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Archival Report| Volume 88, ISSUE 2, P169-184, July 15, 2020

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

Published:October 31, 2019DOI:https://doi.org/10.1016/j.biopsych.2019.10.015
The Genetics of the Mood Disorder Spectrum: Genome-wide Association Analyses of More Than 185,000 Cases and 439,000 Controls
Previous ArticleShared Transcriptional Signatures in Major Depressive Disorder and Mouse Chronic Stress Models
Next ArticlePeripheral Blood Cell–Stratified Subgroups of Inflamed Depression

      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.

      Keywords

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      Article Info

      Publication History

      Published online: October 31, 2019
      Accepted: October 15, 2019
      Received in revised form: September 27, 2019
      Received: May 2, 2019

      Footnotes

      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 Supplement 1): 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. 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      DOI: https://doi.org/10.1016/j.biopsych.2019.10.015

      Copyright

      © 2019 Society of Biological Psychiatry.

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