title: Association study of nonsynonymous single nucleotide polymorphisms in schizophrenia.
abstract: BACKGROUND
  Genome-wide association studies using several hundred thousand anonymous markers present limited statistical power. Alternatively, association studies restricted to common nonsynonymous single nucleotide polymorphisms (nsSNPs) have the advantage of strongly reducing the multiple testing problem, while increasing the probability of testing functional single nucleotide polymorphisms (SNPs).
  
  
  METHODS
  We performed a case-control association study of common nsSNPs in Galician (northwest Spain) samples using the Affymetrix GeneChip Human 20k cSNP Kit, followed by a replication study of the more promising results. After quality control procedures, the discovery sample consisted of 5100 nsSNPs at minor allele frequency >5% analyzed in 476 schizophrenia patients and 447 control subjects. The replication sample consisted of 4069 cases and 15,128 control subjects of European origin. We also performed multilocus analysis, using aggregated scores of nsSNPs at liberal significance thresholds and cross-validation procedures.
  
  
  RESULTS
  The 5 independent nsSNPs with false discovery rate q ≤ .25, as well as 13 additional nsSNPs at p < .01 and located in functional candidate genes, were genotyped in the replication samples. One SNP, rs13107325, located at the metal ions transporter gene SLC39A8, reached significance in the combined sample after Bonferroni correction (trend test, p = 2.7 × 10(-6), allelic odds ratio = 1.32). This SNP presents minor allele frequency of 5% to 10% in many European populations but is rare outside Europe. We also confirmed the polygenic component of susceptibility.
  
  
  CONCLUSIONS
  Taking into account that another metal ions transporter gene, SLC39A3, is associated to bipolar disorder, our findings reveal a role for brain metal homeostasis in psychosis.
authors.affiliation: Fundación Pública Galega de Medicina Xenómica-SERGAS, Hospital Clínico Universitario, Santiago de Compostela, Spain.
authors.forename: Noa
authors.initials: N
authors.lastname: Carrera
authors.forename: Manuel
authors.initials: M
authors.lastname: Arrojo
authors.forename: Julio
authors.initials: J
authors.lastname: Sanjuán
authors.forename: Ramón
authors.initials: R
authors.lastname: Ramos-Ríos
authors.forename: Eduardo
authors.initials: E
authors.lastname: Paz
authors.forename: Jose J
authors.initials: JJ
authors.lastname: Suárez-Rama
authors.forename: Mario
authors.initials: M
authors.lastname: Páramo
authors.forename: Santiago
authors.initials: S
authors.lastname: Agra
authors.forename: Julio
authors.initials: J
authors.lastname: Brenlla
authors.forename: Silvia
authors.initials: S
authors.lastname: Martínez
authors.forename: Olga
authors.initials: O
authors.lastname: Rivero
authors.forename: David A
authors.initials: DA
authors.lastname: Collier
authors.forename: Aarno
authors.initials: A
authors.lastname: Palotie
authors.forename: Sven
authors.initials: S
authors.lastname: Cichon
authors.forename: Markus M
authors.initials: MM
authors.lastname: Nöthen
authors.forename: Marcella
authors.initials: M
authors.lastname: Rietschel
authors.forename: Dan
authors.initials: D
authors.lastname: Rujescu
authors.forename: Hreinn
authors.initials: H
authors.lastname: Stefansson
authors.forename: Stacy
authors.initials: S
authors.lastname: Steinberg
authors.forename: Engilbert
authors.initials: E
authors.lastname: Sigurdsson
authors.forename: David
authors.initials: D
authors.lastname: St Clair
authors.forename: Sarah
authors.initials: S
authors.lastname: Tosato
authors.forename: Thomas
authors.initials: T
authors.lastname: Werge
authors.forename: Kari
authors.initials: K
authors.lastname: Stefansson
authors.forename: Jose Carlos
authors.initials: JC
authors.lastname: González
authors.forename: Joaquín
authors.initials: J
authors.lastname: Valero
authors.forename: Alfonso
authors.initials: A
authors.lastname: Gutiérrez-Zotes
authors.forename: Antonio
authors.initials: A
authors.lastname: Labad
authors.forename: Lourdes
authors.initials: L
authors.lastname: Martorell
authors.forename: Elisabet
authors.initials: E
authors.lastname: Vilella
authors.forename: Ángel
authors.initials: Á
authors.lastname: Carracedo
authors.forename: Javier
authors.initials: J
authors.lastname: Costas
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D027682:Cation Transport Proteins / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies / Q000379:methods / Q000706:statistics & numerical data*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012559:Schizophrenia / Q000235:genetics*; D013030:Spain
chemical_list: D027682:Cation Transport Proteins; C530151:SLC39A8 protein, human