Bidirectional causal effects between bipolar disorder and immune cell traits

The complexity of the pathogenesis hinders the diagnosis and treatment of bipolar disorder (BD). Despite studies finding a correlation between immune function and BD, the causative relationship between the two remains poorly explained.

We investigated the causative relationships between BD (41,917 cases and 371,549 controls) and levels of six types of white blood cells and further evaluated the causative relationships between BD and 731 immune cell traits) using a two-sample Mendelian randomization method, prioritizing the inverse variance weighted approach, based on publicly available GWAS data. Sensitivity analysis was based on MR-Egger intercept method and Cochran's Q test.

We did not find a significant causative relationship between BD and 6 white blood cell traits (FDR > 0.05). However, we found 38 immune cell traits had a causal effect to BD. Among them, 26 immune cell traits increased the risk of BD (OR: 1.01-1.07), including CD4+/CD28+ T cells and CD20+/CD27+ B cells. The remaining 12 including had a protective effect on BD (OR: 0.92-0.99). The backward MR results showed that BD had negative causal effects on 23 immune cell traits (n = 23, OR: 0.79-0.89), which included monocyte, majority of CD4+ T cells, and CD20+ B cells. BD had Positive causal effects 10 immune cell traits (OR: 1.13-1.19), especially CD19+ B cells. The overall causal effect of BD on immune cell traits was significantly higher than the inverse effect (0.011 ± 0.049 vs. 0.001 ± 0.016, p < 0.001).

A complex network of bidirectional causative relationships exists between BD and various phenotypic features of immune cells. These findings provide new insights into the diagnosis and treatment of BD from an immunotherapeutic perspective.