Elsevier

Biological Psychiatry

Volume 69, Issue 6, 15 March 2011, Pages 526-533
Biological Psychiatry

Archival Report
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

https://doi.org/10.1016/j.biopsych.2010.10.010Get rights and content

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.

Section snippets

Spanish Sample

Between 2001 and 2006, 203 consecutive adult Spanish outpatients (mean age 35.89 ± 9.74 years, 151 women; mean age of PD onset 29.44 ± 9.44 years) with PD recruited from the psychiatry unit in Hospital del Mar (Barcelona) were studied. The diagnosis of PD was independently assigned by two senior psychiatrists with the Structured Clinical Interview for DSM-IV Disorders—Clinician Version. Concurrent agoraphobia was present in 135 (66.5%) patients. Exclusion criteria were age under 18, organic

Association of miRNA Regions with PD in the Spanish Population

Case-control studies in 203 patients with PD and 341 control subjects from Spain were performed for the 712 SNPs in the miRNA SNP panel that passed quality control criteria. As shown in Table 1, the strongest association was found for rs11763020, an SNP tagging miR-339, which remained significant after correction for the 712 SNPs tested (unadjusted p = .00008) but not after correction for the different genetic models analyzed. Besides miR-339, two SNPs tagging miR-22 were also found to

Discussion

Increasing evidence indicates that genetic variation in regulatory regions could be a major contributor to phenotypic diversity in human populations (37, 38). This might be particularly true in the case of psychiatric disorders; changes in regulatory elements leading to small variations in the dosage of proteins involved in neuronal pathways might disrupt the fine-tuned equilibrium of complex brain functions and contribute to the development of psychiatric disorders. Recently, miRNAs have

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  • Cited by (0)

    Authors MM-G and YE-P contributed equally to this work.

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