Pathway-Specific Polygenic Scores for Predicting Clinical Lithium Treatment Response in Patients With Bipolar Disorder
Journal
Biological Psychiatry Global Open Science
Journal Volume
5
Journal Issue
5
Start Page
100558
ISSN
2667-1743
Date Issued
2025-09
Author(s)
Sharew, Nigussie T
Clark, Scott R
Papiol, Sergi
Heilbronner, Urs
Degenhardt, Franziska
Fullerton, Janice M
Hou, Liping
Shekhtman, Tatyana
Adli, Mazda
Akula, Nirmala
Akiyama, Kazufumi
Ardau, Raffaella
Arias, Bárbara
Hasler, Roland
Richard-Lepouriel, Hélène
Perroud, Nader
Backlund, Lena
Bhattacharjee, Abesh Kumar
Bellivier, Frank
Benabarre, Antonio
Bengesser, Susanne
Biernacka, Joanna M
Birner, Armin
Marie-Claire, Cynthia
Cervantes, Pablo
Chillotti, Caterina
Cichon, Sven
Cruceanu, Cristiana
Czerski, Piotr M
Dalkner, Nina
Del Zompo, Maria
DePaulo, J Raymond
Étain, Bruno
Jamain, Stephane
Falkai, Peter
Forstner, Andreas J
Frisen, Louise
Frye, Mark A
Gard, Sébastien
Garnham, Julie S
Goes, Fernando S
Grigoroiu-Serbanescu, Maria
Fallgatter, Andreas J
Stegmaier, Sophia
Ethofer, Thomas
Biere, Silvia
Petrova, Kristiyana
Schuster, Ceylan
Adorjan, Kristina
Budde, Monika
Heilbronner, Maria
Kalman, Janos L
Kohshour, Mojtaba Oraki
Reich-Erkelenz, Daniela
Schaupp, Sabrina K
Schulte, Eva C
Senner, Fanny
Vogl, Thomas
Anghelescu, Ion-George
Arolt, Volker
Dannlowski, Udo
Dietrich, Detlef E
Figge, Christian
Jäger, Markus
Lang, Fabian U
Juckel, Georg
Konrad, Carsten
Reimer, Jens
Schmauß, Max
Schmitt, Andrea
Spitzer, Carsten
von Hagen, Martin
Wiltfang, Jens
Zimmermann, Jörg
Andlauer, Till F M
Fischer, Andre
Bermpohl, Felix
Ritter, Philipp
Matura, Silke
Gryaznova, Anna
Falkenberg, Irina
Yildiz, Cüneyt
Kircher, Tilo
Schmidt, Julia
Koch, Marius
Gade, Kathrin
Trost, Sarah
Haussleiter, Ida S
Lambert, Martin
Rohenkohl, Anja C
Kraft, Vivien
Grof, Paul
Hashimoto, Ryota
Hauser, Joanna
Herms, Stefan
Hoffmann, Per
Jiménez, Esther
Kahn, Jean-Pierre
Kassem, Layla
Kato, Tadafumi
Kelsoe, John
Kittel-Schneider, Sarah
Ferensztajn-Rochowiak, Ewa
König, Barbara
Kusumi, Ichiro
Laje, Gonzalo
Landén, Mikael
Lavebratt, Catharina
Leboyer, Marion
Leckband, Susan G
Tortorella, Alfonso
Manchia, Mirko
Martinsson, Lina
McCarthy, Michael J
McElroy, Susan
Colom, Francesc
Millischer, Vincent
Mitjans, Marina
Mondimore, Francis M
Monteleone, Palmiero
Nievergelt, Caroline M
Nöthen, Markus M
Novák, Tomas
O'Donovan, Claire
Ozaki, Norio
Pfennig, Andrea
Pisanu, Claudia
Potash, James B
Reif, Andreas
Reininghaus, Eva
Rouleau, Guy A
Rybakowski, Janusz K
Schalling, Martin
Schofield, Peter R
Schweizer, Barbara W
Severino, Giovanni
Shilling, Paul D
Shimoda, Katzutaka
Simhandl, Christian
Slaney, Claire M
Squassina, Alessio
Stamm, Thomas
Stopkova, Pavla
Maj, Mario
Turecki, Gustavo
Vieta, Eduard
Veeh, Julia
Viswanath, Biju
Witt, Stephanie H
Wright, Adam
Zandi, Peter P
Mitchell, Philip B
Bauer, Michael
Alda, Martin
Rietschel, Marcella
McMahon, Francis J
Schulze, Thomas G
Baune, Bernhard T
Schubert, Klaus Oliver
Amare, Azmeraw T
Abstract
