title: Phenotypically distinct subtypes of psychosis accompany novel or rare variants in four different signaling genes.
abstract: BACKGROUND
  Rare gene variants are important sources of schizophrenia vulnerability that likely interact with polygenic susceptibility loci. This study examined if novel or rare missense coding variants in any of four different signaling genes in sporadic schizophrenia cases were associated with clinical phenotypes in an exceptionally well-characterized sample.
  
  
  METHODS
  Structured interviews, cognition, symptoms and life course features were assessed in 48 ethnically-diverse cases with psychosis who underwent targeted exome sequencing of PTPRG (Protein Tyrosine Phosphatase, Receptor Type G), SLC39A13 (Solute Carrier Family 39 (Zinc Transporter) Member 13), TGM5 (transglutaminase 5) and ARMS/KIDINS220 (Ankyrin repeat-rich membrane spanning protein or Kinase D-Interacting Substrate of 220kDa). Cases harboring rare missense coding polymorphisms or novel mutations in one or more of these genes were compared to other cases not carrying any rare missense coding polymorphisms or novel mutations in these genes and healthy controls.
  
  
  RESULTS
  Fifteen of 48 cases (31.25%) carried rare or novel missense coding variants in one or more of these genes. The subgroups significantly differed in important features, including specific working memory deficits for PTPRG (n=5); severe negative symptoms, global cognitive deficits and poor educational attainment, suggesting a developmental disorder, for SLC39A13 (n=4); slow processing speed, childhood attention deficit disorder and milder symptoms for TGM5 (n=4); and global cognitive deficits with good educational attainment suggesting neurodegeneration for ARMS/KIDINS220 (n=5). Case vignettes are included in the appendix.
  
  
  CONCLUSIONS
  Genes prone to missense coding polymorphisms and/or mutations in sporadic cases may highlight influential genes for psychosis and illuminate heterogeneous pathways to schizophrenia. Ethnicity appears less important at the level of genetic variability. The sequence variations that potentially alter the function of specific genes or their signaling partners may contribute to particular subtypes of psychosis. This approach may be applicable to other complex disorders.
authors.affiliation: Skirball Institute of Biomolecular Medicine, Departments of Cell Biology, Physiology & Neuroscience and Psychiatry, New York University, NY, NY 10016, USA. Electronic address: Thorsten.kranz@nyumc.org.
authors.forename: Thorsten M
authors.initials: TM
authors.lastname: Kranz
authors.affiliation: Institute for Social and Psychiatric Initiatives (InSPIRES), Department of Psychiatry, New York University School of Medicine, New York, NY 10016, USA. Electronic address: Adam.berns@med.nyu.edu.
authors.forename: Adam
authors.initials: A
authors.lastname: Berns
authors.affiliation: Institute for Social and Psychiatric Initiatives (InSPIRES), Department of Psychiatry, New York University School of Medicine, New York, NY 10016, USA. Electronic address: jeshields@chpnet.org.
authors.forename: Jerry
authors.initials: J
authors.lastname: Shields
authors.affiliation: Institute for Social and Psychiatric Initiatives (InSPIRES), Department of Psychiatry, New York University School of Medicine, New York, NY 10016, USA. Electronic address: Karen.rothman@nyumc.org.
authors.forename: Karen
authors.initials: K
authors.lastname: Rothman
authors.affiliation: University of Dayton, Department of Psychology, Dayton, OH, USA. Electronic address: jmessinger1@udayton.edu.
authors.forename: Julie
authors.initials: J
authors.lastname: Walsh-Messinger
authors.affiliation: New York State Psychiatric Institute, Division of Clinical Phenomenology, 1051 Riverside Drive, New York, NY 10032, USA. Electronic address: Goetzra@nyspi.columbia.edu.
authors.forename: Raymond R
authors.initials: RR
authors.lastname: Goetz
authors.affiliation: Skirball Institute of Biomolecular Medicine, Departments of Cell Biology, Physiology & Neuroscience and Psychiatry, New York University, NY, NY 10016, USA. Electronic address: Moses.chao@med.nyu.edu.
authors.forename: Moses V
authors.initials: MV
authors.lastname: Chao
authors.affiliation: Institute for Social and Psychiatric Initiatives (InSPIRES), Department of Psychiatry, New York University School of Medicine, New York, NY 10016, USA. Electronic address: Dolores.malaspina@nyumc.org.
authors.forename: Dolores
authors.initials: D
authors.lastname: Malaspina
mesh_terms: D000328:Adult; D027682:Cation Transport Proteins / Q000235:genetics; D059472:Exome; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics; D011618:Psychotic Disorders / Q000145:classification* / Q000235:genetics*; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5 / Q000235:genetics; D012559:Schizophrenia / Q000235:genetics*; D017422:Sequence Analysis, DNA; D015398:Signal Transduction; D011795:Surveys and Questionnaires; D011503:Transglutaminases / Q000235:genetics
chemical_list: D027682:Cation Transport Proteins; C482591:KIDINS220 protein, human; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C521172:SLC39A13 protein, human; C418703:transglutaminase 5; D011503:Transglutaminases; C516850:PTPRG protein, human; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5
keywords: ARMS/KIDINS220; Diagnosis; Endophenotype; Human genetics; Neurotrophins; Psychosis; Schizophrenia