title: Hippocampal N-acetyl aspartate in unaffected siblings of patients with schizophrenia: a possible intermediate neurobiological phenotype.
abstract: BACKGROUND
  Shared neurobiological characteristics of patients with schizophrenia and their siblings may represent "intermediate phenotypes" that may more closely reflect the genetic susceptibility underlying this illness. We sought evidence of such phenotypes using magnetic resonance spectroscopy based on previously described regional abnormalities in levels of the neuronal marker N-acetyl-aspartate (NAA) in the hippocampal area and dorsolateral prefrontal cortex of patients with schizophrenia.
  
  
  METHODS
  We studied 47 schizophrenics, 60 unaffected siblings, and 66 healthy control subjects with long echo time multislice proton magnetic resonance spectroscopic imaging, primarily measuring NAA, creatine plus phosphocreatine (CRE), and choline-containing compounds.
  
  
  RESULTS
  Both patients and their unaffected siblings had significant reductions in hippocampal area NAA/CRE as compared with control subjects. As exploratory analyses, estimates of heritability were performed. Although quantitative correlation of hippocampal NAA between patients and sibs was low (likely reflecting measurement noise), qualitatively defined "low hippocampal NAA/CRE phenotypes" yielded relative risk estimates (lambda s) of between 3.8 and 8.8, suggesting this characteristic is heritable.
  
  
  CONCLUSIONS
  Our finding adds to the evidence that hippocampal abnormalities are associated with schizophrenia and may represent a novel biological phenotype for genetic studies of schizophrenia.
authors.forename: J H
authors.initials: JH
authors.lastname: Callicott
authors.forename: M F
authors.initials: MF
authors.lastname: Egan
authors.forename: A
authors.initials: A
authors.lastname: Bertolino
authors.forename: V S
authors.initials: VS
authors.lastname: Mattay
authors.forename: F J
authors.initials: FJ
authors.lastname: Langheim
authors.forename: J A
authors.initials: JA
authors.lastname: Frank
authors.forename: D R
authors.initials: DR
authors.lastname: Weinberger
mesh_terms: D000328:Adult; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000378:metabolism; D015415:Biomarkers; D002794:Choline / Q000378:metabolism; D003401:Creatine / Q000378:metabolism; D005190:Family; D005260:Female; D006624:Hippocampus / Q000033:anatomy & histology / Q000378:metabolism*; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D010641:Phenotype; D010725:Phosphocreatine / Q000378:metabolism; D017397:Prefrontal Cortex / Q000378:metabolism* / Q000473:pathology; D012306:Risk; D012559:Schizophrenia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: D015415:Biomarkers; D010725:Phosphocreatine; D001224:Aspartic Acid; C000179:N-acetylaspartate; D003401:Creatine; D002794:Choline