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

Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium

doi:10.1038/s41398-021-01702-2

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

Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium

Medicine

Résultat de recherche: Article › examen par les pairs

38 Citations (Scopus)

Résumé

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.

Langue d'origine	English
Numéro d'article	606
Journal	Translational Psychiatry
Volume	11
Numéro de publication	1
DOI	https://doi.org/10.1038/s41398-021-01702-2
Statut de publication	Published - déc. 2021

Note bibliographique

Funding Information:
ATA is supported by 2019–2021 National Alliance for Research on Schizophrenia and Depression (NARSAD) Young Investigator Grant from the Brain & Behaviour Research Foundation (BBRF). EV has received grants and served as consultant, advisor or CME speaker for the following entities: AB-Biotics, Allergan, Angelini, AstraZeneca, Bristol-Myers Squibb, Dainippon Sumitomo Pharma, Farmindustria, Ferrer, Forest Research Institute, Gedeon Richter, Glaxo-Smith-Kline, Janssen, Lundbeck, Otsuka, Pfizer, Roche, Sanofi-Aventis, Servier, Shire, Sunovion, Takeda, the Brain and Behaviour Foundation, the Spanish Ministry of Science and Innovation (CIBERSAM), and the Stanley Medical Research Institute. MB has received grants from the Deutsche Forschungsgemeinschaft (DFG), and Bundesministeriums für Bildung und Forschung (BMBF), and served as consultant, advisor or CME speaker for the following entities: Allergan, Aristo, Janssen, Lilly, Lundbeck, neuraxpharm, Otsuka, Sandoz, Servier, and Sunovion outside the submitted work. SK-S has received grants and served as consultant, advisor or speaker for the following entities: Medice Arzneimittel Pütter GmbH and Shire. BB has received grants and served as consultant, advisor or CME speaker for the following entities: AstraZeneca, Bristol-Myers Squibb, Janssen, Lundbeck, Otsuka, Servier, the National Health and Medical Research Council, the Fay Fuller Foundation, the James and Diana Ramsay Foundation. TK received honoraria for lectures, manuscripts, and/or consultancy, from Kyowa Hakko Kirin Co., Ltd., Eli Lilly Japan K.K., Otsuka Pharmaceutical Co., Ltd., GlaxoSmithKline K.K., Taisho Toyama Pharmaceutical Co., Ltd., Dainippon Sumitomo Pharma Co., Ltd., Meiji Seika Pharma Co., Ltd., Pfizer Japan Inc., Mochida Pharmaceutical Co., Ltd., Shionogi & Co., Ltd., Janssen Pharmaceutical K.K., Janssen Asia Pacific, Yoshitomiyakuhin, Astellas Pharma Inc., Wako Pure Chemical Industries, Ltd., Wiley Publishing Japan, Nippon Boehringer Ingelheim Co. Ltd., Kanae Foundation for the Promotion of Medical Science, MSD K.K., Kyowa Pharmaceutical Industry Co., Ltd. and Takeda Pharmaceutical Co., Ltd. TK also received a research grant from Takeda Pharmaceutical Co., Ltd. PF has received grants and served as consultant, advisor or CME speaker for the following entities Abbott, GlaxoSmithKline, Janssen, Essex, Lundbeck, Otsuka, Gedeon Richter, Servier and Takeda as well as the German Ministry of Science and the German Ministry of Health. ER has received grants and served as consultant, advisor or CME speaker for the following entities: Janssen and Institut Allergosan. ML declares that, over the past 36 months, he has received lecture honoraria from Lundbeck and served as a scientific consultant for EPID Research Oy; no other equity ownership, profit-sharing agreements, royalties, or patent. KA has received consulting honoraria from Taisho Toyama Pharmaceutical Co., Ltd. The remaining authors declare no competing interests.

Publisher Copyright:
© 2021, The Author(s).

ASJC Scopus Subject Areas

Psychiatry and Mental health
Cellular and Molecular Neuroscience
Biological Psychiatry

PubMed: MeSH publication types

Journal Article
Meta-Analysis
Research Support, Non-U.S. Gov't

ODD de l’ONU

Cette action contribue à la réalisation des objectifs de développement durable suivants

Accès au document

10.1038/s41398-021-01702-2

Autres fichiers et liens

Citer

@article{44ce705cfc8448ec80581774faf244d7,

title = "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 lithium treatment response phenotype may generate novel molecular insights into lithium{\textquoteright}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.",

