Association of polygenic score and the involvement of cholinergic and glutamatergic pathways with lithium treatment response in patients with bipolar disorder

Azmeraw T. Amare; Anbupalam Thalamuthu; Klaus Oliver Schubert; Janice M. Fullerton; Muktar Ahmed; Simon Hartmann; Sergi Papiol; Urs Heilbronner; Franziska Degenhardt; Fasil Tekola-Ayele; Liping Hou; Yi Hsiang Hsu; Tatyana Shekhtman; Mazda Adli; Nirmala Akula; Kazufumi Akiyama; Raffaella Ardau; Bárbara Arias; Jean Michel Aubry; Roland Hasler; Hélène Richard-Lepouriel; Nader Perroud; Lena Backlund; Abesh Kumar Bhattacharjee; Frank Bellivier; Antonio Benabarre; Susanne Bengesser; Joanna M. Biernacka; Armin Birner; Cynthia Marie-Claire; Pablo Cervantes; Hsi Chung Chen; Caterina Chillotti; Sven Cichon; Cristiana Cruceanu; Piotr M. Czerski; Nina Dalkner; Maria Del Zompo; J. Raymond DePaulo; Bruno Étain; Stephane Jamain; Peter Falkai; Andreas J. Forstner; Louise Frisen; Mark A. Frye; Sébastien Gard; Julie S. Garnham; Fernando S. Goes; Maria Grigoroiu-Serbanescu; Andreas J. Fallgatter; Sophia Stegmaier; Thomas Ethofer; Silvia Biere; Kristiyana Petrova; Ceylan Schuster; Kristina Adorjan; Monika Budde; Maria Heilbronner; Janos L. Kalman; Mojtaba Oraki Kohshour; Daniela Reich-Erkelenz; Sabrina K. Schaupp; Eva C. Schulte; Fanny Senner; Thomas Vogl; Ion George Anghelescu; Volker Arolt; Udo Dannlowski; Detlef Dietrich; Christian Figge; Markus Jäger; Fabian U. Lang; Georg Juckel; Carsten Konrad; Jens Reimer; Max Schmauß; Andrea Schmitt; Carsten Spitzer; Martin von Hagen; Jens Wiltfang; Jörg Zimmermann; Till F.M. Andlauer; Andre Fischer; Felix Bermpohl; Philipp Ritter; Silke Matura; Anna Gryaznova; Irina Falkenberg; Cüneyt Yildiz; Tilo Kircher; Julia Schmidt; Marius Koch; Kathrin Gade; Sarah Trost; Ida S. Haussleiter; Martin Lambert; Anja C. Rohenkohl; Vivien Kraft; Paul Grof; Ryota Hashimoto; Joanna Hauser; Stefan Herms; Per Hoffmann; 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; Alfonso Tortorella; Mirko Manchia; Lina Martinsson; Michael J. McCarthy; Susan McElroy; Francesc Colom; Vincent Millischer; Marina Mitjans; Francis M. Mondimore; Palmiero Monteleone; Caroline M. Nievergelt; Markus M. Nöthen; Tomas Novák; Claire O’Donovan; Norio Ozaki; 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; Paul D. Shilling; Katzutaka Shimoda; Christian Simhandl; Claire M. Slaney; Alessio Squassina; Thomas Stamm; Pavla Stopkova; Mario Maj; Gustavo Turecki; Eduard Vieta; Julia Veeh; Stephanie H. Witt; Adam Wright; Peter P. Zandi; Philip B. Mitchell; Michael Bauer; Martin Alda; Marcella Rietschel; Francis J. McMahon; Thomas G. Schulze; Scott R. Clark; Bernhard T. Baune

doi:10.1038/s41380-023-02149-1

Association of polygenic score and the involvement of cholinergic and glutamatergic pathways with lithium treatment response in patients with bipolar disorder

