Immunogenetics of lithium response and psychiatric phenotypes in patients with bipolar disorder

Marisol Herrera-Rivero; Karina Gutiérrez-Fragoso; Joachim Kurtz; Bernhard T. Baune; Anbupalam Thalamuthu; Azmeraw T. Amare; Mazda Adli; Kazufumi Akiyama; Nirmala Akula; Raffaella Ardau; B. rbara Arias; Jean-Michel Aubry; Lena Backlund; Frank Bellivier; Antonio Benabarre; Susanne Bengesser; Abesh Kumar Bhattacharjee; Joanna M. Biernacka; Armin Birner; Micah Cearns; Pablo Cervantes; Hsi-Chung Chen; Caterina Chillotti; Sven Cichon; Scott R. Clark; Francesc Colom; Cristiana Cruceanu; Piotr M. Czerski; Nina Dalkner; Franziska Degenhardt; Maria del Zompo; J. Raymond DePaulo; Bruno Etain; Peter Falkai; Ewa Ferensztajn-Rochowiak; Andreas J. Forstner; Josef Frank; Louise Frisén; Mark A. Frye; Janice M. Fullerton; Carla Gallo; S. bastien Gard; Julie S. Garnham; Fernando S. Goes; Maria Grigoroiu-Serbanescu; Paul Grof; Ryota Hashimoto; Roland Hasler; Joanna Hauser; Urs Heilbronner; Stefan Herms; Per Hoffmann; Liping Hou; Yi-Hsiang Hsu; Stéphane Jamain; Esther Jiménez; Jean-Pierre Kahn; Layla Kassem; Tadafumi Kato; John Kelsoe; Sarah Kittel-Schneider; Po-Hsiu Kuo; Ichiro Kusumi; Barbara König; Gonzalo Laje; Mikael Landén; Catharina Lavebratt; Marion Leboyer; Susan G. Leckband; Mario Maj; Mirko Manchia; Cynthia Marie-Claire; Lina Martinsson; Michael J. McCarthy; Susan L. McElroy; Vincent Millischer; Marina Mitjans; Francis M. Mondimore; Palmiero Monteleone; Caroline M. Nievergelt; Tomas Novák; Markus M. Nöthen; Claire O’Donovan; Norio Ozaki; Sergi Papiol; Andrea Pfennig; Claudia Pisanu; James B. Potash; Andreas Reif; Eva Reininghaus; H. lène Richard-Lepouriel; Gloria Roberts; Guy A. Rouleau; Janusz K. Rybakowski; Martin Schalling; Peter R. Schofield; Klaus Oliver Schubert; Eva C. Schulte; Barbara W. Schweizer; Giovanni Severino; Tatyana Shekhtman; Paul D. Shilling; Katzutaka Shimoda; Christian Simhandl; Claire M. Slaney; Alessio Squassina; Thomas Stamm; Pavla Stopkova; Fabian Streit; Fasil Tekola-Ayele; Alfonso Tortorella; Gustavo Turecki; Julia Veeh; Eduard Vieta; Biju Viswanath; Stephanie H. Witt; Peter P. Zandi; Martin Alda; Michael Bauer; Francis J. McMahon; Philip B. Mitchell; Marcella Rietschel; Thomas G. Schulze

doi:10.1038/s41398-024-02865-4

Immunogenetics of lithium response and psychiatric phenotypes in patients with bipolar disorder

