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 Agartz; Sofie 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

doi:10.1192/bjp.2021.102

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

Research output: Contribution to journal › Article › peer-review

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 language	English (US)
Pages (from-to)	659-669
Number of pages	11
Journal	British Journal of Psychiatry
Volume	219
Issue number	6
DOIs	https://doi.org/10.1192/bjp.2021.102
State	Published - Dec 11 2021

Keywords

Age at onset
Bipolar disorder
GWAS
Polarity at onset
Polygenic score

ASJC Scopus subject areas

Psychiatry and Mental health

Access to Document

10.1192/bjp.2021.102

Cite this

Kalman, J. L., Loohuis, L. M. O., Vreeker, A., McQuillin, A., Stahl, E. A., Ruderfer, D., Grigoroiu-Serbanescu, M., Panagiotaropoulou, G., Ripke, S., Bigdeli, T. B., Stein, F., Meller, T., Meinert, S., Pelin, H., Streit, F., Papiol, S., Adams, M. J., Adolfsson, R., Adorjan, K., ... Ophoff, R. A. (2021). Characterisation of age and polarity at onset in bipolar disorder. British Journal of Psychiatry, 219(6), 659-669. https://doi.org/10.1192/bjp.2021.102

Kalman, JL, Loohuis, LMO, Vreeker, A, McQuillin, A, Stahl, EA, Ruderfer, D, Grigoroiu-Serbanescu, M, Panagiotaropoulou, G, Ripke, S, Bigdeli, TB, Stein, F, Meller, T, Meinert, S, Pelin, H, Streit, F, Papiol, S, Adams, MJ, Adolfsson, R, Adorjan, K, Agartz, I, Aminoff, SR, Anderson-Schmidt, H, Andreassen, OA, Ardau, R, Aubry, JM, Balaban, C, Bass, N, Baune, BT, Bellivier, F, Benabarre, A, Bengesser, S, Berrettini, WH, Boks, MP, Bromet, EJ, Brosch, K, Budde, M, Byerley, W, Cervantes, P, Chillotti, C, Cichon, S, Clark, SR, Comes, AL, Corvin, A, Coryell, W, Craddock, N, Craig, DW, Croarkin, PE, Cruceanu, C, Czerski, PM, Dalkner, N, Dannlowski, U, Degenhardt, F, Del Zompo, M, Depaulo, JR, Djurovic, S, Edenberg, HJ, Al Eissa, M, Elvsåshagen, T, Etain, B, Fanous, AH, Fellendorf, F, Fiorentino, A, Forstner, AJ, Frye, MA, Fullerton, JM, Gade, K, Garnham, J, Gershon, E, Gill, M, Goes, FS, Gordon-Smith, K, Grof, P, Guzman-Parra, J, Hahn, T, Hasler, R, Heilbronner, M, Heilbronner, U, Jamain, S, Jimenez, E, Jones, I, Jones, L, Jonsson, L, Kahn, RS, Kelsoe, JR, Kennedy, JL, Kircher, T, Kirov, G, Kittel-Schneider, S, Klöhn-Saghatolislam, F, Knowles, JA, Kranz, TM, Lagerberg, TV, Landen, M, Lawson, WB, Leboyer, M, Li, QS, Maj, M, Malaspina, D, Manchia, M, Mayoral, F, McElroy, SL, McInnis, MG, McIntosh, AM, Medeiros, H, Melle, I, Milanova, V, Mitchell, PB, Monteleone, P, Monteleone, AM, Nöthen, MM, Novak, T, Nurnberger, JI, O'Brien, N, O'Connell, KS, O'Donovan, C, O'Donovan, MC, Opel, N, Ortiz, A, Owen, MJ, Pålsson, E, Pato, C, Pato, MT, Pawlak, J, Pfarr, JK, Pisanu, C, Potash, JB, Rapaport, MH, Reich-Erkelenz, D, Reif, A, Reininghaus, E, Repple, J, Richard-Lepouriel, H, Rietschel, M, Ringwald, K, Roberts, G, Rouleau, G, Schaupp, S, Scheftner, WA, Schmitt, S, Schofield, PR, Schubert, KO, Schulte, EC, Schweizer, B, Senner, F, Severino, G, Sharp, S, Slaney, C, Smeland, OB, Sobell, JL, Squassina, A, Stopkova, P, Strauss, J, Tortorella, A, Turecki, G, Twarowska-Hauser, J, Veldic, M, Vieta, E, Vincent, JB, Xu, W, Zai, CC, Zandi, PP, Di Florio, A, Smoller, JW, Biernacka, JM, McMahon, FJ, Alda, M, Müller-Myhsok, B, Koutsouleris, N, Falkai, P, Freimer, NB, Andlauer, TFM, Schulze, TG & Ophoff, RA 2021, 'Characterisation of age and polarity at onset in bipolar disorder', British Journal of Psychiatry, vol. 219, no. 6, pp. 659-669. https://doi.org/10.1192/bjp.2021.102