Azmeraw T. Amare, Anbupalam Thalamuthu, Klaus Oliver Schubert, Janice M. Fullerton, Muktar Ahmed, Simon Hartmann, Sergi Papiol, Urs Heilbronner, Franziska Degenhardt, Fasil Tekola-Ayele, Liping Hou, Yi Hsiang Hsu, Tatyana Shekhtman, Mazda Adli, Nirmala Akula, Kazufumi Akiyama, Raffaella Ardau, Bárbara Arias, Jean Michel Aubry, Roland HaslerHélène Richard-Lepouriel, Nader Perroud, Lena Backlund, Abesh Kumar Bhattacharjee, Frank Bellivier, Antonio Benabarre, Susanne Bengesser, Joanna M. Biernacka, Armin Birner, Cynthia Marie-Claire, Pablo Cervantes, Hsi Chung Chen, Caterina Chillotti, Sven Cichon, Cristiana Cruceanu, Piotr M. Czerski, Nina Dalkner, Maria Del Zompo, J. Raymond DePaulo, Bruno Étain, Stephane Jamain, Peter Falkai, Andreas J. Forstner, Louise Frisen, Mark A. Frye, Sébastien Gard, Julie S. Garnham, Fernando S. Goes, Maria Grigoroiu-Serbanescu, Andreas J. Fallgatter, Sophia Stegmaier, Thomas Ethofer, Silvia Biere, Kristiyana Petrova, Ceylan Schuster, Kristina Adorjan, Monika Budde, Maria Heilbronner, Janos L. Kalman, Mojtaba Oraki Kohshour, Daniela Reich-Erkelenz, Sabrina K. Schaupp, Eva C. Schulte, Fanny Senner, Thomas Vogl, Ion George Anghelescu, Volker Arolt, Udo Dannlowski, Detlef Dietrich, Christian Figge, Markus Jäger, Fabian U. Lang, Georg Juckel, Carsten Konrad, Jens Reimer, Max Schmauß, Andrea Schmitt, Carsten Spitzer, Martin von Hagen, Jens Wiltfang, Jörg Zimmermann, Till F.M. Andlauer, Andre Fischer, Felix Bermpohl, Philipp Ritter, Silke Matura, Anna Gryaznova, Irina Falkenberg, Cüneyt Yildiz, Tilo Kircher, Julia Schmidt, Marius Koch, Kathrin Gade, Sarah Trost, Ida S. Haussleiter, Martin Lambert, Anja C. Rohenkohl, Vivien Kraft, Paul Grof, Ryota Hashimoto, Joanna Hauser, Stefan Herms, Per Hoffmann, 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, Alfonso Tortorella, Mirko Manchia, Lina Martinsson, Michael J. McCarthy, Susan McElroy, Francesc Colom, Vincent Millischer, Marina Mitjans, Francis M. Mondimore, Palmiero Monteleone, Caroline M. Nievergelt, Markus M. Nöthen, Tomas Novák, Claire O’Donovan, Norio Ozaki, 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, Paul D. Shilling, Katzutaka Shimoda, Christian Simhandl, Claire M. Slaney, Alessio Squassina, Thomas Stamm, Pavla Stopkova, Mario Maj, Gustavo Turecki, Eduard Vieta, Julia Veeh, Stephanie H. Witt, Adam Wright, Peter P. Zandi, Philip B. Mitchell, Michael Bauer, Martin Alda, Marcella Rietschel, Francis J. McMahon, Thomas G. Schulze, Scott R. Clark, Bernhard T. Baune

Research output: Contribution to journal › Article › peer-review

Abstract

Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental health disorder that affects about 1% of the population worldwide. Nevertheless, lithium is not consistently effective, with only 30% of patients showing a favorable response to treatment. To provide personalized treatment options for bipolar patients, it is essential to identify prediction biomarkers such as polygenic scores. In this study, we developed a polygenic score for lithium treatment response (Li⁺_PGS) in patients with BD. To gain further insights into lithium’s possible molecular mechanism of action, we performed a genome-wide gene-based analysis. Using polygenic score modeling, via methods incorporating Bayesian regression and continuous shrinkage priors, Li⁺_PGS was developed in the International Consortium of Lithium Genetics cohort (ConLi⁺Gen: N = 2367) and replicated in the combined PsyCourse (N = 89) and BipoLife (N = 102) studies. The associations of Li⁺_PGS and lithium treatment response — defined in a continuous ALDA scale and a categorical outcome (good response vs. poor response) were tested using regression models, each adjusted for the covariates: age, sex, and the first four genetic principal components. Statistical significance was determined at P < 0.05. Li⁺_PGS was positively associated with lithium treatment response in the ConLi⁺Gen cohort, in both the categorical (P = 9.8 × 10⁻¹², R² = 1.9%) and continuous (P = 6.4 × 10⁻⁹, R² = 2.6%) outcomes. Compared to bipolar patients in the 1^st decile of the risk distribution, individuals in the 10^th decile had 3.47-fold (95%CI: 2.22–5.47) higher odds of responding favorably to lithium. The results were replicated in the independent cohorts for the categorical treatment outcome (P = 3.9 × 10⁻⁴, R² = 0.9%), but not for the continuous outcome (P = 0.13). Gene-based analyses revealed 36 candidate genes that are enriched in biological pathways controlled by glutamate and acetylcholine. Li⁺_PGS may be useful in the development of pharmacogenomic testing strategies by enabling a classification of bipolar patients according to their response to treatment.

