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[Preprint]. 2023 Feb 14:rs.3.rs-2580252.
doi: 10.21203/rs.3.rs-2580252/v1.

Association of Polygenic Score and the involvement of Cholinergic and Glutamatergic Pathways with Lithium Treatment Response in Patients with Bipolar Disorder

Azmeraw Amare  1 , Anbupalam Thalamuthu  2 , Klaus Oliver Schubert  3 , Janice Fullerton  4 , Muktar Ahmed  5 , Simon Hartmann  5 , Sergi Papiol  5 , Urs Heilbronner  6 , Franziska Degenhardt  7 , Fasil Tekola-Ayele  8 , Liping Hou  8 , Yi-Hsiang Hsu  9 , Tatyana Shekhtman  9 , Mazda Adli  10 , Nirmala Akula  11 , Kazufumi Akiyama  11 , Raffaella Ardau  12 , Bárbara Arias  13 , Jean-Michel Aubry  14 , Lena Backlund  9 , Abesh Kumar Bhattacharjee  9 , Frank Bellivier  15 , Antoni Benabarre  16 , Susanne Bengesser  17 , Joanna Biernacka  18 , Armin Birner  17 , Cynthia Marie-Claire  19 , Pablo Cervantes  20 , Hsi-Chung Chen  21 , Caterina Chillotti  22 , Sven Cichon  22 , Cristiana Cruceanu  23 , Piotr Czerski  24 , Nina Dalkner  17 , Maria Del Zompo  25 , J Raymond DePaulo  26 , Bruno Etain  27 , Stéphane Jamain  28 , Peter Falkai  5 , Andreas J Forstner  29 , Louise Frisén  30 , Mark Frye  18 , Sébastien Gard  31 , Julie Garnham, Fernando Goes, Maria Grigoroiu-Serbanescu  32 , Andreas Fallgatter  33 , Sophia Stegmaier  33 , Thomas Ethofer  34 , Silvia Biere  34 , Kristiyana Petrova  34 , Ceylan Schuster  34 , Kristina Adorjan  35 , Monika Budde  35 , Maria Heilbronner  34 , Janos Kalman  36 , Mojtaba Oraki Kohshour  36 , Daniela Reich-Erkelenz  37 , Sabrina Schaupp  34 , Eva Schulte  6 , Fanny Senner  37 , Thomas Vogl  34 , Ion-George Anghelescu  38 , Volker Arolt  38 , Udo Dannlowski  38 , Detlef E Dietrich  38 , Christian Figge  38 , Markus Jäger  38 , Fabian Lang  38 , Georg Juckel  38 , Carsten Spitzer  39 , Jens Reimer  39 , Max Schmauß  39 , Andrea Schmitt  39 , Carsten Konrad  40 , Martin von Hagen  40 , Jens Wiltfang  40 , Jörg Zimmermann  41 , Till Andlauer  41 , Andre Fischer  42 , Felix Bermpohl  43 , Vivien Kraft  44 , Silke Matura  44 , Anna Gryaznova  45 , Irina Falkenberg  45 , Cüneyt Yildiz  45 , Tilo Kircher  45 , Julia Schmidt  45 , Marius Koch  45 , Katrin Gade  45 , Sarah Trost  45 , Ida Haußleiter  45 , Martin Lambert  45 , Anja C Rohenkohl  45 , Vivien Kraft  45 , Paul Grof  46 , Ryota Hashimoto  47 , Joanna Hauser  47 , Stefan Herms  47 , Per Hoffmann  47 , Esther Jiménez  48 , Jean-Pierre Kahn  48 , Layla Kassem  48 , Po-Hsiu Kuo  48 , Tadafumi Kato  49 , John Kelsoe  49 , Sarah Kittel-Schneider  49 , Ewa Ferensztajn-Rochowiak  50 , Barbara König  50 , Ichiro Kusumi  51 , Gonzalo Laje  52 , Mikael Landén  52 , Catharina Lavebratt  53 , Marion Leboyer  54 , Susan G Leckband  54 , Alfonso Tortorella  55 , Mirko Manchia  54 , Lina Martinsson  54 , Michael McCarthy  54 , Susan L McElroy  56 , Francesc Colom  57 , Marina Mitjans  58 , Francis Mondimore  26 , Palmiero Monteleone  59 , Caroline Nievergelt  60 , Markus Nöthen  60 , Tomas Novak  61 , Claire O'Donovan  61 , Norio Ozaki  59 , Andrea Pfennig  62 , Claudia Pisanu  25 , James Potash  63 , Andreas Reif  63 , Eva Reininghaus  46 , Guy Rouleau  46 , Janusz K Rybakowski  24 , Martin Schalling  53 , Peter Schofield  4 , Barbara W Schweizer  26 , Giovanni Severino  25 , Paul D Shilling  59 , Kazutaka Shimoda  64 , Christian Simhandl  64 , Claire Slaney  64 , Alessio Squassina  64 , Thomas Stamm  10 , Pavla Stopkova  8 , Mario Maj  65 , Gustavo Turecki  46 , Eduard Vieta  16 , Julia Veeh  66 , Stephanie Witt  67 , Adam Wright  2 , Peter Zandi  68 , Philip Mitchell  61 , Michael Bauer  61 , Martin Alda  61 , Marcella Rietschel  69 , Francis McMahon  70 , Thomas G Schulze  71 , Vincent Millischer  18 , Scott Clark  3 , Bernhard Baune  72
Affiliations

