Investigating polygenic burden in age at disease onset in bipolar disorder: Findings from an international multicentric study

Janos L. Kalman, Sergi Papiol, Andreas J. Forstner, Urs Heilbronner, Franziska Degenhardt, Jana Strohmaier, Mazda Adli, Kristina Adorjan, Nirmala Akula, Martin Alda, Heike Anderson-Schmidt, Till F.M. Andlauer, Ion George Anghelescu, Raffaella Ardau, Bárbara Arias, Volker Arolt, Jean Michel Aubry, Lena Backlund, Kim Bartholdi, Michael BauerBernhard T. Baune, Thomas Becker, Frank Bellivier, Antonio Benabarre, Susanne Bengesser, Abesh Kumar Bhattacharjee, Joanna M. Biernacka, Armin Birner, Clara Brichant-Petitjean, Monika Budde, Pablo Cervantes, Caterina Chillotti, Sven Cichon, Scott R. Clark, Francesc Colom, Ashley L. Comes, Cristiana Cruceanu, Piotr M. Czerski, Udo Dannlowski, Alexandre Dayer, Maria Del Zompo, Jay Raymond DePaulo, Detlef E. Dietrich, Bruno Étain, Thomas Ethofer, Peter Falkai, Andreas Fallgatter, Christian Figge, Laura Flatau, Here Folkerts, Louise Frisen, Mark A. Frye, Janice M. Fullerton, Katrin Gade, Sébastien Gard, Julie S. Garnham, Fernando S. Goes, Maria Grigoroiu-Serbanescu, Anna Gryaznova, Maria Hake, Joanna Hauser, Stefan Herms, Per Hoffmann, Liping Hou, Markus Jäger, Stephane Jamain, Esther Jiménez, Georg Juckel, Jean Pierre Kahn, Layla Kassem, John Kelsoe, Sarah Kittel-Schneider, Sebastian Kliwicki, Farah Klohn-Sagatholislam, Manfred Koller, Barbara König, Carsten Konrad, Nina Lackner, Gonzalo Laje, Mikael Landén, Fabian U. Lang, Catharina Lavebratt, Marion Leboyer, Susan G. Leckband, Mario Maj, Mirko Manchia, Lina Martinsson, Michael J. McCarthy, Susan L. McElroy, Francis J. McMahon, Philip B. Mitchell, Marina Mitjans, Francis M. Mondimore, Palmiero Monteleone, Vanessa Nieratschker, Caroline M. Nievergelt, Tomas Novák, Urban Ösby, Andrea Pfennig, James B. Potash, Daniela Reich-Erkelenz, Andreas Reif, Jens Reimer, Eva Reininghaus, Markus Reitt, Stephan Ripke, Guy A. Rouleau, Janusz K. Rybakowski, Martin Schalling, Harald Scherk, Max Schmauß, Peter R. Schofield, K. Oliver Schubert, Eva C. Schulte, Sybille Schulz, Fanny Senner, Giovanni Severino, Tatyana Shekhtman, Paul D. Shilling, Christian Simhandl, Claire M. Slaney, Carsten Spitzer, Alessio Squassina, Thomas Stamm, Sophia Stegmaier, Sebastian Stierl, Pavla Stopkova, Andreas Thiel, Sarah K. Tighe, Alfonso Tortorella, Gustavo Turecki, Eduard Vieta, Julia Veeh, Martin von Hagen, Moritz E. Wigand, Jens Wiltfang, Stephanie Witt, Adam Wright, Peter P. Zandi, Jörg Zimmermann, Markus Nöthen, Marcella Rietschel, Thomas G. Schulze

Research output: Contribution to journalArticlepeer-review

12 Scopus citations


Objectives: Bipolar disorder (BD) with early disease onset is associated with an unfavorable clinical outcome and constitutes a clinically and biologically homogenous subgroup within the heterogeneous BD spectrum. Previous studies have found an accumulation of early age at onset (AAO) in BD families and have therefore hypothesized that there is a larger genetic contribution to the early-onset cases than to late onset BD. To investigate the genetic background of this subphenotype, we evaluated whether an increased polygenic burden of BD- and schizophrenia (SCZ)-associated risk variants is associated with an earlier AAO in BD patients. Methods: A total of 1995 BD type 1 patients from the Consortium of Lithium Genetics (ConLiGen), PsyCourse and Bonn-Mannheim samples were genotyped and their BD and SCZ polygenic risk scores (PRSs) were calculated using the summary statistics of the Psychiatric Genomics Consortium as a training data set. AAO was either separated into onset groups of clinical interest (childhood and adolescence [≤18 years] vs adulthood [>18 years]) or considered as a continuous measure. The associations between BD- and SCZ-PRSs and AAO were evaluated with regression models. Results: BD- and SCZ-PRSs were not significantly associated with age at disease onset. Results remained the same when analyses were stratified by site of recruitment. Conclusions: The current study is the largest conducted so far to investigate the association between the cumulative BD and SCZ polygenic risk and AAO in BD patients. The reported negative results suggest that such a polygenic influence, if there is any, is not large, and highlight the importance of conducting further, larger scale studies to obtain more information on the genetic architecture of this clinically relevant phenotype.

Original languageEnglish (US)
Pages (from-to)68-75
Number of pages8
JournalBipolar disorders
Issue number1
StatePublished - Feb 2019


  • age at onset
  • bipolar disorder
  • early onset
  • polygenic risk score
  • schizophrenia

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Biological Psychiatry


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