Abstract
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.
Highlights
Almost half a century ago, Fred Plum[1] called schizophrenia “the graveyard of neuropathologists”, and in many ways the situation has not appreciably changed: In spite of decades of anatomic, histologic, and molecular inroads, little progress has been made elucidating the pathobiology of schizophrenia.A longstanding hypothesis to explain this lack of progress is that schizophrenia is a heterogeneous disease and that meaningful results have been obscured in studies which pool data from biologically different patients
The first dataset was generated by scientists in the Clinical Brain Disorders Branch of the Intramural Research Program at the National Institute of Mental Health (NIMH), under the direction of Dr Daniel Weinberger; it consists of Illumina HumanHT-12 v4 expression array data from the dorsolateral prefrontal cortex (DLPFC) of post-mortem brains of almost a thousand patients with psychiatric disease and neurologically normal matched controls
Gene expression in schizophrenics The NIMH expression arrays included data from 11,883 probes after censoring data from probes which did not detect mRNA in the DLPFC at a statistically significant level or which contained common polymorphisms in the probe sequence
Summary
Almost half a century ago, Fred Plum[1] called schizophrenia “the graveyard of neuropathologists”, and in many ways the situation has not appreciably changed: In spite of decades of anatomic, histologic, and molecular inroads, little progress has been made elucidating the pathobiology of schizophrenia.A longstanding hypothesis to explain this lack of progress is that schizophrenia is a heterogeneous disease and that meaningful results have been obscured in studies which pool data from biologically different patients. The first dataset was generated by scientists in the Clinical Brain Disorders Branch of the Intramural Research Program at the National Institute of Mental Health (NIMH), under the direction of Dr Daniel Weinberger; it consists of Illumina HumanHT-12 v4 expression array data from the dorsolateral prefrontal cortex (DLPFC) of post-mortem brains of almost a thousand patients with psychiatric disease (including schizophrenia and other diagnoses) and neurologically normal matched controls. Those investigators have never published their analysis of that data, the data itself are publicly available (dbGaP study accession phs000979.v1.p1).
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