Association of Polygenic Score and the involvement of Cholinergic and Glutamatergic Pathways with Lithium Treatment Response in Patients with Bipolar Disorder

Azmeraw Amare et al. Res Sq. .

Update in

  • Association of polygenic score and the involvement of cholinergic and glutamatergic pathways with lithium treatment response in patients with bipolar disorder.
    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, Jiméne… See abstract for full author list ➔ Amare AT, et al. Mol Psychiatry. 2023 Dec;28(12):5251-5261. doi: 10.1038/s41380-023-02149-1. Epub 2023 Jul 11. Mol Psychiatry. 2023. PMID: 37433967 Free PMC article.

Abstract

Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental 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=2,367) 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<����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������.

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Conflict of interest statement

Eduard Vieta 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, GlaxoSmith-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. Michael Bauer 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. Sarah Kittel-Schneider has received grants and served as consultant, advisor or speaker for the following entities: Medice Arzneimittel Pütter GmbH and Shire/Takeda. Bernhard Baune 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. Scott Clark has received grants and served as consultant, advisor or CME speaker for the following entities: Otsuka Austalia, Lundbeck Australia, Janssen-Cilag Australia, Servier Australia. Tadafumi Kato 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. Tadafumi Kato also received a research grant from Takeda Pharmaceutical Co, Ltd. Peter Falkai 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. Eva Reininghaus has received grants and served as consultant, advisor or CME speaker for the following entities: Janssen and Institut Allergosan. Mikael Landén 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. Kazufumi Akiyama has received consulting honoraria from Taisho Toyama Pharmaceutical Co, Ltd. In 2021, Jörg Zimmermann served as an advisor for Biogen concerning Aducanumab (Alzheimer`s Disease).The other authors have no other conflict of interest to disclose.

Figures

Figure 1
Figure 1
Overview of input datasets and steps of data analyses. ConLi+Gen = the International Consortium on Lithium Genetics, ALDA = Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder scale, HRC= Haplotype Reference Consortium (HRC), SNPs = Single Nucleotide Polymorphisms, MAF=Minor Allele Frequency, GWAS = Genome Wide Association analysis, Li+PGS = polygenic score for lithium treatment response, LOG=Leave-one-group out procedure; PsyCourse = Pathomechanisms and Signature in the Longitudinal Course of Psychosis study and BipoLife = German research consortium for the study of bipolar disorder.
Figure 2
Figure 2
Trends in the odds ratios (ORs) for favourable treatment response to lithium for patients with bipolar disorder in the higher genetic loading for lithium responsive variants, deciles (2nd to 10th) compared with patients in the lowest (decile 1st) of genetic loading for lithium response (n = 2,367). The X mark on the line plot indicates that the association is not statistically significant at that decile. Abbreviations: OR= odds ratio, CI=Confidence interval, Li+PGS =polygenic score for lithium treatment response.
Figure 3
Figure 3
Manhattan plots showing the SNP-based GWAS results of lithium treatment response in patients with bipolar disorder; A) in the categorical outcome and B) continuous scale, highlighting the loci that showed genome-wide significance (orange). The −log10 (p-value) is plotted against the physical position of each SNP on each chromosome. The threshold for genome-wide significance (p-value < 5 × 10–8) is indicated by the red dotted horizontal line
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References

    1. Grande I, Berk M, Birmaher B, Vieta E. Bipolar disorder. Lancet 2016; 387(10027): 1561–1572. - PubMed
    1. DALYs GBD, Collaborators H. Global, regional, and national disability-adjusted life-years (DALYs) for 359 diseases and injuries and healthy life expectancy (HALE) for 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet 2018; 392(10159): 1859–1922. - PMC - PubMed
    1. Walker S, Mackay E, Barnett P, Sheridan Rains L, Leverton M, Dalton-Locke C et al. Clinical and social factors associated with increased risk for involuntary psychiatric hospitalisation: a systematic review, meta-analysis, and narrative synthesis. Lancet Psychiatry 2019; 6(12): 1039–1053. - PMC - PubMed
    1. Chesney E, Goodwin GM, Fazel S. Risks of all-cause and suicide mortality in mental disorders: a meta-review. World Psychiatry 2014; 13(2): 153–160. - PMC - PubMed
    1. Cade JF. Lithium salts in the treatment of psychotic excitement. The Medical journal of Australia 1949; 2(10): 349–352. - PubMed

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