TY - JOUR
T1 - DLPFC transcriptome defines two molecular subtypes of schizophrenia
AU - Bowen, Elijah F.W.
AU - Burgess, Jack L.
AU - Granger, Richard
AU - Kleinman, Joel E.
AU - Rhodes, C. Harker
N1 - Funding Information:
First and foremost we would like to acknowledge the families of the subjects in this study for consenting to the study of this autopsy tissue and for providing clinical information to help establish the psychiatric diagnoses. We would also like to acknowledge the current and former scientific staff of the Intramural Program of the NIMH for collecting the clinical material and expression array data and for making it publicly available on dbGaP (dbGaP accession phs000979.v1.p1). Similarly, we are grateful to the members of the CMC consortium for making their RNAseq data available. This research was supported in part by grant N00014-15-1-2132 from the Office of Naval Research to R.G. C.H.R. is grateful for support from the Henry M. Jackson Foundation and the Center for Neuroscience and Regenerative Medicine at the Uniformed Services University. NIMH cohort data were provided by support from the Intramural Research Program of the NIMH (NCT00001260, 900142). Data were generated as part of the NIMH Human Brain Collection Core (NCT00001260, 999917073).
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - Little is known about the molecular pathogenesis of schizophrenia, possibly because of unrecognized heterogeneity in diagnosed patient populations. We analyzed gene expression data collected from the dorsolateral prefrontal cortex (DLPFC) of post-mortem frozen brains of 189 adult diagnosed schizophrenics and 206 matched controls. Transcripts from 633 genes are differentially expressed in the DLPFC of schizophrenics as compared to controls at Bonferroni-corrected significance levels. Seventeen of those genes are differentially expressed at very high significance levels (<10−8 after Bonferroni correction). The findings were closely replicated in a dataset from an entirely unrelated source. The statistical significance of this differential gene expression is being driven by about half of the schizophrenic DLPFC samples, and importantly, it is the same half of the samples that is driving the significance for almost all of the differentially expressed transcripts. Weighted gene co-expression network analysis (WGCNA) of the schizophrenic subjects, based on the transcripts differentially expressed in the schizophrenics as compared to controls, divides them into two groups. “Type 1” schizophrenics have a DLPFC transcriptome similar to that of controls with only four differentially expressed genes identified. “Type 2” schizophrenics have a DLPFC transcriptome dramatically different from that of controls, with 3529 expression array probes to 3092 genes detecting transcripts that are differentially expressed at very high significance levels. These findings were re-tested and replicated in a separate independent cohort, using the RNAseq data from the DLPFC of an independent set of schizophrenics and control subjects. We suggest the hypothesis that these striking differences in DLPFC transcriptomes, identified and replicated in two populations, imply a fundamental biologic difference between these two groups of diagnosed schizophrenics, and we propose specific paths for further testing and expanding the hypothesis.
AB - Little is known about the molecular pathogenesis of schizophrenia, possibly because of unrecognized heterogeneity in diagnosed patient populations. We analyzed gene expression data collected from the dorsolateral prefrontal cortex (DLPFC) of post-mortem frozen brains of 189 adult diagnosed schizophrenics and 206 matched controls. Transcripts from 633 genes are differentially expressed in the DLPFC of schizophrenics as compared to controls at Bonferroni-corrected significance levels. Seventeen of those genes are differentially expressed at very high significance levels (<10−8 after Bonferroni correction). The findings were closely replicated in a dataset from an entirely unrelated source. The statistical significance of this differential gene expression is being driven by about half of the schizophrenic DLPFC samples, and importantly, it is the same half of the samples that is driving the significance for almost all of the differentially expressed transcripts. Weighted gene co-expression network analysis (WGCNA) of the schizophrenic subjects, based on the transcripts differentially expressed in the schizophrenics as compared to controls, divides them into two groups. “Type 1” schizophrenics have a DLPFC transcriptome similar to that of controls with only four differentially expressed genes identified. “Type 2” schizophrenics have a DLPFC transcriptome dramatically different from that of controls, with 3529 expression array probes to 3092 genes detecting transcripts that are differentially expressed at very high significance levels. These findings were re-tested and replicated in a separate independent cohort, using the RNAseq data from the DLPFC of an independent set of schizophrenics and control subjects. We suggest the hypothesis that these striking differences in DLPFC transcriptomes, identified and replicated in two populations, imply a fundamental biologic difference between these two groups of diagnosed schizophrenics, and we propose specific paths for further testing and expanding the hypothesis.
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U2 - 10.1038/s41398-019-0472-z
DO - 10.1038/s41398-019-0472-z
M3 - Article
C2 - 31073119
AN - SCOPUS:85065570452
SN - 2158-3188
VL - 9
JO - Translational psychiatry
JF - Translational psychiatry
IS - 1
M1 - 147
ER -