We used RNA-seq data and genotypes from ROSMAP to impute the cis genetic component of expression/intron usage37,40 into large-scale late-onset Alzheimer’s disease GWAS of 74,046 individuals from the International Genomics of Alzheimer’s Project (IGAP)14. The complete TWAS pipeline is implemented in FUSION suite of tools40. The details steps implemented in FUSION are: (1) estimate heritability of gene expression or intron usage unit and stop if not significant. We estimated using a robust version of GCTA-GREML62, which generates heritability estimates per feature as well as the as well as the likelihood ratio test (LRT) P-value. Only features that have a heritability of Bonferroni-corrected P < 0.05 were retained for TWAS analysis. (2) The expression or intron usage weights were computed by modeling all cis-SNPs (1MB +/− from TSS) using best linear unbiased prediction (BLUP), or modeling SNPs and effect sizes (BSLMM), LASSO, Elastic Net and top SNPs37,40. A cross-validation for each of the desired models are performed; (3) Perform a final estimate of weights for each of the desired models and store results. The imputed unit is treated as a linear
