title: Proteomic and genomic evidence implicates the postsynaptic density in schizophrenia.
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.
authors.affiliation: Department of Psychiatry, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: M
authors.initials: M
authors.lastname: Föcking
authors.affiliation: Department of Psychiatry, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: L M
authors.initials: LM
authors.lastname: Lopez
authors.affiliation: Department of Psychiatry, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: J A
authors.initials: JA
authors.lastname: English
authors.affiliation: Departments of Epidemiology and Public Health, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: P
authors.initials: P
authors.lastname: Dicker
authors.affiliation: Department of Psychiatry, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: A
authors.initials: A
authors.lastname: Wolff
authors.affiliation: Department of Psychiatry, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: E
authors.initials: E
authors.lastname: Brindley
authors.affiliation: Proteome Research Centre, UCD Conway Institute of Biomolecular and Biomedical Research, School of Medicine and Medical Sciences, University College Dublin, Dublin, Ireland.
authors.forename: K
authors.initials: K
authors.lastname: Wynne
authors.affiliation: Proteome Research Centre, UCD Conway Institute of Biomolecular and Biomedical Research, School of Medicine and Medical Sciences, University College Dublin, Dublin, Ireland.
authors.forename: G
authors.initials: G
authors.lastname: Cagney
authors.affiliation: 1] Department of Psychiatry, Royal College of Surgeons in Ireland, Dublin, Ireland [2] Department of Psychiatry, Beaumont Hospital, Dublin, Ireland.
authors.forename: D R
authors.initials: DR
authors.lastname: Cotter
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D004705:Endocytosis / Q000187:drug effects / Q000502:physiology; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics*; D056726:Genetic Association Studies; D023281:Genomics; D006179:Gyrus Cinguli / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D006220:Haloperidol / Q000494:pharmacology; D006801:Humans; D008297:Male; D016202:N-Methylaspartate / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D057907:Post-Synaptic Density / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D040901:Proteomics; D051381:Rats; D015203:Reproducibility of Results; D012559:Schizophrenia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D050857:Synaptotagmins / Q000378:metabolism; D053719:Tandem Mass Spectrometry
chemical_list: D014150:Antipsychotic Agents; C583132:ESYT1 protein, human; D009419:Nerve Tissue Proteins; C033652:postsynaptic density proteins; D050857:Synaptotagmins; D016202:N-Methylaspartate; D006220:Haloperidol