Abstract
Lithium (Li) is the cornerstone maintenance treatment for bipolar disorders (BD), but response rates are highly variable. To date, no clinical or biological marker is available to reliably define eligibility criteria for a maintenance treatment with Li. We examined whether the prophylactic response to Li (assessed retrospectively) is associated with distinct blood DNA methylation profiles. Bisulfite-treated total blood DNA samples from individuals with BD type 1 (15 excellent-responders (LiERs) versus 11 non-responders (LiNRs)) were used for targeted enrichment of CpG rich genomic regions followed by high-resolution next-generation sequencing to identify differentially methylated regions (DMRs). After controlling for potential confounders we identified 111 DMRs that significantly differ between LiERs and LiNRs with a significant enrichment in neuronal cell components. Logistic regression and receiver operating curves identified a combination of 7 DMRs with a good discriminatory power for response to Li (Area Under the Curve 0.806). Annotated genes associated with these DMRs include Eukaryotic Translation Initiation Factor 2B Subunit Epsilon (EIF2B5), Von Willebrand Factor A Domain Containing 5B2 (VWA5B2), Ral GTPase Activating Protein Catalytic Alpha Subunit 1 (RALGAPA1). Although preliminary and deserving replication, these results suggest that biomarkers of response to Li may be identified through peripheral epigenetic measures.
Highlights
Lithium (Li) is the cornerstone maintenance treatment for bipolar disorders (BD), but response rates are highly variable
The present study is the first genome-wide analysis of DNA methylation profiles in patients with BD selected for their level of response to long-term treatment with Li
In total blood DNA, we identified 111 significant differentially methylated regions (DMRs) in LiERs as compared to LiNRs
Summary
Lithium (Li) is the cornerstone maintenance treatment for bipolar disorders (BD), but response rates are highly variable. No clinical or biological marker is available to reliably define eligibility criteria for a maintenance treatment with Li. We examined whether the prophylactic response to Li (assessed retrospectively) is associated with distinct blood DNA methylation profiles. Bisulfite-treated total blood DNA samples from individuals with BD type 1 (15 excellent-responders (LiERs) versus 11 non-responders (LiNRs)) were used for targeted enrichment of CpG rich genomic regions followed by high-resolution next-generation sequencing to identify differentially methylated regions (DMRs). An early age at onset, a high rate of mood recurrences, the associated medical health and psychosocial burdens make bipolar disorder (BD) one of the leading causes of disability in the young population[1,2]. N Alda range Ratio Male/Female Age BD type 1 BMI Smokers yes/no Current medication Li yes/no Anticonvulsants yes/no Atypical antipsychotic yes/no Antidepressants yes/no Number of psychotropic drugs 1/2/3
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