Characterisation of age and polarity at onset in bipolar disorder

Janos L. Kalman*, Loes M.Olde Loohuis, Annabel Vreeker, Andrew McQuillin, Eli A. Stahl, Douglas Ruderfer, Maria Grigoroiu-Serbanescu, Georgia Panagiotaropoulou, Stephan Ripke, Tim B. Bigdeli, Frederike Stein, Tina Meller, Susanne Meinert, Helena Pelin, Fabian Streit, Sergi Papiol, Mark J. Adams, Rolf Adolfsson, Kristina Adorjan, Ingrid AgartzSofie R. Aminoff, Heike Anderson-Schmidt, Ole A. Andreassen, Raffaella Ardau, Jean Michel Aubry, Ceylan Balaban, Nicholas Bass, Bernhard T. Baune, Frank Bellivier, Antoni Benabarre, Susanne Bengesser, Wade H. Berrettini, Marco P. Boks, Evelyn J. Bromet, Katharina Brosch, Monika Budde, William Byerley, Pablo Cervantes, Catina Chillotti, Sven Cichon, Scott R. Clark, Ashley L. Comes, Aiden Corvin, William Coryell, Nick Craddock, David W. Craig, Paul E. Croarkin, Cristiana Cruceanu, Piotr M. Czerski, Nina Dalkner, Udo Dannlowski, Franziska Degenhardt, Maria Del Zompo, J. Raymond Depaulo, Srdjan Djurovic, Howard J. Edenberg, Mariam Al Eissa, Torbjorn Elvsåshagen, Bruno Etain, Ayman H. Fanous, Frederike Fellendorf, Alessia Fiorentino, Andreas J. Forstner, Mark A. Frye, Janice M. Fullerton, Katrin Gade, Julie Garnham, Elliot Gershon, Michael Gill, Fernando S. Goes, Katherine Gordon-Smith, Paul Grof, Jose Guzman-Parra, Tim Hahn, Roland Hasler, Maria Heilbronner, Urs Heilbronner, Stephane Jamain, Esther Jimenez, Ian Jones, Lisa Jones, Lina Jonsson, Rene S. Kahn, John R. Kelsoe, James L. Kennedy, Tilo Kircher, George Kirov, Sarah Kittel-Schneider, Farah Klöhn-Saghatolislam, James A. Knowles, Thorsten M. Kranz, Trine Vik Lagerberg, Mikael Landen, William B. Lawson, Marion Leboyer, Qingqin S. Li, Mario Maj, Dolores Malaspina, Mirko Manchia, Fermin Mayoral, Susan L. McElroy, Melvin G. McInnis, Andrew M. McIntosh, Helena Medeiros, Ingrid Melle, Vihra Milanova, Philip B. Mitchell, Palmiero Monteleone, Alessio Maria Monteleone, Markus M. Nöthen, Tomas Novak, John I. Nurnberger, Niamh O'Brien, Kevin S. O'Connell, Claire O'Donovan, Michael C. O'Donovan, Nils Opel, Abigail Ortiz, Michael J. Owen, Erik Pålsson, Carlos Pato, Michele T. Pato, Joanna Pawlak, Julia Katharina Pfarr, Claudia Pisanu, James B. Potash, Mark H. Rapaport, Daniela Reich-Erkelenz, Andreas Reif, Eva Reininghaus, Jonathan Repple, Hélène Richard-Lepouriel, Marcella Rietschel, Kai Ringwald, Gloria Roberts, Guy Rouleau, Sabrina Schaupp, William A. Scheftner, Simon Schmitt, Peter R. Schofield, K. Oliver Schubert, Eva C. Schulte, Barbara Schweizer, Fanny Senner, Giovanni Severino, Sally Sharp, Claire Slaney, Olav B. Smeland, Janet L. Sobell, Alessio Squassina, Pavla Stopkova, John Strauss, Alfonso Tortorella, Gustavo Turecki, Joanna Twarowska-Hauser, Marin Veldic, Eduard Vieta, John B. Vincent, Wei Xu, Clement C. Zai, Peter P. Zandi, Arianna Di Florio, Jordan W. Smoller, Joanna M. Biernacka, Francis J. McMahon, Martin Alda, Bertram Müller-Myhsok, Nikolaos Koutsouleris, Peter Falkai, Nelson B. Freimer, Till F.M. Andlauer, Thomas G. Schulze, Roel A. Ophoff

