Identifying novel proteins underlying bipolar disorder via integrating pQTLs of the plasma, CSF, and brain with GWAS summary data

Bipolar disorder (BD) presents a significant challenge due to its chronic and relapsing nature, with its underlying pathogenesis remaining elusive. This study employs Mendelian randomization (MR), a widely recognized genetic approach, to unveil intricate causal associations between proteins and BD, leveraging protein quantitative trait loci (pQTL) as key exposures. We integrate pQTL data from brain, cerebrospinal fluid (CSF), and plasma with genome-wide association study (GWAS) findings of BD within a comprehensive systems analysis framework. Our analyses, including two-sample MR, Steiger filtering, and Bayesian colocalization, reveal noteworthy associations. Elevated levels of AGRP, FRZB, and IL36A in CSF exhibit significant associations with increased BDALL risk, while heightened levels of CTSF and LRP8 in CSF, and FLRT3 in plasma, correlate with decreased BDALL risk. Specifically for Bipolar I disorder (BDI), increased CSF AGRP levels are significantly linked to heightened BDI risk, whereas elevated CSF levels of CTSF and LRP8, and plasma FLRT3, are associated with reduced BDI risk. Notably, genes linked to BD-related proteins demonstrate substantial enrichment in functional pathways such as "antigen processing and presentation, " "metabolic regulation, " and "regulation of myeloid cell differentiation. " In conclusion, our findings provide beneficial evidence to support the potential causal relationship between IL36A, AGRP, FRZB, LRP8 in cerebrospinal fluid, and FLRT3 in plasma, and BD and BDI, providing insights for future mechanistic studies and therapeutic development.