Abstract
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 language | English (US) |
|---|---|
| Pages (from-to) | 68-75 |
| Number of pages | 8 |
| Journal | Bipolar Disorders |
| Volume | 21 |
| Issue number | 1 |
| DOIs | |
| State | Published - Feb 1 2019 |
Keywords
- 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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Investigating polygenic burden in age at disease onset in bipolar disorder : Findings from an international multicentric study. / Kalman, Janos L.; Papiol, Sergi; Forstner, Andreas J.; Heilbronner, Urs; Degenhardt, Franziska; Strohmaier, Jana; Adli, Mazda; Adorjan, Kristina; Akula, Nirmala; Alda, Martin; Anderson-Schmidt, Heike; Andlauer, Till F.M.; Anghelescu, Ion George; Ardau, Raffaella; Arias, Bárbara; Arolt, Volker; Aubry, Jean Michel; Backlund, Lena; Bartholdi, Kim; Bauer, Michael; Baune, Bernhard T.; Becker, Thomas; Bellivier, Frank; Benabarre, Antonio; Bengesser, Susanne; Bhattacharjee, Abesh Kumar; Biernacka, Joanna M.; Birner, Armin; Brichant-Petitjean, Clara; Budde, Monika; Cervantes, Pablo; Chillotti, Caterina; Cichon, Sven; Clark, Scott R.; Colom, Francesc; Comes, Ashley L.; Cruceanu, Cristiana; Czerski, Piotr M.; Dannlowski, Udo; Dayer, Alexandre; Del Zompo, Maria; DePaulo, Jay Raymond; Dietrich, Detlef E.; Étain, Bruno; Ethofer, Thomas; Falkai, Peter; Fallgatter, Andreas; Figge, Christian; Flatau, Laura; Folkerts, Here; Frisen, Louise; Frye, Mark A.; Fullerton, Janice M.; Gade, Katrin; Gard, Sébastien; Garnham, Julie S.; Goes, Fernando S.; Grigoroiu-Serbanescu, Maria; Gryaznova, Anna; Hake, Maria; Hauser, Joanna; Herms, Stefan; Hoffmann, Per; Hou, Liping; Jäger, Markus; Jamain, Stephane; Jiménez, Esther; Juckel, Georg; Kahn, Jean Pierre; Kassem, Layla; Kelsoe, John; Kittel-Schneider, Sarah; Kliwicki, Sebastian; Klohn-Sagatholislam, Farah; Koller, Manfred; König, Barbara; Konrad, Carsten; Lackner, Nina; Laje, Gonzalo; Landén, Mikael; Lang, Fabian U.; Lavebratt, Catharina; Leboyer, Marion; Leckband, Susan G.; Maj, Mario; Manchia, Mirko; Martinsson, Lina; McCarthy, Michael J.; McElroy, Susan L.; McMahon, Francis J.; Mitchell, Philip B.; Mitjans, Marina; Mondimore, Francis M.; Monteleone, Palmiero; Nieratschker, Vanessa; Nievergelt, Caroline M.; Novák, Tomas; Ösby, Urban; Pfennig, Andrea; Potash, James B.; Reich-Erkelenz, Daniela; Reif, Andreas; Reimer, Jens; Reininghaus, Eva; Reitt, Markus; Ripke, Stephan; Rouleau, Guy A.; Rybakowski, Janusz K.; Schalling, Martin; Scherk, Harald; Schmauß, Max; Schofield, Peter R.; Schubert, K. Oliver; Schulte, Eva C.; Schulz, Sybille; Senner, Fanny; Severino, Giovanni; Shekhtman, Tatyana; Shilling, Paul D.; Simhandl, Christian; Slaney, Claire M.; Spitzer, Carsten; Squassina, Alessio; Stamm, Thomas; Stegmaier, Sophia; Stierl, Sebastian; Stopkova, Pavla; Thiel, Andreas; Tighe, Sarah K.; Tortorella, Alfonso; Turecki, Gustavo; Vieta, Eduard; Veeh, Julia; von Hagen, Martin; Wigand, Moritz E.; Wiltfang, Jens; Witt, Stephanie; Wright, Adam; Zandi, Peter P.; Zimmermann, Jörg; Nöthen, Markus; Rietschel, Marcella; Schulze, Thomas G.
