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

Identifieur interne : 002642 ( PubMed/Curation ); précédent : 002641; suivant : 002643

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

Auteurs : A J Forstner [Allemagne] ; A. Hofmann [Allemagne] ; A. Maaser [Allemagne] ; S. Sumer [Allemagne] ; S. Khudayberdiev [Allemagne] ; T W Mühleisen [Allemagne] ; M. Leber [Allemagne] ; T G Schulze [Allemagne] ; J. Strohmaier [Allemagne] ; F. Degenhardt [Allemagne] ; J. Treutlein [Allemagne] ; M. Mattheisen [Danemark] ; J. Schumacher [Allemagne] ; R. Breuer [Allemagne] ; S. Meier [Allemagne] ; S. Herms [Allemagne] ; P. Hoffmann [Allemagne] ; A. Lacour [Allemagne] ; S H Witt [Allemagne] ; A. Reif [Allemagne] ; B. Müller-Myhsok [Allemagne] ; S. Lucae [Allemagne] ; W. Maier [Allemagne] ; M. Schwarz [Allemagne] ; H. Vedder [Allemagne] ; J. Kammerer-Ciernioch [Allemagne] ; A. Pfennig [Allemagne] ; M. Bauer [Allemagne] ; M. Hautzinger [Allemagne] ; S. Moebus [Allemagne] ; L. Priebe [Allemagne] ; S. Sivalingam [Allemagne] ; A. Verhaert [Allemagne] ; H. Schulz [Allemagne] ; P M Czerski [Pologne] ; J. Hauser [Pologne] ; J. Lissowska [Pologne] ; N. Szeszenia-Dabrowska [Pologne] ; P. Brennan [France] ; J D Mckay [France] ; A. Wright [Australie] ; P B Mitchell [Australie] ; J M Fullerton [Australie] ; P R Schofield [Australie] ; G W Montgomery [Australie] ; S E Medland [Australie] ; S D Gordon [Australie] ; N G Martin [Australie] ; V. Krasnov [Russie] ; A. Chuchalin [Russie] ; G. Babadjanova [Russie] ; G. Pantelejeva [Russie] ; L I Abramova [Russie] ; A S Tiganov [Russie] ; A. Polonikov [Russie] ; E. Khusnutdinova [Russie] ; M. Alda [Canada] ; C. Cruceanu [Canada] ; G A Rouleau [Canada] ; G. Turecki [Canada] ; C. Laprise [Canada] ; F. Rivas [Espagne] ; F. Mayoral [Espagne] ; M. Kogevinas [Espagne] ; M. Grigoroiu-Serbanescu [Roumanie] ; P. Propping [Allemagne] ; T. Becker [Allemagne] ; M. Rietschel [Allemagne] ; S. Cichon [Allemagne] ; G. Schratt [Allemagne] ; M M Nöthen [Allemagne]

Source :

RBID : pubmed:26556287

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English descriptors

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.