Marisol Herrera-Rivero, Karina Gutiérrez-Fragoso, Joachim Kurtz, Bernhard T. Baune, Anbupalam Thalamuthu, Azmeraw T. Amare, Mazda Adli, Kazufumi Akiyama, Nirmala Akula, Raffaella Ardau, B. rbara Arias, Jean-Michel Aubry, Lena Backlund, Frank Bellivier, Antonio Benabarre, Susanne Bengesser, Abesh Kumar Bhattacharjee, Joanna M. Biernacka, Armin Birner, Micah CearnsPablo Cervantes, Hsi-Chung Chen, Caterina Chillotti, Sven Cichon, Scott R. Clark, Francesc Colom, Cristiana Cruceanu, Piotr M. Czerski, Nina Dalkner, Franziska Degenhardt, Maria del Zompo, J. Raymond DePaulo, Bruno Etain, Peter Falkai, Ewa Ferensztajn-Rochowiak, Andreas J. Forstner, Josef Frank, Louise Frisén, Mark A. Frye, Janice M. Fullerton, Carla Gallo, S. bastien Gard, Julie S. Garnham, Fernando S. Goes, Maria Grigoroiu-Serbanescu, Paul Grof, Ryota Hashimoto, Roland Hasler, Joanna Hauser, Urs Heilbronner, Stefan Herms, Per Hoffmann, Liping Hou, Yi-Hsiang Hsu, Stéphane Jamain, Esther Jiménez, Jean-Pierre Kahn, Layla Kassem, Tadafumi Kato, John Kelsoe, Sarah Kittel-Schneider, Po-Hsiu Kuo, Ichiro Kusumi, Barbara König, Gonzalo Laje, Mikael Landén, Catharina Lavebratt, Marion Leboyer, Susan G. Leckband, Mario Maj, Mirko Manchia, Cynthia Marie-Claire, Lina Martinsson, Michael J. McCarthy, Susan L. McElroy, Vincent Millischer, Marina Mitjans, Francis M. Mondimore, Palmiero Monteleone, Caroline M. Nievergelt, Tomas Novák, Markus M. Nöthen, Claire O’Donovan, Norio Ozaki, Sergi Papiol, Andrea Pfennig, Claudia Pisanu, James B. Potash, Andreas Reif, Eva Reininghaus, H. lène Richard-Lepouriel, Gloria Roberts, Guy A. Rouleau, Janusz K. Rybakowski, Martin Schalling, Peter R. Schofield, Klaus Oliver Schubert, Eva C. Schulte, Barbara W. Schweizer, Giovanni Severino, Tatyana Shekhtman, Paul D. Shilling, Katzutaka Shimoda, Christian Simhandl, Claire M. Slaney, Alessio Squassina, Thomas Stamm, Pavla Stopkova, Fabian Streit, Fasil Tekola-Ayele, Alfonso Tortorella, Gustavo Turecki, Julia Veeh, Eduard Vieta, Biju Viswanath, Stephanie H. Witt, Peter P. Zandi, Martin Alda, Michael Bauer, Francis J. McMahon, Philip B. Mitchell, Marcella Rietschel, Thomas G. Schulze

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

Abstract

The link between bipolar disorder (BP) and immune dysfunction remains controversial. While epidemiological studies have long suggested an association, recent research has found only limited evidence of such a relationship. To clarify this, we performed an exploratory study of the contributions of immune-relevant genetic factors to the response to lithium (Li) treatment and the clinical presentation of BP. First, we assessed the association of a large collection of immune-related genes (4925) with Li response, defined by the Retrospective Assessment of the Lithium Response Phenotype Scale (Alda scale), and clinical characteristics in patients with BP from the International Consortium on Lithium Genetics (ConLi ⁺Gen, N = 2374). Second, we calculated here previously published polygenic scores (PGSs) for immune-related traits and evaluated their associations with Li response and clinical features. Overall, we observed relatively weak associations (p < 1 × 10 ⁻⁴) with BP phenotypes within immune-related genes. Network and functional enrichment analyses of the top findings from the association analyses of Li response variables showed an overrepresentation of pathways participating in cell adhesion and intercellular communication. These appeared to converge on the well-known Li-induced inhibition of GSK-3β. Association analyses of age-at-onset, number of mood episodes, and presence of psychosis, substance abuse and/or suicidal ideation suggested modest contributions of genes such as RTN4, XKR4, NRXN1, NRG1/3 and GRK5 to disease characteristics. PGS analyses returned weak associations (p < 0.05) between inflammation markers and the studied BP phenotypes. Our results suggest a modest relationship between immunity and clinical features in BP. More research is needed to assess the potential therapeutic relevance.