Polygenic scores (PGSs) hold the potential to identify patients who respond favorably to specific psychiatric treatments. However, their biological interpretation remains unclear. In this study, we developed pathway-specific PGSs (PSPGSs) for lithium response and assessed their association with clinical lithium response in patients with bipolar disorder. Using sets of genes involved in pathways affected by lithium, we developed 9 PSPGSs and evaluated their associations with lithium response in the International Consortium on Lithium Genetics (ConLi+Gen) (N = 2367), with validation in combined PsyCourse (Pathomechanisms and Signatures in the Longitudinal Course of Psychosis) (N = 105) and BipoLife (N = 102) cohorts. The association between each PSPGS and lithium response-defined both as a continuous ALDA score and a categorical outcome (good vs. poor responses)-was evaluated using regression models, with adjustment for confounders. The cutoff for a significant association was p < .05 after multiple testing correction. The PGSs for acetylcholine, GABA (gamma-aminobutyric acid), and mitochondria were associated with response to lithium in both categorical and continuous outcomes. However, the PGSs for calcium channel, circadian rhythm, and GSK (glycogen synthase kinase) were associated only with the continuous outcome. Each score explained 0.29% to 1.91% of the variance in the categorical and 0.30% to 1.54% of the variance in the continuous outcomes. A multivariate model combining PSPGSs that showed significant associations in the univariate analysis (combined PSPGS) increased the percentage of variance explained (R 2) to 3.71% and 3.18% for the categorical and continuous outcomes, respectively. Associations for PGSs for GABA and circadian rhythm were replicated. Patients with the highest genetic loading (10th decile) for acetylcholine variants were 3.03 times more likely (95% CI, 1.95 to 4.69) to show a good lithium response (categorical outcome) than patients with the lowest genetic loading (1st decile). PSPGSs achieved predictive performance comparable to the conventional genome-wide PGSs, with the added advantage of biological interpretability using a smaller list of genetic variants. Polygenic scores (PGSs) have the potential to identify patients likely to respond to specific psychiatric treatments, but their biological interpretation remains unclear. In this study, we developed 9 pathway-specific PGSs (PSPGSs) for lithium response by aggregating genetic variants involved in pathways affected by lithium. We assessed their associations with lithium response in the International Consortium on Lithium Genetics (ConLi+Gen) (N = 2367) cohort and validated the findings in the PsyCourse (N = 105) and BipoLife (N = 102) cohorts. Clinical response to lithium treatment was significantly associated with PSPGSs for acetylcholine, GABA (gamma-aminobutyric acid), calcium channel signaling, mitochondria, circadian rhythm, and GSK pathways, with explained variance (R 2) ranging from 0.29% to 1.91%. The combined PSPGS explained up to 3.71% of the variability. Associations for GABA and circadian rhythm PGSs were successfully replicated. In a decile-based analysis, patients with the highest genetic load (10th decile) for acetylcholine pathway variants were 3.03 times more likely to respond well to lithium compared with those in the lowest decile (1st decile). PSPGSs achieved predictive performance comparable to conventional genome-wide PGSs, with better biological interpretability and a more focused set of genetic variants.
Subjects
Bipolar disorder
Lithium
Pharmacogenomics
Polygenic score
Psychiatry
SDGs
Type
journal article