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Genomic dissection of bipolar disorder and schizophrenia including 28 subphenotypes

By Douglas M Ruderfer, Stephan Ripke, Andrew McQuillin, James Boocock, Eli A Stahl, Jennifer M Whitehead Pavlides, Niamh Mullins, Alexander W Charney, Anil P. S. Ori, Loes M Olde Loohuis, Enrico Domenici, Arianna Di Florio, Sergi Papiol, Janos L. Kalman, Rolf Adolfsson, Ingrid Agartz, Esben Agerbo, Huda Akil, Diego Albani, Margot Albus, Martin Alda, Madeline Alexander, Judith Allardyce, Ney Alliey-Rodriguez, Thomas D Als, Farooq Amin, Adebayo Anjorin, Maria J Arranz, Swapnil Awasthi, Silviu A Bacanu, Judith A Badner, Marie Baekvad-Hansen, Steven Bakker, Gavin Band, Jack D. Barchas, Ines Barroso, Nicholas Bass, Michael Bauer, Bernhard T. Baune, Martin Begemann, Celine Bellenguez, Richard A Belliveau, Frank Bellivier, Stephan Bender, Judit Bene, Sarah E Bergen, Wade H Berrettini, Elizabeth Bevilacqua, Joanna M Biernacka, Tim B Bigdeli, Donald W Black, Hannah Blackburn, Jenefer M. Blackwell, Douglas HR Blackwood, Carsten Bocker Pedersen, Michael Boehnke, Marco Boks, Anders D Borglum, Elvira Bramon, Gerome Breen, Matthew A Brown, Richard Bruggeman, Nancy G Buccola, Randy L. Buckner, Monika Budde, Brendan Bulik-Sullivan, Suzannah J Bumpstead, William Bunney, Margit Burmeister, Joseph D. Buxbaum, Jonas Bybjerg-Grauholm, William Byerley, Wiepke Cahn, Guiqing Cai, Murray J Cairns, Dominique Campion, Rita M Cantor, Vaughan J Carr, Noa Carrera, Juan P Casas, Miquel Casas, Stanley V Catts, Pablo Cervantes, Kimberley D Chambert, Raymond CK Chan, Eric YH Chen, Ronald YL Chen, Wei Cheng, Eric FC Cheung, Siow Ann Chong, Toni-Kim Clarke, C Robert Cloninger, David Cohen, Nadine Cohen, Jonathan R. I. Coleman, David A. Collier, Paul Cormican, William Coryell, Nicholas Craddock, David W Craig, Benedicto Crespo-Facorro, James J. Crowley, Cristiana Cruceanu, David Curtis, Piotr M Czerski, Anders M Dale, Mark J. Daly, Udo Dannlowski, Ariel Darvasi, Michael Davidson, Kenneth L Davis, Christiaan A de Leeuw, Franziska Degenhardt, Jurgen Del Favero, Lynn E DeLisi, Panos Deloukas, Ditte Demontis, J. Raymond DePaulo, Marta di Forti, Dimitris Dikeos, Timothy Dinan, Srdjan Djurovic, Amanda L Dobbyn, Peter Donnelly, Gary Donohoe, Elodie Drapeau, Serge Dronov, Jubao Duan, Frank Dudbridge, Audrey Duncanson, Howard Edenberg, Sarah Edkins, Hannelore Ehrenreich, Peter Eichhammer, Torbjorn Elvsashagen, Johan Eriksson, Valentina Escott-Price, Tonu Esko, Laurent Essioux, Bruno Etain, Chun Chieh Fan, Kai-How Farh, Martilias S Farrell, Matthew Flickinger, Tatiana M. Foroud, Liz Forty, Josef Frank, Lude Franke, Christine Fraser, Robert Freedman, Colin Freeman, Nelson B. Freimer, Joseph I Friedman, Menachem Fromer, Mark A Frye, Janice M Fullerton, Katrin Gade, Julie Garnham, Helena A Gaspar, Pablo V Gejman, Giulio Genovese, Lyudmila Georgieva, Claudia Giambartolomei, Eleni Giannoulatou, Ina