Pharmacogenomics of antiepileptic drug mood stabilizer treatment response in bipolar disorder: A MoStGen Consortium study

Identifying biological and clinical factors associated with response to mood-stabilizing medications is critical for improving bipolar disorder (BD) treatment. The Mood Stabilizer Genomics (MoStGen) Consortium was established to investigate pharmacogenomic and clinical predictors of response to treatment of BD with antiepileptic drug mood stabilizers (AMS). Here we present the first pharmacogenomic analyses of AMS treatment outcomes based on MoStGen Consortium data, including 917 individuals across contributing sites. We performed genome-wide association analyses in subcohorts followed by meta-analyses, with AMS treatment response measured quantitatively using the Alda scale. Medication-stratified analyses were performed for valproic acid (VPA) and lamotrigine (LTG) treatment response. Additionally, polygenic score (PGS) analyses were used to evaluate the overall genetic contribution to AMS response across cohorts and to test whether genetic liability for various neuropsychiatric illnesses impacts AMS response. We detected genome-wide significant associations with LTG treatment response for SNPs in the gene ROBO2 (top SNP: rs985123, p = 1.9E-10) and for POLR1E at the gene-level (p = 2.53E-06). No significant associations were found for overall AMS or VPA treatment response. Leave-one-out PGS analyses provided significant evidence for a polygenic signal for AMS treatment response. Furthermore, the epilepsy PGS was nominally significantly associated with AMS response (p = 0.024), suggesting higher genetic liability to epilepsy predicts a better response to treatment with AMS. These findings provide insights into the genetic contribution to AMS treatment outcomes, and in particular LTG response, and may contribute to the development of more precise treatments for BD.

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Journal
Molecular Psychiatry
Published
2026-02-19
DOI
https://doi.org/10.1038/s41380-026-03478-7
Primary Topic
Genetic Associations and Epidemiology
Type
article
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article

Pharmacogenomics of antiepileptic drug mood stabilizer treatment response in bipolar disorder: A MoStGen Consortium study

Abraham Vas Nunes, Bruno Millet, C. Fullerton, B. Carpiniello et al.
Molecular Psychiatry
Genetic Associations and Epidemiology
article

Pharmacogenomics of antiepileptic drug mood stabilizer treatment response in bipolar disorder: A MoStGen Consortium study

Abraham Vas Nunes, Bruno Millet, C. Fullerton, B. Carpiniello, G. Fico, Adrien Legrand, Katie Scott, Susanne Bengesser, Michelle Skime, Narjès Bendjemaa, Martina Contu, F. Mouaffak, Eva Z. Reininghaus, Mikel Prieto, Nina Dalkner, Nématollah Jaafari, Sofia Luna-Garza, Claudia Pisanu, M. Pinna, E. Vilella, A. Meloni, M. Gardea-Reséndez, Ada Man-Choi Ho, Richard Pendegraft, Francisco Romo-Nava, Esther Jiménez, Mirko Manchia, Claire O’Donovan, Susan L. McElroy, Mark A. Frye, Alessandro Serretti, Frederike T. Fellendorf, Martin Alda, Sarai Gonzalez-Garza, Alfredo B. Cuellar-Barboza, Edith Pomarol-Clotet, Oussama Kebir, Brandon J. Coombes, Eduard Vieta, Joanna M. Biernacka, Boris Chaumette, Raúl F. Sánchez
article en

Abstract

Identifying biological and clinical factors associated with response to mood-stabilizing medications is critical for improving bipolar disorder (BD) treatment. The Mood Stabilizer Genomics (MoStGen) Consortium was established to investigate pharmacogenomic and clinical predictors of response to treatment of BD with antiepileptic drug mood stabilizers (AMS). Here we present the first pharmacogenomic analyses of AMS treatment outcomes based on MoStGen Consortium data, including 917 individuals across contributing sites. We performed genome-wide association analyses in subcohorts followed by meta-analyses, with AMS treatment response measured quantitatively using the Alda scale. Medication-stratified analyses were performed for valproic acid (VPA) and lamotrigine (LTG) treatment response. Additionally, polygenic score (PGS) analyses were used to evaluate the overall genetic contribution to AMS response across cohorts and to test whether genetic liability for various neuropsychiatric illnesses impacts AMS response. We detected genome-wide significant associations with LTG treatment response for SNPs in the gene ROBO2 (top SNP: rs985123, p = 1.9E-10) and for POLR1E at the gene-level (p = 2.53E-06). No significant associations were found for overall AMS or VPA treatment response. Leave-one-out PGS analyses provided significant evidence for a polygenic signal for AMS treatment response. Furthermore, the epilepsy PGS was nominally significantly associated with AMS response (p = 0.024), suggesting higher genetic liability to epilepsy predicts a better response to treatment with AMS. These findings provide insights into the genetic contribution to AMS treatment outcomes, and in particular LTG response, and may contribute to the development of more precise treatments for BD.

Molecular Psychiatry
Dalhousie University (CA), Mayo Clinic (US), Inserm (FR), Universidad Autónoma de Nuevo León (MX), University of Cagliari (IT), Neurosciences Institute (US), Universidad de Los Andes, Chile (CL), Medical University of Graz (AT), Université Paris Cité (FR), Università degli Studi di Enna Kore (IT), Instituto de Salud Carlos III (ES), Institut Pere Mata (ES), WinnMed (US), Sorbonne Université (FR), Oasi Maria SS (IT), Centro de Investigación Biomédica en Red de Salud Mental (ES), Institut de Recerca Biomèdica Catalunya Sud (ES), Agencia Nacional de Investigación y Desarrollo (CL), Hospital Clínic de Barcelona (ES), Lindner Center of HOPE (US), Pitié-Salpêtrière Hospital (FR), Hôpital de Ville-Évrard (FR), Fidmag Sisters Hospitallers (ES), Centre Hospitalier Sainte-Anne (FR), Mayo Clinic in Arizona (US), Institut de Psychiatrie et Neurosciences de Paris (FR), Mayo Clinic in Florida (US), Centre Hospitalier Henri Laborit (FR), Istituti di Ricovero e Cura a Carattere Scientifico (IT), National Institute of Mental Health (CZ), McGill University (CA), Universitat Rovira i Virgili (ES), Universitat de Barcelona (ES), University of Cincinnati Medical Center (US)
Genome Canada, Regeneron Pharmaceuticals, J. Willard and Alice S. Marriott Foundation, Centres de Recerca de Catalunya, European Commission, Generalitat de Catalunya, Ministerio de Ciencia e Innovación, Agencia Nacional de Investigación y Desarrollo, Horizon 2020 Framework Programme, Canadian Institutes of Health Research, Comisión Nacional de Investigación Científica y Tecnológica, Instituto de Salud Carlos III, European Regional Development Fund, National Institute of Mental Health, Fondo de Fomento al Desarrollo Científico y Tecnológico, EIT Health
Good health and well-being
Openalex Percentile: Top 48%
Genetic Associations and Epidemiology
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