Original language	English (US)
Journal	Molecular Psychiatry
DOIs	https://doi.org/10.1038/s41380-023-02149-1
State	Accepted/In press - 2023

ASJC Scopus subject areas

Molecular Biology
Cellular and Molecular Neuroscience
Psychiatry and Mental health

Access to Document

10.1038/s41380-023-02149-1

Cite this

Amare, A. T., Thalamuthu, A., Schubert, K. O., Fullerton, J. M., Ahmed, M., Hartmann, S., Papiol, S., Heilbronner, U., Degenhardt, F., Tekola-Ayele, F., Hou, L., Hsu, Y. H., Shekhtman, T., Adli, M., Akula, N., Akiyama, K., Ardau, R., Arias, B., Aubry, J. M., ... Baune, B. T. (Accepted/In press). Association of polygenic score and the involvement of cholinergic and glutamatergic pathways with lithium treatment response in patients with bipolar disorder. Molecular Psychiatry. https://doi.org/10.1038/s41380-023-02149-1

Amare, AT, Thalamuthu, A, Schubert, KO, Fullerton, JM, Ahmed, M, Hartmann, S, Papiol, S, Heilbronner, U, Degenhardt, F, Tekola-Ayele, F, Hou, L, Hsu, YH, Shekhtman, T, Adli, M, Akula, N, Akiyama, K, Ardau, R, Arias, B, Aubry, JM, Hasler, R, Richard-Lepouriel, H, Perroud, N, Backlund, L, Bhattacharjee, AK, Bellivier, F, Benabarre, A, Bengesser, S, Biernacka, JM, Birner, A, Marie-Claire, C, Cervantes, P, Chen, HC, Chillotti, C, Cichon, S, Cruceanu, C, Czerski, PM, Dalkner, N, Del Zompo, M, DePaulo, JR, Étain, B, Jamain, S, Falkai, P, Forstner, AJ, Frisen, L, Frye, MA, Gard, S, Garnham, JS, Goes, FS, Grigoroiu-Serbanescu, M, Fallgatter, AJ, Stegmaier, S, Ethofer, T, Biere, S, Petrova, K, Schuster, C, Adorjan, K, Budde, M, Heilbronner, M, Kalman, JL, Kohshour, MO, Reich-Erkelenz, D, Schaupp, SK, Schulte, EC, Senner, F, Vogl, T, Anghelescu, IG, Arolt, V, Dannlowski, U, Dietrich, D, Figge, C, Jäger, M, Lang, FU, Juckel, G, Konrad, C, Reimer, J, Schmauß, M, Schmitt, A, Spitzer, C, von Hagen, M, Wiltfang, J, Zimmermann, J, Andlauer, TFM, Fischer, A, Bermpohl, F, Ritter, P, Matura, S, Gryaznova, A, Falkenberg, I, Yildiz, C, Kircher, T, Schmidt, J, Koch, M, Gade, K, Trost, S, Haussleiter, IS, Lambert, M, Rohenkohl, AC, Kraft, V, Grof, P, Hashimoto, R, Hauser, J, Herms, S, Hoffmann, P, Jiménez, E, Kahn, JP, Kassem, L, Kuo, PH, Kato, T, Kelsoe, J, Kittel-Schneider, S, Ferensztajn-Rochowiak, E, König, B, Kusumi, I, Laje, G, Landén, M, Lavebratt, C, Leboyer, M, Leckband, SG, Tortorella, A, Manchia, M, Martinsson, L, McCarthy, MJ, McElroy, S, Colom, F, Millischer, V, Mitjans, M, Mondimore, FM, Monteleone, P, Nievergelt, CM, Nöthen, MM, Novák, T, O’Donovan, C, Ozaki, N, Pfennig, A, Pisanu, C, Potash, JB, Reif, A, Reininghaus, E, Rouleau, GA, Rybakowski, JK, Schalling, M, Schofield, PR, Schweizer, BW, Severino, G, Shilling, PD, Shimoda, K, Simhandl, C, Slaney, CM, Squassina, A, Stamm, T, Stopkova, P, Maj, M, Turecki, G, Vieta, E, Veeh, J, Witt, SH, Wright, A, Zandi, PP, Mitchell, PB, Bauer, M, Alda, M, Rietschel, M, McMahon, FJ, Schulze, TG, Clark, SR & Baune, BT 2023, 'Association of polygenic score and the involvement of cholinergic and glutamatergic pathways with lithium treatment response in patients with bipolar disorder', Molecular Psychiatry. https://doi.org/10.1038/s41380-023-02149-1

