title: Uncovering the hidden risk architecture of the schizophrenias: confirmation in three independent genome-wide association studies.
abstract: OBJECTIVE
  The authors sought to demonstrate that schizophrenia is a heterogeneous group of heritable disorders caused by different genotypic networks that cause distinct clinical syndromes.
  
  
  METHODS
  In a large genome-wide association study of cases with schizophrenia and controls, the authors first identified sets of interacting single-nucleotide polymorphisms (SNPs) that cluster within particular individuals (SNP sets) regardless of clinical status. Second, they examined the risk of schizophrenia for each SNP set and tested replicability in two independent samples. Third, they identified genotypic networks composed of SNP sets sharing SNPs or subjects. Fourth, they identified sets of distinct clinical features that cluster in particular cases (phenotypic sets or clinical syndromes) without regard for their genetic background. Fifth, they tested whether SNP sets were associated with distinct phenotypic sets in a replicable manner across the three studies.
  
  
  RESULTS
  The authors identified 42 SNP sets associated with a 70% or greater risk of schizophrenia, and confirmed 34 (81%) or more with similar high risk of schizophrenia in two independent samples. Seventeen networks of SNP sets did not share any SNP or subject. These disjoint genotypic networks were associated with distinct gene products and clinical syndromes (i.e., the schizophrenias) varying in symptoms and severity. Associations between genotypic networks and clinical syndromes were complex, showing multifinality and equifinality. The interactive networks explained the risk of schizophrenia more than the average effects of all SNPs (24%).
  
  
  CONCLUSIONS
  Schizophrenia is a group of heritable disorders caused by a moderate number of separate genotypic networks associated with several distinct clinical syndromes.
authors.affiliation: From the Department of Psychiatry and the Department of Genetics, Washington University School of Medicine, St. Louis; the Department of Computer Science and Artificial Intelligence, University of Granada, Granada, Spain; St. Louis VA Medical Center, St. Louis; Roskamp Laboratory of Brain Development, Modulation, and Repair, Department of Psychiatry and Behavioral Neurosciences, University of South Florida, Tampa; Washington DC VA Medical Center, Washington, D.C.; and the Department of Psychiatry, University of Southern California, Los Angeles.
authors.forename: Javier
authors.initials: J
authors.lastname: Arnedo
authors.forename: Dragan M
authors.initials: DM
authors.lastname: Svrakic
authors.forename: Coral
authors.initials: C
authors.lastname: Del Val
authors.forename: Rocío
authors.initials: R
authors.lastname: Romero-Zaliz
authors.forename: Helena
authors.initials: H
authors.lastname: Hernández-Cuervo
authors.forename: Ayman H
authors.initials: AH
authors.lastname: Fanous
authors.forename: Michele T
authors.initials: MT
authors.lastname: Pato
authors.forename: Carlos N
authors.initials: CN
authors.lastname: Pato
authors.forename: Gabriel A
authors.initials: GA
authors.lastname: de Erausquin
authors.forename: C Robert
authors.initials: CR
authors.lastname: Cloninger
authors.forename: Igor
authors.initials: I
authors.lastname: Zwir
mesh_terms: D000328:Adult; D005260:Female; D056726:Genetic Association Studies / Q000379:methods*; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D009434:Neural Pathways; D020641:Polymorphism, Single Nucleotide; D011569:Psychiatric Status Rating Scales; D018570:Risk Assessment; D012559:Schizophrenia / Q000175:diagnosis / Q000235:genetics / Q000503:physiopathology; D012565:Schizophrenic Psychology; D012720:Severity of Illness Index; D009435:Synaptic Transmission / Q000235:genetics*