Combining schizophrenia and depression polygenic risk scores improves the genetic prediction of lithium response in bipolar disorder patients

Abstract Lithium is the gold standard therapy for Bipolar Disorder (BD) but its effectiveness differs widely between individuals. The molecular mechanisms underlying treatment response heterogeneity are not well understood, and personalized treatment in BD remains elusive. Genetic analyses of the li...

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Autores principales:	Klaus Oliver Schubert, Anbupalam Thalamuthu, Azmeraw T. Amare, Joseph Frank, Fabian Streit, Mazda Adl, Nirmala Akula, Kazufumi Akiyama, Raffaella Ardau, Bárbara Arias, Jean-Michel Aubry, Lena Backlund, Abesh Kumar Bhattacharjee, Frank Bellivier, Antonio Benabarre, Susanne Bengesser, Joanna M. Biernacka, Armin Birner, Cynthia Marie-Claire, Micah Cearns, Pablo Cervantes, Hsi-Chung Chen, Caterina Chillotti, Sven Cichon, Scott R. Clark, Cristiana Cruceanu, Piotr M. Czerski, Nina Dalkner, Alexandre Dayer, Franziska Degenhardt, Maria Del Zompo, J. Raymond DePaulo, Bruno Étain, Peter Falkai, Andreas J. Forstner, Louise Frisen, Mark A. Frye, Janice M. Fullerton, Sébastien Gard, Julie S. Garnham, Fernando S. Goes, Maria Grigoroiu-Serbanescu, Paul Grof, Ryota Hashimoto, Joanna Hauser, Urs Heilbronner, Stefan Herms, Per Hoffmann, Liping Hou, Yi-Hsiang Hsu, Stephane Jamain, Esther Jiménez, Jean-Pierre Kahn, Layla Kassem, Po-Hsiu Kuo, Tadafumi Kato, John Kelsoe, Sarah Kittel-Schneider, Ewa Ferensztajn-Rochowiak, Barbara König, Ichiro Kusumi, Gonzalo Laje, Mikael Landén, Catharina Lavebratt, Marion Leboyer, Susan G. Leckband, Mario Maj, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Mirko Manchia, Lina Martinsson, Michael J. McCarthy, Susan McElroy, Francesc Colom, Marina Mitjans, Francis M. Mondimore, Palmiero Monteleone, Caroline M. Nievergelt, Markus M. Nöthen, Tomas Novák, Claire O’Donovan, Norio Ozaki, Urban Ösby, Sergi Papiol, Andrea Pfennig, Claudia Pisanu, James B. Potash, Andreas Reif, Eva Reininghaus, Guy A. Rouleau, Janusz K. Rybakowski, Martin Schalling, Peter R. Schofield, Barbara W. Schweizer, Giovanni Severino, Tatyana Shekhtman, Paul D. Shilling, Katzutaka Shimoda, Christian Simhandl, Claire M. Slaney, Alessio Squassina, Thomas Stamm, Pavla Stopkova, Fasil Tekola-Ayele, Alfonso Tortorella, Gustavo Turecki, Julia Veeh, Eduard Vieta, Stephanie H. Witt, Gloria Roberts, Peter P. Zandi, Martin Alda, Michael Bauer, Francis J. McMahon, Philip B. Mitchell, Thomas G. Schulze, Marcella Rietschel, Bernhard T. Baune
Formato:	article
Lenguaje:	EN
Publicado:	Nature Publishing Group 2021
Materias:	Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571
Acceso en línea:	https://doaj.org/article/57b110aeea5c4d71a7bcb2b214859244
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id	oai:doaj.org-article:57b110aeea5c4d71a7bcb2b214859244
record_format	dspace
institution	DOAJ
collection	DOAJ
language	EN
topic	Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571