@article{990b449bf4034e749da6f519986282fb,

title = "Association of polygenic score and the involvement of cholinergic and glutamatergic pathways with lithium treatment response in patients with bipolar disorder",

abstract = "Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental health disorder that affects about 1% of the population worldwide. Nevertheless, lithium is not consistently effective, with only 30% of patients showing a favorable response to treatment. To provide personalized treatment options for bipolar patients, it is essential to identify prediction biomarkers such as polygenic scores. In this study, we developed a polygenic score for lithium treatment response (Li+PGS) in patients with BD. To gain further insights into lithium{\textquoteright}s possible molecular mechanism of action, we performed a genome-wide gene-based analysis. Using polygenic score modeling, via methods incorporating Bayesian regression and continuous shrinkage priors, Li+PGS was developed in the International Consortium of Lithium Genetics cohort (ConLi+Gen: N = 2367) and replicated in the combined PsyCourse (N = 89) and BipoLife (N = 102) studies. The associations of Li+PGS and lithium treatment response — defined in a continuous ALDA scale and a categorical outcome (good response vs. poor response) were tested using regression models, each adjusted for the covariates: age, sex, and the first four genetic principal components. Statistical significance was determined at P < 0.05. Li+PGS was positively associated with lithium treatment response in the ConLi+Gen cohort, in both the categorical (P = 9.8 × 10−12, R2 = 1.9%) and continuous (P = 6.4 × 10−9, R2 = 2.6%) outcomes. Compared to bipolar patients in the 1st decile of the risk distribution, individuals in the 10th decile had 3.47-fold (95%CI: 2.22–5.47) higher odds of responding favorably to lithium. The results were replicated in the independent cohorts for the categorical treatment outcome (P = 3.9 × 10−4, R2 = 0.9%), but not for the continuous outcome (P = 0.13). Gene-based analyses revealed 36 candidate genes that are enriched in biological pathways controlled by glutamate and acetylcholine. Li+PGS may be useful in the development of pharmacogenomic testing strategies by enabling a classification of bipolar patients according to their response to treatment.",

