We selected 17 traits associated with BD in clinical or epidemiological studies for Mendelian randomization (MR) to dissect their relationship with BD (Supplementary Note). Bi-directional generalized summary statistics-based MR (GSMR)51 analyses were performed between BD and the traits of interest using GWAS summary statistics, implemented in GCTA software (v1.93.1f beta). The instrumental variables (IVs) were selected by a clumping procedure internal to the GSMR software with parameters: --gwas-thresh 5e-8 --clump-r2 0.01. Traits with less than 10 IVs available were excluded from the GSMR analyses to avoid conducting underpowered tests51, resulting in 10 traits tested (Bonferroni-corrected P-value threshold < 2.5 × 10−3). The HEIDI-outlier test (heterogeneity in dependent instruments) was applied to test for horizontal pleiotropy (PHEIDI < 0.01)51. For comparison, the MR analyses were also performed using the inverse variance weighted regression method, implemented via the TwoSampleMR R package, using the IVs selected by GSMR119,120. To further investigate horizontal pleiotropy, the MR Egger intercept test was conducted using the TwoSampleMR package119,120 and MR-PRESSO software was used to perform the Global Test and Distortion Test121.