Giegling, Michael Gill, Matthew Gillman, Marianne Giortz Pedersen, Paola Giusti-Rodriguez, Stephanie Godard, Fernando Goes, Jacqueline I Goldstein, Srihari Gopal, Scott D Gordon, Katherine Gordon-Smith, Jacob Gratten, Emma Gray, Elaine K Green, Melissa J Green, Tiffany A Greenwood, Maria Grigoroiu-Serbanescu, Jakob Grove, Weihua Guan, Hugh Gurling, Jose Guzman Parra, Rhian Gwilliam, Lieuwe de Haan, Jeremy Hall, Mei-Hua Hall, Christian Hammer, Naomi Hammond, Marian L Hamshere, Mark Hansen, Thomas Hansen, Vahram Haroutunian, Annette M Hartmann, Joanna Hauser, Martin Hautzinger, Urs Heilbronner, Garrett Hellenthal, Frans A Henskens, Stefan Herms, Maria Hipolito, Joel N Hirschhorn, Per Hoffmann, Mads V Hollegaard, David M Hougaard, Hailiang Huang, Laura Huckins, Christina M Hultman, Sarah E Hunt, Masashi Ikeda, Nakao Iwata, Conrad Iyegbe, Assen V Jablensky, Stephane Jamain, Janusz Jankowski, Alagurevathi Jayakumar, Inge Joa, Ian Jones, Lisa A Jones, Erik G Jonsson, Antonio Julia, Anders Jureus, Anna K Kahler, Rene S Kahn, Luba Kalaydjieva, Radhika Kandaswamy, Sena Karachanak-Yankova, Juha Karjalainen, Robert Karlsson, David Kavanagh, Matthew C. Keller, Brian J Kelly, John Kelsoe, James L Kennedy, Andrey Khrunin, Yunjung Kim, George Kirov, Sarah Kittel-Schneider, Janis Klovins, Jo Knight, Sarah V Knott, James A. Knowles, Manolis Kogevinas, Bettina Konte, Eugenia Kravariti, Vaidutis Kucinskas, Zita Ausrele Kucinskiene, Ralph Kupka, Hana Kuzelova-Ptackova, Mikael Landen, Cordelia Langford, Claudine Laurent, Jacob Lawrence, Stephen Lawrie, William B Lawson, Markus Leber, Marion Leboyer, Phil H. Lee, Jimmy Lee Chee Keong, Sophie E Legge, Todd Lencz, Bernard Lerer, Douglas F. Levinson, Shawn E. Levy, Cathryn M Lewis, Jun Z Li, Miaoxin Li, Qingqin S Li, Tao Li, Kung-Yee Liang, Jennifer Liddle, Jeffrey Lieberman, Svetlana Limborska, Kuang Lin, Don H Linszen, Jolanta Lissowska, Chunyu Liu, Jianjun Liu, Jouko Lonnqvist, Carmel M Loughland, Jan Lubinski, Susanne Lucae, Milan Macek, Donald J MacIntyre, Patrik K.E. Magnusson, Brion S Maher, Pamela B Mahon, Wolfgang Maier, Anil K. Malhotra, Jacques Mallet, Ulrik F. Malt, Hugh S Markus, Sara Marsal, Nicholas G Martin, Ignacio Mata, Christopher G. Mathew, Manuel Mattheisen, Morten Mattingsdal, Fermin Mayoral, Owen T McCann, Robert W McCarley, Steven A McCarroll, Mark I McCarthy, Colm McDonald, Susan L McElroy, Peter McGuffin, Melvin G Mclnnis, Andrew M McIntosh, James D McKay, Francis J McMahon, Helena Medeiros, Sarah E Medland, Sandra Meier, Carin J Meijer, Bela Melegh, Ingrid Melle, Fan Meng, Raquelle I Mesholam-Gately, Andres Metspalu, Patricia T Michie, Lili Milani, Vihra Milanova, Philip B Mitchell, Younes Mokrab, Grant W. Montgomery, Jennifer L Moran, Gunnar Morken, Derek W Morris, Ole Mors, Preben B Mortensen, Bryan J Mowry, Thomas W Mühleisen, Bertram Müller-Myhsok, Kieran C Murphy, Robin M Murray, Richard M. Myers, Inez Myin-Germeys, Benjamin M Neale, Mari