*Corresponding author for this work

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Abstract

Background Studying phenotypic and genetic characteristics of age at onset (AAO) and polarity at onset (PAO) in bipolar disorder can provide new insights into disease pathology and facilitate the development of screening tools. Aims To examine the genetic architecture of AAO and PAO and their association with bipolar disorder disease characteristics. Method Genome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (n = 12 977) and PAO (n = 6773) were conducted in patients with bipolar disorder from 34 cohorts and a replication sample (n = 2237). The association of onset with disease characteristics was investigated in two of these cohorts. Results Earlier AAO was associated with a higher probability of psychotic symptoms, suicidality, lower educational attainment, not living together and fewer episodes. Depressive onset correlated with suicidality and manic onset correlated with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in single-nucleotide variant-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased PGS for autism spectrum disorder (β = -0.34 years, s.e. = 0.08), major depression (β = -0.34 years, s.e. = 0.08), schizophrenia (β = -0.39 years, s.e. = 0.08), and educational attainment (β = -0.31 years, s.e. = 0.08) were associated with an earlier AAO. The AAO GWAS identified one significant locus, but this finding did not replicate. Neither GWAS nor PGS analyses yielded significant associations with PAO. Conclusions AAO and PAO are associated with indicators of bipolar disorder severity. Individuals with an earlier onset show an increased polygenic liability for a broad spectrum of psychiatric traits. Systematic differences in AAO across cohorts, continents and phenotype definitions introduce significant heterogeneity, affecting analyses.

Original languageEnglish
Pages (from-to)659-669
Number of pages11
JournalBritish Journal of Psychiatry
Volume219
Issue number6
DOIs
Publication statusPublished - 11 Dec 2021

Bibliographical note

Funding Information:
Amare T. Azmeraw: has received 2020–2022 NARSAD Young Investigator Grant from the Brain & Behaviour Research Foundation. Ole A. Andreassen: speaker’s honorarium Sunovion, Lundbeck. Consultant HealthLytix. Bernhard Baune: Honoraria: Lundbeck, Janssen, LivaNova, Servier. Carrie Bearden: Novartis Scientific Advisory Board. Clark Scott: Honoraria and Investigator-initiated project funding from Jannsen-Cilag Australia, Lundbeck-Otsuka Australia. J. Raymond DePaulo: owns stock in CVS Health; JRD was unpaid consultant for Myriad Neuroscience 2017 & 2019. Michael C. O´Donovan: research unrelated to this manuscript supported by a collaborative research grant from Takeda Pharmaceuticals. Bruno Etain: honoraria for Sanofi. Mark A. Frye: grant Support Assurex Health, Mayo Foundation, Medibio Consultant (Mayo) Actify Neurotherapies, Allergan, Intra-Cellular Therapies, Inc., Janssen, Myriad, Neuralstem Inc., Sanofi, Takeda, Teva Pharmaceuticals. Per Hoffmann: employee of Life&Brain GmbH, Member of the Scientific Advisory Board of HMG Systems Engeneering GmbH. Mikael Landen: Speaker’s honoraria Lundbeck pharmaceuticals. Andrew M McIntosh: research funding from The Sackler Trust, speaker fees from Illumina and Janssen. Philip B. Mitchell: remuneration for lectures in China on bipolar disorder research by Sanofi (Hangzhou). John Nurnberger: investigator for Janssen. Benjamin M. Neale: is a member of the scientific advisory board at Deep Genomics and RBNC Therapeutics. A consultant for Camp4 Therapeutics, Takeda Pharmaceutical and Biogen. Andreas Reif: apeaker’s honoraria / Advisory boards: Janssen, Shire/Takeda, Medice, SAGE and Servier. Eli Stahl: now employed by the Regeneron Genetics Center. Kato Tadafumi: honoraria: Kyowa Hakko Kirin Co., Ltd., Eli Lilly Japan K.K., Otsuka Pharmaceutical Co., Ltd., GlaxoSmithKline K.K., Taisho Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Taisho Toyama Pharmaceutical Co., Ltd., Dainippon Sumitomo Pharma Co., Ltd., Meiji Seika Pharma Co., Ltd., Pfizer Japan Inc., Mochida Pharmaceutical Co., Ltd., Shionogi & Co., Ltd., Janssen Pharmaceutical K.K., Janssen Asia Pacific, Yoshitomiyakuhin, Astellas Pharma Inc., Nippon, Boehringer Ingelheim Co. Ltd., MSD K.K., Kyowa Pharmaceutical Industry Co., Ltd., Takeda Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Eisai Co., Ltd. Grants: Takeda Pharmaceutical Co., Ltd., Dainippon Sumitomo Pharma Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Shionogi & Co., Ltd., Eisai Co., Ltd., Mitsubishi Tanabe Pharma Corporation. Thomas G. Schulze: is a member of the editorial board of The British Journal of Psychiatry. He did not take part in the review or decision-making process of this paper. Eduard Vieta: has received grants and served as consultant, advisor or CME speaker for the following entities: AB-Biotics, Abbott, Allergan, Angelini, Dainippon Sumitomo Pharma, Ferrer, Gedeon Richter, Janssen, Lundbeck, Otsuka, Sage, Sanofi-Aventis, Sunovion and Takeda. None of the other authors reported any biomedical financial interests or potential conflicts of interest. ICMJE forms are in the supplementary material, available online at https://doi.org/10.1192/10.1192/bjp.2021.102.

Publisher Copyright:
Copyright © The Author(s), 2021.

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