spellingShingle	Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571 Klaus Oliver Schubert Anbupalam Thalamuthu Azmeraw T. Amare Joseph Frank Fabian Streit Mazda Adl Nirmala Akula Kazufumi Akiyama Raffaella Ardau Bárbara Arias Jean-Michel Aubry Lena Backlund Abesh Kumar Bhattacharjee Frank Bellivier Antonio Benabarre Susanne Bengesser Joanna M. Biernacka Armin Birner Cynthia Marie-Claire Micah Cearns Pablo Cervantes Hsi-Chung Chen Caterina Chillotti Sven Cichon Scott R. Clark Cristiana Cruceanu Piotr M. Czerski Nina Dalkner Alexandre Dayer Franziska Degenhardt Maria Del Zompo J. Raymond DePaulo Bruno Étain Peter Falkai Andreas J. Forstner Louise Frisen Mark A. Frye Janice M. Fullerton Sébastien Gard Julie S. Garnham Fernando S. Goes Maria Grigoroiu-Serbanescu Paul Grof Ryota Hashimoto Joanna Hauser Urs Heilbronner Stefan Herms Per Hoffmann Liping Hou Yi-Hsiang Hsu Stephane Jamain Esther Jiménez Jean-Pierre Kahn Layla Kassem Po-Hsiu Kuo Tadafumi Kato John Kelsoe Sarah Kittel-Schneider Ewa Ferensztajn-Rochowiak Barbara König Ichiro Kusumi Gonzalo Laje Mikael Landén Catharina Lavebratt Marion Leboyer Susan G. Leckband Mario Maj Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium Mirko Manchia Lina Martinsson Michael J. McCarthy Susan McElroy Francesc Colom Marina Mitjans Francis M. Mondimore Palmiero Monteleone Caroline M. Nievergelt Markus M. Nöthen Tomas Novák Claire O’Donovan Norio Ozaki Urban Ösby Sergi Papiol Andrea Pfennig Claudia Pisanu James B. Potash Andreas Reif Eva Reininghaus Guy A. Rouleau Janusz K. Rybakowski Martin Schalling Peter R. Schofield Barbara W. Schweizer Giovanni Severino Tatyana Shekhtman Paul D. Shilling Katzutaka Shimoda Christian Simhandl Claire M. Slaney Alessio Squassina Thomas Stamm Pavla Stopkova Fasil Tekola-Ayele Alfonso Tortorella Gustavo Turecki Julia Veeh Eduard Vieta Stephanie H. Witt Gloria Roberts Peter P. Zandi Martin Alda Michael Bauer Francis J. McMahon Philip B. Mitchell Thomas G. Schulze Marcella Rietschel Bernhard T. Baune Combining schizophrenia and depression polygenic risk scores improves the genetic prediction of lithium response in bipolar disorder patients
description	Abstract Lithium is the gold standard therapy for Bipolar Disorder (BD) but its effectiveness differs widely between individuals. The molecular mechanisms underlying treatment response heterogeneity are not well understood, and personalized treatment in BD remains elusive. Genetic analyses of the lithium treatment response phenotype may generate novel molecular insights into lithium’s therapeutic mechanisms and lead to testable hypotheses to improve BD management and outcomes. We used fixed effect meta-analysis techniques to develop meta-analytic polygenic risk scores (MET-PRS) from combinations of highly correlated psychiatric traits, namely schizophrenia (SCZ), major depression (MD) and bipolar disorder (BD). We compared the effects of cross-disorder MET-PRS and single genetic trait PRS on lithium response. For the PRS analyses, we included clinical data on lithium treatment response and genetic information for n = 2283 BD cases from the International Consortium on Lithium Genetics (ConLi+Gen; www.ConLiGen.org ). Higher SCZ and MD PRSs were associated with poorer lithium treatment response whereas BD-PRS had no association with treatment outcome. The combined MET2-PRS comprising of SCZ and MD variants (MET2-PRS) and a model using SCZ and MD-PRS sequentially improved response prediction, compared to single-disorder PRS or to a combined score using all three traits (MET3-PRS). Patients in the highest decile for MET2-PRS loading had 2.5 times higher odds of being classified as poor responders than patients with the lowest decile MET2-PRS scores. An exploratory functional pathway analysis of top MET2-PRS variants was conducted. Findings may inform the development of future testing strategies for personalized lithium prescribing in BD.