Nelis, Igor Nenadic, Deborah A Nertney, Gerald Nestadt, Kristin K Nicodemus, Caroline M Nievergelt, Liene Nikitina-Zake, Vishwajit Nimgaonkar, Laura Nisenbaum, Merete Nordentoft, Annelie Nordin, Markus M Nöthen, Evaristus A Nwulia, Eadbhard O’Callaghan, Claire O’Donovan, O’Dushlaine Colm, F Anthony O’Neill, Ketil J Oedegaard, Sang-Yun Oh, Ann Olincy, Line Olsen, Lilijana Oruc, Jim Van Os, Michael J Owen, Sara A Paciga, Colin N A Palmer, Aarno Palotie, Christos Pantelis, George N Papadimitriou, Elena Parkhomenko, Carlos Pato, Michele T Pato, Tiina Paunio, Richard Pearson, Psychosis Endophenotypes International Consortium, Diana O Perkins, Roy H Perlis, Amy Perry, Tune H. Pers, Tracey L Petryshen, Andrea Pfennig, Marco Picchioni, Olli Pietilainen, Jonathan Pimm, Matti Pirinen, Robert Plomin, Andrew J Pocklington, Danielle Posthuma, James B. Potash, Simon C Potter, John Powell, Alkes Price, Ann E Pulver, Shaun M. Purcell, Digby Quested, Josep Antoni Ramos-Quiroga, Henrik B Rasmussen, Anna Rautanen, Radhi Ravindrarajah, Eline J Regeer, Abraham Reichenberg, Andreas Reif, Mark A Reimers, Marta Ribases, John P. Rice, Alexander L Richards, Michelle Ricketts, Brien P. Riley, Fabio Rivas, Margarita Rivera, Joshua L. Roffman, Guy A Rouleau, Panos Roussos, Dan Rujescu, Veikko Salomaa, Cristina Sanchez-Mora, Alan R. Sanders, Stephen J Sawcer, Ulrich Schall, Alan F. Schatzberg, William A Scheftner, Peter R. Schofield, Nicholas J Schork, Sibylle G Schwab, Edward M Scolnick, Laura J. Scott, Rodney J. Scott, Larry J Seidman, Alessandro Serretti, Pak C Sham, Cynthia Shannon Weickert, Tatyana Shehktman, Jianxin Shi, Paul D Shilling, Engilbert Sigurdsson, Jeremy M Silverman, Kang Sim, Claire Slaney, Petr Slominsky, Olav B. Smeland, Jordan W. Smoller, Hon-Cheong So, Janet L Sobell, Erik Soderman, Christine Soholm Hansen, Chris C. A. Spencer, Anne T Spijker, David St Clair, Hreinn Stefansson, Kari Stefansson, Stacy Steinberg, Elisabeth Stogmann, Eystein Stordal, Amy Strange, Richard E Straub, John S Strauss, Fabian Streit, Eric Strengman, Jana Strohmaier, T Scott Stroup, Zhan Su, Mythily Subramaniam, Jaana Suvisaari, Dragan M Svrakic, Jin P Szatkiewicz, Szabolcs Szelinger, Avazeh Tashakkori-Ghanbaria, Srinivas Thirumalai, Robert C Thompson, Thorgeir E. Thorgeirsson, Draga Toncheva, Paul A Tooney, Sarah Tosato, Timothea Toulopoulou, Richard C Trembath, Jens Treutlein, Vassily Trubetskoy, Gustavo Turecki, Arne E Vaaler, Helmut Vedder, Eduard Vieta, John Vincent, Peter M. Visscher, Ananth C Viswanathan, Damjan Vukcevic, John Waddington, Matthew Waller, Dermot Walsh, Muriel Walshe, James TR Walters, Dai Wang, Qiang Wang, Weiqing Wang, Yunpeng Wang, Stanley J. Watson, Bradley T Webb, Thomas W Weickert, Daniel R Weinberger, Matthias Weisbrod, Mark Weiser, Thomas Werge, Paul Weston, Pamela Whittaker, Sara Widaa, Durk Wiersma, Dieter B Wildenauer, Nigel M Williams, Stephanie Williams, Stephanie H. Witt, Aaron R