title: Analyzing the Role of MicroRNAs in Schizophrenia in the Context of Common Genetic Risk Variants.
abstract: OBJECTIVE
  The recent implication of 108 genomic loci in schizophrenia marked a great advancement in our understanding of the disease. Against the background of its polygenic nature there is a necessity to identify how schizophrenia risk genes interplay. As regulators of gene expression, microRNAs (miRNAs) have repeatedly been implicated in schizophrenia etiology. It is therefore of interest to establish their role in the regulation of schizophrenia risk genes in disease-relevant biological processes.
  
  
  OBJECTIVE
  To examine the role of miRNAs in schizophrenia in the context of disease-associated genetic variation.
  
  
  METHODS
  The basis of this study was summary statistics from the largest schizophrenia genome-wide association study meta-analysis to date (83 550 individuals in a meta-analysis of 52 genome-wide association studies) completed in 2014 along with publicly available data for predicted miRNA targets. We examined whether schizophrenia risk genes were more likely to be regulated by miRNA. Further, we used gene set analyses to identify miRNAs that are regulators of schizophrenia risk genes.
  
  
  METHODS
  Results from association tests for miRNA targetomes and related analyses.
  
  
  RESULTS
  In line with previous studies, we found that similar to other complex traits, schizophrenia risk genes were more likely to be regulated by miRNAs (P < 2 × 10-16). Further, the gene set analyses revealed several miRNAs regulating schizophrenia risk genes, with the strongest enrichment for targets of miR-9-5p (P = .0056 for enrichment among the top 1% most-associated single-nucleotide polymorphisms, corrected for multiple testing). It is further of note that MIR9-2 is located in a genomic region showing strong evidence for association with schizophrenia (P = 7.1 × 10-8). The second and third strongest gene set signals were seen for the targets of miR-485-5p and miR-137, respectively.
  
  
  CONCLUSIONS
  This study provides evidence for a role of miR-9-5p in the etiology of schizophrenia. Its implication is of particular interest as the functions of this neurodevelopmental miRNA tie in with established disease biology: it has a regulatory loop with the fragile X mental retardation homologue FXR1 and regulates dopamine D2 receptor density.
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark2Lundbeck Foundation Initiative of Integrative Psychiatric Research, Lundbeck, Denmark3Centre for Integrative Sequencing, Aarhus University, Aarhus, Denmark.
authors.forename: Mads Engel
authors.initials: ME
authors.lastname: Hauberg
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York5Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York6Institute for Genomics and Multiscale Biology, Icahn School of M.
authors.forename: Panos
authors.initials: P
authors.lastname: Roussos
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark2Lundbeck Foundation Initiative of Integrative Psychiatric Research, Lundbeck, Denmark3Centre for Integrative Sequencing, Aarhus University, Aarhus, Denmark9Bioinformatics Research Centre, Aarhu.
authors.forename: Jakob
authors.initials: J
authors.lastname: Grove
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark2Lundbeck Foundation Initiative of Integrative Psychiatric Research, Lundbeck, Denmark3Centre for Integrative Sequencing, Aarhus University, Aarhus, Denmark10Research Department P, Aarhus Univer.
authors.forename: Anders Dupont
authors.initials: AD
authors.lastname: Børglum
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark2Lundbeck Foundation Initiative of Integrative Psychiatric Research, Lundbeck, Denmark3Centre for Integrative Sequencing, Aarhus University, Aarhus, Denmark.
authors.forename: Manuel
authors.initials: M
authors.lastname: Mattheisen
mesh_terms: D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D016601:RNA-Binding Proteins / Q000235:genetics; D012307:Risk Factors; D012559:Schizophrenia / Q000235:genetics*
chemical_list: D051860:Fragile X Messenger Ribonucleoprotein 1; D035683:MicroRNAs; D016601:RNA-Binding Proteins; C497683:FMR1 protein, human; C096916:FXR1 protein, human; C541874:MIRN92 microRNA, human