author = "{Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium} and Schubert, {Klaus Oliver} and Anbupalam Thalamuthu and Amare, {Azmeraw T.} and Joseph Frank and Fabian Streit and Mazda Adl and Nirmala Akula and Kazufumi Akiyama and Raffaella Ardau and B{\'a}rbara Arias and Aubry, {Jean Michel} and Lena Backlund and Bhattacharjee, {Abesh Kumar} and Frank Bellivier and Antonio Benabarre and Susanne Bengesser and Biernacka, {Joanna M.} and Armin Birner and Cynthia Marie-Claire and Micah Cearns and Pablo Cervantes and Chen, {Hsi Chung} and Caterina Chillotti and Sven Cichon and Clark, {Scott R.} and Cristiana Cruceanu and Czerski, {Piotr M.} and Nina Dalkner and Alexandre Dayer and Franziska Degenhardt and {Del Zompo}, Maria and DePaulo, {J. Raymond} and Bruno {\'E}tain and Peter Falkai and Forstner, {Andreas J.} and Louise Frisen and Frye, {Mark A.} and Fullerton, {Janice M.} and S{\'e}bastien Gard and Garnham, {Julie S.} and Goes, {Fernando S.} and Maria Grigoroiu-Serbanescu and Paul Grof and Ryota Hashimoto and Joanna Hauser and Urs Heilbronner and Stefan Herms and Mirko Manchia and Claire O{\textquoteright}Donovan and Slaney, {Claire M.}",

note = "Funding Information: ATA is supported by 2019–2021 National Alliance for Research on Schizophrenia and Depression (NARSAD) Young Investigator Grant from the Brain & Behaviour Research Foundation (BBRF). EV has received grants and served as consultant, advisor or CME speaker for the following entities: AB-Biotics, Allergan, Angelini, AstraZeneca, Bristol-Myers Squibb, Dainippon Sumitomo Pharma, Farmindustria, Ferrer, Forest Research Institute, Gedeon Richter, Glaxo-Smith-Kline, Janssen, Lundbeck, Otsuka, Pfizer, Roche, Sanofi-Aventis, Servier, Shire, Sunovion, Takeda, the Brain and Behaviour Foundation, the Spanish Ministry of Science and Innovation (CIBERSAM), and the Stanley Medical Research Institute. MB has received grants from the Deutsche Forschungsgemeinschaft (DFG), and Bundesministeriums f{\"u}r Bildung und Forschung (BMBF), and served as consultant, advisor or CME speaker for the following entities: Allergan, Aristo, Janssen, Lilly, Lundbeck, neuraxpharm, Otsuka, Sandoz, Servier, and Sunovion outside the submitted work. SK-S has received grants and served as consultant, advisor or speaker for the following entities: Medice Arzneimittel P{\"u}tter GmbH and Shire. BB has received grants and served as consultant, advisor or CME speaker for the following entities: AstraZeneca, Bristol-Myers Squibb, Janssen, Lundbeck, Otsuka, Servier, the National Health and Medical Research Council, the Fay Fuller Foundation, the James and Diana Ramsay Foundation. TK received honoraria for lectures, manuscripts, and/or consultancy, from Kyowa Hakko Kirin Co., Ltd., Eli Lilly Japan K.K., Otsuka Pharmaceutical Co., Ltd., GlaxoSmithKline K.K., Taisho Toyama Pharmaceutical Co., Ltd., Dainippon Sumitomo Pharma Co., Ltd., Meiji Seika Pharma Co., Ltd., Pfizer Japan Inc., Mochida Pharmaceutical Co., Ltd., Shionogi & Co., Ltd., Janssen Pharmaceutical K.K., Janssen Asia Pacific, Yoshitomiyakuhin, Astellas Pharma Inc., Wako Pure Chemical Industries, Ltd., Wiley Publishing Japan, Nippon Boehringer Ingelheim Co. Ltd., Kanae Foundation for the Promotion of Medical Science, MSD K.K., Kyowa Pharmaceutical Industry Co., Ltd. and Takeda Pharmaceutical Co., Ltd. TK also received a research grant from Takeda Pharmaceutical Co., Ltd. PF has received grants and served as consultant, advisor or CME speaker for the following entities Abbott, GlaxoSmithKline, Janssen, Essex, Lundbeck, Otsuka, Gedeon Richter, Servier and Takeda as well as the German Ministry of Science and the German Ministry of Health. ER has received grants and served as consultant, advisor or CME speaker for the following entities: Janssen and Institut Allergosan. ML declares that, over the past 36 months, he has received lecture honoraria from Lundbeck and served as a scientific consultant for EPID Research Oy; no other equity ownership, profit-sharing agreements, royalties, or patent. KA has received consulting honoraria from Taisho Toyama Pharmaceutical Co., Ltd. The remaining authors declare no competing interests. Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = dec,

doi = "10.1038/s41398-021-01702-2",

language = "English",

volume = "11",

journal = "Translational Psychiatry",

issn = "2158-3188",

publisher = "Nature Publishing Group",

number = "1",

}

TY - JOUR

T1 - Combining schizophrenia and depression polygenic risk scores improves the genetic prediction of lithium response in bipolar disorder patients

AU - Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium

AU - Schubert, Klaus Oliver

AU - Thalamuthu, Anbupalam

AU - Amare, Azmeraw T.

AU - Frank, Joseph

AU - Streit, Fabian

AU - Adl, Mazda

AU - Akula, Nirmala

AU - Akiyama, Kazufumi

AU - Ardau, Raffaella

AU - Arias, Bárbara

AU - Aubry, Jean Michel

AU - Backlund, Lena

AU - Bhattacharjee, Abesh Kumar

AU - Bellivier, Frank

AU - Benabarre, Antonio

AU - Bengesser, Susanne

AU - Biernacka, Joanna M.

