We performed transcriptome-wide association studies (TWASs) via splicing SMulti-Xcan33,34, to assess how DNA associations predicted alternative mRNA splicing associations in human tissues. To increase power, we performed spicing TWASs on all of the 49 available Genotype-Tissue Expression (GTEx) database tissues (which included up to 838 human donors; https://www.gtexportal.org/home/) as done previously2. Since alternative mRNA splicing is tissue-specific, we also re-ran a splicing TWAS on AUD incorporating only the 13 GTEx brain tissues. The brain-specific splicing TWAS and the all-tissue splicing TWAS yielded fairly similar results (see Supplementary File S1). That is, 42.42% of the genes identified in the brain TWAS were identified in the all-tissue TWAS. Our manuscript focuses on the splicing TWAS using all 49 GTEx tissues, given that this analysis increased power and specifically boosted the number of significant genes over threefold compared to the splicing brain TWAS. 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
