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Transl Psychiatry. 2015 Nov 10;5:e678. doi: 10.1038/tp.2015.159.

Genome-wide analysis implicates microRNAs and their target genes in the development of bipolar disorder.

Author information

1
Institute of Human Genetics, University of Bonn, Bonn, Germany.
2
Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
3
Institute of Physiological Chemistry, Philipps-University Marburg, Marburg, Germany.
4
Institute of Neuroscience and Medicine, Research Center Juelich, Juelich, Germany.
5
Institute for Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany.
6
Institute of Psychiatric Phenomics and Genomics, Ludwig-Maximilians-University Munich, Munich, Germany.
7
Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim/University of Heidelberg, Heidelberg, Germany.
8
Department of Biomedicine, Aarhus University, Aarhus, Denmark.
9
Institute for Genomics Mathematics, University of Bonn, Bonn, Germany.
10
National Center Register-Based Research, Aarhus University, Aarhus, Denmark.
11
Division of Medical Genetics, Department of Biomedicine, University of Basel, Basel, Switzerland.
12
German Center for Neurodegenerative Diseases, Bonn, Germany.
13
Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt am Main, Frankfurt, Germany.
14
Max Planck Institute of Psychiatry, Munich, Germany.
15
Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
16
University of Liverpool, Institute of Translational Medicine, Liverpool, UK.
17
Department of Psychiatry, University of Bonn, Bonn, Germany.
18
Psychiatric Center Nordbaden, Wiesloch, Germany.
19
Center of Psychiatry Weinsberg, Weinsberg, Germany.
20
Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, TU Dresden, Dresden, Germany.
21
Department of Psychology, Clinical Psychology and Psychotherapy, Eberhard Karls University Tübingen, Tübingen, Germany.
22
Institute of Medical Informatics, Biometry and Epidemiology, University Duisburg-Essen, Essen, Germany.
23
Cologne Center for Genomics, University of Cologne, Cologne, Germany.
24
Department of Psychiatry, Laboratory of Psychiatric Genetics, Poznan University of Medical Sciences, Poznan, Poland.
25
Department of Cancer Epidemiology and Prevention, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology Warsaw, Warsaw, Poland.
26
Department of Epidemiology, Nofer Institute of Occupational Medicine, Lodz, Poland.
27
Genetic Epidemiology Group, International Agency for Research on Cancer, Lyon, France.
28
Genetic Cancer Susceptibility Group, International Agency for Research on Cancer, Lyon, France.
29
School of Psychiatry, University of New South Wales, Randwick, NSW, Australia.
30
Black Dog Institute, Prince of Wales Hospital, Randwick, NSW, Australia.
31
Neuroscience Research Australia, Sydney, NSW, Australia.
32
School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia.
33
Queensland Institute of Medical Research, Brisbane, QLD, Australia.
34
Moscow Research Institute of Psychiatry, Moscow, Russian Federation.
35
Institute of Pulmonology, Russian State Medical University, Moscow, Russian Federation.
36
Russian Academy of Medical Sciences, Mental Health Research Center, Moscow, Russian Federation.
37
Department of Biology, Medical Genetics and Ecology, Kursk State Medical University, Kursk, Russian Federation.
38
Institute of Biochemistry and Genetics, Ufa Scientific Center of Russian Academy of Sciences, Ufa, Russian Federation.
39
Department of Genetics and Fundamental Medicine, Bashkir State University, Ufa, Russian Federation.
40
Department of Psychiatry, Dalhousie University, Halifax, NS, Canada.
41
National Institute of Mental Health, Klecany, Czech Republic.
42
Montreal Neurological Institute, McGill University, Montreal, QC, Canada.
43
Department of Human Genetics, McGill University, Montreal, QC, Canada.
44
McGill Group for Suicide Studies and Douglas Research Institute, Montreal, QC, Canada.
45
Department of Psychiatry, McGill University, Montreal, QC, Canada.
46
Département des sciences fondamentales, Université du Québec à Chicoutimi (UQAC), Chicoutimi, QC, Canada.
47
Department of Psychiatry, Hospital Regional Universitario, Biomedical Institute of Malaga, Malaga, Spain.
48
Center for Research in Environmental Epidemiology, Barcelona, Spain.
49
Biometric Psychiatric Genetics Research Unit, Alexandru Obregia Clinical Psychiatric Hospital, Bucharest, Romania.

Abstract

Bipolar disorder (BD) is a severe and highly heritable neuropsychiatric disorder with a lifetime prevalence of 1%. Molecular genetic studies have identified the first BD susceptibility genes. However, the disease pathways remain largely unknown. Accumulating evidence suggests that microRNAs, a class of small noncoding RNAs, contribute to basic mechanisms underlying brain development and plasticity, suggesting their possible involvement in the pathogenesis of several psychiatric disorders, including BD. In the present study, gene-based analyses were performed for all known autosomal microRNAs using the largest genome-wide association data set of BD to date (9747 patients and 14 278 controls). Associated and brain-expressed microRNAs were then investigated in target gene and pathway analyses. Functional analyses of miR-499 and miR-708 were performed in rat hippocampal neurons. Ninety-eight of the six hundred nine investigated microRNAs showed nominally significant P-values, suggesting that BD-associated microRNAs might be enriched within known microRNA loci. After correction for multiple testing, nine microRNAs showed a significant association with BD. The most promising were miR-499, miR-708 and miR-1908. Target gene and pathway analyses revealed 18 significant canonical pathways, including brain development and neuron projection. For miR-499, four Bonferroni-corrected significant target genes were identified, including the genome-wide risk gene for psychiatric disorder CACNB2. First results of functional analyses in rat hippocampal neurons neither revealed nor excluded a major contribution of miR-499 or miR-708 to dendritic spine morphogenesis. The present results suggest that research is warranted to elucidate the precise involvement of microRNAs and their downstream pathways in BD.

PMID:
26556287
PMCID:
PMC5068755
DOI:
10.1038/tp.2015.159
[Indexed for MEDLINE]
Free PMC Article

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