title: Genome-wide association study of multiplex schizophrenia pedigrees.
abstract: OBJECTIVE
  The authors used a genome-wide association study (GWAS) of multiply affected families to investigate the association of schizophrenia to common single-nucleotide polymorphisms (SNPs) and rare copy number variants (CNVs).
  
  
  METHODS
  The family sample included 2,461 individuals from 631 pedigrees (581 in the primary European-ancestry analyses). Association was tested for single SNPs and genetic pathways. Polygenic scores based on family study results were used to predict case-control status in the Schizophrenia Psychiatric GWAS Consortium (PGC) data set, and consistency of direction of effect with the family study was determined for top SNPs in the PGC GWAS analysis. Within-family segregation was examined for schizophrenia-associated rare CNVs.
  
  
  RESULTS
  No genome-wide significant associations were observed for single SNPs or for pathways. PGC case and control subjects had significantly different genome-wide polygenic scores (computed by weighting their genotypes by log-odds ratios from the family study) (best p=10(-17), explaining 0.4% of the variance). Family study and PGC analyses had consistent directions for 37 of the 58 independent best PGC SNPs (p=0.024). The overall frequency of CNVs in regions with reported associations with schizophrenia (chromosomes 1q21.1, 15q13.3, 16p11.2, and 22q11.2 and the neurexin-1 gene [NRXN1]) was similar to previous case-control studies. NRXN1 deletions and 16p11.2 duplications (both of which were transmitted from parents) and 22q11.2 deletions (de novo in four cases) did not segregate with schizophrenia in families.
  
  
  CONCLUSIONS
  Many common SNPs are likely to contribute to schizophrenia risk, with substantial overlap in genetic risk factors between multiply affected families and cases in large case-control studies. Our findings are consistent with a role for specific CNVs in disease pathogenesis, but the partial segregation of some CNVs with schizophrenia suggests that researchers should exercise caution in using them for predictive genetic testing until their effects in diverse populations have been fully studied.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, Calif., USA. dflev@stanford.edu
authors.forename: Douglas F
authors.initials: DF
authors.lastname: Levinson
authors.forename: Jianxin
authors.initials: J
authors.lastname: Shi
authors.forename: Kai
authors.initials: K
authors.lastname: Wang
authors.forename: Sang
authors.initials: S
authors.lastname: Oh
authors.forename: Brien
authors.initials: B
authors.lastname: Riley
authors.forename: Ann E
authors.initials: AE
authors.lastname: Pulver
authors.forename: Dieter B
authors.initials: DB
authors.lastname: Wildenauer
authors.forename: Claudine
authors.initials: C
authors.lastname: Laurent
authors.forename: Bryan J
authors.initials: BJ
authors.lastname: Mowry
authors.forename: Pablo V
authors.initials: PV
authors.lastname: Gejman
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Owen
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Kendler
authors.forename: Gerald
authors.initials: G
authors.lastname: Nestadt
authors.forename: Sibylle G
authors.initials: SG
authors.lastname: Schwab
authors.forename: Jacques
authors.initials: J
authors.lastname: Mallet
authors.forename: Deborah
authors.initials: D
authors.lastname: Nertney
authors.forename: Alan R
authors.initials: AR
authors.lastname: Sanders
authors.forename: Nigel M
authors.initials: NM
authors.lastname: Williams
authors.forename: Brandon
authors.initials: B
authors.lastname: Wormley
authors.forename: Virginia K
authors.initials: VK
authors.lastname: Lasseter
authors.forename: Margot
authors.initials: M
authors.lastname: Albus
authors.forename: Stephanie
authors.initials: S
authors.lastname: Godard-Bauché
authors.forename: Madeline
authors.initials: M
authors.lastname: Alexander
authors.forename: Jubao
authors.initials: J
authors.lastname: Duan
authors.forename: Michael C
authors.initials: MC
authors.lastname: O'Donovan
authors.forename: Dermot
authors.initials: D
authors.lastname: Walsh
authors.forename: Anthony
authors.initials: A
authors.lastname: O'Neill
authors.forename: George N
authors.initials: GN
authors.lastname: Papadimitriou
authors.forename: Dimitris
authors.initials: D
authors.lastname: Dikeos
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Maier
authors.forename: Bernard
authors.initials: B
authors.lastname: Lerer
authors.forename: Dominique
authors.initials: D
authors.lastname: Campion
authors.forename: David
authors.initials: D
authors.lastname: Cohen
authors.forename: Maurice
authors.initials: M
authors.lastname: Jay
authors.forename: Ayman
authors.initials: A
authors.lastname: Fanous
authors.forename: Peter
authors.initials: P
authors.lastname: Eichhammer
authors.forename: Jeremy M
authors.initials: JM
authors.lastname: Silverman
authors.forename: Nadine
authors.initials: N
authors.lastname: Norton
authors.forename: Nancy
authors.initials: N
authors.lastname: Zhang
authors.forename: Hakon
authors.initials: H
authors.lastname: Hakonarson
authors.forename: Cynthia
authors.initials: C
authors.lastname: Gao
authors.forename: Ami
authors.initials: A
authors.lastname: Citri
authors.forename: Mark
authors.initials: M
authors.lastname: Hansen
authors.forename: Stephan
authors.initials: S
authors.lastname: Ripke
authors.forename: Frank
authors.initials: F
authors.lastname: Dudbridge
authors.forename: Peter A
authors.initials: PA
authors.lastname: Holmans
mesh_terms: D044383:Black People / Q000235:genetics; D016022:Case-Control Studies; D056915:DNA Copy Number Variations / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods / Q000706:statistics & numerical data*; D005838:Genotype; D006801:Humans; D008297:Male; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012559:Schizophrenia / Q000235:genetics*; D044465:White People / Q000235:genetics