Immunogenetics of lithium response and psychiatric phenotypes in patients with bipolar disorder

Abstract

The link between bipolar disorder (BP) and immune dysfunction remains controversial. While epidemiological studies have long suggested an association, recent research has found only limited evidence of such a relationship. To clarify this, we investigated the contributions of immune-relevant genetic factors to the response to lithium (Li) treatment and the clinical presentation of BP. First, we assessed the association of a large collection of immune-related genes (4,925) with Li response, defined by the Retrospective Assessment of the Lithium Response Phenotype Scale (Alda scale), and clinical characteristics in patients with BP from the International Consortium on Lithium Genetics (ConLi⁺Gen, N = 2,374). Second, we calculated here previously published polygenic scores (PGSs) for immune-related traits and evaluated their associations with Li response and clinical features. We found several genes associated with Li response at p < 1×10^{- 4} values, including HAS3, CNTNAP5 and NFIB. Network and functional enrichment analyses uncovered an overrepresentation of pathways involved in cell adhesion and intercellular communication, which appear to converge on the well-known Li-induced inhibition of GSK-3β. We also found various genes associated with BP's age-at-onset, number of mood episodes, and presence of psychosis, substance abuse and/or suicidal ideation at the exploratory threshold. These included RTN4, XKR4, NRXN1, NRG1/3 and GRK5. Additionally, PGS analyses suggested serum FAS, ECP, TRANCE and cytokine ligands, amongst others, might represent potential circulating biomarkers of Li response and clinical presentation. Taken together, our results support the notion of a relatively weak association between immunity and clinically relevant features of BP at the genetic level.

Keywords: bipolar disorder; genetics; immunity; lithium; polygenic scores.

Figure 1

Exploratory findings for the ImmuneSet in ConLi⁺Gen. A) Gene-based phenogram of associations of the ImmuneSet with Li response and clinical features in ConLi⁺Gen. B) Protein-protein interaction network of Li response phenotype associations in the ImmuneSet. Circles represent input genes and diamonds represent linker genes. Dotted lines denote predicted interactions.

Figure 2

A) Gene-based phenogram of eQTL annotations for the exploratory-level findings of the ImmuneSet in ConLi⁺Gen. Those eQTL genes that were different from the mapped gene and those that were the same are presented in circle and diamond shapes, respectively. Only protein-coding genes are shown. In addition, overlaps with BP genetic associations reported in the GWAS Catalog are presented. B) Exploratory findings for the immune-related polygenic scores calculated in ConLi⁺Gen. Significance of calculated PGSs for BP phenotypes in ConLi⁺Gen “GWAS1”. The heatmap shows the z-values obtained for each PGS-phenotype pair. Increasing color darkness alludes to increasing effect, with red and blue colors at the negativ and positive extremes, respectively.