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

Biol Psychiatry. 2011 Mar 15;69(6):526-33. doi: 10.1016/j.biopsych.2010.10.010. Epub 2010 Dec 17.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Anxiety / genetics*
  • Case-Control Studies
  • Cell Line, Tumor
  • Cross-Cultural Comparison
  • Estonia
  • Female
  • Finland
  • Gene Expression Profiling / methods
  • Gene Expression Regulation / genetics
  • Genetic Predisposition to Disease*
  • Genome-Wide Association Study / methods
  • Genotype
  • Humans
  • Male
  • MicroRNAs / genetics*
  • Middle Aged
  • Monoamine Oxidase / genetics
  • Monoamine Oxidase / metabolism
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Neuroblastoma / pathology
  • Panic Disorder / ethnology
  • Panic Disorder / genetics*
  • Polymorphism, Single Nucleotide / genetics*
  • Pro-Opiomelanocortin / genetics
  • Pro-Opiomelanocortin / metabolism
  • RGS Proteins / genetics
  • RGS Proteins / metabolism
  • Receptors, Cholecystokinin / genetics
  • Receptors, Cholecystokinin / metabolism
  • Receptors, GABA-A / metabolism
  • Receptors, Serotonin, 5-HT2 / genetics
  • Receptors, Serotonin, 5-HT2 / metabolism
  • Spain
  • Transfection
  • Young Adult


  • GABRA6 protein, human
  • MIRN138 microRNA, human
  • MIRN22 microRNA, human
  • MicroRNAs
  • Nerve Tissue Proteins
  • RGS Proteins
  • RGS2 protein, human
  • Receptors, Cholecystokinin
  • Receptors, GABA-A
  • Receptors, Serotonin, 5-HT2
  • Pro-Opiomelanocortin
  • Monoamine Oxidase