@article{cd3a8495c67a495e8f46231a8d95663a,

title = "Characterisation of age and polarity at onset in bipolar disorder",

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.",

keywords = "Age at onset, Bipolar disorder, GWAS, Polarity at onset, Polygenic score",

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

note = "Funding Information: Amare T. Azmeraw: has received 2020–2022 NARSAD Young Investigator Grant from the Brain & Behaviour Research Foundation. Ole A. Andreassen: speaker{\textquoteright}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{\textquoteright}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{\textquoteright}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 {\textcopyright} The Author(s), 2021.",

year = "2021",

month = dec,

day = "11",

doi = "10.1192/bjp.2021.102",

language = "English (US)",

volume = "219",

pages = "659--669",

journal = "British Journal of Psychiatry",

issn = "0007-1250",

publisher = "Royal College of Psychiatrists",

number = "6",

}

TY - JOUR

T1 - Characterisation of age and polarity at onset in bipolar disorder

AU - Kalman, Janos L.

AU - Loohuis, Loes M.Olde

AU - Vreeker, Annabel

AU - McQuillin, Andrew

AU - Stahl, Eli A.

AU - Ruderfer, Douglas

AU - Grigoroiu-Serbanescu, Maria

AU - Panagiotaropoulou, Georgia

AU - Ripke, Stephan

AU - Bigdeli, Tim B.

AU - Stein, Frederike

AU - Meller, Tina

AU - Meinert, Susanne

AU - Pelin, Helena

AU - Streit, Fabian

AU - Papiol, Sergi

AU - Adams, Mark J.

AU - Adolfsson, Rolf

AU - Adorjan, Kristina

AU - Agartz, Ingrid

AU - Aminoff, Sofie R.

AU - Anderson-Schmidt, Heike

AU - Andreassen, Ole A.

AU - Ardau, Raffaella

AU - Aubry, Jean Michel

AU - Balaban, Ceylan

AU - Bass, Nicholas

AU - Baune, Bernhard T.

AU - Bellivier, Frank

AU - Benabarre, Antoni

AU - Bengesser, Susanne

AU - Berrettini, Wade H.

AU - Boks, Marco P.

AU - Bromet, Evelyn J.

AU - Brosch, Katharina

AU - Budde, Monika

AU - Byerley, William

AU - Cervantes, Pablo

AU - Chillotti, Catina

AU - Cichon, Sven

AU - Clark, Scott R.

AU - Comes, Ashley L.

AU - Corvin, Aiden

AU - Coryell, William

AU - Craddock, Nick

AU - Craig, David W.

AU - Croarkin, Paul E.

AU - Cruceanu, Cristiana

AU - Czerski, Piotr M.

AU - Dalkner, Nina

AU - Dannlowski, Udo

AU - Degenhardt, Franziska

AU - Del Zompo, Maria

AU - Depaulo, J. Raymond

AU - Djurovic, Srdjan

AU - Edenberg, Howard J.

AU - Al Eissa, Mariam

AU - Elvsåshagen, Torbjorn

AU - Etain, Bruno

AU - Fanous, Ayman H.

AU - Fellendorf, Frederike

AU - Fiorentino, Alessia

AU - Forstner, Andreas J.

AU - Frye, Mark A.

AU - Fullerton, Janice M.

AU - Gade, Katrin

AU - Garnham, Julie

AU - Gershon, Elliot

AU - Gill, Michael

AU - Goes, Fernando S.

