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

@article{sharew2026pathwayspecific,
  title = {{Pathway-Specific Polygenic Scores for Predicting Clinical Lithium Treatment Response in Patients With Bipolar Disorder}},
  author = {Nigussie Sharew and Scott Clark and Sergi Papiol and Urs Heilbronner and Franziska Degenhardt and Janice Fullerton and Liping Hou and Tatyana Shekhtman and Mazda Adli and Nirmala Akula and Kazufumi Akiyama and Raffaella Ardau and Bárbara Arias and Roland Hasler and Hélène Richard-Lepouriel and Nader Perroud and Lena Backlund and Abesh Kumar Bhattacharjee and Frank Bellivier and Antonio Benabarre and Susanne Bengesser and Joanna Biernacka and Armin Birner and Cynthia Marie-Claire and Pablo Cervantes and Hsi-Chung Chen and Caterina Chillotti and Sven Cichon and Cristiana Cruceanu and Piotr Czerski and Nina Dalkner and Maria del Zompo and J. Raymond Depaulo and Bruno Étain and Stéphane Jamain and Peter Falkai and Andreas Forstner and Louise Frisen and Mark Frye and Sébastien Gard and Julie Garnham and Fernando Goes and Maria Grigoroiu-Serbanescu and Andreas Fallgatter 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 Janos Kalman and Mojtaba Oraki Kohshour and Daniela Reich-Erkelenz and Sabrina Schaupp and Eva Schulte and Fanny Senner and Thomas Vogl and Ion-George Anghelescu},
  journal = {Biological Psychiatry Global Open Science},
  year = {2026},
  month = oct,
  doi = {10.1016/j.bpsgos.2025.100558},
  url = {https://hal.science/hal-05784810v1},
  note = {CC BY-NC-ND},
}

TY  - JOUR
TI  - Pathway-Specific Polygenic Scores for Predicting Clinical Lithium Treatment Response in Patients With Bipolar Disorder
AU  - Nigussie Sharew
AU  - Scott Clark
AU  - Sergi Papiol
AU  - Urs Heilbronner
AU  - Franziska Degenhardt
AU  - Janice Fullerton
AU  - Liping Hou
AU  - Tatyana Shekhtman
AU  - Mazda Adli
AU  - Nirmala Akula
AU  - Kazufumi Akiyama
AU  - Raffaella Ardau
AU  - Bárbara Arias
AU  - Roland Hasler
AU  - Hélène Richard-Lepouriel
AU  - Nader Perroud
AU  - Lena Backlund
AU  - Abesh Kumar Bhattacharjee
AU  - Frank Bellivier
AU  - Antonio Benabarre
AU  - Susanne Bengesser
AU  - Joanna Biernacka
AU  - Armin Birner
AU  - Cynthia Marie-Claire
AU  - Pablo Cervantes
AU  - Hsi-Chung Chen
AU  - Caterina Chillotti
AU  - Sven Cichon
AU  - Cristiana Cruceanu
AU  - Piotr Czerski
AU  - Nina Dalkner
AU  - Maria del Zompo
AU  - J. Raymond Depaulo
AU  - Bruno Étain
AU  - Stéphane Jamain
AU  - Peter Falkai
AU  - Andreas Forstner
AU  - Louise Frisen
AU  - Mark Frye
AU  - Sébastien Gard
AU  - Julie Garnham
AU  - Fernando Goes
AU  - Maria Grigoroiu-Serbanescu
AU  - Andreas Fallgatter
AU  - Sophia Stegmaier
AU  - Thomas Ethofer
AU  - Silvia Biere
AU  - Kristiyana Petrova
AU  - Ceylan Schuster
AU  - Kristina Adorjan
AU  - Monika Budde
AU  - Maria Heilbronner
AU  - Janos Kalman
AU  - Mojtaba Oraki Kohshour
AU  - Daniela Reich-Erkelenz
AU  - Sabrina Schaupp
AU  - Eva Schulte
AU  - Fanny Senner
AU  - Thomas Vogl
AU  - Ion-George Anghelescu
PY  - 2026
DA  - 2026/10/07
JO  - Biological Psychiatry Global Open Science
DO  - 10.1016/j.bpsgos.2025.100558
UR  - https://hal.science/hal-05784810v1
AB  - Background Polygenic scores (PGSs) hold the potential to identify patients who respond favourably to specific psychiatric treatments. However, their biological interpretation remains 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. 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 (ConLi + Gen: N=2367), validated in combined PsyCourse (N=105) and BipoLife (N=102) cohorts. The association between each PS PGS and lithium response — defined both as a continuous ALDA score and a categorical outcome (good vs poor responses) — was evaluated using regression models, adjusted for confounders. A significant association was determined after multiple testing correction at p<0.05. Results The PGS for acetylcholine, GABA and mitochondria were associated with response to lithium both in categorical and continuous outcomes. However, the PGS for calcium channel, circadian rhythm and GSK were associated only with the continuous outcome. Each score explained 0.29%–1.91% of variance in categorical and 0.30–1.54% in continuous outcomes. A multivariate modelling combining PS PGS that showed significant associations in the univariate analysis (combined PS PGS ), has increased the R 2 to 3.71% (categorical) and 3.18% (continuous) outcomes. Associations for PGSs for GABA and circadian rhythm were replicated. Patients with the highest genetic loading (10 th decile) for acetylcholine variants were 3.03 times more likely (95%CI: 1.95– 4.69) to show a good lithium response (categorical outcome) than those in the lowest (1 st decile). Conclusion PS PGSs achieved predictive performance comparable to the conventional genome-wide PGSs, with the added advantage of biological interpretability using a smaller list of genetic variants.
SN  - 2667-1743
ER  -