Transcriptomic Imputation of Bipolar Disorder and Bipolar subtypes reveals 29 novel associated genes

Laura M. Huckins, Amanda Dobbyn, Whitney McFadden, Weiqing Wang, Douglas M. Ruderfer, Gabriel Hoffman, Veera Rajagopal, Hoang T. Nguyen, Panos Roussos, Menachem Fromer, Robin Kramer, Enrico Domenci, Eric Gamazon, Vahram Haroutunian, Mette A. Peters, Bernie Devlin, Solveig K. Sieberts, Nancy Cox, Hae Kyung Im, Pamela SklarEli A. Stahl, Laura Huckins, James Boocock, Claudia Giambartolomei, Panos Roussos, Niamh Mullins, Swapnil Awasthi, Esben Agerbo, Thomas D. Als, Carsten Bøcker Pedersen, Jakob Grove, Ralph Kupka, Eline J. Regeer, Adebayo Anjorin, Miquel Casas, Cristina Sánchez-Mora, Pamela B. Mahon, Shaun M. Purcell, Steve McCarroll, Judith Allardyce, Valentina Escott-Price, Liz Forty, Christine Fraser, Marian L. Hamshere, George Kirov, Manolis Kogevinas, Josef Frank, Fabian Streit, Jana Strohmaier, Jens Treutlein, Stephanie H. Witt, James L. Kennedy, John S. Strauss, Julie Garnham, Claire O’Donovan, Claire Slaney, Stacy Steinberg, Thorgeir E. Thorgeirsson, Martin Hautzinger, Michael Steffens, Ralph Kupka, Steve McCarroll, Roy H. Perlis, Miquel Casas, Cristina Sánchez-Mora, Maria Hipolito, William B. Lawson, Evaristus A. Nwulia, Shawn E. Levy, Shaun M. Purcell, Tatiana M. Foroud, Stéphane Jamain, Allan H. Young, James D. McKay, Thomas D. Als, Carsten Bøcker Pedersen, Jakob Grove, Diego Albani, Peter Zandi, Pamela Lynn Belmonte Mahon, James B. Potash, Peng Zhang, J. Raymond DePaulo, Sarah E. Bergen, Anders Juréus, Robert Karlsson, Radhika Kandaswamy, Peter McGuffin, Margarita Rivera, Jolanta Lissowska, Roy H. Perlis, Cristiana Cruceanu, Susanne Lucae, Pablo Cervantes, Monika Budde, Katrin Gade, Urs Heilbronner, Marianne Giørtz Pedersen, Carsten Bøcker Pedersen, Derek W. Morris, Cynthia Shannon Weickert, Thomas W. Weickert, Donald J. MacIntyre, Jacob Lawrence, Torbjørn Elvsåshagen, Olav B. Smeland, Srdjan Djurovic, Simon Xi, Elaine K. Green, Piotr M. Czerski, Joanna Hauser, Wei Xu, Helmut Vedder, Lilijana Oruc, Anne T. Spijker, Scott D. Gordon, Sarah E. Medland, David Curtis, Thomas W. Mühleisen, Judith Badner, William A. Scheftner, Engilbert Sigurdsson, Nicholas J. Schork, Alan F. Schatzberg, Marie B¾kvad-Hansen, Jonas Bybjerg-Grauholm, Christine Søholm Hansen, James A. Knowles, Helena Medeiros, Szabolcs Szelinger, Grant W. Montgomery, Derek W. Morris, Marco Boks, Annelie Nordin Adolfsson, Miquel Casas, Stéphane Jamain, Nicholas Bass, David Curtis, Per Hoffmann, Michael Bauer, Andrea Pfennig, Markus Leber, Sarah Kittel-Schneider, Andreas Reif, Katrin Gade, Jurgen Del-Favero, Sascha B. Fischer, Stefan Herms, Per Hoffmann, Thomas W. Mühleisen, Céline S. Reinbold, Srdjan Djurovic, Franziska Degenhardt, Stefan Herms, Per Hoffmann, Anna C. Koller, Anna Maaser, Wolfgang Maier, Nelson B. Freimer, Anil Ori, Anders M. Dale, Chun Chieh Fan, Tiffany A. Greenwood, Caroline M. Nievergelt, Tatyana Shehktman, Paul D. Shilling, Olav B. Smeland, William Byerley, William Bunney, Ney Alliey-Rodriguez, Douglas H.R. Blackwood, Toni Kim Clarke, Donald J. MacIntyre, Margarita Rivera, Chunyu Liu, William Coryell, Huda Akil, Margit Burmeister, Matthew Flickinger, Jun Z. Li, Melvin G. McInnis, Fan Meng, Robert C. Thompson, Stanley J. Watson, Sebastian Zollner, Weihua Guan, Melissa J. Green, Cynthia Shannon Weickert, Thomas W. Weickert, Olav B. Smeland, David Craig, Janet L. Sobell, Lili Milani, James L. Kennedy, John S. Strauss, Wei Xu, Katherine Gordon-Smith, Sarah V. Knott, Amy Perry, José Guzman Parra, Fermin Mayoral, Fabio Rivas, Miquel Casas, Cristina Sánchez-Mora, Caroline M. Nievergelt, Ralph Kupka, John P. Rice, Jack D. Barchas, Anders D. Børglum, Preben Bo Mortensen, Ole Mors, Maria Grigoroiu-Serbanescu, Frank Bellivier, Bruno Etain, Marion Leboyer, Josep Antoni Ramos-Quiroga, Marta Ribasés, Tõnu Esko, Jordan W. Smoller, Nicholas Craddock, Ian Jones, Michael J. Owen, Marcella Rietschel, Thomas G. Schulze, John Vincent, Tõnu Esko, Eduard Vieta, Merete Nordentoft, Martin Alda, Hreinn Stefansson, Kari Stefansson, Danielle Posthuma, Ingrid Agartz, Frank Bellivier, Tõnu Esko, Ketil J. Oedegaard, Eystein Stordal, Josep Antoni Ramos-Quiroga, Marta Ribasés, Richard M. Myers, René S. Kahn, Frank Bellivier, Bruno Etain, Marion Leboyer, Bruno Etain, Anders D. Børglum, Ole Mors, Thomas Werge, Qingqin S. Li, Thomas G. Schulze, Fernando Goes, Ingrid Agartz, Christina M. Hultman, Mikael Landén, Patrick F. Sullivan, Cathryn M. Lewis, Susan L. McElroy, Jordan W. Smoller, Bertram Müller-Myhsok, Joanna M. Biernacka, Mark Frye, Gustavo Turecki, Guy A. Rouleau, Thomas G. Schulze, Thomas Werge, Guy A. Rouleau, Bertram Müller-Myhsok, Martin Alda, Francis J. McMahon, Thomas G. Schulze, Janice M. Fullerton, Peter R. Schofield, Eystein Stordal, Gunnar Morken, Ulrik F. Malt, Ingrid Melle, Sara A. Paciga, Nicholas G. Martin, Arne E. Vaaler, Gunnar Morken, David M. Hougaard, Carlos Pato, Michele T. Pato, Nicholas G. Martin, Aiden Corvin, Michael Gill, René S. Kahn, Rolf Adolfsson, Josep Antoni Ramos-Quiroga, Frank Bellivier, Bruno Etain, Marion Leboyer, Thomas G. Schulze, Bernhard T. Baune, Ketil J. Oedegaard, Alessandro Serretti, Markus M. Nöthen, Elliot S. Gershon, Thomas Werge, Andrew M. McIntosh, Mikael Landén, Kari Stefansson, Bertram Müller-Myhsok, Michael Boehnke, Udo Dannlowski, Janice M. Fullerton, Philip B. Mitchell, Peter R. Schofield, Patrick F. Sullivan, Ingrid Agartz, Ingrid Melle, Wade H. Berrettini, Vishwajit Nimgaonkar, Tõnu Esko, Andres Metspalu, Lisa A. Jones, Josep Antoni Ramos-Quiroga, Marta Ribasés, John Nurnberger, Naomi R. Wray, Arianna Di Florio, Michael C. O’Donovan, Howard Edenberg, Roel A. Ophoff, Laura J. Scott, Sven Cichon, Ole A. Andreassen, Pamela Sklar, John Kelsoe, Gerome Breen

