estimate gene-trait associations. Within-tissue Bonferroni correction was applied to identify statistically significant TWAS genes. Finally, we used summary-data-based Mendelian randomization (SMR)32 to 1) test the extent to which gene expression mediated the relationship between SNPs and the phenotype and 2) identify genes that are more likely to be functionally relevant to the phenotype using the heterogeneity in dependent instruments (HEIDI) test. The HEIDI test distinguishes causality and pleiotropy models, in which the effect of a genetic variant on a trait is mediated by gene expression or where the genetic variant has direct effects on both the trait and expression, from the linkage model, in which associations between gene expression and trait are due to LD between two distinct causal variants. Evidence of causal or pleiotropic effects suggests that the gene should be prioritized for follow up analyses. We identified genes of interest as those that met SMR test Bonferroni correction significance threshold and had a HEIDI test two-sided p-value > .05. We also used MAGMA to identify genes associated with each residual SUD phenotype.
