title: MicroRNA Dysregulation, Gene Networks, and Risk for Schizophrenia in 22q11.2 Deletion Syndrome.
abstract: The role of microRNAs (miRNAs) in the etiology of schizophrenia is increasingly recognized. Microdeletions at chromosome 22q11.2 are recurrent structural variants that impart a high risk for schizophrenia and are found in up to 1% of all patients with schizophrenia. The 22q11.2 deletion region overlaps gene DGCR8, encoding a subunit of the miRNA microprocessor complex. We identified miRNAs overlapped by the 22q11.2 microdeletion and for the first time investigated their predicted target genes, and those implicated by DGCR8, to identify targets that may be involved in the risk for schizophrenia. The 22q11.2 region encompasses seven validated or putative miRNA genes. Employing two standard prediction tools, we generated sets of predicted target genes. Functional enrichment profiles of the 22q11.2 region miRNA target genes suggested a role in neuronal processes and broader developmental pathways. We then constructed a protein interaction network of schizophrenia candidate genes and interaction partners relevant to brain function, independent of the 22q11.2 region miRNA mechanisms. We found that the predicted gene targets of the 22q11.2 deletion miRNAs, and targets of the genome-wide miRNAs predicted to be dysregulated by DGCR8 hemizygosity, were significantly represented in this schizophrenia network. The findings provide new insights into the pathway from 22q11.2 deletion to expression of schizophrenia, and suggest that hemizygosity of the 22q11.2 region may have downstream effects implicating genes elsewhere in the genome that are relevant to the general schizophrenia population. These data also provide further support for the notion that robust genetic findings in schizophrenia may converge on a reasonable number of final pathways.
authors.affiliation: The Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children , Toronto, ON , Canada.
authors.forename: Daniele
authors.initials: D
authors.lastname: Merico
authors.affiliation: Clinical Genetics Research Program, Centre for Addiction and Mental Health , Toronto, ON , Canada.
authors.forename: Gregory
authors.initials: G
authors.lastname: Costain
authors.affiliation: Clinical Genetics Research Program, Centre for Addiction and Mental Health , Toronto, ON , Canada ; Institute of Medical Science, University of Toronto , Toronto, ON , Canada.
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Butcher
authors.affiliation: Clinical Genetics Research Program, Centre for Addiction and Mental Health , Toronto, ON , Canada.
authors.forename: William
authors.initials: W
authors.lastname: Warnica
authors.affiliation: Clinical Genetics Research Program, Centre for Addiction and Mental Health , Toronto, ON , Canada.
authors.forename: Lucas
authors.initials: L
authors.lastname: Ogura
authors.affiliation: Clinical Genetics Research Program, Centre for Addiction and Mental Health , Toronto, ON , Canada.
authors.forename: Simon E
authors.initials: SE
authors.lastname: Alfred
authors.affiliation: Department of Genetics and the Human Genetics Institute of New Jersey, Rutgers University , Piscataway, NJ , USA.
authors.forename: Linda M
authors.initials: LM
authors.lastname: Brzustowicz
authors.affiliation: Clinical Genetics Research Program, Centre for Addiction and Mental Health , Toronto, ON , Canada ; Institute of Medical Science, University of Toronto , Toronto, ON , Canada ; The Dalglish Family Hearts and Minds Clinic for 22q11.2 Deletion Syndrome, Toronto General Hospital, University Health Network , Toronto, ON , Canada ; Department of Psychiatry, Toronto General Research Institute, University Health Network , Toronto, ON , Canada ; Department of Psychiatry, University of Toronto , Toronto, ON , Canada.
authors.forename: Anne S
authors.initials: AS
authors.lastname: Bassett
keywords: 22q11 deletion; 22q11.2; DGCR8; DiGeorge syndrome; miRNA; protein interaction network; schizophrenia; synapse