Lithium response in bipolar disorder: Epigenome-wide DNA methylation signatures and epigenetic aging

Marina Zafrilla-López; Miriam Acosta-Díez; Marina Mitjans; Anna Giménez-Palomo; Pilar A Saiz; Carme Barrot-Feixat; Ester Jiménez; Sergi Papiol; Victoria Ruiz; Patrícia Gavín; María Paz García-Portilla; Leticia González-Blanco; Julio Bobes; Thomas G Schulze; Eduard Vieta; Antoni Benabarre; Bárbara Arias

doi:10.1016/j.euroneuro.2024.03.010

Lithium response in bipolar disorder: Epigenome-wide DNA methylation signatures and epigenetic aging

Eur Neuropsychopharmacol. 2024 Apr 25:85:23-31. doi: 10.1016/j.euroneuro.2024.03.010. Online ahead of print.

Authors

Marina Zafrilla-López¹, Miriam Acosta-Díez¹, Marina Mitjans², Anna Giménez-Palomo³, Pilar A Saiz⁴, Carme Barrot-Feixat⁵, Ester Jiménez⁶, Sergi Papiol⁷, Victoria Ruiz³, Patrícia Gavín³, María Paz García-Portilla⁴, Leticia González-Blanco⁴, Julio Bobes⁴, Thomas G Schulze⁸, Eduard Vieta⁶, Antoni Benabarre⁶, Bárbara Arias⁹

Affiliations

¹ Department of Evolutionary Biology, Ecology and Environmental Sciences, Faculty of Biology, University of Barcelona, Barcelona, Spain.
² Department of Genetics, Microbiology, and Statistics, Faculty of Biology, University of Barcelona, Barcelona, Spain; Institute of Biomedicine of the University of Barcelona (IBUB), Spain; CIBER de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain; Institut de Recerca Sant Joan de Déu (IRSJD), Esplugues de Llobregat, Spain. Electronic address: marina.mitjans@ub.edu.
³ Bipolar and Depressive Disorders Unit, Psychiatry and Psychology Service, Clinical Institute of Neuroscience, Hospital Clinic de Barcelona, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi Sunyer (IDIBAPS), Barcelona, Spain.
⁴ Department of Psychiatry, Servicio de Salud del Principado de Asturias (SESPA), School of Medicine, University of Oviedo, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Instituto de Neurociencias del Principado de Asturias (INEUROPA), Oviedo, Spain; CIBER de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain.
⁵ Forensic Genetic Laboratory, University of Barcelona, Catalonia, Spain.
⁶ Bipolar and Depressive Disorders Unit, Psychiatry and Psychology Service, Clinical Institute of Neuroscience, Hospital Clinic de Barcelona, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi Sunyer (IDIBAPS), Barcelona, Spain; Institut de Neurociències, Department of Medicine, University of Barcelona, Barcelona, Spain; CIBER de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain.
⁷ CIBER de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain; Institute of Psychiatric Phenomics and Genomics (IPPG), University Hospital, LMU Munich, Munich, Germany; Max Planck Institute of Psychiatry, Munich, Germany.
⁸ Institute of Psychiatric Phenomics and Genomics (IPPG), University Hospital, LMU Munich, Munich, Germany; Department of Psychiatry and Behavioral Sciences, SUNY Upstate Medical University, Syracuse, NY, USA; Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁹ Department of Evolutionary Biology, Ecology and Environmental Sciences, Faculty of Biology, University of Barcelona, Barcelona, Spain; Institute of Biomedicine of the University of Barcelona (IBUB), Spain; CIBER de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain.

PMID: 38669938
DOI: 10.1016/j.euroneuro.2024.03.010

Abstract

Lithium (Li) is the first-line treatment for bipolar disorder (BD) even though only 30 % of BD patients are considered excellent responders. The mechanisms by which Li exerts its action are not clearly understood, but it has been suggested that specific epigenetic mechanisms, such as methylation processes, may play a role. In this regard, DNA methylation patterns can be used to estimate epigenetic age (EpiAge), which is accelerated in BD patients and reversed by Li treatment. Our first aim was to compare the DNA methylation profile in peripheral blood between BD patients categorized as excellent responders to Li (Ex-Rp) and non-responders (N-Rp). Secondly, EpiAge was estimated to detect differential age acceleration between the two groups. A total of 130 differentially methylated positions (DMPs) and 16 differentially methylated regions (DMRs) between Ex-Rp (n = 26) and N-Rp (n = 37) were identified (FDR adjusted p-value < 0.05). We found 122 genes mapping the DMPs and DMRs, nine of which (HOXB6, HOXB3, HOXB-AS3, TENM2, CACNA1B, ANK3, EEF2K, CYP1A1, and SORCS2) had previously been linked to Li response. We found genes related to the GSK3β pathway to be highly represented. Using FUMA, we found enrichment in Gene Ontology Cell Component for the synapse. Gene network analysis highlighted functions related to the cell cycle, nervous system development and function, and gene expression. No significant differences in age acceleration were found between Ex-Rp and N-Rp for any of the epigenetic clocks analysed. Our findings indicate that a specific methylation pattern could determine the response to Li in BD patients. We also found that a significant portion of the differentially methylated genes are closely associated with the GSK3β pathway, reinforcing the role of this system in Li response. Future longitudinal studies with larger samples will help to elucidate the epigenetic mechanisms underlying Li response.

Keywords: Bipolar disorder; DNA methylation; Epigenetic aging; Epigenetics; Lithium response.