DOI: 10.1038/tp.2015.159
PubMed: 26556287

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<wicri:regionArea>Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim/University of Heidelberg, Heidelberg</wicri:regionArea>
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<name sortKey="Reif, A" sort="Reif, A" uniqKey="Reif A" first="A" last="Reif">A. Reif</name>
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<nlm:affiliation>Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt am Main, Frankfurt, Germany.</nlm:affiliation>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea>Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt am Main, Frankfurt</wicri:regionArea>
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<name sortKey="Muller Myhsok, B" sort="Muller Myhsok, B" uniqKey="Muller Myhsok B" first="B" last="Müller-Myhsok">B. Müller-Myhsok</name>
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<nlm:affiliation>Max Planck Institute of Psychiatry, Munich, Germany.</nlm:affiliation>
<country xml:lang="fr">Allemagne</country>
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<name sortKey="Lucae, S" sort="Lucae, S" uniqKey="Lucae S" first="S" last="Lucae">S. Lucae</name>
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<nlm:affiliation>Max Planck Institute of Psychiatry, Munich, Germany.</nlm:affiliation>
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<name sortKey="Maier, W" sort="Maier, W" uniqKey="Maier W" first="W" last="Maier">W. Maier</name>
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<nlm:affiliation>Department of Psychiatry, University of Bonn, Bonn, Germany.</nlm:affiliation>
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<name sortKey="Schwarz, M" sort="Schwarz, M" uniqKey="Schwarz M" first="M" last="Schwarz">M. Schwarz</name>
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<nlm:affiliation>Psychiatric Center Nordbaden, Wiesloch, Germany.</nlm:affiliation>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea>Psychiatric Center Nordbaden, Wiesloch</wicri:regionArea>
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<name sortKey="Vedder, H" sort="Vedder, H" uniqKey="Vedder H" first="H" last="Vedder">H. Vedder</name>
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<nlm:affiliation>Psychiatric Center Nordbaden, Wiesloch, Germany.</nlm:affiliation>
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<name sortKey="Kammerer Ciernioch, J" sort="Kammerer Ciernioch, J" uniqKey="Kammerer Ciernioch J" first="J" last="Kammerer-Ciernioch">J. Kammerer-Ciernioch</name>
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<nlm:affiliation>Center of Psychiatry Weinsberg, Weinsberg, Germany.</nlm:affiliation>
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<name sortKey="Pfennig, A" sort="Pfennig, A" uniqKey="Pfennig A" first="A" last="Pfennig">A. Pfennig</name>
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<nlm:affiliation>Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, TU Dresden, Dresden, Germany.</nlm:affiliation>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea>Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, TU Dresden, Dresden</wicri:regionArea>
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<name sortKey="Bauer, M" sort="Bauer, M" uniqKey="Bauer M" first="M" last="Bauer">M. Bauer</name>
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<nlm:affiliation>Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, TU Dresden, Dresden, Germany.</nlm:affiliation>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea>Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, TU Dresden, Dresden</wicri:regionArea>
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<name sortKey="Hautzinger, M" sort="Hautzinger, M" uniqKey="Hautzinger M" first="M" last="Hautzinger">M. Hautzinger</name>
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<nlm:affiliation>Department of Psychology, Clinical Psychology and Psychotherapy, Eberhard Karls University Tübingen, Tübingen, Germany.</nlm:affiliation>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea>Department of Psychology, Clinical Psychology and Psychotherapy, Eberhard Karls University Tübingen, Tübingen</wicri:regionArea>
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<name sortKey="Moebus, S" sort="Moebus, S" uniqKey="Moebus S" first="S" last="Moebus">S. Moebus</name>
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<nlm:affiliation>Institute of Medical Informatics, Biometry and Epidemiology, University Duisburg-Essen, Essen, Germany.</nlm:affiliation>
<country xml:lang="fr">Allemagne</country>
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<name sortKey="Priebe, L" sort="Priebe, L" uniqKey="Priebe L" first="L" last="Priebe">L. Priebe</name>
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<nlm:affiliation>Institute of Human Genetics, University of Bonn, Bonn, Germany.</nlm:affiliation>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea>Institute of Human Genetics, University of Bonn, Bonn</wicri:regionArea>
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<name sortKey="Sivalingam, S" sort="Sivalingam, S" uniqKey="Sivalingam S" first="S" last="Sivalingam">S. Sivalingam</name>
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<nlm:affiliation>Institute of Human Genetics, University of Bonn, Bonn, Germany.</nlm:affiliation>
<country xml:lang="fr">Allemagne</country>
