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  Characterisation of age and polarity at onset in bipolar disorder

Kalman, J. L., Loohuis, L. M. O., Vreeker, A., McQuillin, A., Stahl, E. A., Ruderfer, D., et al. (2021). Characterisation of age and polarity at onset in bipolar disorder. BRITISH JOURNAL OF PSYCHIATRY, 219(6): PII S0007125021001021, pp. 659-669. doi:10.1192/bjp.2021.102.

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Kalman, Janos L.1, Author           
Loohuis, Loes M. Olde, Author
Vreeker, Annabel, Author
McQuillin, Andrew, Author
Stahl, Eli A., Author
Ruderfer, Douglas, Author
Grigoroiu-Serbanescu, Maria, Author
Panagiotaropoulou, Georgia, Author
Ripke, Stephan, Author
Bigdeli, Tim B., Author
Stein, Frederike, Author
Meller, Tina, Author
Meinert, Susanne, Author
Pelin, Helena1, 2, Author           
Streit, Fabian, Author
Papiol, Sergi, Author
Adams, Mark J., Author
Adolfsson, Rolf, Author
Adorjan, Kristina, Author
Agartz, Ingrid, Author
Aminoff, Sofie R., AuthorAnderson-Schmidt, Heike, AuthorAndreassen, Ole A., AuthorArdau, Raffaella, AuthorAubry, Jean-Michel, AuthorBalaban, Ceylan, AuthorBass, Nicholas, AuthorBaune, Bernhard T., AuthorBellivier, Frank, AuthorBenabarre, Antoni, AuthorBengesser, Susanne, AuthorBerrettini, Wade H., AuthorBoks, Marco P., AuthorBromet, Evelyn J., AuthorBrosch, Katharina, AuthorBudde, Monika, AuthorByerley, William, AuthorCervantes, Pablo, AuthorChillotti, Catina, AuthorCichon, Sven, AuthorClark, Scott R., AuthorComes, Ashley L., AuthorCorvin, Aiden, AuthorCoryell, William, AuthorCraddock, Nick, AuthorCraig, David W., AuthorCroarkin, Paul E., AuthorCruceanu, Cristiana3, Author           Czerski, Piotr M., AuthorDalkner, Nina, AuthorDannlowski, Udo, AuthorDegenhardt, Franziska, AuthorDel Zompo, Maria, AuthorDePaulo, J. Raymond, AuthorDjurovic, Srdjan, AuthorEdenberg, Howard J., AuthorAl Eissa, Mariam, AuthorElvsashagen, Torbjorn, AuthorEtain, Bruno, AuthorFanous, Ayman H., AuthorFellendorf, Frederike, AuthorFiorentino, Alessia, AuthorForstner, Andreas J., AuthorFrye, Mark A., AuthorFullerton, Janice M., AuthorGade, Katrin, AuthorGarnham, Julie, AuthorGershon, Elliot, AuthorGill, Michael, AuthorGoes, Fernando S., AuthorGordon-Smith, Katherine, AuthorGrof, Paul, AuthorGuzman-Parra, Jose, AuthorHahn, Tim, AuthorHasler, Roland, AuthorHeilbronner, Maria, AuthorHeilbronner, Urs, AuthorJamain, Stephane, AuthorJimenez, Esther, AuthorJones, Ian, AuthorJones, Lisa, AuthorJonsson, Lina, AuthorKahn, Rene S., AuthorKelsoe, John R., AuthorKennedy, James L., AuthorKircher, Tilo, AuthorKirov, George, AuthorKittel-Schneider, Sarah, AuthorKlohn-Saghatolislam, Farah, AuthorKnowles, James A., AuthorKranz, Thorsten M., AuthorLagerberg, Trine Vik, AuthorLanden, Mikael, AuthorLawson, William B., AuthorLeboyer, Marion, AuthorLi, Qingqin S., AuthorMaj, Mario, AuthorMalaspina, Dolores, AuthorManchia, Mirko, AuthorMayoral, Fermin, AuthorMcElroy, Susan L., AuthorMcInnis, Melvin G., AuthorMcIntosh, Andrew M., AuthorMedeiros, Helena, AuthorMelle, Ingrid, AuthorMilanova, Vihra, AuthorMitchell, Philip B., AuthorMonteleone, Palmiero, AuthorMonteleone, Alessio Maria, AuthorNothen, Markus M., AuthorNovak, Tomas, AuthorNurnberger I, John, AuthorO'Brien, Niamh, AuthorO'Connell, Kevin S., AuthorO'Donovan, Claire, AuthorO'Donovan, Michael C., AuthorOpel, Nils, AuthorOrtiz, Abigail, AuthorOwen, Michael J., AuthorPalsson, Erik, AuthorPato, Carlos, AuthorPato, Michele T., AuthorPawlak, Joanna, AuthorPfarr, Julia-Katharina, AuthorPisanu, Claudia, AuthorPotash, James B., AuthorRapaport, Mark H., AuthorReich-Erkelenz, Daniela, AuthorReif, Andreas, AuthorReininghaus, Eva, AuthorRepple, Jonathan, AuthorRichard-Lepouriel, Helene, AuthorRietschel, Marcella, AuthorRingwald, Kai, AuthorRoberts, Gloria, AuthorRouleau, Guy, AuthorSchaupp, Sabrina, AuthorScheftner, William A., AuthorSchmitt, Simon, AuthorSchofield, Peter R., AuthorSchubert, K. Oliver, AuthorSchulte, Eva C., AuthorSchweizer, Barbara, AuthorSenner, Fanny, AuthorSeverino, Giovanni, AuthorSharp, Sally, AuthorSlaney, Claire, AuthorSmeland, Olav B., AuthorSobell, Janet L., AuthorSquassina, Alessio, AuthorStopkova, Pavla, AuthorStrauss, John, AuthorTortorella, Alfonso, AuthorTurecki, Gustavo, AuthorTwarowska-Hauser, Joanna, AuthorVeldic, Marin, AuthorVieta, Eduard, AuthorVincent, John B., AuthorXu, Wei, AuthorZai, Clement C., AuthorZandi, Peter P., AuthorDi Florio, Arianna, AuthorSmoller, Jordan W., AuthorBiernacka, Joanna M., AuthorMcMahon, Francis J., AuthorAlda, Martin, AuthorMuller-Myhsok, Bertram2, Author           Koutsouleris, Nikolaos4, Author           Falkai, Peter, AuthorFreimer, Nelson B., AuthorAndlauer, Till F. M., AuthorSchulze, Thomas G., AuthorOphoff, Roel A., Author more..
1IMPRS Translational Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society, ou_3318616              
2RG Statistical Genetics, Max Planck Institute of Psychiatry, Max Planck Society, ou_2040288              
3Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society, ou_2035295              
4Max Planck Fellow Group Precision Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society, ou_3318615              


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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 (beta = -0.34 years, s.e. = 0.08), major depression (beta = -0.34 years, s.e. = 0.08), schizophrenia (beta = -0.39 years, s.e. = 0.08), and educational attainment (beta = -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.


 Dates: 2021
 Publication Status: Published online
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Identifiers: ISI: 000723150400009
DOI: 10.1192/bjp.2021.102
 Degree: -



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Source Genre: Journal
Publ. Info: -
Pages: - Volume / Issue: 219 (6) Sequence Number: PII S0007125021001021 Start / End Page: 659 - 669 Identifier: ISSN: 0007-1250