title: MicroRNA Profiling of Neurons Generated Using Induced Pluripotent Stem Cells Derived from Patients with Schizophrenia and Schizoaffective Disorder, and 22q11.2 Del.
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.
authors.affiliation: Department of Neurology, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, New York, United States of America.
authors.forename: Dejian
authors.initials: D
authors.lastname: Zhao
authors.affiliation: Department of Genetics, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, New York, United States of America.
authors.forename: Mingyan
authors.initials: M
authors.lastname: Lin
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, New York, United States of America.
authors.forename: Jian
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, New York, United States of America.
authors.forename: Erika
authors.initials: E
authors.lastname: Pedrosa
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, New York, United States of America.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Hrabovsky
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, New York, United States of America.
authors.forename: H Matthew
authors.initials: HM
authors.lastname: Fourcade
authors.affiliation: Department of Neurology, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, New York, United States of America; Department of Genetics, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, New York, United States of America; Department of Neuroscience, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, New York, United States of America.
authors.forename: Deyou
authors.initials: D
authors.lastname: Zheng
authors.affiliation: Department of Genetics, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, New York, United States of America; Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, New York, United States of America; Department of Neuroscience, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, New York, United States of America; Department of Medicine, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, New York, United States of America.
authors.forename: Herbert M
authors.initials: HM
authors.lastname: Lachman
mesh_terms: D000328:Adult; D002872:Chromosome Deletion; D002892:Chromosomes, Human, Pair 22 / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000473:pathology; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D011618:Psychotic Disorders / Q000235:genetics* / Q000473:pathology; D012559:Schizophrenia / Q000235:genetics* / Q000473:pathology; D017423:Sequence Analysis, RNA
chemical_list: D035683:MicroRNAs