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<name sortKey="Verhaert, A" sort="Verhaert, A" uniqKey="Verhaert A" first="A" last="Verhaert">A. Verhaert</name>
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<nlm:affiliation>Institute of Human Genetics, University of Bonn, Bonn, Germany.</nlm:affiliation>
<country xml:lang="fr">Allemagne</country>
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<name sortKey="Schulz, H" sort="Schulz, H" uniqKey="Schulz H" first="H" last="Schulz">H. Schulz</name>
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<nlm:affiliation>Cologne Center for Genomics, University of Cologne, Cologne, Germany.</nlm:affiliation>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea>Cologne Center for Genomics, University of Cologne, Cologne</wicri:regionArea>
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<name sortKey="Czerski, P M" sort="Czerski, P M" uniqKey="Czerski P" first="P M" last="Czerski">P M Czerski</name>
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<nlm:affiliation>Department of Psychiatry, Laboratory of Psychiatric Genetics, Poznan University of Medical Sciences, Poznan, Poland.</nlm:affiliation>
<country xml:lang="fr">Pologne</country>
<wicri:regionArea>Department of Psychiatry, Laboratory of Psychiatric Genetics, Poznan University of Medical Sciences, Poznan</wicri:regionArea>
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<author>
<name sortKey="Hauser, J" sort="Hauser, J" uniqKey="Hauser J" first="J" last="Hauser">J. Hauser</name>
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<nlm:affiliation>Department of Psychiatry, Laboratory of Psychiatric Genetics, Poznan University of Medical Sciences, Poznan, Poland.</nlm:affiliation>
<country xml:lang="fr">Pologne</country>
<wicri:regionArea>Department of Psychiatry, Laboratory of Psychiatric Genetics, Poznan University of Medical Sciences, Poznan</wicri:regionArea>
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<name sortKey="Lissowska, J" sort="Lissowska, J" uniqKey="Lissowska J" first="J" last="Lissowska">J. Lissowska</name>
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<nlm:affiliation>Department of Cancer Epidemiology and Prevention, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology Warsaw, Warsaw, Poland.</nlm:affiliation>
<country xml:lang="fr">Pologne</country>
<wicri:regionArea>Department of Cancer Epidemiology and Prevention, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology Warsaw, Warsaw</wicri:regionArea>
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<name sortKey="Szeszenia Dabrowska, N" sort="Szeszenia Dabrowska, N" uniqKey="Szeszenia Dabrowska N" first="N" last="Szeszenia-Dabrowska">N. Szeszenia-Dabrowska</name>
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<nlm:affiliation>Department of Epidemiology, Nofer Institute of Occupational Medicine, Lodz, Poland.</nlm:affiliation>
<country xml:lang="fr">Pologne</country>
<wicri:regionArea>Department of Epidemiology, Nofer Institute of Occupational Medicine, Lodz</wicri:regionArea>
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<name sortKey="Brennan, P" sort="Brennan, P" uniqKey="Brennan P" first="P" last="Brennan">P. Brennan</name>
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<nlm:affiliation>Genetic Epidemiology Group, International Agency for Research on Cancer, Lyon, France.</nlm:affiliation>
<country xml:lang="fr">France</country>
<wicri:regionArea>Genetic Epidemiology Group, International Agency for Research on Cancer, Lyon</wicri:regionArea>
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<name sortKey="Mckay, J D" sort="Mckay, J D" uniqKey="Mckay J" first="J D" last="Mckay">J D Mckay</name>
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<nlm:affiliation>Genetic Cancer Susceptibility Group, International Agency for Research on Cancer, Lyon, France.</nlm:affiliation>
<country xml:lang="fr">France</country>
<wicri:regionArea>Genetic Cancer Susceptibility Group, International Agency for Research on Cancer, Lyon</wicri:regionArea>
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<name sortKey="Wright, A" sort="Wright, A" uniqKey="Wright A" first="A" last="Wright">A. Wright</name>
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<nlm:affiliation>School of Psychiatry, University of New South Wales, Randwick, NSW, Australia.</nlm:affiliation>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>School of Psychiatry, University of New South Wales, Randwick, NSW</wicri:regionArea>
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<author>
<name sortKey="Mitchell, P B" sort="Mitchell, P B" uniqKey="Mitchell P" first="P B" last="Mitchell">P B Mitchell</name>
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<nlm:affiliation>School of Psychiatry, University of New South Wales, Randwick, NSW, Australia.</nlm:affiliation>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>School of Psychiatry, University of New South Wales, Randwick, NSW</wicri:regionArea>
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<country xml:lang="fr">Allemagne</country>
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<name sortKey="Schwarz, M" sort="Schwarz, M" uniqKey="Schwarz M" first="M" last="Schwarz">M. Schwarz</name>
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<author>
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<name sortKey="Bauer, M" sort="Bauer, M" uniqKey="Bauer M" first="M" last="Bauer">M. Bauer</name>
