title: Copy number variable microRNAs in schizophrenia and their neurodevelopmental gene targets.
abstract: BACKGROUND
  MicroRNAs (miRNAs) are key regulators of gene expression in the human genome and may contribute to risk for neuropsychiatric disorders. miRNAs play an acknowledged role in the strongest of genetic risk factors for schizophrenia, 22q11.2 deletions. We hypothesized that in schizophrenia there would be an enrichment of other rare copy number variants (CNVs) that overlap miRNAs.
  
  
  METHODS
  Using high-resolution genome-wide microarrays and rigorous methods, we compared the miRNA content of rare CNVs in well-characterized cohorts of schizophrenia cases (n = 420) and comparison subjects, excluding 22q11.2 CNVs. We also performed a gene-set enrichment analysis of the predicted miRNA target genes.
  
  
  RESULTS
  The schizophrenia group was enriched for the proportion of individuals with a rare CNV overlapping a miRNA (3.29-fold increase over comparison subjects, p < .0001). The presence of a rare CNV overlapping a miRNA remained a significant predictor of schizophrenia case status (p = .0072) in a multivariate logistic regression model correcting for total CNV size. In contrast, comparable analyses correcting for CNV size showed no enrichment of rare CNVs overlapping protein-coding genes. A gene-set enrichment analysis indicated that predicted target genes of recurrent CNV-overlapped miRNAs in schizophrenia may be functionally enriched for neurodevelopmental processes, including axonogenesis and neuron projection development. Predicted gene targets driving these results included CAPRIN1, NEDD4, NTRK2, PAK2, RHOA, and SYNGAP1.
  
  
  CONCLUSIONS
  These data are the first to demonstrate a genome-wide role for CNVs overlapping miRNAs in the genetic risk for schizophrenia. The results provide support for an expanded multihit model of causation, with potential implications for miRNA-based therapeutics.
authors.affiliation: Clinical Genetics Research Program, Centre for Addiction and Mental Health, Ontario, Canada.
authors.forename: William
authors.initials: W
authors.lastname: Warnica
authors.affiliation: The Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children, Ontario, Canada.
authors.forename: Daniele
authors.initials: D
authors.lastname: Merico
authors.affiliation: Clinical Genetics Research Program, Centre for Addiction and Mental Health, Ontario, Canada.
authors.forename: Gregory
authors.initials: G
authors.lastname: Costain
authors.affiliation: Clinical Genetics Research Program, Centre for Addiction and Mental Health, Ontario, Canada.
authors.forename: Simon E
authors.initials: SE
authors.lastname: Alfred
authors.affiliation: The Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children, Ontario, Canada; Department of Molecular Genetics and McLaughlin Centre, Ontario, Canada.
authors.forename: John
authors.initials: J
authors.lastname: Wei
authors.affiliation: The Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children, Ontario, Canada; Department of Molecular Genetics and McLaughlin Centre, Ontario, Canada.
authors.forename: Christian R
authors.initials: CR
authors.lastname: Marshall
authors.affiliation: The Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children, Ontario, Canada; Department of Molecular Genetics and McLaughlin Centre, Ontario, Canada.
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Scherer
authors.affiliation: Clinical Genetics Research Program, Centre for Addiction and Mental Health, Ontario, Canada; Department of Psychiatry, University of Toronto, Ontario, Canada; Department of Psychiatry, University Health Network, Toronto, Ontario, Canada; Division of Cardiology, Department of Medicine, University Health Network, Toronto, Ontario, Canada. Electronic address: anne.bassett@utoronto.ca.
authors.forename: Anne S
authors.initials: AS
authors.lastname: Bassett
mesh_terms: D056915:DNA Copy Number Variations; D020022:Genetic Predisposition to Disease; D060005:Genotyping Techniques; D006801:Humans; D016015:Logistic Models; D035683:MicroRNAs; D046228:Microarray Analysis; D015999:Multivariate Analysis; D011446:Prospective Studies; D012559:Schizophrenia / Q000235:genetics*; D044465:White People / Q000235:genetics
chemical_list: D035683:MicroRNAs
keywords: 16p13.11; CAPRIN1; Copy number variation; MicroRNA; NEDD4; NTRK2; PAK2; RHOA; SYNGAP1; Schizophrenia