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author	Klaus Oliver Schubert Anbupalam Thalamuthu Azmeraw T. Amare Joseph Frank Fabian Streit Mazda Adl Nirmala Akula Kazufumi Akiyama Raffaella Ardau Bárbara Arias Jean-Michel Aubry Lena Backlund Abesh Kumar Bhattacharjee Frank Bellivier Antonio Benabarre Susanne Bengesser Joanna M. Biernacka Armin Birner Cynthia Marie-Claire Micah Cearns Pablo Cervantes Hsi-Chung Chen Caterina Chillotti Sven Cichon Scott R. Clark Cristiana Cruceanu Piotr M. Czerski Nina Dalkner Alexandre Dayer Franziska Degenhardt Maria Del Zompo J. Raymond DePaulo Bruno Étain Peter Falkai Andreas J. Forstner Louise Frisen Mark A. Frye Janice M. Fullerton Sébastien Gard Julie S. Garnham Fernando S. Goes Maria Grigoroiu-Serbanescu Paul Grof Ryota Hashimoto Joanna Hauser Urs Heilbronner Stefan Herms Per Hoffmann Liping Hou Yi-Hsiang Hsu Stephane Jamain Esther Jiménez Jean-Pierre Kahn Layla Kassem Po-Hsiu Kuo Tadafumi Kato John Kelsoe Sarah Kittel-Schneider Ewa Ferensztajn-Rochowiak Barbara König Ichiro Kusumi Gonzalo Laje Mikael Landén Catharina Lavebratt Marion Leboyer Susan G. Leckband Mario Maj Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium Mirko Manchia Lina Martinsson Michael J. McCarthy Susan McElroy Francesc Colom Marina Mitjans Francis M. Mondimore Palmiero Monteleone Caroline M. Nievergelt Markus M. Nöthen Tomas Novák Claire O’Donovan Norio Ozaki Urban Ösby Sergi Papiol Andrea Pfennig Claudia Pisanu James B. Potash Andreas Reif Eva Reininghaus Guy A. Rouleau Janusz K. Rybakowski Martin Schalling Peter R. Schofield Barbara W. Schweizer Giovanni Severino Tatyana Shekhtman Paul D. Shilling Katzutaka Shimoda Christian Simhandl Claire M. Slaney Alessio Squassina Thomas Stamm Pavla Stopkova Fasil Tekola-Ayele Alfonso Tortorella Gustavo Turecki Julia Veeh Eduard Vieta Stephanie H. Witt Gloria Roberts Peter P. Zandi Martin Alda Michael Bauer Francis J. McMahon Philip B. Mitchell Thomas G. Schulze Marcella Rietschel Bernhard T. Baune
author_facet	Klaus Oliver Schubert Anbupalam Thalamuthu Azmeraw T. Amare Joseph Frank Fabian Streit Mazda Adl Nirmala Akula Kazufumi Akiyama Raffaella Ardau Bárbara Arias Jean-Michel Aubry Lena Backlund Abesh Kumar Bhattacharjee Frank Bellivier Antonio Benabarre Susanne Bengesser Joanna M. Biernacka Armin Birner Cynthia Marie-Claire Micah Cearns Pablo Cervantes Hsi-Chung Chen Caterina Chillotti Sven Cichon Scott R. Clark Cristiana Cruceanu Piotr M. Czerski Nina Dalkner Alexandre Dayer Franziska Degenhardt Maria Del Zompo J. Raymond DePaulo Bruno Étain Peter Falkai Andreas J. Forstner Louise Frisen Mark A. Frye Janice M. Fullerton Sébastien Gard Julie S. Garnham Fernando S. Goes Maria Grigoroiu-Serbanescu Paul Grof Ryota Hashimoto Joanna Hauser Urs Heilbronner Stefan Herms Per Hoffmann Liping Hou Yi-Hsiang Hsu Stephane Jamain Esther Jiménez Jean-Pierre Kahn Layla Kassem Po-Hsiu Kuo Tadafumi Kato John Kelsoe Sarah Kittel-Schneider Ewa Ferensztajn-Rochowiak Barbara König Ichiro Kusumi Gonzalo Laje Mikael Landén Catharina Lavebratt Marion Leboyer Susan G. Leckband Mario Maj Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium Mirko