Original language	English
Article number	174
Journal	Translational Psychiatry
Volume	14
Issue number	1
DOIs	https://doi.org/10.1038/s41398-024-02865-4
Publication status	Published - 1 Dec 2024

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Herrera-Rivero, M., Gutiérrez-Fragoso, K., Kurtz, J., Baune, B. T., Thalamuthu, A., Amare, A. T., Adli, M., Akiyama, K., Akula, N., Ardau, R., Arias, B. R., Aubry, J.-M., Backlund, L., Bellivier, F., Benabarre, A., Bengesser, S., Bhattacharjee, A. K., Biernacka, J. M., Birner, A., ... Schulze, T. G. (2024). Immunogenetics of lithium response and psychiatric phenotypes in patients with bipolar disorder. Translational Psychiatry, 14(1), Article 174. https://doi.org/10.1038/s41398-024-02865-4

@article{561ea40e95a94ae5b507279660f78446,

title = "Immunogenetics of lithium response and psychiatric phenotypes in patients with bipolar disorder",

abstract = "The link between bipolar disorder (BP) and immune dysfunction remains controversial. While epidemiological studies have long suggested an association, recent research has found only limited evidence of such a relationship. To clarify this, we performed an exploratory study of the contributions of immune-relevant genetic factors to the response to lithium (Li) treatment and the clinical presentation of BP. First, we assessed the association of a large collection of immune-related genes (4925) with Li response, defined by the Retrospective Assessment of the Lithium Response Phenotype Scale (Alda scale), and clinical characteristics in patients with BP from the International Consortium on Lithium Genetics (ConLi +Gen, N = 2374). Second, we calculated here previously published polygenic scores (PGSs) for immune-related traits and evaluated their associations with Li response and clinical features. Overall, we observed relatively weak associations (p < 1 × 10 −4) with BP phenotypes within immune-related genes. Network and functional enrichment analyses of the top findings from the association analyses of Li response variables showed an overrepresentation of pathways participating in cell adhesion and intercellular communication. These appeared to converge on the well-known Li-induced inhibition of GSK-3β. Association analyses of age-at-onset, number of mood episodes, and presence of psychosis, substance abuse and/or suicidal ideation suggested modest contributions of genes such as RTN4, XKR4, NRXN1, NRG1/3 and GRK5 to disease characteristics. PGS analyses returned weak associations (p < 0.05) between inflammation markers and the studied BP phenotypes. Our results suggest a modest relationship between immunity and clinical features in BP. More research is needed to assess the potential therapeutic relevance.",

author = "Marisol Herrera-Rivero and Karina Guti{\'e}rrez-Fragoso and Joachim Kurtz and Baune, {Bernhard T.} and Anbupalam Thalamuthu and Amare, {Azmeraw T.} and Mazda Adli and Kazufumi Akiyama and Nirmala Akula and Raffaella Ardau and Arias, {B. rbara} and Jean-Michel Aubry and Lena Backlund and Frank Bellivier and Antonio Benabarre and Susanne Bengesser and Bhattacharjee, {Abesh Kumar} and Biernacka, {Joanna M.} and Armin Birner and Micah Cearns and Pablo Cervantes and Hsi-Chung Chen and Caterina Chillotti and Sven Cichon and Clark, {Scott R.} and Francesc Colom and Cristiana Cruceanu and Czerski, {Piotr M.} and Nina Dalkner and Franziska Degenhardt and {del Zompo}, Maria and DePaulo, {J. Raymond} and Bruno Etain and Peter Falkai and Ewa Ferensztajn-Rochowiak and Forstner, {Andreas J.} and Josef Frank and Louise Fris{\'e}n and Frye, {Mark A.} and Fullerton, {Janice M.} and Carla Gallo and Gard, {S. bastien} and Garnham, {Julie S.} and Goes, {Fernando S.} and Maria Grigoroiu-Serbanescu and Paul Grof and Ryota Hashimoto and Roland Hasler and Joanna Hauser and Urs Heilbronner and Stefan Herms and Per Hoffmann and Liping Hou and Yi-Hsiang Hsu and St{\'e}phane Jamain and Esther Jim{\'e}nez and Jean-Pierre Kahn and Layla Kassem and Tadafumi Kato and John Kelsoe and Sarah Kittel-Schneider and Po-Hsiu Kuo and Ichiro Kusumi and Barbara K{\"o}nig and Gonzalo Laje and Mikael Land{\'e}n and Catharina Lavebratt and Marion Leboyer and Leckband, {Susan G.} and Mario Maj and Mirko Manchia and Cynthia Marie-Claire and Lina Martinsson and McCarthy, {Michael J.} and McElroy, {Susan L.} and Vincent Millischer and Marina Mitjans and Mondimore, {Francis M.} and Palmiero Monteleone and Nievergelt, {Caroline M.} and Tomas Nov{\'a}k and N{\"o}then, {Markus M.} and Claire O{\textquoteright}Donovan and Norio Ozaki and Sergi Papiol and Andrea Pfennig and Claudia Pisanu and Potash, {James B.} and Andreas Reif and Eva Reininghaus and Richard-Lepouriel, {H. l{\`e}ne} and Gloria Roberts and Rouleau, {Guy A.} and Rybakowski, {Janusz K.} and Martin Schalling and Schofield, {Peter R.} and Schubert, {Klaus Oliver} and Schulte, {Eva C.} and Schweizer, {Barbara W.} and Giovanni Severino and Tatyana Shekhtman and Shilling, {Paul D.} and Katzutaka Shimoda and Christian Simhandl and Slaney, {Claire M.} and Alessio Squassina and Thomas Stamm and Pavla Stopkova and Fabian Streit and Fasil Tekola-Ayele and Alfonso Tortorella and Gustavo Turecki and Julia Veeh and Eduard Vieta and Biju Viswanath and Witt, {Stephanie H.} and Zandi, {Peter P.} and Martin Alda and Michael Bauer and McMahon, {Francis J.} and Mitchell, {Philip B.} and Marcella Rietschel and Schulze, {Thomas G.}",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2024.",

