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 journalArticle

3 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)68-75
Number of pages8
JournalBipolar disorders
Volume21
Issue number1
DOIs
StatePublished - Feb 1 2019

Fingerprint

Bipolar Disorder
Age of Onset
Schizophrenia
Public Opinion
Genomics
Lithium
Psychiatry
Phenotype

Keywords

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

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Biological Psychiatry

Cite this

Kalman, J. L., Papiol, S., Forstner, A. J., Heilbronner, U., Degenhardt, F., Strohmaier, J., ... Schulze, T. G. (2019). Investigating polygenic burden in age at disease onset in bipolar disorder: Findings from an international multicentric study. Bipolar disorders, 21(1), 68-75. https://doi.org/10.1111/bdi.12659

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 journalArticle

Kalman, JL, Papiol, S, Forstner, AJ, Heilbronner, U, Degenhardt, F, Strohmaier, J, Adli, M, Adorjan, K, Akula, N, Alda, M, Anderson-Schmidt, H, Andlauer, TFM, Anghelescu, IG, Ardau, R, Arias, B, Arolt, V, Aubry, JM, Backlund, L, Bartholdi, K, Bauer, M, Baune, BT, Becker, T, Bellivier, F, Benabarre, A, Bengesser, S, Bhattacharjee, AK, Biernacka, JM, Birner, A, Brichant-Petitjean, C, Budde, M, Cervantes, P, Chillotti, C, Cichon, S, Clark, SR, Colom, F, Comes, AL, Cruceanu, C, Czerski, PM, Dannlowski, U, Dayer, A, Del Zompo, M, DePaulo, JR, Dietrich, DE, Étain, B, Ethofer, T, Falkai, P, Fallgatter, A, Figge, C, Flatau, L, Folkerts, H, Frisen, L, Frye, MA, Fullerton, JM, Gade, K, Gard, S, Garnham, JS, Goes, FS, Grigoroiu-Serbanescu, M, Gryaznova, A, Hake, M, Hauser, J, Herms, S, Hoffmann, P, Hou, L, Jäger, M, Jamain, S, Jiménez, E, Juckel, G, Kahn, JP, Kassem, L, Kelsoe, J, Kittel-Schneider, S, Kliwicki, S, Klohn-Sagatholislam, F, Koller, M, König, B, Konrad, C, Lackner, N, Laje, G, Landén, M, Lang, FU, Lavebratt, C, Leboyer, M, Leckband, SG, Maj, M, Manchia, M, Martinsson, L, McCarthy, MJ, McElroy, SL, McMahon, FJ, Mitchell, PB, Mitjans, M, Mondimore, FM, Monteleone, P, Nieratschker, V, Nievergelt, CM, Novák, T, Ösby, U, Pfennig, A, Potash, JB, Reich-Erkelenz, D, Reif, A, Reimer, J, Reininghaus, E, Reitt, M, Ripke, S, Rouleau, GA, Rybakowski, JK, Schalling, M, Scherk, H, Schmauß, M, Schofield, PR, Schubert, KO, Schulte, EC, Schulz, S, Senner, F, Severino, G, Shekhtman, T, Shilling, PD, Simhandl, C, Slaney, CM, Spitzer, C, Squassina, A, Stamm, T, Stegmaier, S, Stierl, S, Stopkova, P, Thiel, A, Tighe, SK, Tortorella, A, Turecki, G, Vieta, E, Veeh, J, von Hagen, M, Wigand, ME, Wiltfang, J, Witt, S, Wright, A, Zandi, PP, Zimmermann, J, Nöthen, M, Rietschel, M & Schulze, TG 2019, 'Investigating polygenic burden in age at disease onset in bipolar disorder: Findings from an international multicentric study', Bipolar disorders, vol. 21, no. 1, pp. 68-75. https://doi.org/10.1111/bdi.12659
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. / Investigating polygenic burden in age at disease onset in bipolar disorder : Findings from an international multicentric study. In: Bipolar disorders. 2019 ; Vol. 21, No. 1. pp. 68-75.
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title = "Investigating polygenic burden in age at disease onset in bipolar disorder: Findings from an international multicentric study",
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.",
keywords = "age at onset, bipolar disorder, early onset, polygenic risk score, schizophrenia",