author = "Amare, {Azmeraw T.} and Anbupalam Thalamuthu and Schubert, {Klaus Oliver} and Fullerton, {Janice M.} and Muktar Ahmed and Simon Hartmann and Sergi Papiol and Urs Heilbronner and Franziska Degenhardt and Fasil Tekola-Ayele and Liping Hou and Hsu, {Yi Hsiang} and Tatyana Shekhtman and Mazda Adli and Nirmala Akula and Kazufumi Akiyama and Raffaella Ardau and B{\'a}rbara Arias and Aubry, {Jean Michel} and Roland Hasler and H{\'e}l{\`e}ne Richard-Lepouriel and Nader Perroud 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 Pablo Cervantes and Chen, {Hsi Chung} and Caterina Chillotti and Sven Cichon and Cristiana Cruceanu and Czerski, {Piotr M.} and Nina Dalkner and {Del Zompo}, Maria and DePaulo, {J. Raymond} and Bruno {\'E}tain and Stephane Jamain and Peter Falkai and Forstner, {Andreas J.} and Louise Frisen and Frye, {Mark A.} and S{\'e}bastien Gard and Garnham, {Julie S.} and Goes, {Fernando S.} and Maria Grigoroiu-Serbanescu and Fallgatter, {Andreas J.} and Sophia Stegmaier and Thomas Ethofer and Silvia Biere and Kristiyana Petrova and Ceylan Schuster and Kristina Adorjan and Monika Budde and Maria Heilbronner and Kalman, {Janos L.} and Kohshour, {Mojtaba Oraki} and Daniela Reich-Erkelenz and Schaupp, {Sabrina K.} and Schulte, {Eva C.} and Fanny Senner and Thomas Vogl and Anghelescu, {Ion George} and Volker Arolt and Udo Dannlowski and Detlef Dietrich and Christian Figge and Markus J{\"a}ger and Lang, {Fabian U.} and Georg Juckel and Carsten Konrad and Jens Reimer and Max Schmau{\ss} and Andrea Schmitt and Carsten Spitzer and {von Hagen}, Martin and Jens Wiltfang and J{\"o}rg Zimmermann and Andlauer, {Till F.M.} and Andre Fischer and Felix Bermpohl and Philipp Ritter and Silke Matura and Anna Gryaznova and Irina Falkenberg and C{\"u}neyt Yildiz and Tilo Kircher and Julia Schmidt and Marius Koch and Kathrin Gade and Sarah Trost and Haussleiter, {Ida S.} and Martin Lambert and Rohenkohl, {Anja C.} and Vivien Kraft and Paul Grof and Ryota Hashimoto and Joanna Hauser and Stefan Herms and Per Hoffmann and Esther Jim{\'e}nez and Kahn, {Jean Pierre} and Layla Kassem and Kuo, {Po Hsiu} and Tadafumi Kato and John Kelsoe and Sarah Kittel-Schneider and Ewa Ferensztajn-Rochowiak and Barbara K{\"o}nig and Ichiro Kusumi and Gonzalo Laje and Mikael Land{\'e}n and Catharina Lavebratt and Marion Leboyer and Leckband, {Susan G.} and Alfonso Tortorella and Mirko Manchia and Lina Martinsson and McCarthy, {Michael J.} and Susan McElroy and Francesc Colom and Vincent Millischer and Marina Mitjans and Mondimore, {Francis M.} and Palmiero Monteleone and Nievergelt, {Caroline M.} and N{\"o}then, {Markus M.} and Tomas Nov{\'a}k and Claire O{\textquoteright}Donovan and Norio Ozaki and Andrea Pfennig and Claudia Pisanu and Potash, {James B.} and Andreas Reif and Eva Reininghaus and Rouleau, {Guy A.} and Rybakowski, {Janusz K.} and Martin Schalling and Schofield, {Peter R.} and Schweizer, {Barbara W.} and Giovanni Severino and Shilling, {Paul D.} and Katzutaka Shimoda and Christian Simhandl and Slaney, {Claire M.} and Alessio Squassina and Thomas Stamm and Pavla Stopkova and Mario Maj and Gustavo Turecki and Eduard Vieta and Julia Veeh and Witt, {Stephanie H.} and Adam Wright and Zandi, {Peter P.} and Mitchell, {Philip B.} and Michael Bauer and Martin Alda and Marcella Rietschel and McMahon, {Francis J.} and Schulze, {Thomas G.} and Clark, {Scott R.} and Baune, {Bernhard T.}",

note = "Publisher Copyright: {\textcopyright} 2023, The Author(s).",

year = "2023",

doi = "10.1038/s41380-023-02149-1",

language = "English (US)",

journal = "Molecular Psychiatry",

issn = "1359-4184",

publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Association of polygenic score and the involvement of cholinergic and glutamatergic pathways with lithium treatment response in patients with bipolar disorder

AU - Amare, Azmeraw T.

AU - Thalamuthu, Anbupalam

AU - Schubert, Klaus Oliver

AU - Fullerton, Janice M.

AU - Ahmed, Muktar

AU - Hartmann, Simon

AU - Papiol, Sergi

AU - Heilbronner, Urs

AU - Degenhardt, Franziska

AU - Tekola-Ayele, Fasil

AU - Hou, Liping

AU - Hsu, Yi Hsiang

AU - Shekhtman, Tatyana

AU - Adli, Mazda

AU - Akula, Nirmala

AU - Akiyama, Kazufumi

AU - Ardau, Raffaella

AU - Arias, Bárbara

AU - Aubry, Jean Michel

AU - Hasler, Roland

AU - Richard-Lepouriel, Hélène

AU - Perroud, Nader

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 - Cervantes, Pablo

AU - Chen, Hsi Chung

AU - Chillotti, Caterina

AU - Cichon, Sven

AU - Cruceanu, Cristiana

AU - Czerski, Piotr M.