year = "2024",

month = dec,

day = "1",

doi = "10.1038/s41398-024-02865-4",

language = "English",

volume = "14",

journal = "Translational Psychiatry",

issn = "2158-3188",

publisher = "Nature Publishing Group",

number = "1",

}

Herrera-Rivero, M, Gutiérrez-Fragoso, K, Kurtz, J, Baune, BT, Thalamuthu, A, Amare, AT, Adli, M, Akiyama, K, Akula, N, Ardau, R, Arias, BR, Aubry, J-M, Backlund, L, Bellivier, F, Benabarre, A, Bengesser, S, Bhattacharjee, AK, Biernacka, JM, Birner, A, Cearns, M, Cervantes, P, Chen, H-C, Chillotti, C, Cichon, S, Clark, SR, Colom, F, Cruceanu, C, Czerski, PM, Dalkner, N, Degenhardt, F, del Zompo, M, DePaulo, JR, Etain, B, Falkai, P, Ferensztajn-Rochowiak, E, Forstner, AJ, Frank, J, Frisén, L, Frye, MA, Fullerton, JM, Gallo, C, Gard, SB, Garnham, JS, Goes, FS, Grigoroiu-Serbanescu, M, Grof, P, Hashimoto, R, Hasler, R, Hauser, J, Heilbronner, U, Herms, S, Hoffmann, P, Hou, L, Hsu, Y-H, Jamain, S, Jiménez, E, Kahn, J-P, Kassem, L, Kato, T, Kelsoe, J, Kittel-Schneider, S, Kuo, P-H, Kusumi, I, König, B, Laje, G, Landén, M, Lavebratt, C, Leboyer, M, Leckband, SG, Maj, M, Manchia, M, Marie-Claire, C, Martinsson, L, McCarthy, MJ, McElroy, SL, Millischer, V, Mitjans, M, Mondimore, FM, Monteleone, P, Nievergelt, CM, Novák, T, Nöthen, MM, O’Donovan, C, Ozaki, N, Papiol, S, Pfennig, A, Pisanu, C, Potash, JB, Reif, A, Reininghaus, E, Richard-Lepouriel, HL, Roberts, G, Rouleau, GA, Rybakowski, JK, Schalling, M, Schofield, PR, Schubert, KO, Schulte, EC, Schweizer, BW, Severino, G, Shekhtman, T, Shilling, PD, Shimoda, K, Simhandl, C, Slaney, CM, Squassina, A, Stamm, T, Stopkova, P, Streit, F, Tekola-Ayele, F, Tortorella, A, Turecki, G, Veeh, J, Vieta, E, Viswanath, B, Witt, SH, Zandi, PP, Alda, M, Bauer, M, McMahon, FJ, Mitchell, PB, Rietschel, M & Schulze, TG 2024, 'Immunogenetics of lithium response and psychiatric phenotypes in patients with bipolar disorder', Translational Psychiatry, vol. 14, no. 1, 174. https://doi.org/10.1038/s41398-024-02865-4

