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The genome-wide supported microRNA-137 variant predicts phenotypic heterogeneity within schizophrenia

Molecular Psychiatry volume 18, pages 443–450 (2013)Cite this article

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A Corrigendum to this article was published on 26 March 2013

Abstract

We examined the influence of the genome-wide significant schizophrenia risk variant rs1625579 near the microRNA (miRNA)-137 (MIR137) gene on well-established sources of phenotypic variability in schizophrenia: age-at-onset of psychosis and brain structure. We found that the MIR137 risk genotype strongly predicts an earlier age-at-onset of psychosis across four independently collected samples of patients with schizophrenia (n=510; F1,506=17.7, P=3.1 × 10−5). In an imaging-genetics subsample that included additional matched controls (n=213), patients with schizophrenia who had the MIR137 risk genotype had reduced white matter integrity (F3,209=13.6, P=3.88 × 10−8) throughout the brain as well as smaller hippocampi and larger lateral ventricles; the brain structure of patients who were carriers of the protective allele was no different from healthy control subjects on these neuroimaging measures. Our findings suggest that MIR137 substantially influences variation in phenotypes that are thought to have an important role in clinical outcome and treatment response. Finally, the possible consequences of genetic risk factors may be distinct in patients with schizophrenia compared with healthy controls.

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Acknowledgements

This work was supported by the Canadian Institutes of Health Research Clinician Scientist Award (ANV); NARSAD (ANV, TKR), Ontario Mental Health Foundation (ANV) and the CAMH and the CAMH Foundation thanks to the Kimel Family, Koerner New Scientist Award and Paul E Garfinkel New Investigator Catalyst Award. We also like to thank Mr Gabriel Oh for manuscript comments. Mr Lett, Dr Kennedy, and Dr Voineskos had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. No sponsor or funder had any role in the design and conduct of the study; collection, management, analysis and interpretation of the data; and preparation, review or approval of the manuscript.

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  1. J L Kennedy and A N Voineskos: JLK and ANV are the co-senior authors.

Authors and Affiliations

  1. Centre for Addiction and Mental Health, Toronto, ON, Canada

    T A Lett, M M Chakavarty, D Felsky, E J Brandl, A K Tiwari, V F Gonçalves, T K Rajji, Z J Daskalakis, B H Mulsant, J L Kennedy & A N Voineskos

  2. Institute of Medical Science, University of Toronto, Toronto, ON, Canada

    T A Lett, M M Chakavarty, D Felsky, V F Gonçalves, T K Rajji, Z J Daskalakis, B H Mulsant, J L Kennedy & A N Voineskos

  3. Department of Psychiatry, University of Toronto, Toronto, ON, Canada

    M M Chakavarty, T K Rajji, Z J Daskalakis, B H Mulsant, J L Kennedy & A N Voineskos

  4. Department of Psychiatry and Behavioral Sciences, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA

    H Y Meltzer

  5. Department of Psychiatry, College of Physicians and Surgeons, Columbia University and the New York State Psychiatric Institute, New York City, NY, USA

    J A Lieberman

  6. Program in Neuroscience and Mental Health, Hospital for Sick Children, Toronto, ON, Canada

    J P Lerch

  7. Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada

    J P Lerch

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We report the following conflicts of interest: JAL has received research funding or is a member of the advisory board of Allon, Alkermes Bioline, GlaxoSmithKline Intracellular Therapies, Lilly, Merck, Novartis, Pfizer, Pierre Fabre, Psychogenics, F Hoffmann-La Roche LTD, Sepracor (Sunovion) and Targacept. HYM reports having received research funding or is a member of the advisory board of Novartis, Janssen, ACADIA, TEVA, Lilly, Jazz Pharmaceuticals, Sunovion, Dainippon–Sumitomo, Envivo. JLK has been a consultant to GlaxoSmithKline, Sanofi-Aventis and Dainippon–Sumitomo. BHM has received travel support from Roche.

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Lett, T., Chakavarty, M., Felsky, D. et al. The genome-wide supported microRNA-137 variant predicts phenotypic heterogeneity within schizophrenia. Mol Psychiatry 18, 443–450 (2013). https://doi.org/10.1038/mp.2013.17

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