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<name sortKey="Szeszenia Dabrowska, N" sort="Szeszenia Dabrowska, N" uniqKey="Szeszenia Dabrowska N" first="N" last="Szeszenia-Dabrowska">N. Szeszenia-Dabrowska</name>
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<nlm:affiliation>Genetic Epidemiology Group, International Agency for Research on Cancer, Lyon, France.</nlm:affiliation>
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<nlm:affiliation>Genetic Cancer Susceptibility Group, International Agency for Research on Cancer, Lyon, France.</nlm:affiliation>
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<name sortKey="Wright, A" sort="Wright, A" uniqKey="Wright A" first="A" last="Wright">A. Wright</name>
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<nlm:affiliation>School of Psychiatry, University of New South Wales, Randwick, NSW, Australia.</nlm:affiliation>
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<nlm:affiliation>School of Psychiatry, University of New South Wales, Randwick, NSW, Australia.</nlm:affiliation>
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<nlm:affiliation>Queensland Institute of Medical Research, Brisbane, QLD, Australia.</nlm:affiliation>
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<nlm:affiliation>Queensland Institute of Medical Research, Brisbane, QLD, Australia.</nlm:affiliation>
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<nlm:affiliation>Queensland Institute of Medical Research, Brisbane, QLD, Australia.</nlm:affiliation>
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<name sortKey="Martin, N G" sort="Martin, N G" uniqKey="Martin N" first="N G" last="Martin">N G Martin</name>
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<nlm:affiliation>Queensland Institute of Medical Research, Brisbane, QLD, Australia.</nlm:affiliation>
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<name sortKey="Krasnov, V" sort="Krasnov, V" uniqKey="Krasnov V" first="V" last="Krasnov">V. Krasnov</name>
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<nlm:affiliation>Moscow Research Institute of Psychiatry, Moscow, Russian Federation.</nlm:affiliation>
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<name sortKey="Chuchalin, A" sort="Chuchalin, A" uniqKey="Chuchalin A" first="A" last="Chuchalin">A. Chuchalin</name>
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<nlm:affiliation>Institute of Pulmonology, Russian State Medical University, Moscow, Russian Federation.</nlm:affiliation>
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<name sortKey="Babadjanova, G" sort="Babadjanova, G" uniqKey="Babadjanova G" first="G" last="Babadjanova">G. Babadjanova</name>
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<nlm:affiliation>Institute of Pulmonology, Russian State Medical University, Moscow, Russian Federation.</nlm:affiliation>
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<name sortKey="Pantelejeva, G" sort="Pantelejeva, G" uniqKey="Pantelejeva G" first="G" last="Pantelejeva">G. Pantelejeva</name>
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<nlm:affiliation>Russian Academy of Medical Sciences, Mental Health Research Center, Moscow, Russian Federation.</nlm:affiliation>
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<name sortKey="Abramova, L I" sort="Abramova, L I" uniqKey="Abramova L" first="L I" last="Abramova">L I Abramova</name>
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<nlm:affiliation>Russian Academy of Medical Sciences, Mental Health Research Center, Moscow, Russian Federation.</nlm:affiliation>
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<name sortKey="Tiganov, A S" sort="Tiganov, A S" uniqKey="Tiganov A" first="A S" last="Tiganov">A S Tiganov</name>
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<country xml:lang="fr">Russie</country>
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<name sortKey="Khusnutdinova, E" sort="Khusnutdinova, E" uniqKey="Khusnutdinova E" first="E" last="Khusnutdinova">E. Khusnutdinova</name>
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<country xml:lang="fr">Russie</country>
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<nlm:affiliation>Montreal Neurological Institute, McGill University, Montreal, QC, Canada.</nlm:affiliation>
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<name sortKey="Turecki, G" sort="Turecki, G" uniqKey="Turecki G" first="G" last="Turecki">G. Turecki</name>
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<nlm:affiliation>Department of Human Genetics, McGill University, Montreal, QC, Canada.</nlm:affiliation>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Department of Human Genetics, McGill University, Montreal, QC</wicri:regionArea>
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<name sortKey="Laprise, C" sort="Laprise, C" uniqKey="Laprise C" first="C" last="Laprise">C. Laprise</name>
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<nlm:affiliation>Département des sciences fondamentales, Université du Québec à Chicoutimi (UQAC), Chicoutimi, QC, Canada.</nlm:affiliation>
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<name sortKey="Rivas, F" sort="Rivas, F" uniqKey="Rivas F" first="F" last="Rivas">F. Rivas</name>
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<nlm:affiliation>Department of Psychiatry, Hospital Regional Universitario, Biomedical Institute of Malaga, Malaga, Spain.</nlm:affiliation>
