Failure to replicate the association between NRG1 and schizophrenia using Japanese large sample

Masashi Ikeda, Nagahide Takahashi, Shinichi Saito, Branko Aleksic, Yuichiro Watanabe, Ayako Nunokawa, Yoshio Yamanouchi, Tsuyoshi Kitajima, Yoko Kinoshita, Taro Kishi, Kunihiro Kawashima, Ryota Hashimoto, Hiroshi Ujike, Toshiya Inada, Toshiyuki Someya, Masatoshi Takeda, Norio Ozaki, Nakao Iwata

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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 HAPICE 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.

Original languageEnglish
Pages (from-to)1-8
Number of pages8
JournalSchizophrenia Research
Volume101
Issue number1-3
DOIs
Publication statusPublished - 01-04-2008

Fingerprint

Neuregulin-1
Single Nucleotide Polymorphism
Schizophrenia
HapMap Project
Haplotypes
Databases
Population
Genes
Chromosome Mapping
Linkage Disequilibrium
Sample Size
Exons
Mutation

All Science Journal Classification (ASJC) codes

  • Psychiatry and Mental health
  • Biological Psychiatry

Cite this

Ikeda, Masashi ; Takahashi, Nagahide ; Saito, Shinichi ; Aleksic, Branko ; Watanabe, Yuichiro ; Nunokawa, Ayako ; Yamanouchi, Yoshio ; Kitajima, Tsuyoshi ; Kinoshita, Yoko ; Kishi, Taro ; Kawashima, Kunihiro ; Hashimoto, Ryota ; Ujike, Hiroshi ; Inada, Toshiya ; Someya, Toshiyuki ; Takeda, Masatoshi ; Ozaki, Norio ; Iwata, Nakao. / Failure to replicate the association between NRG1 and schizophrenia using Japanese large sample. In: Schizophrenia Research. 2008 ; Vol. 101, No. 1-3. pp. 1-8.
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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 HAPICE 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.",
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Ikeda, M, Takahashi, N, Saito, S, Aleksic, B, Watanabe, Y, Nunokawa, A, Yamanouchi, Y, Kitajima, T, Kinoshita, Y, Kishi, T, Kawashima, K, Hashimoto, R, Ujike, H, Inada, T, Someya, T, Takeda, M, Ozaki, N & Iwata, N 2008, 'Failure to replicate the association between NRG1 and schizophrenia using Japanese large sample', Schizophrenia Research, vol. 101, no. 1-3, pp. 1-8. https://doi.org/10.1016/j.schres.2008.01.010

Failure to replicate the association between NRG1 and schizophrenia using Japanese large sample. / Ikeda, Masashi; Takahashi, Nagahide; Saito, Shinichi; Aleksic, Branko; Watanabe, Yuichiro; Nunokawa, Ayako; Yamanouchi, Yoshio; Kitajima, Tsuyoshi; Kinoshita, Yoko; Kishi, Taro; Kawashima, Kunihiro; Hashimoto, Ryota; Ujike, Hiroshi; Inada, Toshiya; Someya, Toshiyuki; Takeda, Masatoshi; Ozaki, Norio; Iwata, Nakao.

In: Schizophrenia Research, Vol. 101, No. 1-3, 01.04.2008, p. 1-8.

Research output: Contribution to journalArticle

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T1 - Failure to replicate the association between NRG1 and schizophrenia using Japanese large sample

AU - Ikeda, Masashi

AU - Takahashi, Nagahide

AU - Saito, Shinichi

AU - Aleksic, Branko

AU - Watanabe, Yuichiro

AU - Nunokawa, Ayako

AU - Yamanouchi, Yoshio

AU - Kitajima, Tsuyoshi

AU - Kinoshita, Yoko

AU - Kishi, Taro

AU - Kawashima, Kunihiro

AU - Hashimoto, Ryota

AU - Ujike, Hiroshi

AU - Inada, Toshiya

AU - Someya, Toshiyuki

AU - Takeda, Masatoshi

AU - Ozaki, Norio

AU - Iwata, Nakao

PY - 2008/4/1

Y1 - 2008/4/1

N2 - 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 HAPICE 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.

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