SMultiXcan (the method used for our splicing TWAS) combines multiple regression and elastic neural networks to predict alternative mRNA splicing from cis-sQTLs. This method accounts for linkage disequilibrium (LD) of European ancestry using the 1000 Genomes Phase 3 data. Our study assessed the convergence between the splicing TWAS on AUD and the differentially spliced genes in the brain associated with AUD. Of the overlapping genes, we assessed SNP associations mapped to these genes that were associated with other traits via https://www.ebi.ac.uk/gwas/. For these genes that also had a significant sQTL we evaluated the LD between the lead sQTL SNP (smallest p-value for the gene) with the SNP listed in the GWAS catalog using LDlink (European Ancestry; https://ldlink.nci.nih.gov/?tab=home). Lastly, we investigated how splicing associations generalized across substance use traits by correlating splicing TWAS results from three other GWASs: cigarettes per day (n = 263,954)35, opioid use disorder (n = 82,707)36 and cannabis use disorder (n = 374,287)37.
