MicroRNA profiling of neurons generated using induced pluripotent stem cells derived from patients with schizophrenia and schizoaffective disorder, and 22q11.2 del

Dejian Zhao, Mingyan Lin, Jian Chen, Erika Pedrosa, Anastasia Hrabovsky, H. Matthew Fourcade, Deyou Zheng, Herbert M. Lachman

Research output: Contribution to journalArticle

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Abstract

We are using induced pluripotent stem cell (iPSC) technology to study neuropsychiatric disorders associated with 22q11.2 microdeletions (del), the most common known schizophrenia (SZ)-associated genetic factor. Several genes in the region have been implicated; a promising candidate is DGCR8, which codes for a protein involved in microRNA (miRNA) biogenesis. We carried out miRNA expression profiling (miRNA-seq) on neurons generated from iPSCs derived from controls and SZ patients with 22q11.2 del. Using thresholds of p<0.01 for nominal significance and 1.5-fold differences in expression, 45 differentially expressed miRNAs were detected (13 lower in SZ and 32 higher). Of these, 6 were significantly down-regulated in patients after correcting for genome wide significance (FDR<0.05), including 4 miRNAs that map to the 22q11.2 del region. In addition, a nominally significant increase in the expression of several miRNAs was found in the 22q11.2 neurons that were previously found to be differentially expressed in autopsy samples and peripheral blood in SZ and autism spectrum disorders (e.g., miR-34, miR-4449, miR-146b-3p, and miR-23a-5p). Pathway and function analysis of predicted mRNA targets of the differentially expressed miRNAs showed enrichment for genes involved in neurological disease and psychological disorders for both up and down regulated miRNAs. Our findings suggest that: i. neurons with 22q11.2 del recapitulate the miRNA expression patterns expected of 22q11.2 haploinsufficiency, ii. differentially expressed miRNAs previously identified using autopsy samples and peripheral cells, both of which have significant methodological problems, are indeed disrupted in neuropsychiatric disorders and likely have an underlying genetic basis.

Original languageEnglish (US)
Article numbere0132387
JournalPLoS One
Volume10
Issue number7
DOIs
StatePublished - Jul 14 2015

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Induced Pluripotent Stem Cells
Stem cells
MicroRNAs
microRNA
Psychotic Disorders
Neurons
Schizophrenia
neurons
necropsy
Genes
genes
Autopsy
sampling
genome
schizophrenia
induced pluripotent stem cells
blood
Haploinsufficiency
proteins
cells

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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MicroRNA profiling of neurons generated using induced pluripotent stem cells derived from patients with schizophrenia and schizoaffective disorder, and 22q11.2 del. / Zhao, Dejian; Lin, Mingyan; Chen, Jian; Pedrosa, Erika; Hrabovsky, Anastasia; Fourcade, H. Matthew; Zheng, Deyou; Lachman, Herbert M.

In: PLoS One, Vol. 10, No. 7, e0132387, 14.07.2015.

Research output: Contribution to journalArticle

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