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

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

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

Andreas J. Forstner, MD*; F. Buket Basmanav, MSc*; Manuel Mattheisen, MD; GROUP Investigators; Anne C. Böhmer, MSc; Mads V. Hollegaard, PhD; Esther Janson, BAS; Eric Strengman, MSc; Lutz Priebe, MSc; Franziska Degenhardt, MD; Per Hoffmann, PhD; Stefan Herms, MSc; Wolfgang Maier, MD; Rainald Mössner, MD; Dan Rujescu, MD; Roel A. Ophoff, PhD; Susanne Moebus, PhD; Preben B. Mortensen, MD, DMSc; Anders D. Børglum, MD, PhD; David M. Hougaard, MD, DSc; Josef Frank, MSc; Stephanie H. Witt, PhD; Marcella Rietschel, MD; Andreas Zimmer, PhD; Markus M. Nöthen, MD*; Xavier Miró, PhD*; Sven Cichon, PhD*

Forstner, Basmanav, Böhmer, Priebe, Degenhardt, Hoffmann, Herms, Nöthen, Cichon — Institute of Human Genetics, University of Bonn, Germany; Forstner, Basmanav, Böhmer, Priebe, Degenhardt, Hoffmann, Herms, Nöthen, Cichon — Department of Genomics, Life and Brain Center, Bonn, Germany; Mattheisen, Børglum — Department of Biomedicine, Human Genetics, and Centre for Integrative Sequencing, iSEQ, Aarhus University, Aarhus, Denmark; Mattheisen — Department of Genomics Mathematics, University of Bonn, Germany; Mattheisen, Mortensen, Børglum — The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus and Copenhagen, Denmark; Hollegaard, Hougaard — Section of Neonatal Screening and Hormones, Statens Serum Institute, Copenhagen, Denmark; Janson, Strengman — Department of Medical Genetics, University Medical Centre Utrecht, Utrecht, the Netherlands; Hoffmann, Herms, Cichon — Division of Medical Genetics, University Hospital Basel and Department of Biomedicine, University of Basel, Switzerland; Maier, Mössner — Department of Psychiatry, University of Bonn, Germany; Rujescu — Department of Psychiatry, University of Halle-Wittenberg, Halle, Germany; Ophoff — Center for Neurobehavioral Genetics, University of California Los Angeles, USA; Ophoff — Rudolf Magnus Institute of Neuroscience, Department of Psychiatry, University Medical Center, Utrecht, the Netherlands; Moebus — Institute of Medical Informatics, Biometry and Epidemiology, University Duisburg-Essen, Essen, Germany; Mortensen — National Centre for Register-based Research, Aarhus University, Aarhus, Denmark; Børglum — Centre for Psychiatric Research, Aarhus University Hospital, Risskov, Denmark; Frank, Witt, Rietschel — Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Germany; Zimmer, Miró — Institute of Molecular Psychiatry, University of Bonn, Germany; Cichon — Institute of Neuroscience and Medicine INM-1, Research Center Juelich, Germany

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.


*These authors contributed equally to this work.

Submitted Aug. 29, 2013; Revised Jan. 17, Mar. 4, 2014; Accepted Mar. 17, 2014; Early-released June 17, 2014.

Acknowledgements: We are grateful to all of the patients and control individuals who contributed to this study. We also thank the probands from the Heinz Nixdorf Recall (HNR) study. We thank Marie Luise Dreisow and Peter Tessmann for their excellent technical assistance. We also thank Christine Schmäl for her careful reading of the manuscript. We are grateful to the Psychiatric Genomics Consortium for contributing to this study by sharing of their data. We confirm that these data will be used for noncommercial research purposes only. We have complied with all applicable state, local and federal laws or regulations and institutional policies regarding human subjects and genetic research. We acknowledge that secondary distribution of the data without registration by secondary parties is prohibited and confirm that we will cite the appropriate PGC publication in any communications or publications arising directly or indirectly from these data.

Funding: This study was supported by the German Federal Ministry of Education and Research (BMBF) through the Integrated Genome Research Network (IG) MooDS (Systematic Investigation of the Molecular Causes of Major Mood Disorders and Schizophrenia; grant 01GS08144 to M.M. Nöthen and S. Cichon; grant 01GS08147 to M. Rietschel), under the auspices of the National Genome Research Network plus (NGFNplus). M.M. Nöthen is a member of the DFG-funded Excellence-Cluster ImmunoSensation. M.M. Nöthen also received support from the Alfried Krupp von Bohlen und Halbach-Stiftung. A.J. Forstner received support from the BONFOR program of the Medical Faculty of the University of Bonn. This study was partially supported by a grant from the European Union (EUTwinsS network; RTN, FP6), which supported work in which F.B. Basmanav was a Marie Curie Fellow and M.M. Nöthen and S. Cichon were principal investigators. The HNR cohort was established with the support of the Heinz Nixdorf Foundation. These funding sources had no involvement in the study design; the collection, analysis, and interpretation of data; the writing of the report; or the decision to submit the paper for publication.

Competing interests: A.D. Børglum is the co-founder and CEO of PsychoGenetics, which pursues strategies for new diagnostic and therapeutic approaches for mental disorders.

Contributors: A.J. Forstner, F.B. Basmanav, M.M. Mattheisen, M. Rietschel, A. Zimmer, M.M. Nöthen, X. Miró and S. Cichon designed the study. A.J. Forstner, F.B. Basmanav, A.C. Böhmer, M.V. Hollegaard, E. Janson, E. Strengman, W. Maier, R. Mössner, D. Rujescu, R.A. Ophoff, S. Moebus, P.B. Mortensen, A.D. Børglum, D.M. Hougaard, J. Frank, S.H. Witt, M. Rietschel, A. Zimmer and X. Miró acquired the data. A.J. Forstner, F.B. Basmanav, M. Mattheisen, L. Priebe, F. Degenhardt, P. Hoffmann, S. Herms, A. Zimmer, M.M. Nöthen, X. Miró and S. Cichon analyzed the data. A.J. Forstner, F.B. Basmanav, A. Zimmer, M.M. Nöthen, X. Miró and S. Cichon wrote the article, which all other authors reviewed. All authors approved the final version for publication.

GROUP Investigators: René S. Kahn, Don H. Linszen, Jim van Os, Durk Wiersma, Richard Bruggeman, Wiepke Cahn, Lieuwe de Haan, Lydia Krabbendam and Inez Myin-Germeys. See the Appendix for affiliations and contributor information. These authors declare no competing interests.

DOI: 10.1503/jpn.130189

Correspondence to: M.M. Nöthen, Institute of Human Genetics, University of Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany; markus.noethen@uni-bonn.de