Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
[Preprint]. 2025 Mar 24:2025.03.20.25324216.
doi: 10.1101/2025.03.20.25324216.

Pathway-Specific Polygenic Scores for Lithium Response for Predicting Clinical Lithium Treatment Response in Patients with Bipolar Disorder

Nigussie T Sharew, Scott R Clark, Sergi Papiol, Urs Heilbronner, Franziska Degenhardt, Janice M Fullerton, Liping Hou, Tatyana Shekhtman, Mazda Adli, Nirmala Akula, Kazufumi Akiyama, Raffaella Ardau, Bárbara Arias, 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 E 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, Biju Viswanath, Stephanie H Witt, Adam Wright, Peter P Zandi, Philip B Mitchell, Michael Bauer, Martin Alda, Marcella Rietschel, Francis J McMahon, Thomas G Schulze, Bernhard T Baune, Klaus Oliver Schubert, Azmeraw T Amare

Pathway-Specific Polygenic Scores for Lithium Response for Predicting Clinical Lithium Treatment Response in Patients with Bipolar Disorder

Nigussie T Sharew et al. medRxiv. .

Update in

  • Pathway-Specific Polygenic Scores for Predicting Clinical Lithium Treatment Response in Patients With Bipolar Disorder.
    Sharew NT, Clark SR, Papiol S, Heilbronner U, Degenhardt F, Fullerton JM, Hou L, Shekhtman T, Adli M, Akula N, Akiyama K, Ardau R, Arias B, 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 DE, 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, … See abstract for full author list ➔ Sharew NT, et al. Biol Psychiatry Glob Open Sci. 2025 Jun 25;5(5):100558. doi: 10.1016/j.bpsgos.2025.100558. eCollection 2025 Sep. Biol Psychiatry Glob Open Sci. 2025. PMID: 40821394 Free PMC article.

Abstract

Background: Polygenic scores (PGSs) hold the potential to identify patients who respond favourably to specific psychiatric treatments. However, their biological interpretations remain unclear. In this study, we developed pathway-specific PGSs (PS PGS ) for lithium response and assessed their association with clinical lithium response in patients with bipolar disorder (BD).

Methods: Using sets of genes involved in pathways affected by lithium, we developed nine PS PGSs and evaluated their associations with lithium response in the International Consortium on Lithium Genetics cohort (ConLi + Gen: N = 2367), validated in the combined PsyCourse (N = 105) and BipoLife (N = 102) cohorts. Lithium responsiveness was assessed using the Retrospective Assessment of the Lithium Response Phenotype Scale (ALDA scale), for categorical outcome (good vs poor response) and continuous ALDA total score. Logistic and linear regressions, adjusting for age, sex, chip type, and the first four genetic principal components, were used to test associations, after multiple testing corrections ( p <0.05).

Results: Response to lithium was associated with PS PGS for acetylcholine, GABA, calcium channel signalling, mitochondria, circadian rhythm, and GSK pathways, R² ranging from 0.29% to 1.91%, with R² of 3.71% for the combined PS PGS. Associations for GABA PGS and CIR PGS were replicated. In decile-based stratified analysis, patients with the highest genetic loading (10 th decile) for acetylcholine pathway genetic variants were 3.03 times (95%CI: 1.95 - 4.69) more likely to have a good lithium response than the lowest decile (1 st decile).

Conclusion: PS PGSs achieved predictive performance comparable with conventional genome-wide PGSs, with more biological interpretability and using a smaller list of genetic variants, facilitating further investigation into the interaction of variants and biological pathways underlying lithium response.

PubMed Disclaimer

Publication types

LinkOut - more resources