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

A. J. Forstner, A. Hofmann, A. Maaser, S. Sumer, S. Khudayberdiev, T. W. Mühleisen, M. Leber, T. G. Schulze, J. Strohmaier, F. Degenhardt, J. Treutlein, M. Mattheisen, J. Schumacher, R. Breuer, S. Meier, S. Herms, P. Hoffmann, A. Lacour, S. H. Witt, A. Reif & 51 others B. Müller-Myhsok, S. Lucae, W. Maier, M. Schwarz, H. Vedder, J. Kammerer-Ciernioch, A. Pfennig, M. Bauer, M. Hautzinger, S. Moebus, L. Priebe, S. Sivalingam, A. Verhaert, H. Schulz, P. M. Czerski, J. Hauser, J. Lissowska, N. Szeszenia-Dabrowska, P. Brennan, J. D. McKay, A. Wright, P. B. Mitchell, J. M. Fullerton, P. R. Schofield, G. W. Montgomery, S. E. Medland, S. D. Gordon, N. G. Martin, V. Krasnov, A. Chuchalin, G. Babadjanova, G. Pantelejeva, L. I. Abramova, A. S. Tiganov, A. Polonikov, E. Khusnutdinova, M. Alda, C. Cruceanu, G. A. Rouleau, G. Turecki, C. Laprise, F. Rivas, F. Mayoral, M. Kogevinas, M. Grigoroiu-Serbanescu, P. Propping, T. Becker, M. Rietsche, S. Cichon, G. Schratt, M. M. Nöthen

Research output: Contribution to journalArticle

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 BDassociated 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.

Original languageEnglish (US)
Article numbere678
JournalTranslational Psychiatry
Volume5
Issue number11
DOIs
StatePublished - Nov 24 2015
Externally publishedYes

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MicroRNAs
Bipolar Disorder
Genome
Genes
Neurons
Psychiatry
Brain
Small Untranslated RNA
Dendritic Spines
Morphogenesis
Molecular Biology
Research

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Psychiatry and Mental health
  • Biological Psychiatry

Cite this

Forstner, A. J., Hofmann, A., Maaser, A., Sumer, S., Khudayberdiev, S., Mühleisen, T. W., ... Nöthen, M. M. (2015). Genome-wide analysis implicates microRNAs and their target genes in the development of bipolar disorder. Translational Psychiatry, 5(11), [e678]. https://doi.org/10.1038/tp.2015.159

Genome-wide analysis implicates microRNAs and their target genes in the development of bipolar disorder. / Forstner, A. J.; Hofmann, A.; Maaser, A.; Sumer, S.; Khudayberdiev, S.; Mühleisen, T. W.; Leber, M.; Schulze, T. G.; Strohmaier, J.; Degenhardt, F.; Treutlein, J.; Mattheisen, M.; Schumacher, J.; Breuer, R.; Meier, S.; Herms, S.; Hoffmann, P.; Lacour, A.; Witt, S. H.; Reif, A.; Müller-Myhsok, B.; Lucae, S.; Maier, W.; Schwarz, M.; Vedder, H.; Kammerer-Ciernioch, J.; Pfennig, A.; Bauer, M.; Hautzinger, M.; Moebus, S.; Priebe, L.; Sivalingam, S.; Verhaert, A.; Schulz, H.; Czerski, P. M.; Hauser, J.; Lissowska, J.; Szeszenia-Dabrowska, N.; Brennan, P.; McKay, J. D.; Wright, A.; Mitchell, P. B.; Fullerton, J. M.; Schofield, P. R.; Montgomery, G. W.; Medland, S. E.; Gordon, S. D.; Martin, N. G.; Krasnov, V.; Chuchalin, A.; Babadjanova, G.; Pantelejeva, G.; Abramova, L. I.; Tiganov, A. S.; Polonikov, A.; Khusnutdinova, E.; Alda, M.; Cruceanu, C.; Rouleau, G. A.; Turecki, G.; Laprise, C.; Rivas, F.; Mayoral, F.; Kogevinas, M.; Grigoroiu-Serbanescu, M.; Propping, P.; Becker, T.; Rietsche, M.; Cichon, S.; Schratt, G.; Nöthen, M. M.

In: Translational Psychiatry, Vol. 5, No. 11, e678, 24.11.2015.

