1Mol. Psychiatry 2012 Jul 17: 827-40
TitleImprinted DLK1-DIO3 region of 14q32 defines a schizophrenia-associated miRNA signature in peripheral blood mononuclear cells.
AbstractMicroRNAs (miRNAs) regulate gene expression at the post-transcriptional level and are important for coordinating nervous system development and neuronal function in the mature brain. We have recently identified schizophrenia-associated alteration of cortical miRNA biogenesis and expression in post-mortem brain tissue with implications for the dysregulation of schizophrenia candidate genes. Although these changes were observed in the central nervous system, it is plausible that schizophrenia-associated miRNA expression signatures may also be detected in non-neural tissue. To explore this possibility, we investigated the miRNA expression profile of peripheral blood mononuclear cells (PBMCs) from 112 patients with schizophrenia and 76 non-psychiatric controls. miRNA expression analysis of total RNA conducted using commercial miRNA arrays revealed that 33 miRNAs were significantly downregulated after correction for multiple testing with a false discovery rate (FDR) of 0%, which increased to 83 when we considered miRNA with an FDR<5%. Seven miRNAs altered in microarray analysis of schizophrenia were also confirmed to be downregulated by quantitative real-time reverse transcription-polymerase chain reaction. A large subgroup consisting of 17 downregulated miRNAs is transcribed from a single imprinted locus at the maternally expressed DLK1-DIO3 region on chromosome 14q32. This pattern of differentially expressed miRNA in PBMCs may be indicative of significant underlying genetic or epigenetic alteration associated with schizophrenia.
SCZ Keywordsschizophrenia
2Transl Psychiatry 2014 -1 4: e452
TitleAlteration of imprinted Dlk1-Dio3 miRNA cluster expression in the entorhinal cortex induced by maternal immune activation and adolescent cannabinoid exposure.
AbstractA significant feature of the cortical neuropathology of schizophrenia is a disturbance in the biogenesis of short non-coding microRNA (miRNA) that regulate translation and stability of mRNA. While the biological origin of this phenomenon has not been defined, it is plausible that it relates to major environmental risk factors associated with the disorder such as exposure to maternal immune activation (MIA) and adolescent cannabis use. To explore this hypothesis, we administered the viral mimic poly I:C to pregnant rats and further exposed some of their maturing offsprings to daily injections of the synthetic cannabinoid HU210 for 14 days starting on postnatal day 35. Whole-genome miRNA expression analysis was then performed on the left and right hemispheres of the entorhinal cortex (EC), a region strongly associated with schizophrenia. Animals exposed to either treatment alone or in combination exhibited significant differences in the expression of miRNA in the left hemisphere, whereas the right hemisphere was less responsive. Hemisphere-associated differences in miRNA expression were greatest in the combined treatment and highly over-represented in a single imprinted locus on chromosome 6q32. This observation was significant as the syntenic 14q32 locus in humans encodes a large proportion of miRNAs differentially expressed in peripheral blood lymphocytes from patients with schizophrenia, suggesting that interaction of early and late environmental insults may affect miRNA expression, in a manner that is relevant to schizophrenia.
SCZ Keywordsschizophrenia
3Mol. Psychiatry 2015 Dec -1: -1
TitlePolygenic associations of neurodevelopmental genes in suicide attempt.
AbstractThe risk for suicidal behavior (SB) is elevated in schizophrenia (SCZ), bipolar disorder (BPD) and major depressive disorder (MDD), but also occurs in subjects without psychiatric diagnoses. Genome-wide association studies (GWAS) on SB may help to understand this risk, but have been hampered by low power due to limited sample sizes, weakly ascertained SB or a reliance on single-nucleotide protein (SNP)-by-SNP analyses. Here, we tried to mitigate such issues with polygenic risk score (PRS) association tests combined with hypothesis-driven strategies using a family-based sample of 660 trios with a well-ascertained suicide attempt (SA) outcome in the offspring (Genetic Investigation of Suicide and SA, GISS). Two complementary sources of PRS information were used. First, a PRS that was discovered and validated in the GISS SA revealed the polygenic association of SNPs in 750 neurodevelopmental genes, which was driven by the SA phenotype, rather than the major psychiatric diagnoses. Second, a PRS based on three different genome-wide association studies (on SCZ, BPD or MDD) from the Psychiatric Genomics Consortium (PGC) showed an association of the PGC-SCZ PRS in the SA subjects with and without major psychiatric diagnoses. We characterized the PGC-SCZ overlap in the SA subjects without diagnoses. The extended major histocompatibility complex region did not contribute to the overlap, but we delineated the genic overlap to neurodevelopmental genes that partially overlapped with those identified by the GISS PRS. Among the 590 SA polygenes implicated here, there were several developmentally important functions (cell adhesion/migration, small GTPase and receptor tyrosine kinase signaling), and 16 of the SA polygenes have previously been studied in SB (BDNF, CDH10, CDH12, CDH13, CDH9, CREB1, DLK1, DLK2, EFEMP1, FOXN3, IL2, LSAMP, NCAM1, nerve growth factor (NGF), NTRK2 and TBC1D1). These novel genome-wide insights, supported by two lines of evidence, suggested the importance of a polygenic neurodevelopmental etiology in SB, even in the absence of major psychiatric diagnoses.Molecular Psychiatry advance online publication, 15 December 2015; doi:10.1038/mp.2015.187.
SCZ Keywordsschizophrenia