title: Behavioural and molecular endophenotypes in psychotic disorders reveal heritable abnormalities in glutamatergic neurotransmission.
abstract: Psychotic disorders such as schizophrenia are biologically complex and carry huge population morbidity due to their prevalence, persistence and associated disability. Defined by features such as delusions and hallucinations, they involve cognitive dysfunction and neurotransmitter dysregulations that appear mostly to involve the dopaminergic and glutamatergic systems. A number of genetic and environmental factors are associated with these disorders but it has been difficult to identify the biological pathways underlying the principal symptoms. The endophenotype concept of stable, heritable traits that form a mechanistic link between genes and an overt expression of the disorder has potential to reduce the complexity of psychiatric phenotypes. In this study, we used a genetically sensitive design with individuals with a first episode of psychosis, their non-affected first-degree relatives and non-related healthy controls. Metabolomic analysis was combined with neurocognitive assessment to identify multilevel endophenotypic patterns: one concerned reaction times during the performance of cognitive and emotional tests that have previously been associated with the glutamate neurotransmission system, the other involved metabolites involved directly and indirectly in the co-activation of the N-methyl-D-aspartate receptor, a major receptor of the glutamate system. These cognitive and metabolic endophenotypes may comprise a single construct, such that genetically mediated dysfunction in the glutamate system may be responsible for delays in response to cognitive and emotional functions in psychotic disorders. This focus on glutamatergic neurotransmission should guide drug discovery and experimental medicine programmes in schizophrenia and related disorders.
authors.affiliation: 1] Department of Psychiatry, University of Cambridge, Cambridge, UK [2] Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: L
authors.initials: L
authors.lastname: Scoriels
authors.affiliation: 1] Department of Biochemistry, University of Cambridge, Cambridge, UK [2] European Bioinformatics Institute (EMBL-EBI) European Molecular Biology Laboratory, Wellcome Trust Genome Campus, Hinxton, UK.
authors.forename: R M
authors.initials: RM
authors.lastname: Salek
authors.affiliation: Department of Psychiatry, University of Cambridge, Cambridge, UK.
authors.forename: E
authors.initials: E
authors.lastname: Goodby
authors.affiliation: Index Ventures, London, UK.
authors.forename: D
authors.initials: D
authors.lastname: Grainger
authors.affiliation: Department of Psychiatry, University of Cambridge, Cambridge, UK.
authors.forename: A M
authors.initials: AM
authors.lastname: Dean
authors.affiliation: Department of Biochemistry, University of Cambridge, Cambridge, UK.
authors.forename: J A
authors.initials: JA
authors.lastname: West
authors.affiliation: Department of Biochemistry, University of Cambridge, Cambridge, UK.
authors.forename: J L
authors.initials: JL
authors.lastname: Griffin
authors.affiliation: Department of Psychiatry, University of Cambridge, Cambridge, UK.
authors.forename: J
authors.initials: J
authors.lastname: Suckling
authors.affiliation: 1] Department of Psychiatry, University of Cambridge, Cambridge, UK [2] School of Psychology and Psychiatry, Monash University, Clayton Campus, VIC, Australia.
authors.forename: P J
authors.initials: PJ
authors.lastname: Nathan
authors.affiliation: Department of Psychiatry, University of Cambridge, Cambridge, UK.
authors.forename: B R
authors.initials: BR
authors.lastname: Lennox
authors.affiliation: 1] Department of Psychiatry, University of Cambridge, Cambridge, UK [2] NIHR Biomedical Research Centre, Cambridge, UK.
authors.forename: G K
authors.initials: GK
authors.lastname: Murray
authors.affiliation: 1] Department of Psychiatry, University of Cambridge, Cambridge, UK [2] NIHR Biomedical Research Centre, Cambridge, UK [3] GlaxoSmithKline Clinical Unit Cambridge, Addenbrooke's Centre for Clinical Investigation (ACCI), Cambridge, UK.
authors.forename: E T
authors.initials: ET
authors.lastname: Bullmore
authors.affiliation: 1] Department of Psychiatry, University of Cambridge, Cambridge, UK [2] NIHR Biomedical Research Centre, Cambridge, UK.
authors.forename: P B
authors.initials: PB
authors.lastname: Jones
mesh_terms: D000328:Adult; D000704:Analysis of Variance; D002853:Chromatography, Liquid; D058068:Endophenotypes / Q000097:blood*; D018846:Excitatory Amino Acids / Q000097:blood*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D018698:Glutamic Acid / Q000097:blood; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D055432:Metabolomics; D009483:Neuropsychological Tests; D025341:Principal Component Analysis; D011618:Psychotic Disorders / Q000097:blood* / Q000235:genetics* / Q000503:physiopathology; D011930:Reaction Time; D016194:Receptors, N-Methyl-D-Aspartate / Q000097:blood; D009435:Synaptic Transmission / Q000235:genetics* / Q000502:physiology; D055815:Young Adult
chemical_list: D018846:Excitatory Amino Acids; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid
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