In: Bipolar Disorders, Vol. 21, No. 1, 01.02.2019, p. 68-75.Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Investigating polygenic burden in age at disease onset in bipolar disorder
T2 - Findings from an international multicentric study
AU - Kalman, Janos L.
AU - Papiol, Sergi
AU - Forstner, Andreas J.
AU - Heilbronner, Urs
AU - Degenhardt, Franziska
AU - Strohmaier, Jana
AU - Adli, Mazda
AU - Adorjan, Kristina
AU - Akula, Nirmala
AU - Alda, Martin
AU - Anderson-Schmidt, Heike
AU - Andlauer, Till F.M.
AU - Anghelescu, Ion George
AU - Ardau, Raffaella
AU - Arias, Bárbara
AU - Arolt, Volker
AU - Aubry, Jean Michel
AU - Backlund, Lena
AU - Bartholdi, Kim
AU - Bauer, Michael
AU - Baune, Bernhard T.
AU - Becker, Thomas
AU - Bellivier, Frank
AU - Benabarre, Antonio
AU - Bengesser, Susanne
AU - Bhattacharjee, Abesh Kumar
AU - Biernacka, Joanna M.
AU - Birner, Armin
AU - Brichant-Petitjean, Clara
AU - Budde, Monika
AU - Cervantes, Pablo
AU - Chillotti, Caterina
AU - Cichon, Sven
AU - Clark, Scott R.
AU - Colom, Francesc
AU - Comes, Ashley L.
AU - Cruceanu, Cristiana
AU - Czerski, Piotr M.
AU - Dannlowski, Udo
AU - Dayer, Alexandre
AU - Del Zompo, Maria
AU - DePaulo, Jay Raymond
AU - Dietrich, Detlef E.
AU - Étain, Bruno
AU - Ethofer, Thomas
AU - Falkai, Peter
AU - Fallgatter, Andreas
AU - Figge, Christian
AU - Flatau, Laura
AU - Folkerts, Here
AU - Frisen, Louise
AU - Frye, Mark A.
AU - Fullerton, Janice M.
AU - Gade, Katrin
AU - Gard, Sébastien
AU - Garnham, Julie S.
AU - Goes, Fernando S.
AU - Grigoroiu-Serbanescu, Maria
AU - Gryaznova, Anna
AU - Hake, Maria
AU - Hauser, Joanna
AU - Herms, Stefan
AU - Hoffmann, Per
AU - Hou, Liping
AU - Jäger, Markus
AU - Jamain, Stephane
AU - Jiménez, Esther
AU - Juckel, Georg
AU - Kahn, Jean Pierre
AU - Kassem, Layla
AU - Kelsoe, John
AU - Kittel-Schneider, Sarah
AU - Kliwicki, Sebastian
AU - Klohn-Sagatholislam, Farah
AU - Koller, Manfred
AU - König, Barbara
AU - Konrad, Carsten
AU - Lackner, Nina
AU - Laje, Gonzalo
AU - Landén, Mikael
AU - Lang, Fabian U.
AU - Lavebratt, Catharina
AU - Leboyer, Marion
AU - Leckband, Susan G.
AU - Maj, Mario
AU - Manchia, Mirko
AU - Martinsson, Lina
AU - McCarthy, Michael J.
AU - McElroy, Susan L.
AU - McMahon, Francis J.
AU - Mitchell, Philip B.
AU - Mitjans, Marina
AU - Mondimore, Francis M.
AU - Monteleone, Palmiero
AU - Nieratschker, Vanessa
AU - Nievergelt, Caroline M.
AU - Novák, Tomas
AU - Ösby, Urban
AU - Pfennig, Andrea
AU - Potash, James B.
AU - Reich-Erkelenz, Daniela
AU - Reif, Andreas
AU - Reimer, Jens
AU - Reininghaus, Eva
AU - Reitt, Markus
AU - Ripke, Stephan
AU - Rouleau, Guy A.
