We investigated two questions with polygenic score analyses. First, did AUD cases have higher mean polygenetic scores for AUD than control samples? Second, are AUD polygenic scores associated with alternative mRNA splicing in the brain? Polygenic score hypotheses were tested using PRScice.2 (version 2.3.3)27. We elected to use standard polygenic score guidelines28. Specifically, we performed quality control on the base data, which was the AUD GWAS summary statistics (minor allele frequency > 0.01, remove duplicate and ambiguous SNPs). Our target data was the cleaned and imputed RNA-seq brain data (genotyping rate > 95%, minor allele frequency > 0.10, Hardy–Weinberg equilibrium < 1e-6, read depth > 5 reads per sample, Phred Score > 20 and imputation score > 0.3). We used the default parameters from PRScice.2, which removed variants in linkage disequilibrium (LD) with each other (clumping) and selected the most associated polygenic score via a p-value threshold approach using a certain number of genes that enhances prediction.
