Profiling gene expression in the human dentate gyrus granule cell layer reveals insights into schizophrenia and its genetic risk

• Published in: Nature neuroscience Vol. 23; no. 4; pp. 510 - 519
• Main Authors: Jaffe, Andrew E., Hoeppner, Daniel J., Saito, Takeshi, Blanpain, Lou, Ukaigwe, Joy, Burke, Emily E., Collado-Torres, Leonardo, Tao, Ran, Tajinda, Katsunori, Maynard, Kristen R., Tran, Matthew N., Martinowich, Keri, Deep-Soboslay, Amy, Shin, Joo Heon, Kleinman, Joel E., Weinberger, Daniel R., Matsumoto, Mitsuyuki, Hyde, Thomas M.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.04.2020; Nature Publishing Group
• Subjects: 38/91; 631/208/199; 631/208/212/2019; 631/208/514/1949; 692/699/476/1799; Adolescent; Adult; Aged; Aged, 80 and over; Aging; Analysis; Animal Genetics and Genomics; Behavioral Sciences; Biological Techniques; Biomedical and Life Sciences; Biomedicine; Bipolar Disorder - genetics; Bipolar Disorder - metabolism; Dentate gyrus; Dentate Gyrus - metabolism; Depressive Disorder, Major - genetics; Depressive Disorder, Major - metabolism; Female; Gene expression; Gene Expression Profiling; Gene mapping; Gene sequencing; Genetic aspects; Genetic diversity; Genetic effects; Genetic Predisposition to Disease; Genome-Wide Association Study; Granular materials; Hippocampus; Humans; Male; Mental disorders; Middle Aged; Neurobiology; Neurons - metabolism; Neurosciences; Nuclei (cytology); Population genetics; Quantitative Trait Loci; Ribonucleic acid; Risk; Risk factors; RNA; Schizophrenia; Schizophrenia - genetics; Schizophrenia - metabolism; Transcriptome; Transcriptomics; Uniqueness; Young Adult; United States
• ISSN: 1097-6256; 1546-1726
• DOI: 10.1038/s41593-020-0604-z

Specific cell populations may have unique contributions to schizophrenia but may be missed in studies of homogenate tissue. Here laser capture microdissection followed by RNA sequencing (LCM-seq) was used to transcriptomically profile the granule cell layer of the dentate gyrus (DG-GCL) in human hippocampus and contrast these data to those obtained from bulk hippocampal homogenate. We identified widespread cell-type-enriched aging and genetic effects in the DG-GCL that were either absent or directionally discordant in bulk hippocampus data. Of the ~9 million expression quantitative trait loci identified in the DG-GCL, 15% were not detected in bulk hippocampus, including 15 schizophrenia risk variants. We created transcriptome-wide association study genetic weights from the DG-GCL, which identified many schizophrenia-associated genetic signals not found in transcriptome-wide association studies from bulk hippocampus, including GRM3 and CACNA1C . These results highlight the improved biological resolution provided by targeted sampling strategies like LCM and complement homogenate and single-nucleus approaches in human brain. Jaffe et al. profile the granule cell layer of the human hippocampus and find unique molecular associations for aging and genetic variation, as well as diagnosis with schizophrenia and its genetic risk, that were previously undiscovered in homogenate tissue.