author = "Kalman, {Janos L.} and Sergi Papiol and Forstner, {Andreas J.} and Urs Heilbronner and Franziska Degenhardt and Jana Strohmaier and Mazda Adli and Kristina Adorjan and Nirmala Akula and Martin Alda and Heike Anderson-Schmidt and Andlauer, {Till F.M.} and Anghelescu, {Ion George} and Raffaella Ardau and B{\'a}rbara Arias and Volker Arolt and Aubry, {Jean Michel} and Lena Backlund and Kim Bartholdi and Michael Bauer and Baune, {Bernhard T.} and Thomas Becker and Frank Bellivier and Antonio Benabarre and Susanne Bengesser and Bhattacharjee, {Abesh Kumar} and Biernacka, {Joanna M} and Armin Birner and Clara Brichant-Petitjean and Monika Budde and Pablo Cervantes and Caterina Chillotti and Sven Cichon and Clark, {Scott R.} and Francesc Colom and Comes, {Ashley L.} and Cristiana Cruceanu and Czerski, {Piotr M.} and Udo Dannlowski and Alexandre Dayer and {Del Zompo}, Maria and DePaulo, {Jay Raymond} and Dietrich, {Detlef E.} and Bruno {\'E}tain and Thomas Ethofer and Peter Falkai and Andreas Fallgatter and Christian Figge and Laura Flatau and Here Folkerts and Louise Frisen and Frye, {Mark A} and Fullerton, {Janice M.} and Katrin Gade and S{\'e}bastien Gard and Garnham, {Julie S.} and Goes, {Fernando S.} and Maria Grigoroiu-Serbanescu and Anna Gryaznova and Maria Hake and Joanna Hauser and Stefan Herms and Per Hoffmann and Liping Hou and Markus J{\"a}ger and Stephane Jamain and Esther Jim{\'e}nez and Georg Juckel and Kahn, {Jean Pierre} and Layla Kassem and John Kelsoe and Sarah Kittel-Schneider and Sebastian Kliwicki and Farah Klohn-Sagatholislam and Manfred Koller and Barbara K{\"o}nig and Carsten Konrad and Nina Lackner and Gonzalo Laje and Mikael Land{\'e}n and Lang, {Fabian U.} and Catharina Lavebratt and Marion Leboyer and Leckband, {Susan G.} and Mario Maj and Mirko Manchia and Lina Martinsson and McCarthy, {Michael J.} and McElroy, {Susan L.} and McMahon, {Francis J.} and Mitchell, {Philip B.} and Marina Mitjans and Mondimore, {Francis M.} and Palmiero Monteleone and Vanessa Nieratschker and Nievergelt, {Caroline M.} and Tomas Nov{\'a}k and Urban {\"O}sby and Andrea Pfennig and Potash, {James B.} and Daniela Reich-Erkelenz and Andreas Reif and Jens Reimer and Eva Reininghaus and Markus Reitt and Stephan Ripke and Rouleau, {Guy A.} and Rybakowski, {Janusz K.} and Martin Schalling and Harald Scherk and Max Schmau{\ss} and Schofield, {Peter R.} and Schubert, {K. Oliver} and Schulte, {Eva C.} and Sybille Schulz and Fanny Senner and Giovanni Severino and Tatyana Shekhtman and Shilling, {Paul D.} and Christian Simhandl and Slaney, {Claire M.} and Carsten Spitzer and Alessio Squassina and Thomas Stamm and Sophia Stegmaier and Sebastian Stierl and Pavla Stopkova and Andreas Thiel and Tighe, {Sarah K.} and Alfonso Tortorella and Gustavo Turecki and Eduard Vieta and Julia Veeh and {von Hagen}, Martin and Wigand, {Moritz E.} and Jens Wiltfang and Stephanie Witt and Adam Wright and Zandi, {Peter P.} and J{\"o}rg Zimmermann and Markus N{\"o}then and Marcella Rietschel and Schulze, {Thomas G.}",
year = "2019",
month = "2",
day = "1",
doi = "10.1111/bdi.12659",
language = "English (US)",
volume = "21",
pages = "68--75",
journal = "Bipolar Disorders",
issn = "1398-5647",
publisher = "Blackwell Munksgaard",
number = "1",

}

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.

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 -