S-PrediXcan analysis26 revealed 133 Bonferroni-corrected significant associations across tissues targeting 21 unique genes (Supplementary Table S4-S5). Eight genes were also significant in the gene-based test, whereas 13 were novel. For genes identified in multiple tissues, directions of effects were largely consistent across tissues (Supplementary Figure S6). Again, the most significant finding was CADM2; genetic variants associated with increased liability to use cannabis are predicted to upregulate expression levels of CADM2 in 8 (non-brain) tissues, including whole blood (Z=5.88, p=4.17e-09). Of note, although CADM2 is expressed more widely in brain compared with other tissues (Supplementary Figure S7), the top SNP rs2875907 regulates the expression of CADM2 only in non-brain tissues (Supplementary Figure S8). Exploration of S-PrediXcan results in UK-Biobank data (https://imlab.shinyapps.io/gene2pheno_ukb_neale/) showed that CADM2 expression is significantly associated with multiple traits, including increased risk-taking, BMI, and reduced feelings of anxiety. Similar to the SNP- and gene-based tests of association, the S-PrediXcan analysis detected a strong signal in a high-LD region at 16p11.2. Supplementary Table S3 provides an overview of all genes that were identified in the gene-based test of association and the S-PrediXcan analyses, along with information about the gene-product and previously identified associations with the gene.
