title: A comprehensive family-based replication study of schizophrenia genes.
abstract: OBJECTIVE
  Schizophrenia (SCZ) is a devastating psychiatric condition. Identifying the specific genetic variants and pathways that increase susceptibility to SCZ is critical to improve disease understanding and address the urgent need for new drug targets.
  
  
  OBJECTIVE
  To identify SCZ susceptibility genes.
  
  
  METHODS
  We integrated results from a meta-analysis of 18 genome-wide association studies (GWAS) involving 1,085,772 single-nucleotide polymorphisms (SNPs) and 6 databases that showed significant informativeness for SCZ. The 9380 most promising SNPs were then specifically genotyped in an independent family-based replication study that, after quality control, consisted of 8107 SNPs.
  
  
  METHODS
  Linkage meta-analysis, brain transcriptome meta-analysis, candidate gene database, OMIM, relevant mouse studies, and expression quantitative trait locus databases.
  
  
  METHODS
  We included 11,185 cases and 10,768 control subjects from 6 databases and, after quality control 6298 individuals (including 3286 cases) from 1811 nuclear families.
  
  
  METHODS
  Case-control status for SCZ.
  
  
  RESULTS
  Replication results showed a highly significant enrichment of SNPs with small P values. Of the SNPs with replication values of P.01, the proportion of SNPs that had the same direction of effects as in the GWAS meta-analysis was 89% in the combined ancestry group (sign test, P < 2.20 x 10(-16) and 93% in subjects of European ancestry only (P < 2.20 < 10(-16)). Our results supported the major histocompatibility complex region showing a3.7-fold overall enrichment of replication values of P < .01 in subjects from European ancestry. We replicated SNPs in TCF4 (P = 2.53 x 10(-10)) and NOTCH4 (P = 3.16 x 10(-7)) that are among the most robust SCZ findings. More novel findings included POM121L2 (P = 3.51 x 10(-7)), AS3MT (P = 9.01 x 10(-7)), CNNM2 (P = 6.07 = 10(-7)), and NT5C2(P = 4.09 x 10(-7)). To explore the many small effects, we performed pathway analyses. The most significant pathways involved neuronal function (axonal guidance, neuronal systems, and L1 cell adhesion molecule interaction)and the immune system (antigen processing, cell adhesion molecules relevant to T cells, and translocation to immunological synapse).
  
  
  CONCLUSIONS
  We replicated novel SCZ disease genes and pathogenic pathways. Better understanding the molecular and biological mechanisms involved with schizophrenia may improve disease management and may identify new drug targets.
authors.affiliation: Center for Biomarker Research and Personalized Medicine, Virginia Commonwealth University, Richmond 23298, USA.
authors.forename: Karolina A
authors.initials: KA
authors.lastname: Aberg
authors.forename: Youfang
authors.initials: Y
authors.lastname: Liu
authors.forename: Jozsef
authors.initials: J
authors.lastname: Bukszár
authors.forename: Joseph L
authors.initials: JL
authors.lastname: McClay
authors.forename: Amit N
authors.initials: AN
authors.lastname: Khachane
authors.forename: Ole A
authors.initials: OA
authors.lastname: Andreassen
authors.forename: Douglas
authors.initials: D
authors.lastname: Blackwood
authors.forename: Aiden
authors.initials: A
authors.lastname: Corvin
authors.forename: Srdjan
authors.initials: S
authors.lastname: Djurovic
authors.forename: Hugh
authors.initials: H
authors.lastname: Gurling
authors.forename: Roel
authors.initials: R
authors.lastname: Ophoff
authors.forename: Carlos N
authors.initials: CN
authors.lastname: Pato
authors.forename: Michele T
authors.initials: MT
authors.lastname: Pato
authors.forename: Brien
authors.initials: B
authors.lastname: Riley
authors.forename: Todd
authors.initials: T
authors.lastname: Webb
authors.forename: Kenneth
authors.initials: K
authors.lastname: Kendler
authors.forename: Mick
authors.initials: M
authors.lastname: O'Donovan
authors.forename: Nick
authors.initials: N
authors.lastname: Craddock
authors.forename: George
authors.initials: G
authors.lastname: Kirov
authors.forename: Mike
authors.initials: M
authors.lastname: Owen
authors.forename: Dan
authors.initials: D
authors.lastname: Rujescu
authors.forename: David
authors.initials: D
authors.lastname: St Clair
authors.forename: Thomas
authors.initials: T
authors.lastname: Werge
authors.forename: Christina M
authors.initials: CM
authors.lastname: Hultman
authors.forename: Lynn E
authors.initials: LE
authors.lastname: Delisi
authors.forename: Patrick
authors.initials: P
authors.lastname: Sullivan
authors.forename: Edwin J
authors.initials: EJ
authors.lastname: van den Oord
mesh_terms: D000818:Animals; D005190:Family; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D006801:Humans; D051379:Mice; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012559:Schizophrenia / Q000235:genetics*
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