title: A population-specific uncommon variant in GRIN3A associated with schizophrenia.
abstract: BACKGROUND
  Genome-wide association studies have successfully identified several common variants showing robust association with schizophrenia. However, individually, these variants only produce a weak effect. To identify genetic variants with larger effect sizes, increasing attention is now being paid to uncommon and rare variants.
  
  
  METHODS
  From the 1000 Genomes Project data, we selected 47 candidate single nucleotide variants (SNVs), which were: 1) uncommon (minor allele frequency < 5%); 2) Asian-specific; 3) missense, nonsense, or splice site variants predicted to be damaging; and 4) located in candidate genes for schizophrenia and bipolar disorder. We examined their association with schizophrenia, using a Japanese case-control cohort (2012 cases and 2781 control subjects). Additional meta-analysis was performed using genotyping data from independent Han-Chinese case-control (333 cases and 369 control subjects) and family samples (9 trios and 284 quads).
  
  
  RESULTS
  We identified disease association of a missense variant in GRIN3A (p.R480G, rs149729514, p = .00042, odds ratio [OR] = 1.58), encoding a subunit of the N-methyl-D-aspartate type glutamate receptor, with study-wide significance (threshold p = .0012). This association was supported by meta-analysis (combined p = 3.3 × 10(-5), OR = 1.61). Nominally significant association was observed in missense variants from FAAH, DNMT1, MYO18B, and CFB, with ORs of risk alleles ranging from 1.41 to 2.35.
  
  
  CONCLUSIONS
  The identified SNVs, particularly the GRIN3A R480G variant, are good candidates for further replication studies and functional evaluation. The results of this study indicate that association analyses focusing on uncommon and rare SNVs are a promising way to discover risk variants with larger effects.
authors.affiliation: Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Saitama, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Takata
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Iwayama
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Fukuo
authors.forename: Masashi
authors.initials: M
authors.lastname: Ikeda
authors.forename: Tomo
authors.initials: T
authors.lastname: Okochi
authors.forename: Motoko
authors.initials: M
authors.lastname: Maekawa
authors.forename: Tomoko
authors.initials: T
authors.lastname: Toyota
authors.forename: Kazuo
authors.initials: K
authors.lastname: Yamada
authors.forename: Eiji
authors.initials: E
authors.lastname: Hattori
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Ohnishi
authors.forename: Manabu
authors.initials: M
authors.lastname: Toyoshima
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ujike
authors.forename: Toshiya
authors.initials: T
authors.lastname: Inada
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kunugi
authors.forename: Norio
authors.initials: N
authors.lastname: Ozaki
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Nanko
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Nakamura
authors.forename: Norio
authors.initials: N
authors.lastname: Mori
authors.forename: Shigenobu
authors.initials: S
authors.lastname: Kanba
authors.forename: Nakao
authors.initials: N
authors.lastname: Iwata
authors.forename: Tadafumi
authors.initials: T
authors.lastname: Kato
authors.forename: Takeo
authors.initials: T
authors.lastname: Yoshikawa
mesh_terms: D044466:Asian People / Q000235:genetics* / Q000523:psychology; D001714:Bipolar Disorder / Q000235:genetics; D016022:Case-Control Studies; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics*; D012559:Schizophrenia / Q000235:genetics*
chemical_list: C548929:GRIN3A protein, human; D016194:Receptors, N-Methyl-D-Aspartate