AU - Rybakowski, Janusz K.
AU - Schalling, Martin
AU - Scherk, Harald
AU - Schmauß, Max
AU - Schofield, Peter R.
AU - Schubert, K. Oliver
AU - Schulte, Eva C.
AU - Schulz, Sybille
AU - Senner, Fanny
AU - Severino, Giovanni
AU - Shekhtman, Tatyana
AU - Shilling, Paul D.
AU - Simhandl, Christian
AU - Slaney, Claire M.
AU - Spitzer, Carsten
AU - Squassina, Alessio
AU - Stamm, Thomas
AU - Stegmaier, Sophia
AU - Stierl, Sebastian
AU - Stopkova, Pavla
AU - Thiel, Andreas
AU - Tighe, Sarah K.
AU - Tortorella, Alfonso
AU - Turecki, Gustavo
AU - Vieta, Eduard
AU - Veeh, Julia
AU - von Hagen, Martin
AU - Wigand, Moritz E.
AU - Wiltfang, Jens
AU - Witt, Stephanie
AU - Wright, Adam
AU - Zandi, Peter P.
AU - Zimmermann, Jörg
AU - Nöthen, Markus
AU - Rietschel, Marcella
AU - Schulze, Thomas G.
N1 - Funding Information: The Swedish collection of samples was funded by the Swedish Research Council, the Stockholm County Council, the Karolinska Institutet and the Söderström-Königska Foundation through grants awarded to Lena Backlund, Louise Frise’n, Martin Schalling and Catharina Lavebratt. Thomas G. Schulze and Peter Falkai are supported by the Deutsche Forschungsgemeinschaft (DFG) within the framework of the projects www. kfo241.de and www.PsyCourse.de (SCHU 1603/4-1, 5-1, 7-1; FA241/16-1). Thomas G. Schulze is further supported by the Dr. Lisa Oehler Foundation (Kassel, Germany). The Romanian sample recruitment and, in part, genotyping was funded by UEFISCDI, Bucharest, Romania, through a grant to M. Grigoroiu-Serbanescu. The genotyping was also funded in part by the German Federal Ministry of Education and Research (BMBF) through the Integrated Network IntegraMent under the auspices of the e:Med Programme (grants awarded to Thomas G. Schulze, Marcella Rietschel, and Markus M. Nöthen). The study was supported by the German Federal Ministry of Education and Research (BMBF) through the Integrated Network IntegraMent (Integrated Understanding of Causes and Mechanisms in Mental Disorders), under the auspices of the e:Med Programme (grant 01ZX1314A/01ZX1614A to M.M.N. and S.C.; grant 01ZX1314G/01ZX1614G to M.R.). M.M.N. is a member of the DFG-funded Excellence-Cluster ImmunoSensation. M.M.N. also received support from the Alfried Krupp von Bohlen und Halbach-Stiftung. The study was supported by the German Research Foundation (DFG; grant FOR2107; RI908/11-1 to M.R.; NO246/10-1 to M.M.N.). The study was also supported by the Swiss National Science Foundation (SNSF, grant 156791 to S.C.). Eva C. Schulte was supported through the LMU Mentoring Program of Ludwig-Maximilians Universität. Sergi Papiol is supported by a 2016 NARSAD Young Investigator Grant (25015) from the Brain & Behavior Research Foundation. Publisher Copyright: © 2018 The Authors. Bipolar Disorders Published by John Wiley & Sons Ltd
PY - 2019/2/1
Y1 - 2019/2/1
N2 - 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.
AB - 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.
KW - age at onset
KW - bipolar disorder
KW - early onset
KW - polygenic risk score
KW - schizophrenia
UR - http://www.scopus.com/inward/record.url?scp=85062093950&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85062093950&partnerID=8YFLogxK
U2 - 10.1111/bdi.12659
DO - 10.1111/bdi.12659
M3 - Article
C2 - 29956436
AN - SCOPUS:85062093950
VL - 21
SP - 68
EP - 75
JO - Bipolar Disorders
JF - Bipolar Disorders
SN - 1398-5647
IS - 1
ER -