TY - JOUR

T1 - Immunogenetics of lithium response and psychiatric phenotypes in patients with bipolar disorder

AU - Herrera-Rivero, Marisol

AU - Gutiérrez-Fragoso, Karina

AU - Kurtz, Joachim

AU - Baune, Bernhard T.

AU - Thalamuthu, Anbupalam

AU - Amare, Azmeraw T.

AU - Adli, Mazda

AU - Akiyama, Kazufumi

AU - Akula, Nirmala

AU - Ardau, Raffaella

AU - Arias, B. rbara

AU - Aubry, Jean-Michel

AU - Backlund, Lena

AU - Bellivier, Frank

AU - Benabarre, Antonio

AU - Bengesser, Susanne

AU - Bhattacharjee, Abesh Kumar

AU - Biernacka, Joanna M.

AU - Birner, Armin

AU - Cearns, Micah

AU - Cervantes, Pablo

AU - Chen, Hsi-Chung

AU - Chillotti, Caterina

AU - Cichon, Sven

AU - Clark, Scott R.

AU - Colom, Francesc

AU - Cruceanu, Cristiana

AU - Czerski, Piotr M.

AU - Dalkner, Nina

AU - Degenhardt, Franziska

AU - del Zompo, Maria

AU - DePaulo, J. Raymond

AU - Etain, Bruno

AU - Falkai, Peter

AU - Ferensztajn-Rochowiak, Ewa

AU - Forstner, Andreas J.

AU - Frank, Josef

AU - Frisén, Louise

AU - Frye, Mark A.

AU - Fullerton, Janice M.

AU - Gallo, Carla

AU - Gard, S. bastien

AU - Garnham, Julie S.

AU - Goes, Fernando S.

AU - Grigoroiu-Serbanescu, Maria

AU - Grof, Paul

AU - Hashimoto, Ryota

AU - Hasler, Roland

AU - Hauser, Joanna

AU - Heilbronner, Urs

AU - Herms, Stefan

AU - Hoffmann, Per

AU - Hou, Liping

AU - Hsu, Yi-Hsiang

AU - Jamain, Stéphane

AU - Jiménez, Esther

AU - Kahn, Jean-Pierre

AU - Kassem, Layla

AU - Kato, Tadafumi

AU - Kelsoe, John

AU - Kittel-Schneider, Sarah

AU - Kuo, Po-Hsiu

AU - Kusumi, Ichiro

AU - König, Barbara

AU - Laje, Gonzalo

AU - Landén, Mikael

AU - Lavebratt, Catharina

AU - Leboyer, Marion

AU - Leckband, Susan G.

AU - Maj, Mario

AU - Manchia, Mirko

AU - Marie-Claire, Cynthia

AU - Martinsson, Lina

AU - McCarthy, Michael J.

AU - McElroy, Susan L.

AU - Millischer, Vincent

AU - Mitjans, Marina

AU - Mondimore, Francis M.

AU - Monteleone, Palmiero

AU - Nievergelt, Caroline M.

AU - Novák, Tomas

AU - Nöthen, Markus M.

AU - O’Donovan, Claire

AU - Ozaki, Norio

AU - Papiol, Sergi

AU - Pfennig, Andrea

AU - Pisanu, Claudia

AU - Potash, James B.

AU - Reif, Andreas

AU - Reininghaus, Eva

AU - Richard-Lepouriel, H. lène

AU - Roberts, Gloria

AU - Rouleau, Guy A.

AU - Rybakowski, Janusz K.

AU - Schalling, Martin

AU - Schofield, Peter R.

AU - Schubert, Klaus Oliver

AU - Schulte, Eva C.

AU - Schweizer, Barbara W.

AU - Severino, Giovanni

AU - Shekhtman, Tatyana

AU - Shilling, Paul D.

AU - Shimoda, Katzutaka

AU - Simhandl, Christian

AU - Slaney, Claire M.

