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Characterisation of age and polarity at onset in bipolar disorder

2021; Cambridge University Press; Volume: 219; Issue: 6 Linguagem: Inglês

10.1192/bjp.2021.102

1472-1465

János Kálmán, Loes M. Olde Loohuis, Annabel Vreeker, Andrew McQuillin, Eli A. Stahl, Douglas M. Ruderfer, Maria Grigoroiu‐Serbânescu, 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, Torbjørn Elvsåshagen, Bruno Étain, Ayman H. Fanous, Frederike T. Fellendorf, Alessia Fiorentino, Andreas J. Forstner, Mark A. Frye, Janice M. Fullerton, Katrin Gade, Julie Garnham, Elliot S. Gershon, Michael Gill, Fernando S. Goes, Katherine Gordon‐Smith, Paul Grof, José Guzmán‐Parra, Tim Hahn, Roland Hasler, Maria Heilbronner, Urs Heilbronner, Stéphane Jamain, Esther Jiménez, Ian Jones, Lisa Jones, Lina Jönsson, René 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 Landén, William Lawson, Marion Leboyer, Qingqin S. Li, Mario Maj, Dolores Malaspina, Mirko Manchia, Fermín 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, Tomáš Novák, John I. Nürnberger, Niamh L. O’Brien, Kevin S. O’Connell, Claire O’Donovan, Michael O’Donovan, Nils Opel, Abigail Ortiz, Michael J. Owen, Erik Pålsson, Carlos N. Pato, Michele T. Pato, Joanna Pawlak, Julia‐Katharina Pfarr, Claudia Pisanu, James B. Potash, Mark Hyman Rapaport, Daniela Reich‐Erkelenz, Andreas Reif, Eva Z. Reininghaus, Jonathan Repple, Hélène Richard-Lepouriel, Marcella Rietschel, Kai G. Ringwald, Gloria Roberts, Guy A. Rouleau, Sabrina K. Schaupp, William A. Scheftner, Simon Schmitt, Peter R. Schofield, Klaus Oliver Schubert, Eva C. Schulte, Barbara Schweizer, Fanny Senner, Giovanni Severino, Sally I. Sharp, Claire Slaney, Olav B. Smeland, Janet L. Sobell, Alessio Squassina, Pavla Stopková, John S. Strauss, Alfonso Tortorella, Gustavo Turecki, Joanna Hauser, Marin Veldić, 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,

Adolescent and Pediatric Healthcare

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.