Lithium-associated peripheral transcriptional signatures correlate with brain white matter microstructure in bipolar disorder

Lithium is the mainstay treatment for bipolar disorder, improving brain white matter microstructure and regulating genes involved in immune response and cell signaling. In 116 patients affected by a major depressive episode in the course of bipolar disorder, we investigated the effect of long-term lithium treatment on gene expression in peripheral blood mononuclear cells and their association with white matter microstructure. Differential gene expression analysis identified three genes significantly upregulated in lithium-treated compared to nontreated patients: SEPTIN11, DGKK, and TPPP3; and two downregulated genes: LEF1-AS1 and PLXDC1. At tract-based spatial statistics, significant lithium-by-gene expression interactions were observed for SEPTIN11, LEF1-AS1, PLXDC1, and DGKK, indicating that the relationship between gene expression and white matter microstructure differed depending on lithium treatment status. Only in lithium-treated participants, LEF1-AS1 and PLXDC1 expression were associated with increased fractional anisotropy and decreased radial diffusivity and mean diffusivity, while SEPTIN11 expression was associated with increased axial diffusivity, mean diffusivity, and radial diffusivity. These genes are widely expressed in the brain, and their peripheral expression correlates with white matter microstructure measures associated with lithium treatment. This observation supports the potential usefulness of peripheral transcriptomic signatures to mark the individual biological impact of lithium treatment on the brain.