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@ARTICLE{Sharew:280742,
author = {Sharew, Nigussie T and Clark, Scott R and Papiol, Sergi and
Heilbronner, Urs and Degenhardt, Franziska and Fullerton,
Janice M and Hou, Liping and Shekhtman, Tatyana and Adli,
Mazda and Akula, Nirmala and Akiyama, Kazufumi and Ardau,
Raffaella and Arias, Bárbara and Hasler, Roland and
Richard-Lepouriel, Hélène and Perroud, Nader and Backlund,
Lena and Bhattacharjee, Abesh Kumar and Bellivier, Frank and
Benabarre, Antonio and Bengesser, Susanne and Biernacka,
Joanna M and Birner, Armin and Marie-Claire, Cynthia and
Cervantes, Pablo and Chen, Hsi-Chung and Chillotti, Caterina
and Cichon, Sven and Cruceanu, Cristiana and Czerski, Piotr
M and Dalkner, Nina and Del Zompo, Maria and DePaulo, J
Raymond and Étain, Bruno and Jamain, Stephane and Falkai,
Peter and Forstner, Andreas J and Frisen, Louise and Frye,
Mark A and Gard, Sébastien and Garnham, Julie S and Goes,
Fernando S and Grigoroiu-Serbanescu, Maria and Fallgatter,
Andreas and Stegmaier, Sophia and Ethofer, Thomas and Biere,
Silvia and Petrova, Kristiyana and Schuster, Ceylan and
Adorjan, Kristina and Budde, Monika and Heilbronner, Maria
and Kalman, Janos L and Kohshour, Mojtaba Oraki and
Reich-Erkelenz, Daniela and Schaupp, Sabrina K and Schulte,
Eva C and Senner, Fanny and Vogl, Thomas and Anghelescu,
Ion-George and Arolt, Volker and Dannlowski, Udo and
Dietrich, Detlef E and Figge, Christian and Jäger, Markus
and Lang, Fabian U and Juckel, Georg and Konrad, Carsten and
Reimer, Jens and Schmauß, Max and Schmitt, Andrea and
Spitzer, Carsten and von Hagen, Martin and Wiltfang, Jens
and Zimmermann, Jörg and Fischer, Andre and Bermpohl, Felix
and Ritter, Philipp and Matura, Silke and Gryaznova, Anna
and Falkenberg, Irina and Yildiz, Cüneyt and Kircher, Tilo
and Schmidt, Julia and Koch, Marius and Gade, Kathrin and
Trost, Sarah and Andlauer, Till F M and Haussleiter, Ida S
and Lambert, Martin and Rohenkohl, Anja C and Kraft, Vivien
and Grof, Paul and Hashimoto, Ryota and Hauser, Joanna and
Herms, Stefan and Hoffmann, Per and Jiménez, Esther and
Kahn, Jean-Pierre and Kassem, Layla and Kuo, Po-Hsiu and
Kato, Tadafumi and Kelsoe, John and Kittel-Schneider, Sarah
and Ferensztajn-Rochowiak, Ewa and König, Barbara and
Kusumi, Ichiro and Laje, Gonzalo and Landén, Mikael and
Lavebratt, Catharina and Leboyer, Marion and Leckband, Susan
G and Tortorella, Alfonso and Manchia, Mirko and Martinsson,
Lina and McCarthy, Michael J and McElroy, Susan and Colom,
Francesc and Millischer, Vincent and Mitjans, Marina and
Mondimore, Francis M and Monteleone, Palmiero and
Nievergelt, Caroline M and Nöthen, Markus M and Novák,
Tomas and O'Donovan, Claire and Ozaki, Norio and Pfennig,
Andrea and Pisanu, Claudia and Potash, James B and Reif,
Andreas and Reininghaus, Eva and Rouleau, Guy A and
Rybakowski, Janusz K and Schalling, Martin and Schofield,
Peter R and Schweizer, Barbara W and Severino, Giovanni and
Shilling, Paul D and Shimoda, Katzutaka and Simhandl,
Christian and Slaney, Claire M and Squassina, Alessio and
Stamm, Thomas and Stopkova, Pavla and Maj, Mario and
Turecki, Gustavo and Vieta, Eduard and Veeh, Julia and
Viswanath, Biju and Witt, Stephanie H and Wright, Adam and
Zandi, Peter P and Mitchell, Philip B and Bauer, Michael and
Alda, Martin and Rietschel, Marcella and McMahon, Francis J
and Schulze, Thomas G and Baune, Bernhard T and Schubert,
Klaus Oliver and Amare, Azmeraw T},
title = {{P}athway-{S}pecific {P}olygenic {S}cores for {P}redicting
{C}linical {L}ithium {T}reatment {R}esponse in {P}atients
{W}ith {B}ipolar {D}isorder.},
journal = {Biological psychiatry: global open science},
volume = {5},
number = {5},
issn = {2667-1743},
address = {Amsterdam},
publisher = {Elsevier},
reportid = {DZNE-2025-00963},
pages = {100558},
year = {2025},
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.},
keywords = {Bipolar disorder (Other) / Lithium (Other) /
Pharmacogenomics (Other) / Polygenic score (Other) /
Psychiatry (Other)},
cin = {AG Wiltfang / AG Fischer},
ddc = {610},
cid = {I:(DE-2719)1410006 / I:(DE-2719)1410002},
pnm = {353 - Clinical and Health Care Research (POF4-353) / 352 -
Disease Mechanisms (POF4-352)},
pid = {G:(DE-HGF)POF4-353 / G:(DE-HGF)POF4-352},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:40821394},
pmc = {pmc:PMC12357302},
doi = {10.1016/j.bpsgos.2025.100558},
url = {https://pub.dzne.de/record/280742},
}
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