui, Mark J. Adams, Annelie Nordin Adolfsson, Esben Agerbo, Huda Akil, Diego Albani, Ney Alliey-Rodriguez, Thomas D. Als, Till F.M. Andlauer, Adebayo Anjorin, Verneri Antilla, Sandra Van der Auwera, Swapnil Awasthi, Silviu-Alin Bacanu, Judith A. Badner, Marie Bækvad-Hansen, Jack D. Barchas, Nicholas Bass, Michael Bauer, Aartjan T.F. Beekman, Richard Belliveau, Sarah E. Bergen, Tim B. Bigdeli, Elisabeth B. Binder, Erlend Bøen, Marco Boks, James Boocock, Monika Budde, William Bunney, Margit Burmeister, Henriette N. Buttenschøn, Jonas Bybjerg-Grauholm, William Byerley, Na Cai, Miquel Casas, Enrique Castelao, Felecia Cerrato, Pablo Cervantes, Kimberly Chambert, Alexander W. Charney, Danfeng Chen, Jane Hvarregaard Christensen, Claire Churchhouse, David St Clair, Toni-Kim Clarke, Lucía Colodro-Conde, William Coryell, Baptiste Couvy-Duchesne, David W. Craig, Gregory E. Crawford, Cristiana Cruceanu, Piotr M. Czerski, Anders M. Dale, Gail Davies, Ian J. Deary, Franziska Degenhardt, Jurgen Del-Favero, J Raymond DePaulo, Eske M. Derks, Nese Direk, Srdjan Djurovic, Amanda L. Dobbyn, Conor V. Dolan, Ashley Dumont, Erin C. Dunn, Thalia C. Eley, Torbjørn Elvsåshagen, Valentina Escott-Price, Chun Chieh Fan, Hilary K. Finucane, Sascha B. Fischer, Matthew Flickinger, Jerome C. Foo, Tatiana M. Foroud, Liz Forty, Josef Frank, Christine Fraser, Nelson B. Freimer, Louise Frisén, Katrin Gade, Diane Gage, Julie Garnham, Claudia Giambartolomei, Fernando S. Goes, Jaqueline Goldstein, Scott D. Gordon, Katherine Gordon-Smith, Elaine K. Green, Melissa J. Green, Tiffany A. Greenwood, Jakob Grove, Weihua Guan, Lynsey S. Hall, Marian L. Hamshere, Christine Søholm Hansen, Thomas F. Hansen, Martin Hautzinger, Urs Heilbronner, Albert M. van Hemert, Stefan Herms, Ian B. Hickie, Maria Hipolito, Per Hoffmann, Dominic Holland, Georg Homuth, Carsten Horn, Jouke-Jan Hottenga, Laura Huckins, Marcus Ising, Stéphane Jamain, Rick Jansen, Jessica S. Johnson, Simone de Jong, Eric Jorgenson, Anders Juréus, Radhika Kandaswamy, Robert Karlsson, James L. Kennedy, Farnush Farhadi Hassan Kiadeh, Sarah Kittel-Schneider, James A. Knowles, Manolis Kogevinas, Isaac S. Kohane, Anna C. Koller, Julia Kraft, Warren W. Kretzschmar, Jesper Krogh, Ralph Kupka, Zoltán Kutalik, Catharina Lavebratt, Jacob Lawrence, William B. Lawson, Markus Leber, Phil H. Lee, Shawn E. Levy, Jun Z. Li, Yihan Li, Penelope A. Lind, Chunyu Liu, Loes M. Olde Loohuis, Anna Maaser, Donald J. MacIntyre, Dean F. MacKinnon, Pamela B. Mahon, Wolfgang Maier, Robert M. Maier, Jonathan Marchini, Lina Martinsson, Hamdi Mbarek, Steve McCarroll, Patrick McGrath, Peter McGuffin, Melvin G. McInnis, James D. McKay, Helena Medeiros, Sarah E. Medland, Divya Mehta, Fan Meng, Christel M. Middeldorp, Evelin Mihailov, Yuri Milaneschi, Lili Milani, Saira Saeed Mirza, Francis M. Mondimore, Grant W. Montgomery, Derek W. Morris, Sara Mostafavi, Thomas W. Mühleisen, Niamh Mullins, Matthias Nauck, Bernard Ng, Hoang Nguyen, Caroline M. Nievergelt, Michel G. Nivard, Evaristus A. Nwulia, Dale R. Nyholt, Claire O'Donovan, Paul F. O'Reilly, Anil P.S. Ori, Lilijana Oruc, Urban Ösby, Hogni Oskarsson, Jodie N. Painter, José Guzman Parra, Carsten Bøcker Pedersen, Marianne Giørtz