title: Human microRNAs miR-22, miR-138-2, miR-148a, and miR-488 are associated with panic disorder and regulate several anxiety candidate genes and related pathways.
abstract: BACKGROUND
  The involvement of microRNAs (miRNAs) in neuronal differentiation and synaptic plasticity suggests a role for miRNAs in psychiatric disorders; association analyses and functional approaches were used to evaluate the implication of miRNAs in the susceptibility for panic disorder.
  
  
  METHODS
  Case-control studies for 712 single-nucleotide polymorphisms (SNPs) tagging 325 human miRNA regions were performed in 203 Spanish patients with panic disorder and 341 control subjects. A sample of 321 anxiety patients and 642 control subjects from Finland and 102 panic disorder patients and 829 control subjects from Estonia was used as a replica. Reporter-gene assays and miRNA overexpression experiments in neuroblastoma cells were used to functionally evaluate the spectrum of genes regulated by the associated miRNAs.
  
  
  RESULTS
  Two SNPs associated with panic disorder: rs6502892 tagging miR-22 (p < .0002), and rs11763020 tagging miR-339 (p < .00008). Other SNPs tagging miR-138-2, miR-488, miR-491, and miR-148a regions associated with different panic disorder phenotypes. Replication in the north-European sample supported several of these associations, although they did not pass correction for multiple testing. Functional studies revealed that miR-138-2, miR-148a, and miR-488 repress (30%-60%) several candidate genes for panic disorder--GABRA6, CCKBR and POMC, respectively--and that miR-22 regulates four other candidate genes: BDNF, HTR2C, MAOA, and RGS2. Transcriptome analysis of neuroblastoma cells transfected with miR-22 and miR-488 showed altered expression of a subset of predicted target genes for these miRNAs and of genes that might be affecting physiological pathways related to anxiety.
  
  
  CONCLUSIONS
  This work represents the first report of a possible implication of miRNAs in the etiology of panic disorder.
authors.affiliation: Genes and Disease Program, Centre for Genomic Regulation (CRG), Public Health and Epidemiology Network Biomedical Research Center (CIBERESP), Barcelona, Catalonia, Spain.
authors.forename: Margarita
authors.initials: M
authors.lastname: Muiños-Gimeno
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Espinosa-Parrilla
authors.forename: Monica
authors.initials: M
authors.lastname: Guidi
authors.forename: Birgit
authors.initials: B
authors.lastname: Kagerbauer
authors.forename: Tessa
authors.initials: T
authors.lastname: Sipilä
authors.forename: Eduard
authors.initials: E
authors.lastname: Maron
authors.forename: Kristi
authors.initials: K
authors.lastname: Pettai
authors.forename: Laura
authors.initials: L
authors.lastname: Kananen
authors.forename: Ricard
authors.initials: R
authors.lastname: Navinés
authors.forename: Rocío
authors.initials: R
authors.lastname: Martín-Santos
authors.forename: Mònica
authors.initials: M
authors.lastname: Gratacòs
authors.forename: Andres
authors.initials: A
authors.lastname: Metspalu
authors.forename: Iiris
authors.initials: I
authors.lastname: Hovatta
authors.forename: Xavier
authors.initials: X
authors.lastname: Estivill
mesh_terms: D000328:Adult; D001007:Anxiety / Q000235:genetics*; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D003431:Cross-Cultural Comparison; D004957:Estonia; D005260:Female; D005387:Finland; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000235:genetics; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study / Q000379:methods; D005838:Genotype; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D008995:Monoamine Oxidase / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009447:Neuroblastoma / Q000473:pathology; D016584:Panic Disorder / Q000208:ethnology / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011333:Pro-Opiomelanocortin / Q000235:genetics / Q000378:metabolism; D020710:RGS Proteins / Q000235:genetics / Q000378:metabolism; D011949:Receptors, Cholecystokinin / Q000235:genetics / Q000378:metabolism; D011963:Receptors, GABA-A / Q000378:metabolism; D044348:Receptors, Serotonin, 5-HT2 / Q000235:genetics / Q000378:metabolism; D013030:Spain; D014162:Transfection; D055815:Young Adult
chemical_list: C546171:GABRA6 protein, human; C546110:MIRN138 microRNA, human; C548375:MIRN22 microRNA, human; D035683:MicroRNAs; D009419:Nerve Tissue Proteins; D020710:RGS Proteins; C087182:RGS2 protein, human; D011949:Receptors, Cholecystokinin; D011963:Receptors, GABA-A; D044348:Receptors, Serotonin, 5-HT2; D011333:Pro-Opiomelanocortin; D008995:Monoamine Oxidase