AU - Dalkner, Nina

AU - Del Zompo, Maria

AU - DePaulo, J. Raymond

AU - Étain, Bruno

AU - Jamain, Stephane

AU - Falkai, Peter

AU - Forstner, Andreas J.

AU - Frisen, Louise

AU - Frye, Mark A.

AU - Gard, Sébastien

AU - Garnham, Julie S.

AU - Goes, Fernando S.

AU - Grigoroiu-Serbanescu, Maria

AU - Fallgatter, Andreas J.

AU - Stegmaier, Sophia

AU - Ethofer, Thomas

AU - Biere, Silvia

AU - Petrova, Kristiyana

AU - Schuster, Ceylan

AU - Adorjan, Kristina

AU - Budde, Monika

AU - Heilbronner, Maria

AU - Kalman, Janos L.

AU - Kohshour, Mojtaba Oraki

AU - Reich-Erkelenz, Daniela

AU - Schaupp, Sabrina K.

AU - Schulte, Eva C.

AU - Senner, Fanny

AU - Vogl, Thomas

AU - Anghelescu, Ion George

AU - Arolt, Volker

AU - Dannlowski, Udo

AU - Dietrich, Detlef

AU - Figge, Christian

AU - Jäger, Markus

AU - Lang, Fabian U.

AU - Juckel, Georg

AU - Konrad, Carsten

AU - Reimer, Jens

AU - Schmauß, Max

AU - Schmitt, Andrea

AU - Spitzer, Carsten

AU - von Hagen, Martin

AU - Wiltfang, Jens

AU - Zimmermann, Jörg

AU - Andlauer, Till F.M.

AU - Fischer, Andre

AU - Bermpohl, Felix

AU - Ritter, Philipp

AU - Matura, Silke

AU - Gryaznova, Anna

AU - Falkenberg, Irina

AU - Yildiz, Cüneyt

AU - Kircher, Tilo

AU - Schmidt, Julia

AU - Koch, Marius

AU - Gade, Kathrin

AU - Trost, Sarah

AU - Haussleiter, Ida S.

AU - Lambert, Martin

AU - Rohenkohl, Anja C.

AU - Kraft, Vivien

AU - Grof, Paul

AU - Hashimoto, Ryota

AU - Hauser, Joanna

AU - Herms, Stefan

AU - Hoffmann, Per

AU - Jiménez, Esther

AU - Kahn, Jean Pierre

AU - Kassem, Layla

AU - Kuo, Po Hsiu

AU - Kato, Tadafumi

AU - Kelsoe, John

AU - Kittel-Schneider, Sarah

AU - Ferensztajn-Rochowiak, Ewa

AU - König, Barbara

AU - Kusumi, Ichiro

AU - Laje, Gonzalo

AU - Landén, Mikael

AU - Lavebratt, Catharina

AU - Leboyer, Marion

AU - Leckband, Susan G.

AU - Tortorella, Alfonso

AU - Manchia, Mirko

AU - Martinsson, Lina

AU - McCarthy, Michael J.

AU - McElroy, Susan

AU - Colom, Francesc

AU - Millischer, Vincent

AU - Mitjans, Marina

AU - Mondimore, Francis M.

AU - Monteleone, Palmiero

AU - Nievergelt, Caroline M.

AU - Nöthen, Markus M.

AU - Novák, Tomas

AU - O’Donovan, Claire

AU - Ozaki, Norio

AU - Pfennig, Andrea

AU - Pisanu, Claudia

AU - Potash, James B.

AU - Reif, Andreas

AU - Reininghaus, Eva

AU - Rouleau, Guy A.

AU - Rybakowski, Janusz K.

AU - Schalling, Martin

AU - Schofield, Peter R.

AU - Schweizer, Barbara W.

AU - Severino, Giovanni

AU - Shilling, Paul D.

AU - Shimoda, Katzutaka

AU - Simhandl, Christian

AU - Slaney, Claire M.

AU - Squassina, Alessio

AU - Stamm, Thomas

AU - Stopkova, Pavla

AU - Maj, Mario

AU - Turecki, Gustavo

AU - Vieta, Eduard

AU - Veeh, Julia

AU - Witt, Stephanie H.

AU - Wright, Adam

AU - Zandi, Peter P.

AU - Mitchell, Philip B.

AU - Bauer, Michael

AU - Alda, Martin

AU - Rietschel, Marcella

AU - McMahon, Francis J.