Research output: Contribution to journalArticle

Forstner, AJ, Hofmann, A, Maaser, A, Sumer, S, Khudayberdiev, S, Mühleisen, TW, Leber, M, Schulze, TG, Strohmaier, J, Degenhardt, F, Treutlein, J, Mattheisen, M, Schumacher, J, Breuer, R, Meier, S, Herms, S, Hoffmann, P, Lacour, A, Witt, SH, Reif, A, Müller-Myhsok, B, Lucae, S, Maier, W, Schwarz, M, Vedder, H, Kammerer-Ciernioch, J, Pfennig, A, Bauer, M, Hautzinger, M, Moebus, S, Priebe, L, Sivalingam, S, Verhaert, A, Schulz, H, Czerski, PM, Hauser, J, Lissowska, J, Szeszenia-Dabrowska, N, Brennan, P, McKay, JD, Wright, A, Mitchell, PB, Fullerton, JM, Schofield, PR, Montgomery, GW, Medland, SE, Gordon, SD, Martin, NG, Krasnov, V, Chuchalin, A, Babadjanova, G, Pantelejeva, G, Abramova, LI, Tiganov, AS, Polonikov, A, Khusnutdinova, E, Alda, M, Cruceanu, C, Rouleau, GA, Turecki, G, Laprise, C, Rivas, F, Mayoral, F, Kogevinas, M, Grigoroiu-Serbanescu, M, Propping, P, Becker, T, Rietsche, M, Cichon, S, Schratt, G & Nöthen, MM 2015, 'Genome-wide analysis implicates microRNAs and their target genes in the development of bipolar disorder', Translational Psychiatry, vol. 5, no. 11, e678. https://doi.org/10.1038/tp.2015.159
Forstner AJ, Hofmann A, Maaser A, Sumer S, Khudayberdiev S, Mühleisen TW et al. Genome-wide analysis implicates microRNAs and their target genes in the development of bipolar disorder. Translational Psychiatry. 2015 Nov 24;5(11). e678. https://doi.org/10.1038/tp.2015.159
Forstner, A. J. ; Hofmann, A. ; Maaser, A. ; Sumer, S. ; Khudayberdiev, S. ; Mühleisen, T. W. ; Leber, M. ; Schulze, T. G. ; Strohmaier, J. ; Degenhardt, F. ; Treutlein, J. ; Mattheisen, M. ; Schumacher, J. ; Breuer, R. ; Meier, S. ; Herms, S. ; Hoffmann, P. ; Lacour, A. ; Witt, S. H. ; Reif, A. ; Müller-Myhsok, B. ; Lucae, S. ; Maier, W. ; Schwarz, M. ; Vedder, H. ; Kammerer-Ciernioch, J. ; Pfennig, A. ; Bauer, M. ; Hautzinger, M. ; Moebus, S. ; Priebe, L. ; Sivalingam, S. ; Verhaert, A. ; Schulz, H. ; Czerski, P. M. ; Hauser, J. ; Lissowska, J. ; Szeszenia-Dabrowska, N. ; Brennan, P. ; McKay, J. D. ; Wright, A. ; Mitchell, P. B. ; Fullerton, J. M. ; Schofield, P. R. ; Montgomery, G. W. ; Medland, S. E. ; Gordon, S. D. ; Martin, N. G. ; Krasnov, V. ; Chuchalin, A. ; Babadjanova, G. ; Pantelejeva, G. ; Abramova, L. I. ; Tiganov, A. S. ; Polonikov, A. ; Khusnutdinova, E. ; Alda, M. ; Cruceanu, C. ; Rouleau, G. A. ; Turecki, G. ; Laprise, C. ; Rivas, F. ; Mayoral, F. ; Kogevinas, M. ; Grigoroiu-Serbanescu, M. ; Propping, P. ; Becker, T. ; Rietsche, M. ; Cichon, S. ; Schratt, G. ; Nöthen, M. M. / Genome-wide analysis implicates microRNAs and their target genes in the development of bipolar disorder. In: Translational Psychiatry. 2015 ; Vol. 5, No. 11.
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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 BDassociated 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.",
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TY - JOUR

T1 - Genome-wide analysis implicates microRNAs and their target genes in the development of bipolar disorder

AU - Forstner, A. J.

AU - Hofmann, A.

AU - Maaser, A.

AU - Sumer, S.

AU - Khudayberdiev, S.

AU - Mühleisen, T. W.

AU - Leber, M.

AU - Schulze, T. G.

AU - Strohmaier, J.

AU - Degenhardt, F.

AU - Treutlein, J.

AU - Mattheisen, M.

AU - Schumacher, J.

AU - Breuer, R.

AU - Meier, S.

AU - Herms, S.

AU - Hoffmann, P.

AU - Lacour, A.

AU - Witt, S. H.

AU - Reif, A.

AU - Müller-Myhsok, B.

AU - Lucae, S.

AU - Maier, W.

AU - Schwarz, M.

AU - Vedder, H.

AU - Kammerer-Ciernioch, J.

AU - Pfennig, A.

AU - Bauer, M.

AU - Hautzinger, M.

AU - Moebus, S.

AU - Priebe, L.

AU - Sivalingam, S.

AU - Verhaert, A.

AU - Schulz, H.

AU - Czerski, P. M.

AU - Hauser, J.

AU - Lissowska, J.

AU - Szeszenia-Dabrowska, N.

AU - Brennan, P.

AU - McKay, J. D.

AU - Wright, A.

AU - Mitchell, P. B.

AU - Fullerton, J. M.

AU - Schofield, P. R.

AU - Montgomery, G. W.

AU - Medland, S. E.

AU - Gordon, S. D.

AU - Martin, N. G.

AU - Krasnov, V.

AU - Chuchalin, A.

AU - Babadjanova, G.

AU - Pantelejeva, G.

AU - Abramova, L. I.

AU - Tiganov, A. S.

AU - Polonikov, A.

AU - Khusnutdinova, E.

AU - Alda, M.

AU - Cruceanu, C.

AU - Rouleau, G. A.

AU - Turecki, G.

AU - Laprise, C.

AU - Rivas, F.

AU - Mayoral, F.

AU - Kogevinas, M.

AU - Grigoroiu-Serbanescu, M.

AU - Propping, P.

AU - Becker, T.

AU - Rietsche, M.

AU - Cichon, S.

AU - Schratt, G.

AU - Nöthen, M. M.

PY - 2015/11/24

Y1 - 2015/11/24

N2 - 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 BDassociated 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.

AB - 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 BDassociated 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.

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