Characterisation of age and polarity at onset in bipolar disorder

Kalman, Janos L., Olde Loohuis, Loes M., Vreeker, Annabel, McQuillin, Andrew, Stahl, Eli A., Ruderfer, Douglas, Grigoroiu-Serbanescu, Maria, Panagiotaropoulou, Georgia, Ripke, Stephan, Bigdeli, Tim B., Stein, Frederike, Meller, Tina, Meinert, Susanne, Pelin, Helena, Streit, Fabian, Papiol, Sergi, Adams, Mark J., Adolfsson, Rolf, Adorjan, Kristina, Agartz, Ingrid, Aminoff, Sofie R., Anderson-Schmidt, Heike, Andreassen, Ole A., Ardau, Raffaella, Aubry, Jean-Michel, Balaban, Ceylan, Bass, Nicholas, Baune, Bernhard T., Bellivier, Frank, Benabarre, Antoni, Bengesser, Susanne, Berrettini, Wade H, Boks, Marco P., Bromet, Evelyn J., Brosch, Katharina, Budde, Monika, Byerley, William, Cervantes, Pablo, Chillotti, Catina, Cichon, Sven, Clark, Scott R., Comes, Ashley L., Corvin, Aiden, Coryell, William, Craddock, Nick, Craig, David W., Croarkin, Paul E., Cruceanu, Cristiana, Czerski, Piotr M., Dalkner, Nina, Dannlowski, Udo, Degenhardt, Franziska, Del Zompo, Maria, DePaulo, J. Raymond, Djurovic, Srdjan, Edenberg, Howard J., Eissa, Mariam Al, Elvsåshagen, Torbjørn, Etain, Bruno, Fanous, Ayman H., Fellendorf, Frederike, Fiorentino, Alessia, Forstner, Andreas J., Frye, Mark A., Fullerton, Janice M., Gade, Katrin, Garnham, Julie, Gershon, Elliot, Gill, Michael, Goes, Fernando S., Gordon-Smith, Katherine, Grof, Paul, Guzman-Parra, Jose, Hahn, Tim, Hasler, Roland, Heilbronner, Maria, Heilbronner, Urs, Jamain, Stephane, Jimenez, Esther, Jones, Ian ORCID: https://orcid.org/0000-0001-5821-5889, Jones, Lisa, Jonsson, Lina, Kahn, Rene S., Kelsoe, John R., Kennedy, James L., Kircher, Tilo, Kirov, George ORCID: https://orcid.org/0000-0002-3427-3950, Kittel-Schneider, Sarah, Klöhn-Saghatolislam, Farah, Knowles, James A., Kranz, Thorsten M., Lagerberg, Trine Vik, Landen, Mikael, Lawson, William B., Leboyer, Marion, Li, Qingqin S., Maj, Mario, Malaspina, Dolores, Manchia, Mirko, Mayoral, Fermin, McElroy, Susan L., McInnis, Melvin G., McIntosh, Andrew M., Medeiros, Helena, Melle, Ingrid, Milanova, Vihra, Mitchell, Philip B., Monteleone, Palmiero, Monteleone, Alessio Maria, Nöthen, Markus M., Novak, Tomas, Nurnberger, John I., O'Brien, Niamh, O'Connell, Kevin S., O'Donovan, Claire, O'Donovan, Michael C. ORCID: https://orcid.org/0000-0001-7073-2379, Opel, Nils, Ortiz, Abigail, Owen, Michael J. ORCID: https://orcid.org/0000-0003-4798-0862, Pålsson, Erik, Pato, Carlos, Pato, Michele T., Pawlak, Joanna, Pfarr, Julia-Katharina, Pisanu, Claudia, Potash, James B., Rapaport, Mark H, Reich-Erkelenz, Daniela, Reif, Andreas, Reininghaus, Eva, Repple, Jonathan, Richard-Lepouriel, Hélène, Rietschel, Marcella, Ringwald, Kai, Roberts, Gloria, Rouleau, Guy, Schaupp, Sabrina, Scheftner, William A, Schmitt, Simon, Schofield, Peter R., Schubert, K. Oliver, Schulte, Eva C., Schweizer, Barbara, Senner, Fanny, Severino, Giovanni, Sharp, Sally, Slaney, Claire, Smeland, Olav B., Sobell, Janet L., Squassina, Alessio, Stopkova, Pavla, Strauss, John, Tortorella, Alfonso, Turecki, Gustavo, Twarowska-Hauser, Joanna, Veldic, Marin, Vieta, Eduard, Vincent, John B., Xu, Wei, Zai, Clement C., Zandi, Peter P., Di Florio, Arianna ORCID: https://orcid.org/0000-0003-0338-2748, Smoller, Jordan W., Biernacka, Joanna M., McMahon, Francis J., Alda, Martin, Müller-Myhsok, Bertram, Koutsouleris, Nikolaos, Falkai, Peter, Freimer, Nelson B., Andlauer, Till F.M., Schulze, Thomas G. and Ophoff, Roel A. 2021. Characterisation of age and polarity at onset in bipolar disorder. The British Journal of Psychiatry 219 (6) , pp. 659-669. 10.1192/bjp.2021.102

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Publisher:	Cambridge University Press
ISSN:	0007-1250
Date of First Compliant Deposit:	16 March 2023
Date of Acceptance:	1 July 2021
Last Modified:	09 May 2023 02:31
URI:	https://orca.cardiff.ac.uk/id/eprint/157768

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