in other brain regions. Currently, we cannot differentiate these three sources of variation in our results. Expression datasets from multiple brain regions exist in the GTEx project49, but the sample size is small (n=88–136) to build a robust transcriptome model for TWAS. The MSBB has RNA-seq data across three brain regions but due to the lack of availability for individual level genotypes we are unable to build reference models from those data. Another limitation of this study is the small sample size of the in vitro experiment; thus, these intriguing results will require testing in a much larger number of iPSC lines to confirm that this effect of MAPT overexpression is generalizable. We note that these MAPT overexpressing iPSC-derived neurons are functioning normally at the time when they were sampled; thus, these in vitro data suggest that at least some of the disease-associated splicing changes that we report may occur very early in the series of molecular events that are caused by perturbation in MAPT expression.