Manchia Lina Martinsson Michael J. McCarthy Susan McElroy Francesc Colom Marina Mitjans Francis M. Mondimore Palmiero Monteleone Caroline M. Nievergelt Markus M. Nöthen Tomas Novák Claire O’Donovan Norio Ozaki Urban Ösby Sergi Papiol Andrea Pfennig Claudia Pisanu James B. Potash Andreas Reif Eva Reininghaus Guy A. Rouleau Janusz K. Rybakowski Martin Schalling Peter R. Schofield Barbara W. Schweizer Giovanni Severino Tatyana Shekhtman Paul D. Shilling Katzutaka Shimoda Christian Simhandl Claire M. Slaney Alessio Squassina Thomas Stamm Pavla Stopkova Fasil Tekola-Ayele Alfonso Tortorella Gustavo Turecki Julia Veeh Eduard Vieta Stephanie H. Witt Gloria Roberts Peter P. Zandi Martin Alda Michael Bauer Francis J. McMahon Philip B. Mitchell Thomas G. Schulze Marcella Rietschel Bernhard T. Baune
author_sort	Klaus Oliver Schubert
title	Combining schizophrenia and depression polygenic risk scores improves the genetic prediction of lithium response in bipolar disorder patients
title_short	Combining schizophrenia and depression polygenic risk scores improves the genetic prediction of lithium response in bipolar disorder patients
title_full	Combining schizophrenia and depression polygenic risk scores improves the genetic prediction of lithium response in bipolar disorder patients
title_fullStr	Combining schizophrenia and depression polygenic risk scores improves the genetic prediction of lithium response in bipolar disorder patients
title_full_unstemmed	Combining schizophrenia and depression polygenic risk scores improves the genetic prediction of lithium response in bipolar disorder patients
title_sort	combining schizophrenia and depression polygenic risk scores improves the genetic prediction of lithium response in bipolar disorder patients
publisher	Nature Publishing Group
publishDate	2021
url	https://doaj.org/article/57b110aeea5c4d71a7bcb2b214859244
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spelling	oai:doaj.org-article:57b110aeea5c4d71a7bcb2b2148592442021-12-05T12:07:45ZCombining schizophrenia and depression polygenic risk scores improves the genetic prediction of lithium response in bipolar disorder patients10.1038/s41398-021-01702-22158-3188https://doaj.org/article/57b110aeea5c4d71a7bcb2b2148592442021-11-01T00:00:00Zhttps://doi.org/10.1038/s41398-021-01702-2https://doaj.org/toc/2158-3188Abstract Lithium is the gold standard therapy for Bipolar Disorder (BD) but its effectiveness differs widely between individuals. The molecular mechanisms underlying treatment response heterogeneity are not well understood, and personalized treatment in BD remains elusive. Genetic analyses of the lithium treatment response phenotype may generate novel molecular insights into lithium’s therapeutic mechanisms and lead to testable hypotheses to improve BD management and outcomes. We used fixed effect meta-analysis techniques to develop meta-analytic polygenic risk scores (MET-PRS) from combinations of highly correlated psychiatric traits, namely schizophrenia (SCZ), major depression (MD) and bipolar disorder (BD). We compared the effects of cross-disorder MET-PRS and single genetic trait PRS on