Original Investigation
April 2016

Analyzing the Role of MicroRNAs in Schizophrenia in the Context of Common Genetic Risk Variants

Author Affiliations
  • 1Department of Biomedicine, Aarhus University, Aarhus, Denmark
  • 2Lundbeck Foundation Initiative of Integrative Psychiatric Research, Lundbeck, Denmark
  • 3Centre for Integrative Sequencing, Aarhus University, Aarhus, Denmark
  • 4Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York
  • 5Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York
  • 6Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York
  • 7Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York
  • 8James J. Peters VA Medical Center, Mental Illness Research Education and Clinical Center, Bronx, New York
  • 9Bioinformatics Research Centre, Aarhus University, Aarhus, Denmark
  • 10Research Department P, Aarhus University Hospital, Risskov, Denmark
  • 11Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Denmark

Copyright 2016 American Medical Association. All Rights Reserved. Applicable FARS/DFARS Restrictions Apply to Government Use.

JAMA Psychiatry. 2016;73(4):369-377. doi:10.1001/jamapsychiatry.2015.3018

Importance  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.

Design, Setting, and Participants  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.

Main Outcomes and Measures  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 and Relevance  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.