Our exploratory study hypothesized that (1) polygenic scores of AUD would be higher in those with AUD than controls, (2) individual SNPs would be associated with abnormal alternative mRNA splicing in the brain, and (3) DNA variants around differentially spliced genes would contribute to the heritability of AUD. To test these hypotheses, our study used polygenic score analyses, splicing quantitative trait loci (sQTL) mapping (specific DNA variants that correlate with alternative mRNA splicing associated with a trait), partitioned heritability analyses, and estimated transcriptome-wide splicing associations from large-scale genome-wide association studies (GWASs). Using RNA-sequencing (RNA-seq) data from humans and primates, we also tested whether alternative mRNA splicing events were consistent across brain regions and whether differentially spliced genes linked with AUD overlapped with primate models of chronic alcohol use. For an overview of our study see Fig. 1.
