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

Jaffe, A. E.; Hoeppner, D. J.; Saito, T.; Blanpain, L.; Ukaigwe, J.; Burke, E. E.; Tao, R.; Tajinda, K.; Deep-Soboslay, A.; Shin, J. H.; Kleinman, J. E.; Weinberger, D. R.; Matsumoto, M.; Hyde, T. M.

doi:10.1101/612200

bioRxiv · 10.1101/612200

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

Jaffe, A. E.·Hoeppner, D. J.·Saito, T.·Blanpain, L.·Ukaigwe, J.·Burke, E. E.·Tao, R.·Tajinda, K.·Deep-Soboslay, A.·Shin, J. H.·Kleinman, J. E.·Weinberger, D. R.·Matsumoto, M.·Hyde, T. M.

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Abstract

Laser capture microdissection followed by RNA-seq (LCM-seq) was used to profile the transcriptional landscape of the granule cell layer 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-seq data 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.

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Jaffe, A. E., Hoeppner, D. J., Saito, T., Blanpain, L., Ukaigwe, J., Burke, E. E., Tao, R., Tajinda, K., Deep-Soboslay, A., Shin, J. H., Kleinman, J. E., Weinberger, D. R., Matsumoto, M., Hyde, T. M.. 2019-04-17. Cell type-specific genetic regulation of expression in the granule cell layer of the human dentate gyrus. https://doi.org/10.1101/612200

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