title: Association study of Nogo-related genes with schizophrenia in a Japanese case-control sample.
abstract: Many studies have suggested that myelin dysfunction may be causally involved in the pathogenesis of schizophrenia. Nogo (RTN4), myelin-associated glycoprotein (MAG) and oligodendrocyte myelin glycoprotein (OMG) all bind to the common receptor, Nogo-66 receptor 1 (RTN4R). We examined 68 single nucleotide polymorphisms (SNPs) (51 with genotyping and 17 with imputation analysis) from these four genes for genetic association with schizophrenia, using a 2,120 case-control sample from the Japanese population. Allelic tests showed nominally significant association of two RTN4 SNPs (P = 0.047 and 0.037 for rs11894868 and rs2968804, respectively) and two MAG SNPs (P = 0.034 and 0.029 for rs7249617 and rs16970218, respectively) with schizophrenia. The MAG SNP rs7249617 also showed nominal significance in a genotypic test (P = 0.017). In haplotype analysis, the MAG haplotype block including rs7249617 and rs16970218 showed nominal significance (P = 0.008). These associations did not remain significant after correction for multiple testing, possibly due to their small genetic effect. In the imputation analysis of RTN4, the untyped SNP rs2972090 showed nominally significant association (P = 0.032) and several imputed SNPs showed marginal associations. Moreover, in silico analysis (PolyPhen) of a missense variant (rs11677099: Asp357Val), which is in strong linkage disequilibrium with rs11894868, predicted a deleterious effect on Nogo protein function. Despite a failure to detect robust associations in this Japanese cohort, our nominally positive signals, taken together with previously reported biological and genetic findings, add further support to the "disturbed myelin system theory of schizophrenia" across different populations.
authors.affiliation: Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Wako, Saitama, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Jitoku
authors.forename: Eiji
authors.initials: E
authors.lastname: Hattori
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Iwayama
authors.forename: Kazuo
authors.initials: K
authors.lastname: Yamada
authors.forename: Tomoko
authors.initials: T
authors.lastname: Toyota
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Kikuchi
authors.forename: Motoko
authors.initials: M
authors.lastname: Maekawa
authors.forename: Toru
authors.initials: T
authors.lastname: Nishikawa
authors.forename: Takeo
authors.initials: T
authors.lastname: Yoshikawa
mesh_terms: D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D005260:Female; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007564:Japan; D008297:Male; D008875:Middle Aged; D009185:Myelin Proteins / Q000235:genetics* / Q000378:metabolism; D018992:Myelin-Associated Glycoprotein / Q000235:genetics* / Q000378:metabolism; D000070798:Nogo Proteins; D000070816:Nogo Receptor 1; D020641:Polymorphism, Single Nucleotide; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000378:metabolism; D012559:Schizophrenia / Q000235:genetics*
chemical_list: D058851:GPI-Linked Proteins; C560487:MOBP protein, human; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D000070798:Nogo Proteins; D000070816:Nogo Receptor 1; C000603199:RTN4 protein, human; C486580:RTN4R protein, human; D011956:Receptors, Cell Surface