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Proteomic and genomic evidence implicates the postsynaptic density in schizophrenia

Molecular Psychiatry volume 20, pages 424–432 (2015)Cite this article

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Abstract

The postsynaptic density (PSD) contains a complex set of proteins of known relevance to neuropsychiatric disorders, and schizophrenia specifically. We enriched for this anatomical structure, in the anterior cingulate cortex, of 20 schizophrenia samples and 20 controls from the Stanley Medical Research Institute, and used unbiased shotgun proteomics incorporating label-free quantitation to identify differentially expressed proteins. Quantitative investigation of the PSD revealed more than 700 protein identifications and 143 differentially expressed proteins. Prominent among these were altered expression of proteins involved in clathrin-mediated endocytosis (CME) (Dynamin-1, adaptor protein 2) and N-methyl-D-aspartate (NMDA)-interacting proteins such as CYFIP2, SYNPO, SHANK3, ESYT and MAPK3 (all P<0.0015). Pathway analysis of the differentially expressed proteins implicated the cellular processes of endocytosis, long-term potentiation and calcium signaling. Both single-gene and gene-set enrichment analyses in genome-wide association data from the largest schizophrenia sample to date of 13 689 cases and 18 226 controls show significant association of HIST1H1E and MAPK3, and enrichment of our PSD proteome. Taken together, our data provide robust evidence implicating PSD-associated proteins and genes in schizophrenia, and suggest that within the PSD, NMDA-interacting and endocytosis-related proteins contribute to disease pathophysiology.

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Acknowledgements

Post-mortem brains were donated by the Stanley Foundation Brain Bank Consortium courtesy of Llewellyn B Bigelow, Maree J Webster and staff. We thank the donors, Daire Quinn, Sinead Kinsella, Alison Gordon and Magdalena Hryniewiecka, for help with western blotting and animal work; Andrew Pocklington and George Kirov for the PSD gene lists, and Aniket Misra, Stuart MacGregor and Dave Hill for help with the gene-based analysis. We thank the Psychiatric Genetics Consortium, DIAGRAM (DIAbetes Genetics Replication And Meta-analysis) Consortium and International Inflammatory Bowel Disease Genetics Consortium (IIBDGC) for providing genome-wide association study data. Access to and use of mass spectrometry instrumentation and computing facilities at the Conway Institute is gratefully acknowledged. This work was supported by a Brain and Behavior Research Foundation Award (to MF), the SMRI and the Irish Health Research Board through a Health Research Award (to DC, GC and MF) and a Health Research Board Clinician Scientist Award (to DC).

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  1. G Cagney and D R Cotter: These are senior authors.

Authors and Affiliations

  1. Department of Psychiatry, Royal College of Surgeons in Ireland, Dublin, Ireland

    M Föcking, L M Lopez, J A English, A Wolff, E Brindley & D R Cotter

  2. Departments of Epidemiology and Public Health, Royal College of Surgeons in Ireland, Dublin, Ireland

    P Dicker

  3. Proteome Research Centre, UCD Conway Institute of Biomolecular and Biomedical Research, School of Medicine and Medical Sciences, University College Dublin, Dublin, Ireland

    K Wynne & G Cagney

  4. Department of Psychiatry, Beaumont Hospital, Dublin, Ireland

    D R Cotter

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  1. M Föcking
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Föcking, M., Lopez, L., English, J. et al. Proteomic and genomic evidence implicates the postsynaptic density in schizophrenia. Mol Psychiatry 20, 424–432 (2015). https://doi.org/10.1038/mp.2014.63

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