title: Analysis of 94 candidate genes and 12 endophenotypes for schizophrenia from the Consortium on the Genetics of Schizophrenia.
abstract: OBJECTIVE
  The authors used a custom array of 1,536 single-nucleotide polymorphisms (SNPs) to interrogate 94 functionally relevant candidate genes for schizophrenia and identify associations with 12 heritable neurophysiological and neurocognitive endophenotypes in data collected by the Consortium on the Genetics of Schizophrenia.
  
  
  METHODS
  Variance-component association analyses of 534 genotyped subjects from 130 families were conducted by using Merlin software. A novel bootstrap total significance test was also developed to overcome the limitations of existing genomic multiple testing methods and robustly demonstrate significant associations in the context of complex family data and possible population stratification effects.
  
  
  RESULTS
  Associations with endophenotypes were observed for 46 genes of potential functional significance, with three SNPs at p<10(-4), 27 SNPs at p<10(-3), and 147 SNPs at p<0.01. The bootstrap analyses confirmed that the 47 SNP-endophenotype combinations with the strongest evidence of association significantly exceeded that expected by chance alone, with 93% of these findings expected to be true. Many of the genes interact on a molecular level, and eight genes (e.g., NRG1 and ERBB4) displayed evidence for pleiotropy, revealing associations with four or more endophenotypes. The results collectively support a strong role for genes related to glutamate signaling in mediating schizophrenia susceptibility.
  
  
  CONCLUSIONS
  This study supports use of relevant endophenotypes and the bootstrap total significance test for identifying genetic variation underlying the etiology of schizophrenia. In addition, the observation of extensive pleiotropy for some genes and singular associations for others suggests alternative, independent pathways mediating pathogenesis in the "group of schizophrenias."
authors.affiliation: Department of Psychiatry, University of California at San Diego, La Jolla, CA 92093-0804, USA.
authors.forename: Tiffany A
authors.initials: TA
authors.lastname: Greenwood
authors.forename: Laura C
authors.initials: LC
authors.lastname: Lazzeroni
authors.forename: Sarah S
authors.initials: SS
authors.lastname: Murray
authors.forename: Kristin S
authors.initials: KS
authors.lastname: Cadenhead
authors.forename: Monica E
authors.initials: ME
authors.lastname: Calkins
authors.forename: Dorcas J
authors.initials: DJ
authors.lastname: Dobie
authors.forename: Michael F
authors.initials: MF
authors.lastname: Green
authors.forename: Raquel E
authors.initials: RE
authors.lastname: Gur
authors.forename: Ruben C
authors.initials: RC
authors.lastname: Gur
authors.forename: Gary
authors.initials: G
authors.lastname: Hardiman
authors.forename: John R
authors.initials: JR
authors.lastname: Kelsoe
authors.forename: Sherry
authors.initials: S
authors.lastname: Leonard
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Light
authors.forename: Keith H
authors.initials: KH
authors.lastname: Nuechterlein
authors.forename: Ann
authors.initials: A
authors.lastname: Olincy
authors.forename: Allen D
authors.initials: AD
authors.lastname: Radant
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Schork
authors.forename: Larry J
authors.initials: LJ
authors.lastname: Seidman
authors.forename: Larry J
authors.initials: LJ
authors.lastname: Siever
authors.forename: Jeremy M
authors.initials: JM
authors.lastname: Silverman
authors.forename: William S
authors.initials: WS
authors.lastname: Stone
authors.forename: Neal R
authors.initials: NR
authors.lastname: Swerdlow
authors.forename: Debby W
authors.initials: DW
authors.lastname: Tsuang
authors.forename: Ming T
authors.initials: MT
authors.lastname: Tsuang
authors.forename: Bruce I
authors.initials: BI
authors.lastname: Turetsky
authors.forename: Robert
authors.initials: R
authors.lastname: Freedman
authors.forename: David L
authors.initials: DL
authors.lastname: Braff
mesh_terms: D003072:Cognition Disorders / Q000175:diagnosis / Q000235:genetics / Q000523:psychology; D058068:Endophenotypes; D004843:Epistasis, Genetic / Q000235:genetics; D056726:Genetic Association Studies; D058685:Genetic Pleiotropy; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006801:Humans; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012559:Schizophrenia / Q000175:diagnosis / Q000235:genetics*