Characterisation of age and polarity at onset in bipolar disorder.
The British journal of psychiatry : the journal of mental science
Authors:
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, Torbjørn 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
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.