<country xml:lang="fr">Espagne</country>
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<name sortKey="Mayoral, F" sort="Mayoral, F" uniqKey="Mayoral F" first="F" last="Mayoral">F. Mayoral</name>
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<nlm:affiliation>Department of Psychiatry, Hospital Regional Universitario, Biomedical Institute of Malaga, Malaga, Spain.</nlm:affiliation>
<country xml:lang="fr">Espagne</country>
<wicri:regionArea>Department of Psychiatry, Hospital Regional Universitario, Biomedical Institute of Malaga, Malaga</wicri:regionArea>
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<nlm:affiliation>Center for Research in Environmental Epidemiology, Barcelona, Spain.</nlm:affiliation>
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<nlm:affiliation>Biometric Psychiatric Genetics Research Unit, Alexandru Obregia Clinical Psychiatric Hospital, Bucharest, Romania.</nlm:affiliation>
<country xml:lang="fr">Roumanie</country>
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<nlm:affiliation>Institute of Human Genetics, University of Bonn, Bonn, Germany.</nlm:affiliation>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea>Institute of Human Genetics, University of Bonn, Bonn</wicri:regionArea>
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<nlm:affiliation>Institute for Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany.</nlm:affiliation>
<country xml:lang="fr">Allemagne</country>
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<country xml:lang="fr">Allemagne</country>
<wicri:regionArea>Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim/University of Heidelberg, Heidelberg</wicri:regionArea>
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<nlm:affiliation>Institute of Human Genetics, University of Bonn, Bonn, Germany.</nlm:affiliation>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea>Institute of Human Genetics, University of Bonn, Bonn</wicri:regionArea>
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<nlm:affiliation>Institute of Physiological Chemistry, Philipps-University Marburg, Marburg, Germany.</nlm:affiliation>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea>Institute of Physiological Chemistry, Philipps-University Marburg, Marburg</wicri:regionArea>
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<nlm:affiliation>Institute of Human Genetics, University of Bonn, Bonn, Germany.</nlm:affiliation>
<country xml:lang="fr">Allemagne</country>
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<title level="j">Translational psychiatry</title>
<idno type="eISSN">2158-3188</idno>
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<date when="2015" type="published">2015</date>
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<term>Genetic Predisposition to Disease (genetics)</term>
<term>Genome-Wide Association Study (statistics & numerical data)</term>
<term>Humans</term>
<term>MicroRNAs (genetics)</term>
<term>Rats</term>
<term>Rats, Sprague-Dawley</term>
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<term>Animaux</term>
<term>Humains</term>
<term>Modèles animaux de maladie humaine</term>
<term>Prédisposition génétique à une maladie (génétique)</term>
<term>Rat Sprague-Dawley</term>
<term>Rats</term>
<term>Trouble bipolaire (génétique)</term>
<term>microARN (génétique)</term>
<term>Étude d'association pangénomique ()</term>
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<term>MicroRNAs</term>
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<term>Bipolar Disorder</term>
<term>Genetic Predisposition to Disease</term>
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<term>Prédisposition génétique à une maladie</term>
<term>Trouble bipolaire</term>
<term>microARN</term>
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<term>Genome-Wide Association Study</term>
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<term>Disease Models, Animal</term>
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<term>Rats, Sprague-Dawley</term>
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<term>Animaux</term>
<term>Humains</term>
<term>Modèles animaux de maladie humaine</term>
<term>Rat Sprague-Dawley</term>
<term>Rats</term>
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<div type="abstract" xml:lang="en">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.</div>
</front>
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<DateCreated>
<Year>2015</Year>
<Month>11</Month>
<Day>11</Day>
</DateCreated>
<DateCompleted>
<Year>2016</Year>
<Month>07</Month>
<Day>19</Day>
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<DateRevised>
<Year>2017</Year>
<Month>02</Month>
<Day>20</Day>
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<ISSN IssnType="Electronic">2158-3188</ISSN>
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<Volume>5</Volume>
<PubDate>
<Year>2015</Year>
<Month>Nov</Month>
<Day>10</Day>
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<Title>Translational psychiatry</Title>
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<ArticleTitle>Genome-wide analysis implicates microRNAs and their target genes in the development of bipolar disorder.</ArticleTitle>
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<AbstractText>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.</AbstractText>
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