Wolen, Emily H.M. Wong, Nicholas W Wood, Brandon K Wormley, Wellcome Trust Case-Control Consortium, Jing Qin Wu, Simon Xi, Wei Xu, Allan H Young, Clement C. Zai, Peter Zandi, Peng Zhang, Xuebin Zheng, Fritz Zimprich, Sebastian Zollner, Aiden Corvin, Ayman H. Fanous, Sven Cichon, Marcella Rietschel, Elliot S Gershon, Thomas G. Schulze, Alfredo B Cuellar-Barboza, Andreas J. Forstner, Peter A Holmans, John I Nurnberger, Ole A Andreassen, S. Hong Lee, Michael C O’Donovan, Patrick F Sullivan, Roel A. Ophoff, Naomi R. Wray, Pamela Sklar, Kenneth Kendler

Posted 08 Aug 2017
bioRxiv DOI: 10.1101/173435 (published DOI: 10.1016/j.cell.2018.05.046)

Schizophrenia (SCZ) and bipolar disorder (BD) are highly heritable disorders that share a significant proportion of common risk variation. Understanding the genetic factors underlying the specific symptoms of these disorders will be crucial for improving diagnosis, intervention and treatment. In case-control data consisting of 53,555 cases (20,129 BD, 33,426 SCZ) and 54,065 controls, we identified 114 genome-wide significant loci (GWS) when comparing all cases to controls, of which 41 represented novel findings. Two genome-wide significant loci were identified when comparing SCZ to BD and a third was found when directly incorporating functional information. Regional joint association identified a genomic region of overlapping association in BD and SCZ with disease-independent causal variants indicating a fourth region contributing to differences between these disorders. Regional SNP-heritability analyses demonstrated that the estimated heritability of BD based on the SCZ GWS regions was significantly higher than that based on the average genomic region (91 regions, p = 1.2x10-6) while the inverse was not significant (19 regions, p=0.89). Using our BD and SCZ GWAS we calculated polygenic risk scores and identified several significant correlations with: 1) SCZ subphenotypes: negative symptoms (SCZ, p=3.6x10-6) and manic symptoms (BD, p=2x10-5), 2) BD subphenotypes: psychotic features (SCZ p=1.2x10-10, BD p=5.3x10-5) and age of onset (SCZ p=7.9x10-4). Finally, we show that psychotic features in BD has significant SNP-heritability (h2snp=0.15, SE=0.06), and a significant genetic correlation with SCZ (rg=0.34) in addition there is a significant sign test result between SCZ GWAS and a GWAS of BD cases contrasting those with and without psychotic features (p=0.0038, one-side binomial test). For the first time, we have identified specific loci pointing to a potential role of 4 genes (DARS2, ARFGEF2, DCAKD and GATAD2A) that distinguish between BD and SCZ, providing an opportunity to understand the biology contributing to clinical differences of these disorders. Our results provide the best evidence so far of genomic components distinguishing between BD and SCZ that contribute directly to specific symptom dimensions.

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