We used MR analyses to test directional causal relationships between significantly genetically correlated traits (N=31) and TUD among EURs only due to the small sample size and limited statistical power in other populations (Supplementary Table 39). There was a positive causal effect of TUD on cross-disorder (IVW β=0.93, SE=0.02, p=5.06E-10, 95% CI = 0.64–1.22). Seven traits showed significant causal effects on TUD. Specifically, we observed a negative causal effect of education attainment (IVW β=−0.25, SE=0.02, p=2.02E-39, 95% CI = −0.29 - [−0.22]), and a positive causal effect of drinks per week (IVW β=0.22, SE=0.02, p=8.53E-28, 95% CI = 0.18–0.26), depression (IVW β=0.09, SE=0.01, p=1.35E-12, 95% CI = 0.06–0.11), BMI (IVW β=0.10, SE=0.01, p=1.85E-38, 95% CI = 0.08–0.11), externalizing (IVW β=0.48, SE=0.02, p=3.38E-131, 95% CI = 0.44–0.52), opioid prescriptions (IVW β=0.04, SE=0.01, p=2.33E-05, 95% CI = 0.02–0.06), and opioid use disorder (IVW β=0.06, SE=0.01, p=1.70E-07, 95% CI = 0.04–0.08) on TUD.