lithium response. For the PRS analyses, we included clinical data on lithium treatment response and genetic information for n = 2283 BD cases from the International Consortium on Lithium Genetics (ConLi+Gen; www.ConLiGen.org ). Higher SCZ and MD PRSs were associated with poorer lithium treatment response whereas BD-PRS had no association with treatment outcome. The combined MET2-PRS comprising of SCZ and MD variants (MET2-PRS) and a model using SCZ and MD-PRS sequentially improved response prediction, compared to single-disorder PRS or to a combined score using all three traits (MET3-PRS). Patients in the highest decile for MET2-PRS loading had 2.5 times higher odds of being classified as poor responders than patients with the lowest decile MET2-PRS scores. An exploratory functional pathway analysis of top MET2-PRS variants was conducted. Findings may inform the development of future testing strategies for personalized lithium prescribing in BD.Klaus Oliver SchubertAnbupalam ThalamuthuAzmeraw T. AmareJoseph FrankFabian StreitMazda AdlNirmala AkulaKazufumi AkiyamaRaffaella ArdauBárbara AriasJean-Michel AubryLena BacklundAbesh Kumar BhattacharjeeFrank BellivierAntonio BenabarreSusanne BengesserJoanna M. BiernackaArmin BirnerCynthia Marie-ClaireMicah CearnsPablo CervantesHsi-Chung ChenCaterina ChillottiSven CichonScott R. ClarkCristiana CruceanuPiotr M. CzerskiNina DalknerAlexandre DayerFranziska DegenhardtMaria Del ZompoJ. Raymond DePauloBruno ÉtainPeter FalkaiAndreas J. ForstnerLouise FrisenMark A. FryeJanice M. FullertonSébastien GardJulie S. GarnhamFernando S. GoesMaria Grigoroiu-SerbanescuPaul GrofRyota HashimotoJoanna HauserUrs HeilbronnerStefan HermsPer HoffmannLiping HouYi-Hsiang HsuStephane JamainEsther JiménezJean-Pierre KahnLayla KassemPo-Hsiu KuoTadafumi KatoJohn KelsoeSarah Kittel-SchneiderEwa Ferensztajn-RochowiakBarbara KönigIchiro KusumiGonzalo LajeMikael LandénCatharina LavebrattMarion LeboyerSusan G. LeckbandMario MajMajor Depressive Disorder Working Group of the Psychiatric Genomics ConsortiumMirko ManchiaLina MartinssonMichael J. McCarthySusan McElroyFrancesc ColomMarina MitjansFrancis M. MondimorePalmiero MonteleoneCaroline M. NievergeltMarkus M. NöthenTomas NovákClaire O’DonovanNorio OzakiUrban ÖsbySergi PapiolAndrea PfennigClaudia PisanuJames B. PotashAndreas ReifEva ReininghausGuy A. RouleauJanusz K. RybakowskiMartin SchallingPeter R. SchofieldBarbara W. SchweizerGiovanni SeverinoTatyana ShekhtmanPaul D. ShillingKatzutaka ShimodaChristian SimhandlClaire M. SlaneyAlessio SquassinaThomas StammPavla StopkovaFasil Tekola-AyeleAlfonso TortorellaGustavo TureckiJulia VeehEduard VietaStephanie H. WittGloria RobertsPeter P. ZandiMartin AldaMichael BauerFrancis J. McMahonPhilip B. MitchellThomas G. SchulzeMarcella RietschelBernhard T. BauneNature Publishing GrouparticleNeurosciences. Biological psychiatry. NeuropsychiatryRC321-571ENTranslational Psychiatry, Vol 11, Iss 1, Pp 1-8 (2021)

Combining schizophrenia and depression polygenic risk scores improves the genetic prediction of lithium response in bipolar disorder patients

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