AU - Birner, Armin

AU - Marie-Claire, Cynthia

AU - Cearns, Micah

AU - Cervantes, Pablo

AU - Chen, Hsi Chung

AU - Chillotti, Caterina

AU - Cichon, Sven

AU - Clark, Scott R.

AU - Cruceanu, Cristiana

AU - Czerski, Piotr M.

AU - Dalkner, Nina

AU - Dayer, Alexandre

AU - Degenhardt, Franziska

AU - Del Zompo, Maria

AU - DePaulo, J. Raymond

AU - Étain, Bruno

AU - Falkai, Peter

AU - Forstner, Andreas J.

AU - Frisen, Louise

AU - Frye, Mark A.

AU - Fullerton, Janice M.

AU - Gard, Sébastien

AU - Garnham, Julie S.

AU - Goes, Fernando S.

AU - Grigoroiu-Serbanescu, Maria

AU - Grof, Paul

AU - Hashimoto, Ryota

AU - Hauser, Joanna

AU - Heilbronner, Urs

AU - Herms, Stefan

AU - Manchia, Mirko

AU - O’Donovan, Claire

AU - Slaney, Claire M.

N1 - Funding Information: ATA is supported by 2019–2021 National Alliance for Research on Schizophrenia and Depression (NARSAD) Young Investigator Grant from the Brain & Behaviour Research Foundation (BBRF). EV has received grants and served as consultant, advisor or CME speaker for the following entities: AB-Biotics, Allergan, Angelini, AstraZeneca, Bristol-Myers Squibb, Dainippon Sumitomo Pharma, Farmindustria, Ferrer, Forest Research Institute, Gedeon Richter, Glaxo-Smith-Kline, Janssen, Lundbeck, Otsuka, Pfizer, Roche, Sanofi-Aventis, Servier, Shire, Sunovion, Takeda, the Brain and Behaviour Foundation, the Spanish Ministry of Science and Innovation (CIBERSAM), and the Stanley Medical Research Institute. MB has received grants from the Deutsche Forschungsgemeinschaft (DFG), and Bundesministeriums für Bildung und Forschung (BMBF), and served as consultant, advisor or CME speaker for the following entities: Allergan, Aristo, Janssen, Lilly, Lundbeck, neuraxpharm, Otsuka, Sandoz, Servier, and Sunovion outside the submitted work. SK-S has received grants and served as consultant, advisor or speaker for the following entities: Medice Arzneimittel Pütter GmbH and Shire. BB has received grants and served as consultant, advisor or CME speaker for the following entities: AstraZeneca, Bristol-Myers Squibb, Janssen, Lundbeck, Otsuka, Servier, the National Health and Medical Research Council, the Fay Fuller Foundation, the James and Diana Ramsay Foundation. TK received honoraria for lectures, manuscripts, and/or consultancy, from Kyowa Hakko Kirin Co., Ltd., Eli Lilly Japan K.K., Otsuka Pharmaceutical Co., Ltd., GlaxoSmithKline K.K., Taisho Toyama Pharmaceutical Co., Ltd., Dainippon Sumitomo Pharma Co., Ltd., Meiji Seika Pharma Co., Ltd., Pfizer Japan Inc., Mochida Pharmaceutical Co., Ltd., Shionogi & Co., Ltd., Janssen Pharmaceutical K.K., Janssen Asia Pacific, Yoshitomiyakuhin, Astellas Pharma Inc., Wako Pure Chemical Industries, Ltd., Wiley Publishing Japan, Nippon Boehringer Ingelheim Co. Ltd., Kanae Foundation for the Promotion of Medical Science, MSD K.K., Kyowa Pharmaceutical Industry Co., Ltd. and Takeda Pharmaceutical Co., Ltd. TK also received a research grant from Takeda Pharmaceutical Co., Ltd. PF has received grants and served as consultant, advisor or CME speaker for the following entities Abbott, GlaxoSmithKline, Janssen, Essex, Lundbeck, Otsuka, Gedeon Richter, Servier and Takeda as well as the German Ministry of Science and the German Ministry of Health. ER has received grants and served as consultant, advisor or CME speaker for the following entities: Janssen and Institut Allergosan. ML declares that, over the past 36 months, he has received lecture honoraria from Lundbeck and served as a scientific consultant for EPID Research Oy; no other equity ownership, profit-sharing agreements, royalties, or patent. KA has received consulting honoraria from Taisho Toyama Pharmaceutical Co., Ltd. The remaining authors declare no competing interests. Publisher Copyright: © 2021, The Author(s).

PY - 2021/12

Y1 - 2021/12

N2 - 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.

AB - 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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U2 - 10.1038/s41398-021-01702-2

DO - 10.1038/s41398-021-01702-2

M3 - Article

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AN - SCOPUS:85120159497

SN - 2158-3188

VL - 11

JO - Translational Psychiatry

JF - Translational Psychiatry

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ER -

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

Résumé

Note bibliographique

ASJC Scopus Subject Areas

PubMed: MeSH publication types

ODD de l’ONU

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