Genomic dimensions deconstruct the clinical heterogeneity of bipolar disorder.
Research square
Authors:
Tracey van der Veen, Markos Tesfaye, Jessica Mei Kay Yang, Toni Boltz, Friederike S David, Shane Crinion, Maria Koromina, Till F M Andlauer, Tim B Bigdeli, Brandon J Coombes, Tiffany A Greenwood, Georgia Panagiotaropoulou, Nadine Parker, Heejong Sung, Nicholas Bass, Jonathan R I Coleman, José Guzman-Parra, Janos L Kalman, Caroline C McGrouther, Brittany L Mitchell, Aaditya V Rangan, Katie Scott, Alexey Shadrin, Daniel J Smith, Annabel Vreeker, Kristina Adorjan, Diego Albani, Silvia Alemany, Ney Alliey-Rodriguez, Anastasia Antoniou, Michael Bauer, Eva C Beins, Marco P Boks, Rosa Bosch, Ben M Brumpton, Nathalie Brunkhorst-Kanaan, Monika Budde, William Byerley, Judit Cabana-Domínguez, Murray J Cairns, Bernardo Carpiniello, Miquel Casas, Pablo Cervantes, Chris Chatzinakos, Toni-Kim Clarke, Isabelle Claus, Cristiana Cruceanu, Alfredo Cuellar-Barboza, Piotr M Czerski, Konstantinos Dafnas, Anders M Dale, Nina Dalkner, J Raymond DePaulo, Franziska Degenhardt, Srdjan Djurovic, Valentina Escott-Price, Ayman H Fanous, Frederike T Fellendorf, I Nicol Ferrier, Liz Forty, Josef Frank, Oleksandr Frei, Nelson B Freimer, Julie Garnham, Ian R Gizer, Scott D Gordon, Katherine Gordon-Smith, Tim Hahn, Marian L Hamshere, Arvid Harder, Martin Hautzinger, Urs Heilbronner, Dennis Hellgren, Stefan Herms, Ian B Hickie, Per Hoffmann, Peter A Holmans, Stéphane Jamain, Lina Jonsson, James L Kennedy, Sarah Kittel-Schneider, James A Knowles, Elise Koch, Manolis Kogevinas, Thorsten M Kranz, Steven A Kushner, Catharina Lavebratt, Jacob Lawrence, Markus Leber, Penelope A Lind, Susanne Lucae, Martin Lundberg, Donald J MacIntyre, Wolfgang Maier, Adam X Maihofer, Dolores Malaspina, Mirko Manchia, Eirini Maratou, Lina Martinsson, Melvin G McInnis, James D McKay, Helena Medeiros, Andreas Meyer-Lindenberg, Vincent Millischer, Derek W Morris, Paraskevi Moutsatsou, Thomas W Mühleisen, Claire O'Donovan, Catherine M Olsen, Sergi Papiol, Antonio F Pardiñas, Amy Perry, Andrea Pfennig, Claudia Pisanu, James B Potash, Digby Quested, Mark H Rapaport, Eline J Regeer, John P Rice, Margarita Rivera, Eva C Schulte, Fanny Senner, Paul D Shilling, Lisa Sindermann, Lea Sirignano, Dan Siskind, Claire Slaney, Olav B Smeland, Janet L Sobell, Maria Soler Artigas, Dan J Stein, Frederike Stein, Beata Swiatkowska, Jackson G Thorp, Claudio Toma, Leonardo Tondo, Paul A Tooney, Marquis P Vawter, Helmut Vedder, James T R Walters, Stephanie H Witt, Allan H Young, Peter P Zandi, Lea Zillich, Rolf Adolfsson, Lars Alfredsson, Lena Backlund, Bernhard T Baune, Frank Bellivier, Susanne Bengesser, Wade H Berrettini, Joanna M Biernacka, Douglas Blackwood, Michael Boehnke, Gerome Breen, Vaughan J Carr, Stanley Catts, Sven Cichon, Aiden Corvin, Nicholas Craddock, Udo Dannlowski, Dimitris Dikeos, Tõnu Esko, Bruno Etain, Panagiotis Ferentinos, Mark Frye, Janice M Fullerton, Micha Gawlik, Elliot S Gershon, Fernando S Goes, Melissa J Green, Joanna Hauser, Frans A Henskens, Jens Hjerling-Leffler, Ian Jones, Lisa A Jones, René S Kahn, John R Kelsoe, Tilo Kircher, George Kirov, Nene Kobayashi, Mikael Landén, Marion Leboyer, Melanie Lenger, Qingqin S Li, Jolanta Lissowska, Carmel Loughland, Jurjen J Luykx, Nicholas G Martin, Carol A Mathews, Fermin Mayoral, Susan L McElroy, Andrew M McIntosh, Sarah E Medland, Ingrid Melle, Philip B Mitchell, Gunnar Morken, Richard M Myers, Chiara Möser, Bertram Müller-Myhsok, Benjamin M Neale, Caroline M Nievergelt, John I Nurnberger, Markus M Nöthen, Michael C O'Donovan, Ketil J Oedegaard, Tomas Olsson, Michael J Owen, Sara A Paciga, Christos Pantelis, Carlos N Pato, Michele T Pato, George P Patrinos, Joanna M Pawlak, Roy Perlis, Josep Antoni Ramos-Quiroga, Andreas Reif, Eva Z Reininghaus, Marta Ribasés, Marcella Rietschel, Stephan Ripke, Guy A Rouleau, Ulrich Schall, Martin Schalling, Peter R Schofield, Thomas G Schulze, Laura J Scott, Rodney J Scott, Alessandro Serretti, Jordan W Smoller, Alessio Squassina, Eli A Stahl, Eystein Stordal, Fabian Streit, Patrick F Sullivan, Gustavo Turecki, Arne E Vaaler, Eduard Vieta, John B Vincent, Irwin D Waldman, Cynthia S Weickert, Thomas W Weickert, David C Whiteman, Martin Alda, Roel A Ophoff, Kevin S O'Connell, Niamh Mullins, Andreas J Forstner, Maria Grigoroiu-Serbanescu, Howard J Edenberg, Francis J McMahon, Ole A Andreassen, Arianna Di Florio, Andrew McQuillin
Bipolar disorder's (BD) clinical heterogeneity has an unresolved genetic basis. We meta-analyzed genome-wide association studies (GWAS) of 16 BD subphenotypes in 226,032 individuals from 57 cohorts (38,022 cases); 10 advanced to multivariate and multi-trait analyses. Four factors (compulsive, psychotic, dysregulated, internalizing) explained 82.8% of shared genetic variance. BD1 and BD2 loaded on distinct factors despite a high genetic correlation; 87.0% of common-factor loci were significant in neither subtype. Unipolar mania aligned with psychosis over internalizing, and was distinguishable from BD1, and rapid cycling showed heritable cross-domain liability. We identified 356 risk loci, 158 novel, including the first univariate-GWAS associations for psychosis, unipolar mania, rapid cycling and schizoaffective disorder-and 249 credible genes (89 high-confidence), 12 with approved-drug or clinical-phase annotations. Cell-type association showed a midbrain dopaminergic-GABAergic gradient along the psychotic factor. BD's genetic architecture appears hierarchical-a general liability resolving into dimensions of course and comorbidity, beyond subtypes.