title: Modification of cognitive performance in schizophrenia by complexin 2 gene polymorphisms.
abstract: BACKGROUND
  Schizophrenia is the collective term for a heterogeneous group of mental disorders with a still obscure biological basis. In particular, the specific contribution of risk or candidate gene variants to the complex schizophrenic phenotype is largely unknown.
  
  
  OBJECTIVE
  To prepare the ground for a novel "phenomics" approach, a unique schizophrenia patient database was established by GRAS (Göttingen Research Association for Schizophrenia), designed to allow association of genetic information with quantifiable phenotypes.Because synaptic dysfunction plays a key role in schizophrenia, the complexin 2 gene (CPLX2) was examined in the first phenotype-based genetic association study (PGAS) of GRAS [corrected]
  
  
  METHODS
  Subsequent to a classic case-control approach, we analyzed the contribution of CPLX2 polymorphisms to discrete cognitive domains within the schizophrenic population. To gain mechanistic insight into how certain CPLX2 variants influence gene expression and function, peripheral blood mononuclear cells of patients, Cplx -null mutant mice, and transfected cells were investigated.
  
  
  METHODS
  Coordinating research center (Max Planck Institute of Experimental Medicine) and 23 collaborating psychiatric centers all over Germany.
  
  
  METHODS
  One thousand seventy-one patients with schizophrenia (DSM-IV) examined by an invariant investigator team, resulting in the GRAS database with more than 3000 phenotypic data points per patient, and 1079 healthy control subjects of comparable ethnicity. Main Outcome Measure Cognitive performance including executive functioning, reasoning, and verbal learning/memory.
  
  
  RESULTS
  Six single-nucleotide polymorphisms, distributed over the whole CPLX2 gene, were found to be highly associated with current cognition of schizophrenic subjects but only marginally with premorbid intelligence. Correspondingly, in Cplx2 -null mutant mice, prominent cognitive loss of function was obtained only in combination with a minor brain lesion applied during puberty, modeling a clinically relevant environmental risk ("second hit") for schizophrenia. In the human CPLX2 gene, 1 of the identified 6 cognition-relevant single-nucleotide polymorphisms, rs3822674 in the 3' untranslated region, was detected to influence microRNA-498 binding and gene expression. The same marker was associated with differential expression of CPLX2 in peripheral blood mononuclear cells.
  
  
  CONCLUSIONS
  The PGAS allows identification of marker-associated clinical/biological traits. Current cognitive performance in schizophrenic patients is modified by CPLX2 variants modulating posttranscriptional gene expression.
authors.affiliation: Max Planck Institute of Experimental Medicine, Göttingen, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Begemann
authors.forename: Sabrina
authors.initials: S
authors.lastname: Grube
authors.forename: Sergi
authors.initials: S
authors.lastname: Papiol
authors.forename: Dörthe
authors.initials: D
authors.lastname: Malzahn
authors.forename: Henning
authors.initials: H
authors.lastname: Krampe
authors.forename: Katja
authors.initials: K
authors.lastname: Ribbe
authors.forename: Heidi
authors.initials: H
authors.lastname: Friedrichs
authors.forename: Konstantin A
authors.initials: KA
authors.lastname: Radyushkin
authors.forename: Ahmed
authors.initials: A
authors.lastname: El-Kordi
authors.forename: Fritz
authors.initials: F
authors.lastname: Benseler
authors.forename: Kathrin
authors.initials: K
authors.lastname: Hannke
authors.forename: Swetlana
authors.initials: S
authors.lastname: Sperling
authors.forename: Dayana
authors.initials: D
authors.lastname: Schwerdtfeger
authors.forename: Ivonne
authors.initials: I
authors.lastname: Thanhäuser
authors.forename: Martin F
authors.initials: MF
authors.lastname: Gerchen
authors.forename: Mohammad
authors.initials: M
authors.lastname: Ghorbani
authors.forename: Stefan
authors.initials: S
authors.lastname: Gutwinski
authors.forename: Constanze
authors.initials: C
authors.lastname: Hilmes
authors.forename: Richard
authors.initials: R
authors.lastname: Leppert
authors.forename: Anja
authors.initials: A
authors.lastname: Ronnenberg
authors.forename: Julia
authors.initials: J
authors.lastname: Sowislo
authors.forename: Sabina
authors.initials: S
authors.lastname: Stawicki
authors.forename: Maren
authors.initials: M
authors.lastname: Stödtke
authors.forename: Christoph
authors.initials: C
authors.lastname: Szuszies
authors.forename: Kerstin
authors.initials: K
authors.lastname: Reim
authors.forename: Joachim
authors.initials: J
authors.lastname: Riggert
authors.forename: Fritz
authors.initials: F
authors.lastname: Eckstein
authors.forename: Peter
authors.initials: P
authors.lastname: Falkai
authors.forename: Heike
authors.initials: H
authors.lastname: Bickeböller
authors.forename: Klaus-Armin
authors.initials: KA
authors.lastname: Nave
authors.forename: Nils
authors.initials: N
authors.lastname: Brose
authors.forename: Hannelore
authors.initials: H
authors.lastname: Ehrenreich
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000818:Animals; D003072:Cognition Disorders / Q000175:diagnosis / Q000235:genetics*; D030541:Databases, Genetic / Q000706:statistics & numerical data; D005260:Female; D015870:Gene Expression / Q000235:genetics / Q000502:physiology; D056726:Genetic Association Studies; D005819:Genetic Markers; D014644:Genetic Variation / Q000235:genetics; D005838:Genotype; D006801:Humans; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009483:Neuropsychological Tests; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012559:Schizophrenia / Q000235:genetics*; D012565:Schizophrenic Psychology
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D005819:Genetic Markers; D009419:Nerve Tissue Proteins; C095993:complexin II