Research output: Contribution to journalArticlepeer-review

Abstract

Bipolar disorder is a complex neuropsychiatric disorder presenting with episodic mood disturbances. In this study we use a transcriptomic imputation approach to identify novel genes and pathways associated with bipolar disorder, as well as three diagnostically and genetically distinct subtypes. Transcriptomic imputation approaches leverage well-curated and publicly available eQTL reference panels to create gene-expression prediction models, which may then be applied to “impute” genetically regulated gene expression (GREX) in large GWAS datasets. By testing for association between phenotype and GREX, rather than genotype, we hope to identify more biologically interpretable associations, and thus elucidate more of the genetic architecture of bipolar disorder.We applied GREX prediction models for 13 brain regions (derived from CommonMind Consortium and GTEx eQTL reference panels) to 21,488 bipolar cases and 54,303 matched controls, constituting the largest transcriptomic imputation study of bipolar disorder (BPD) to date. Additionally, we analyzed three specific BPD subtypes, including 14,938 individuals with subtype 1 (BD-I), 3,543 individuals with subtype 2 (BD-II), and 1,500 individuals with schizoaffective subtype (SAB).We identified 125 gene-tissue associations with BPD, of which 53 represent independent associations after FINEMAP analysis. 29/53 associations were novel; i.e., did not lie within 1Mb of a locus identified in the recent PGC-BD GWAS. We identified 37 independent BD-I gene-tissue associations (10 novel), 2 BD-II associations, and 2 SAB associations. Our BPD, BD-I and BD-II associations were significantly more likely to be differentially expressed in post-mortem brain tissue of BPD, BD-I and BD-II cases than we might expect by chance. Together with our pathway analysis, our results support long-standing hypotheses about bipolar disorder risk, including a role for oxidative stress and mitochondrial dysfunction, the post-synaptic density, and an enrichment of circadian rhythm and clock genes within our results.

Original languageEnglish (US)
JournalUnknown Journal
DOIs
StatePublished - Nov 21 2017

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • Immunology and Microbiology(all)
  • Neuroscience(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)

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