Positive bi-directional relationships were identified between BD and longer sleep duration, problematic alcohol use, educational attainment (EA), and mood instability (Fig. 3). Notably, the instrumental variables for mood instability were selected from a GWAS conducted in the general population, excluding individuals with psychiatric disorders58. For all of the aforementioned BD-trait relationships, the effect size estimates from GSMR were consistent with those calculated using the inverse variance weighted regression method, and there was no evidence of bias from horizontal pleiotropy. Full MR results are in Supplementary Tables 18 and 19. Bivariate gaussian mixture modeling using MiXeR indicated large proportions of variants influencing both BD and all other traits tested, particularly educational attainment, where approximately 98% of variants influencing BD were estimated to also influence EA. While cigarettes per day was a trait of interest, MiXeR could not model these data due to low polygenicity and heritability, and the effect of cigarettes per day on BD was inconsistent between MR methods, suggesting a violation of MR assumptions (Supplementary Tables 18–20).
