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J Psychiatry Neurosci. 2014 Nov;39(6):386-96.

Investigation of the involvement of MIR185 and its target genes in the development of schizophrenia.

Author information

  • 1The Institute of Human Genetics, University of Bonn, and the Department of Genomics, Life and Brain Center, Bonn, Germany.
  • 2The Department of Biomedicine, Human Genetics, and Centre for Integrative Sequencing, iSEQ, Aarhus University, the The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, and Copenhagen, Denmark, and the Department of Genomics Mathematics, University of Bonn, Germany.
  • 3The Section of Neonatal Screening and Hormones, Statens Serum Institute, Copenhagen, Denmark.
  • 4The Department of Medical Genetics, University Medical Centre Utrecht, Utrecht, the Netherlands.
  • 5The Institute of Human Genetics, University of Bonn, the Department of Genomics, Life and Brain Center, Bonn, Germany, and the Division of Medical Genetics, University Hospital Basel and Department of Biomedicine, University of Basel, Switzerland.
  • 6The Department of Psychiatry, University of Bonn, Germany.
  • 7The Department of Psychiatry, University of Halle-Wittenberg, Halle, Germany.
  • 8The Center for Neurobehavioral Genetics, University of California Los Angeles, USA and the Rudolf Magnus Institute of Neuroscience, Department of Psychiatry, University Medical Center, Utrecht, the Netherlands.
  • 9The Institute of Medical Informatics, Biometry and Epidemiology, University Duisburg-Essen, Essen, Germany.
  • 10The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus and Copenhagen, the National Centre for Register-based Research, Aarhus University, Aarhus, Denmark.
  • 11The Department of Biomedicine, Human Genetics, and Centre for Integrative Sequencing, iSEQ, Aarhus University, the The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus and Copenhagen, and the Centre for Psychiatric Research, Aarhus University Hospital, Risskov, Denmark.
  • 12Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Germany.
  • 13The Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Germany.
  • 14The Institute of Molecular Psychiatry, University of Bonn, Germany.
  • 15The Institute of Human Genetics, University of Bonn, the Department of Genomics, Life and Brain Center, Bonn, the Institute of Neuroscience and Medicine INM-1, Research Center Juelich, Germany and the Division of Medical Genetics, University Hospital Basel and Department of Biomedicine, University of Basel, Switzerland.

Abstract

BACKGROUND:

Schizophrenia is a complex neuropsychiatric disorder of unclear etiology. The strongest known genetic risk factor is the 22q11.2 microdeletion. Research has yet to confirm which genes within the deletion region are implicated in schizophrenia. The minimal 1.5 megabase deletion contains MIR185, which encodes microRNA 185.

METHODS:

We determined miR-185 expression in embryonic and adult mouse brains. Common and rare variants at this locus were then investigated using a human genetics approach. First, we performed gene-based analyses for MIR185 common variants and target genes using Psychiatric Genomics Consortium genome-wide association data. Second, MIR185 was resequenced in German patients (n = 1000) and controls (n = 500). We followed up promising variants by genotyping an additional European sample (patients, n = 3598; controls, n = 4082).

RESULTS:

In situ hybridization in mice revealed miR-185 expression in brain regions implicated in schizophrenia. Gene-based tests revealed association between common variants in 3 MIR185 target genes (ATAT1, SH3PXD2A, NTRK3) and schizophrenia. Further analyses in mice revealed overlapping expression patterns for these target genes and miR-185. Resequencing identified 2 rare patient-specific novel variants flanking MIR185. However, follow-up genotyping provided no further evidence of their involvement in schizophrenia.

LIMITATIONS:

Power to detect rare variant associations was limited.

CONCLUSION:

Human genetic analyses generated no evidence of the involvement of MIR185 in schizophrenia. However, the expression patterns of miR-185 and its target genes in mice, and the genetic association results for the 3 target genes, suggest that further research into the involvement of miR-185 and its downstream pathways in schizophrenia is warranted.

PMID:
24936775
[PubMed - indexed for MEDLINE]
PMCID:
PMC4214873
Free PMC Article
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