title: Failure to replicate the association between NRG1 and schizophrenia using Japanese large sample.
abstract: Systematic linkage disequilibrium (LD) mapping of 8p12-21 in the Icelandic population identified neuregulin 1 (NRG1) as a prime candidate gene for schizophrenia. However, results of replication studies have been inconsistent, and no large sample analyses have been reported. Therefore, we designed this study with the aim of assessing this putative association between schizophrenia and NRG1 (especially HAP(ICE) region and exon region) using a gene-based association approach in the Japanese population. This study was a two-stage association analysis with a different panel of samples, in which the significant association found in the first-set screening samples (1126 cases and 1022 controls) was further assessed in the confirmation samples (1262 cases and 1172 controls, and 166 trio samples). In the first-set scan, 60 SNPs (49 tagging SNPs from HapMap database, four SNPs from other papers, and seven SNPs detected in the mutation scan) were examined. One haplotype showed a significant association in the first-set screening samples (Global P-value=0.0244, uncorrected). However, we could not replicate this association in the following independent confirmation samples. Moreover, we could not find sufficient evidence for association of the haplotype identified as being significant in the first-set samples by imputing ungenotyped SNPs from HapMap database. These results indicate that the positionally and functionally attractive regions of NRG1 are unlikely to contribute to susceptibility to schizophrenia in the Japanese population. Moreover, the nature of our results support that two-stage analysis with large sample size is appropriate to examine the susceptibility genes for common diseases.
authors.affiliation: Department of Psychiatry, Fujita Health University School of Medicine, Aichi, Japan. ikeda-ma@fujita-hu.ac.jp
authors.forename: Masashi
authors.initials: M
authors.lastname: Ikeda
authors.forename: Nagahide
authors.initials: N
authors.lastname: Takahashi
authors.forename: Shinichi
authors.initials: S
authors.lastname: Saito
authors.forename: Branko
authors.initials: B
authors.lastname: Aleksic
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Watanabe
authors.forename: Ayako
authors.initials: A
authors.lastname: Nunokawa
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Yamanouchi
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Kitajima
authors.forename: Yoko
authors.initials: Y
authors.lastname: Kinoshita
authors.forename: Taro
authors.initials: T
authors.lastname: Kishi
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Kawashima
authors.forename: Ryota
authors.initials: R
authors.lastname: Hashimoto
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ujike
authors.forename: Toshiya
authors.initials: T
authors.lastname: Inada
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Someya
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Takeda
authors.forename: Norio
authors.initials: N
authors.lastname: Ozaki
authors.forename: Nakao
authors.initials: N
authors.lastname: Iwata
mesh_terms: D000328:Adult; D000368:Aged; D030541:Databases, Genetic / Q000706:statistics & numerical data; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007564:Japan / Q000453:epidemiology; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics*; D020890:Neuregulin-1; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012559:Schizophrenia / Q000235:genetics*
chemical_list: C094131:NRG1 protein, human; D009419:Nerve Tissue Proteins; D020890:Neuregulin-1