Cell type-specific genetic regulation of expression in the granule cell layer of the human dentate gyrus

Laser capture microdissectionfollowed by RNA-seq(LCM-seq) was used to profile the transcriptional landscape of the granule celllayer of the dentate gyrus(DG-GCL) in human hippocampus, and contrasted to homogenate tissue. We identified widespread cell type-specific aging and genetic effects in the DG-GCL that were either missing or directionally discordant in corresponding bulk hippocampus RNA-seqdata from largely the same subjects. Of the ~9 million eQTLs in the DG-GCL, 15% were not in bulk hippocampus, including 15 schizophrenia genome-wide association study(GWAS) risk variants. We then created custom transcriptome-wide association study (TWAS) genetic weights from the DG-GCL which identified many novel schizophrenia-associated genetic signals not found in TWAS from bulk hippocampus, including GRM3 and CACNA1C. These results highlight the biological resolution of cell type-specific expression profiling using targeted sampling strategies like LCM, and complement homogenate and single nuclei approaches in human brain.