AU - Schulze, Thomas G.

AU - Clark, Scott R.

AU - Baune, Bernhard T.

PY - 2023

Y1 - 2023

N2 - Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental health disorder that affects about 1% of the population worldwide. Nevertheless, lithium is not consistently effective, with only 30% of patients showing a favorable response to treatment. To provide personalized treatment options for bipolar patients, it is essential to identify prediction biomarkers such as polygenic scores. In this study, we developed a polygenic score for lithium treatment response (Li+PGS) in patients with BD. To gain further insights into lithium’s possible molecular mechanism of action, we performed a genome-wide gene-based analysis. Using polygenic score modeling, via methods incorporating Bayesian regression and continuous shrinkage priors, Li+PGS was developed in the International Consortium of Lithium Genetics cohort (ConLi+Gen: N = 2367) and replicated in the combined PsyCourse (N = 89) and BipoLife (N = 102) studies. The associations of Li+PGS and lithium treatment response — defined in a continuous ALDA scale and a categorical outcome (good response vs. poor response) were tested using regression models, each adjusted for the covariates: age, sex, and the first four genetic principal components. Statistical significance was determined at P < 0.05. Li+PGS was positively associated with lithium treatment response in the ConLi+Gen cohort, in both the categorical (P = 9.8 × 10−12, R2 = 1.9%) and continuous (P = 6.4 × 10−9, R2 = 2.6%) outcomes. Compared to bipolar patients in the 1st decile of the risk distribution, individuals in the 10th decile had 3.47-fold (95%CI: 2.22–5.47) higher odds of responding favorably to lithium. The results were replicated in the independent cohorts for the categorical treatment outcome (P = 3.9 × 10−4, R2 = 0.9%), but not for the continuous outcome (P = 0.13). Gene-based analyses revealed 36 candidate genes that are enriched in biological pathways controlled by glutamate and acetylcholine. Li+PGS may be useful in the development of pharmacogenomic testing strategies by enabling a classification of bipolar patients according to their response to treatment.

AB - Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental health disorder that affects about 1% of the population worldwide. Nevertheless, lithium is not consistently effective, with only 30% of patients showing a favorable response to treatment. To provide personalized treatment options for bipolar patients, it is essential to identify prediction biomarkers such as polygenic scores. In this study, we developed a polygenic score for lithium treatment response (Li+PGS) in patients with BD. To gain further insights into lithium’s possible molecular mechanism of action, we performed a genome-wide gene-based analysis. Using polygenic score modeling, via methods incorporating Bayesian regression and continuous shrinkage priors, Li+PGS was developed in the International Consortium of Lithium Genetics cohort (ConLi+Gen: N = 2367) and replicated in the combined PsyCourse (N = 89) and BipoLife (N = 102) studies. The associations of Li+PGS and lithium treatment response — defined in a continuous ALDA scale and a categorical outcome (good response vs. poor response) were tested using regression models, each adjusted for the covariates: age, sex, and the first four genetic principal components. Statistical significance was determined at P < 0.05. Li+PGS was positively associated with lithium treatment response in the ConLi+Gen cohort, in both the categorical (P = 9.8 × 10−12, R2 = 1.9%) and continuous (P = 6.4 × 10−9, R2 = 2.6%) outcomes. Compared to bipolar patients in the 1st decile of the risk distribution, individuals in the 10th decile had 3.47-fold (95%CI: 2.22–5.47) higher odds of responding favorably to lithium. The results were replicated in the independent cohorts for the categorical treatment outcome (P = 3.9 × 10−4, R2 = 0.9%), but not for the continuous outcome (P = 0.13). Gene-based analyses revealed 36 candidate genes that are enriched in biological pathways controlled by glutamate and acetylcholine. Li+PGS may be useful in the development of pharmacogenomic testing strategies by enabling a classification of bipolar patients according to their response to treatment.

UR - http://www.scopus.com/inward/record.url?scp=85164527779&partnerID=8YFLogxK

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U2 - 10.1038/s41380-023-02149-1

DO - 10.1038/s41380-023-02149-1

M3 - Article

C2 - 37433967

AN - SCOPUS:85164527779

SN - 1359-4184

JO - Molecular Psychiatry

JF - Molecular Psychiatry

ER -

Association of polygenic score and the involvement of cholinergic and glutamatergic pathways with lithium treatment response in patients with bipolar disorder

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