Pedersen, Amy Perry, Roseann E. Peterson, Erik Pettersson, Wouter J. Peyrot, Andrea Pfennig, Giorgio Pistis, Shaun M. Purcell, Jorge A. Quiroz, Per Qvist, Eline J. Regeer, Andreas Reif, Céline S. Reinbold, John P. Rice, Brien P. Riley, Fabio Rivas, Margarita Rivera, Panos Roussos, Douglas M. Ruderfer, Euijung Ryu, Cristina Sánchez-Mora, Alan F. Schatzberg, William A. Scheftner, Robert Schoevers, Nicholas J. Schork, Eva C. Schulte, Tatyana Shehktman, Ling Shen, Jianxin Shi, Paul D. Shilling, Stanley I. Shyn, Engilbert Sigurdsson, Claire Slaney, Olav B. Smeland, Johannes H. Smit, Daniel J. Smith, Janet L. Sobell, Anne T. Spijker, Michael Steffens, John S. Strauss, Fabian Streit, Jana Strohmaier, Szabolcs Szelinger, Katherine E. Tansey, Henning Teismann, Alexander Teumer, Robert C. Thompson, Wesley Thompson, Pippa A. Thomson, Thorgeir E. Thorgeirsson, Matthew Traylor, Jens Treutlein, André G. Uitterlinden, Daniel Umbricht, Helmut Vedder, Alexander Viktorin, Peter M. Visscher, Weiqing Wang, Stanley J. Watson, Bradley T. Webb, Cynthia Shannon Weickert, Thomas W. Weickert, Shantel Marie Weinsheimer, Jürgen Wellmann, Gonneke Willemsen, Stephanie H. Witt, Yang Wu, Hualin S. Xi, Wei Xu, Jian Yang, Allan H. Young, Peter Zandi, Peng Zhang, Futao Zhang, Sebastian Zollner, Rolf Adolfsson, Ingrid Agartz, Martin Alda, Volker Arolt, Lena Backlund, Bernhard T. Baune, Frank Bellivier, Klaus Berger, Wade H. Berrettini, Joanna M. Biernacka, Douglas H.R. Blackwood, Michael Boehnke, Dorret I. Boomsma, Aiden Corvin, Nicholas Craddock, Mark J. Daly, Udo Dannlowski, Enrico Domenici, Katharina Domschke, Tõnu Esko, Bruno Etain, Mark Frye, Janice M. Fullerton, Elliot S. Gershon, E.J.C. de Geus, Michael Gill, Fernando Goes, Hans J. Grabe, Maria Grigoroiu-Serbanescu, Steven P. Hamilton, Joanna Hauser, Caroline Hayward, Andrew C. Heath, David M. Hougaard, Christina M. Hultman, Ian Jones, Lisa A. Jones, René S. Kahn, Kenneth S. Kendler, George Kirov, Stefan Kloiber, Mikael Landén, Marion Leboyer, Glyn Lewis, Qingqin S. Li, Jolanta Lissowska, Susanne Lucae, Pamela A.F. Madden, Patrik K. Magnusson, Nicholas G. Martin, Fermin 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, Richard M. Myers, Benjamin M. Neale, Vishwajit Nimgaonkar, Merete Nordentoft, Markus M. Nöthen, Michael C. O'Donovan, Ketil J. Oedegaard, Michael J. Owen, Sara A. Paciga, Carlos Pato, Michele T. Pato, Nancy L. Pedersen, Brenda W.J. H. Penninx, Roy H. Perlis, David J. Porteous, Danielle Posthuma, James B. Potash, Martin Preisig, Josep Antoni Ramos-Quiroga, Marta Ribasés, Marcella Rietschel, Guy A. Rouleau, Catherine Schaefer, Martin Schalling, Peter R. Schofield, Thomas G. Schulze, Alessandro Serretti, Jordan W. Smoller, Hreinn Stefansson, Kari Stefansson, Eystein Stordal, Henning Tiemeier, Gustavo Turecki, Rudolf Uher, Arne E. Vaaler, Eduard Vieta, John B. Vincent, Henry Völzke, Myrna M. Weissman, Thomas Werge, Ole A. Andreassen, Anders D. Børglum, Sven Cichon, Howard J. Edenberg, Arianna Di Florio, John Kelsoe, Douglas F. Levinson, Cathryn M. Lewis, John I. Nurnberger, Roel A. Ophoff, Laura J. Scott, Pamela Sklar, Patrick F. Sullivan, Naomi R. Wray

Source Citation

Source Citation   

Gale Document Number: GALE|A627967483