AU - Gordon-Smith, Katherine

AU - Grof, Paul

AU - Guzman-Parra, Jose

AU - Hahn, Tim

AU - Hasler, Roland

AU - Heilbronner, Maria

AU - Heilbronner, Urs

AU - Jamain, Stephane

AU - Jimenez, Esther

AU - Jones, Ian

AU - Jones, Lisa

AU - Jonsson, Lina

AU - Kahn, Rene S.

AU - Kelsoe, John R.

AU - Kennedy, James L.

AU - Kircher, Tilo

AU - Kirov, George

AU - Kittel-Schneider, Sarah

AU - Klöhn-Saghatolislam, Farah

AU - Knowles, James A.

AU - Kranz, Thorsten M.

AU - Lagerberg, Trine Vik

AU - Landen, Mikael

AU - Lawson, William B.

AU - Leboyer, Marion

AU - Li, Qingqin S.

AU - Maj, Mario

AU - Malaspina, Dolores

AU - Manchia, Mirko

AU - Mayoral, Fermin

AU - McElroy, Susan L.

AU - McInnis, Melvin G.

AU - McIntosh, Andrew M.

AU - Medeiros, Helena

AU - Melle, Ingrid

AU - Milanova, Vihra

AU - Mitchell, Philip B.

AU - Monteleone, Palmiero

AU - Monteleone, Alessio Maria

AU - Nöthen, Markus M.

AU - Novak, Tomas

AU - Nurnberger, John I.

AU - O'Brien, Niamh

AU - O'Connell, Kevin S.

AU - O'Donovan, Claire

AU - O'Donovan, Michael C.

AU - Opel, Nils

AU - Ortiz, Abigail

AU - Owen, Michael J.

AU - Pålsson, Erik

AU - Pato, Carlos

AU - Pato, Michele T.

AU - Pawlak, Joanna

AU - Pfarr, Julia Katharina

AU - Pisanu, Claudia

AU - Potash, James B.

AU - Rapaport, Mark H.

AU - Reich-Erkelenz, Daniela

AU - Reif, Andreas

AU - Reininghaus, Eva

AU - Repple, Jonathan

AU - Richard-Lepouriel, Hélène

AU - Rietschel, Marcella

AU - Ringwald, Kai

AU - Roberts, Gloria

AU - Rouleau, Guy

AU - Schaupp, Sabrina

AU - Scheftner, William A.

AU - Schmitt, Simon

AU - Schofield, Peter R.

AU - Schubert, K. Oliver

AU - Schulte, Eva C.

AU - Schweizer, Barbara

AU - Senner, Fanny

AU - Severino, Giovanni

AU - Sharp, Sally

AU - Slaney, Claire

AU - Smeland, Olav B.

AU - Sobell, Janet L.

AU - Squassina, Alessio

AU - Stopkova, Pavla

AU - Strauss, John

AU - Tortorella, Alfonso

AU - Turecki, Gustavo

AU - Twarowska-Hauser, Joanna

AU - Veldic, Marin

AU - Vieta, Eduard

AU - Vincent, John B.

AU - Xu, Wei

AU - Zai, Clement C.

AU - Zandi, Peter P.

AU - Di Florio, Arianna

AU - Smoller, Jordan W.

AU - Biernacka, Joanna M.

AU - McMahon, Francis J.

AU - Alda, Martin

AU - Müller-Myhsok, Bertram

AU - Koutsouleris, Nikolaos

AU - Falkai, Peter

AU - Freimer, Nelson B.

AU - Andlauer, Till F.M.

AU - Schulze, Thomas G.

AU - Ophoff, Roel A.

N1 - 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.

PY - 2021/12/11

Y1 - 2021/12/11

N2 - 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.

AB - 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.

KW - Age at onset

KW - Bipolar disorder

KW - GWAS

KW - Polarity at onset

KW - Polygenic score

UR - http://www.scopus.com/inward/record.url?scp=85114705031&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85114705031&partnerID=8YFLogxK

U2 - 10.1192/bjp.2021.102

DO - 10.1192/bjp.2021.102

M3 - Article

C2 - 35048876

AN - SCOPUS:85114705031

SN - 0007-1250

VL - 219

SP - 659

EP - 669

JO - British Journal of Psychiatry

JF - British Journal of Psychiatry

IS - 6

ER -

Characterisation of age and polarity at onset in bipolar disorder

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