DLPFC transcriptome defines two molecular subtypes of schizophrenia

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.

Chromatin profiling of cortical neurons identifies individual epigenetic signatures in schizophrenia

“…Two patients with SZ in our dataset showed global chromatin alterations, particularly for synaptic genes, that were distant from those in other individuals with SZ. These data were consistent with recent independent observations of differential DNA methylation for some patients with SZ, which was very distant from others in SZ cohort groups 58 and with observation that a subset of schizophrenia subjects form a separate group based on global alteration of transcriptome 59 . The segregation of SZ2 subjects from SZ14 group may be explained by distant etiology or symptomatology of SZ subtypes.…”

Convergent genomic and pharmacological evidence of PI3K/GSK3 signaling alterations in neurons from schizophrenia patients

“…Concordance with genetic/genomic studies While we did not find significant enrichment for GWAS signals in our DEGs (SCZ-p = 0.349, BD + SCZ-p = 0.427, ASD-p = 0.435, MDD-p = 0.572, PTSD-p = 0.572, suicide attempt in SCZ-p = 0.739, OCD-p = 0.74, BD-p = 0.954, ADHD-p = 0.966), we found overlap of five DEGs (CACNA1C, C4A, GRAMD1B, PLCL1, and ZNF804A) with genes annotated to genome-wide significant SNPs in SCZ [1]. We evaluated concordance of our findings with two SCZ gene expression studies in the dorsolateral prefrontal cortex [48,49]. We identified 20 and 6 concordant genes, respectively, in each comparison ( Supplementary Table S3).…”

“…We evaluated concordance of our findings with two SCZ gene expression studies in the dorsolateral prefrontal cortex [ 48 , 49 ]. We identified 20 and 6 concordant genes, respectively, in each comparison (Supplementary Table S3 ).…”

“…We assessed enrichment of genome-wide association study (GWAS) signals using Multi-markers Analysis of GenoMic Annotation (Supplementary Methods) and summary statistics for SCZ [1], bipolar disorder (BD) [40], SCZ + BD [41], OCD [42], suicide attempt in SCZ [43], PTSD [44], major depressive disorder [45], autism spectrum disorder [46], and ADHD [47]. We also assessed concordance of our gene set with gene expression data sets from human postmortem brain and hiPSC studies [4,[48][49][50].…”

Selective vulnerability of supragranular layer neurons in schizophrenia

“…Locations of neural cell subtypes were estimated from the Allen Institute human motor cortex (M1C), temporal cortex (MTG) and anterior cingulate cortex (CgG) datasets 7,8 :…”