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Rare susceptibility variants for bipolar disorder suggest a role for G protein-coupled receptors

Molecular Psychiatry volume 23, pages 2050–2056 (2018)Cite this article

Abstract

Bipolar disorder (BD) is a prevalent mood disorder that tends to cluster in families. Despite high heritability estimates, few genetic susceptibility factors have been identified over decades of genetic research. One possible interpretation for the shortcomings of previous studies to detect causative genes is that BD is caused by highly penetrant rare variants in many genes. We explored this hypothesis by sequencing the exomes of affected individuals from 40 well-characterized multiplex families. We identified rare variants segregating with affected status in many interesting genes, and found an enrichment of deleterious variants in G protein-coupled receptor (GPCR) family genes, which are important drug targets. Furthermore, we showed targeted downstream GPCR dysregulation for some of the variants that may contribute to disease pathology. Particularly interesting was the finding of a rare and functionally relevant nonsense mutation in the corticotropin-releasing hormone receptor 2 (CRHR2) gene that tracked with affected status in one family. By focusing on rare variants in informative families, we identified key biochemical pathways likely implicated in this complex disorder.

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Acknowledgments

We thank the participants and their families for their contribution to this research. Furthermore, we acknowledge Karine Lachapelle and Annie Levert from the laboratory of GAR for technical assistance. This work was funded through a grant from Genome Quebec.

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Authors and Affiliations

  1. Department of Psychiatry, McGill Group for Suicide Studies, Douglas Mental Health University Institute, McGill University, Montreal, QC, Canada

    C Cruceanu, S G Torres-Platas, J P Lopez & G Turecki

  2. Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC, Canada

    C Cruceanu, J-F Schmouth, A Ambalavanan, D Spiegelman, D Rochefort, P Hince, J Gauthier, R G Lafrenière, P A Dion & G A Rouleau

  3. Department of Psychiatry, Faculty of Medicine, Douglas Hospital Research Center, McGill University, Montreal, QC, Canada

    E Darcq, F Gross & B L Kieffer

  4. Domain Therapeutics NA, Montreal, QC, Canada

    B Breton

  5. Department of Psychiatry, Dalhousie University, Halifax, NS, Canada

    J M Petite & M Alda

  6. Lady Davis Research Institute, Jewish General Hospital,, Montreal, QC, Canada

    C M Greenwood

  7. Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, QC, Canada

    C M Greenwood

  8. Department of Oncology and Human Genetics, McGill University, Montreal, QC, Canada

    C M Greenwood

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  1. C Cruceanu
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  2. J-F Schmouth
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  3. S G Torres-Platas
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  4. J P Lopez
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  7. F Gross
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  8. B Breton
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  9. D Spiegelman
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  10. D Rochefort
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  11. P Hince
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  13. J Gauthier
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  14. R G Lafrenière
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  15. P A Dion
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  16. C M Greenwood
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  17. B L Kieffer
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  18. M Alda
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  19. G Turecki
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  20. G A Rouleau
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Contributions

All individuals included as authors have contributed substantially to the scientific process by participating in the study design, execution and the redaction of the manuscript.

Corresponding authors

Correspondence to G Turecki or G A Rouleau.

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The authors declare no conflict of interest.

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Cruceanu, C., Schmouth, JF., Torres-Platas, S.G. et al. Rare susceptibility variants for bipolar disorder suggest a role for G protein-coupled receptors. Mol Psychiatry 23, 2050–2056 (2018). https://doi.org/10.1038/mp.2017.223

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