The causal relationship between circulating biomarkersand the risk of bipolar disorder: A two-sample Mendelian randomization study

To identify susceptible biomarkers for the development of bipolar disorder (BD), we conducted a Mendelian Randomization (MR) design to screen circulating proteins for the potential risk of bipolar disorder systematically. We performed a two-sample Mendelian randomization (MR) analysis to estimate the causality of 4782 human circulating proteins on the risk of bipolar disorder. 376 circulating biomarkers were selected in MR estimation (4406 circulating proteins with less than 3 SNPs were excluded) with 5368 European descents. GWAS meta-analysis of the potential role of all-cause bipolar disorder arose from the Psychiatric Genomics Consortium (41,917 cases, 371,549 controls). After IVW and sensitivity analysis, 4 circulating proteins having causal effects on bipolar disorder were identified. ISG15, as a key player in the innate immune response, decreased the risk of bipolar disorder causally (OR = 0.92, 95% CI = 0.89–0.94, P = 1.46e-09). Furthermore, MLN decreased the risk of bipolar disorder causally (OR = 0.94, 95% CI = 0.91–0.97, P = 1.04e-04). In addition, SFTPC (OR = 0.91, 95% CI = 0.86–0.96, P = 4.47e-04) and VCY (OR = 0.86, 95% CI = 0.77–0.96, P = 8.55e-03) presented a suggestive association with bipolar disorder. Our findings indicated that ISG15 and MLN showed evidence of causality in bipolar disorder and provided a promising target for the diagnosis and treatment of diseases.