title: Psychophysiological endophenotypes to characterize mechanisms of known schizophrenia genetic loci.
abstract: BACKGROUND
  Endophenotypes are laboratory-based measures hypothesized to lie in the causal chain between genes and clinical disorder, and to serve as a more powerful way to identify genes associated with the disorder. One promise of endophenotypes is that they may assist in elucidating the neurobehavioral mechanisms by which an associated genetic polymorphism affects disorder risk in complex traits. We evaluated this promise by testing the extent to which variants discovered to be associated with schizophrenia through large-scale meta-analysis show associations with psychophysiological endophenotypes.
  
  
  METHODS
  We genome-wide genotyped and imputed 4905 individuals. Of these, 1837 were whole-genome-sequenced at 11× depth. In a community-based sample, we conducted targeted tests of variants within schizophrenia-associated loci, as well as genome-wide polygenic tests of association, with 17 psychophysiological endophenotypes including acoustic startle response and affective startle modulation, antisaccade, multiple frequencies of resting electroencephalogram (EEG), electrodermal activity and P300 event-related potential.
  
  
  RESULTS
  Using single variant tests and gene-based tests we found suggestive evidence for an association between contactin 4 (CNTN4) and antisaccade and P300. We were unable to find any other variant or gene within the 108 schizophrenia loci significantly associated with any of our 17 endophenotypes. Polygenic risk scores indexing genetic vulnerability to schizophrenia were not related to any of the psychophysiological endophenotypes after correction for multiple testing.
  
  
  CONCLUSIONS
  The results indicate significant difficulty in using psychophysiological endophenotypes to characterize the genetically influenced neurobehavioral mechanisms by which risk loci identified in genome-wide association studies affect disorder risk.
authors.affiliation: Institute for Behavioral Genetics, University of Colorado Boulder,Boulder, CO,USA.
authors.forename: M
authors.initials: M
authors.lastname: Liu
authors.affiliation: Department of Psychology,University of Minnesota,Minneapolis, MN,USA.
authors.forename: S M
authors.initials: SM
authors.lastname: Malone
authors.affiliation: National Institutes of Health,Bethesda, MD,USA.
authors.forename: U
authors.initials: U
authors.lastname: Vaidyanathan
authors.affiliation: Institute for Behavioral Genetics, University of Colorado Boulder,Boulder, CO,USA.
authors.forename: M C
authors.initials: MC
authors.lastname: Keller
authors.affiliation: Department of Biostatistics,University of Michigan,Ann Arbor, MI,USA.
authors.forename: G
authors.initials: G
authors.lastname: Abecasis
authors.affiliation: Department of Psychology,University of Minnesota,Minneapolis, MN,USA.
authors.forename: M
authors.initials: M
authors.lastname: McGue
authors.affiliation: Department of Psychology,University of Minnesota,Minneapolis, MN,USA.
authors.forename: W G
authors.initials: WG
authors.lastname: Iacono
authors.affiliation: Institute for Behavioral Genetics, University of Colorado Boulder,Boulder, CO,USA.
authors.forename: S I
authors.initials: SI
authors.lastname: Vrieze
mesh_terms: D058966:Contactins; D004569:Electroencephalography; D058068:Endophenotypes; D018913:Event-Related Potentials, P300 / Q000502:physiology*; D056426:Genetic Loci; D016678:Genome / Q000235:genetics*; D006801:Humans; D012438:Saccades / Q000502:physiology; D012559:Schizophrenia / Q000235:genetics* / Q000503:physiopathology*
chemical_list: C098304:CNTN4 protein, human; D058966:Contactins
keywords: Endophenotypes; gene-based tests; polygenic risk scores; schizophrenia; single variant association