AU - Squassina, Alessio

AU - Stamm, Thomas

AU - Stopkova, Pavla

AU - Streit, Fabian

AU - Tekola-Ayele, Fasil

AU - Tortorella, Alfonso

AU - Turecki, Gustavo

AU - Veeh, Julia

AU - Vieta, Eduard

AU - Viswanath, Biju

AU - Witt, Stephanie H.

AU - Zandi, Peter P.

AU - Alda, Martin

AU - Bauer, Michael

AU - McMahon, Francis J.

AU - Mitchell, Philip B.

AU - Rietschel, Marcella

AU - Schulze, Thomas G.

PY - 2024/12/1

Y1 - 2024/12/1

N2 - The link between bipolar disorder (BP) and immune dysfunction remains controversial. While epidemiological studies have long suggested an association, recent research has found only limited evidence of such a relationship. To clarify this, we performed an exploratory study of the contributions of immune-relevant genetic factors to the response to lithium (Li) treatment and the clinical presentation of BP. First, we assessed the association of a large collection of immune-related genes (4925) with Li response, defined by the Retrospective Assessment of the Lithium Response Phenotype Scale (Alda scale), and clinical characteristics in patients with BP from the International Consortium on Lithium Genetics (ConLi +Gen, N = 2374). Second, we calculated here previously published polygenic scores (PGSs) for immune-related traits and evaluated their associations with Li response and clinical features. Overall, we observed relatively weak associations (p < 1 × 10 −4) with BP phenotypes within immune-related genes. Network and functional enrichment analyses of the top findings from the association analyses of Li response variables showed an overrepresentation of pathways participating in cell adhesion and intercellular communication. These appeared to converge on the well-known Li-induced inhibition of GSK-3β. Association analyses of age-at-onset, number of mood episodes, and presence of psychosis, substance abuse and/or suicidal ideation suggested modest contributions of genes such as RTN4, XKR4, NRXN1, NRG1/3 and GRK5 to disease characteristics. PGS analyses returned weak associations (p < 0.05) between inflammation markers and the studied BP phenotypes. Our results suggest a modest relationship between immunity and clinical features in BP. More research is needed to assess the potential therapeutic relevance.

AB - The link between bipolar disorder (BP) and immune dysfunction remains controversial. While epidemiological studies have long suggested an association, recent research has found only limited evidence of such a relationship. To clarify this, we performed an exploratory study of the contributions of immune-relevant genetic factors to the response to lithium (Li) treatment and the clinical presentation of BP. First, we assessed the association of a large collection of immune-related genes (4925) with Li response, defined by the Retrospective Assessment of the Lithium Response Phenotype Scale (Alda scale), and clinical characteristics in patients with BP from the International Consortium on Lithium Genetics (ConLi +Gen, N = 2374). Second, we calculated here previously published polygenic scores (PGSs) for immune-related traits and evaluated their associations with Li response and clinical features. Overall, we observed relatively weak associations (p < 1 × 10 −4) with BP phenotypes within immune-related genes. Network and functional enrichment analyses of the top findings from the association analyses of Li response variables showed an overrepresentation of pathways participating in cell adhesion and intercellular communication. These appeared to converge on the well-known Li-induced inhibition of GSK-3β. Association analyses of age-at-onset, number of mood episodes, and presence of psychosis, substance abuse and/or suicidal ideation suggested modest contributions of genes such as RTN4, XKR4, NRXN1, NRG1/3 and GRK5 to disease characteristics. PGS analyses returned weak associations (p < 0.05) between inflammation markers and the studied BP phenotypes. Our results suggest a modest relationship between immunity and clinical features in BP. More research is needed to assess the potential therapeutic relevance.

UR - http://www.scopus.com/inward/record.url?scp=85189466658&partnerID=8YFLogxK

U2 - 10.1038/s41398-024-02865-4

DO - 10.1038/s41398-024-02865-4

M3 - Article

C2 - 38570518

SN - 2158-3188

VL - 14

JO - Translational Psychiatry

JF - Translational Psychiatry

IS - 1

M1 - 174

ER -

Immunogenetics of lithium response and psychiatric phenotypes in patients with bipolar disorder

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