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

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

doi:10.1101/612200

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

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

Research output: Contribution to journal › Article › peer-review

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.

Original language	English (US)
Journal	Unknown Journal
DOIs	https://doi.org/10.1101/612200
State	Published - Apr 17 2019

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)
Agricultural and Biological Sciences(all)
Immunology and Microbiology(all)
Neuroscience(all)
Pharmacology, Toxicology and Pharmaceutics(all)

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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.

In: Unknown Journal, 17.04.2019.

Research output: Contribution to journal › Article › peer-review

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

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.",

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

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AU - Hoeppner, D. J.

AU - Saito, T.

AU - Blanpain, L.

AU - Ukaigwe, J.

AU - Burke, E. E.

AU - Tao, R.

AU - Tajinda, K.

AU - Deep-Soboslay, A.

AU - Shin, J. H.

AU - Kleinman, J. E.

AU - Weinberger, D. R.

AU - Matsumoto, M.

AU - Hyde, T. M.

N1 - Publisher Copyright: The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.

PY - 2019/4/17

Y1 - 2019/4/17

N2 - 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.

AB - 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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