Identification of rare, single-nucleotide mutations in NDE1 and their contributions to schizophrenia susceptibility

Hiroki Kimura, Daisuke Tsuboi, Chenyao Wang, Itaru Kushima, Takayoshi Koide, Masashi Ikeda, Yoshimi Iwayama, Tomoko Toyota, Noriko Yamamoto, Shohko Kunimoto, Yukako Nakamura, Akira Yoshimi, Masahiro Banno, Jingrui Xing, Yuto Takasaki, Mami Yoshida, Branko Aleksic, Yota Uno, Takashi Okada, Tetsuya Iidaka & 9 others Toshiya Inada, Michio Suzuki, Hiroshi Ujike, Hiroshi Kunugi, Tadafumi Kato, Takeo Yoshikawa, Nakao Iwata, Kozo Kaibuchi, Norio Ozaki

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Background: Nuclear distribution E homolog 1 (NDE1), located within chromosome 16p13.11, plays an essential role in microtubule organization, mitosis, and neuronal migration and has been suggested by several studies of rare copy number variants to be a promising schizophrenia (SCZ) candidate gene. Recently, increasing attention has been paid to rare single-nucleotide variants (SNVs) discovered by deep sequencing of candidate genes, because such SNVs may have large effect sizes and their functional analysis may clarify etiopathology. Methods and Results: We conducted mutation screening of NDE1 coding exons using 433 SCZ and 145 pervasive developmental disorders samples in order to identify rare single nucleotide variants with a minor allele frequency =5%. We then performed genetic association analysis using a large number of unrelated individuals (3554 SCZ, 1041 bipolar disorder [BD], and 4746 controls). Among the discovered novel rare variants, we detected significant associations between SCZ and S214F (P = .039), and between BD and R234C (P = .032). Furthermore, functional assays showed that S214F affected axonal outgrowth and the interaction between NDE1 and YWHAE (14-3-3 epsilon; a neurodevelopmental regulator). Conclusions: This study strengthens the evidence for association between rare variants within NDE1 and SCZ, and may shed light into the molecular mechanisms underlying this severe psychiatric disorder.

Original languageEnglish
Pages (from-to)744-753
Number of pages10
JournalSchizophrenia Bulletin
Volume41
Issue number3
DOIs
Publication statusPublished - 01-01-2015

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Schizophrenia
Nucleotides
Mutation
Bipolar Disorder
High-Throughput Nucleotide Sequencing
Mitosis
Gene Frequency
Microtubules
Genes
Psychiatry
Exons
Chromosomes

All Science Journal Classification (ASJC) codes

  • Psychiatry and Mental health

Cite this

Kimura, Hiroki ; Tsuboi, Daisuke ; Wang, Chenyao ; Kushima, Itaru ; Koide, Takayoshi ; Ikeda, Masashi ; Iwayama, Yoshimi ; Toyota, Tomoko ; Yamamoto, Noriko ; Kunimoto, Shohko ; Nakamura, Yukako ; Yoshimi, Akira ; Banno, Masahiro ; Xing, Jingrui ; Takasaki, Yuto ; Yoshida, Mami ; Aleksic, Branko ; Uno, Yota ; Okada, Takashi ; Iidaka, Tetsuya ; Inada, Toshiya ; Suzuki, Michio ; Ujike, Hiroshi ; Kunugi, Hiroshi ; Kato, Tadafumi ; Yoshikawa, Takeo ; Iwata, Nakao ; Kaibuchi, Kozo ; Ozaki, Norio. / Identification of rare, single-nucleotide mutations in NDE1 and their contributions to schizophrenia susceptibility. In: Schizophrenia Bulletin. 2015 ; Vol. 41, No. 3. pp. 744-753.
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abstract = "Background: Nuclear distribution E homolog 1 (NDE1), located within chromosome 16p13.11, plays an essential role in microtubule organization, mitosis, and neuronal migration and has been suggested by several studies of rare copy number variants to be a promising schizophrenia (SCZ) candidate gene. Recently, increasing attention has been paid to rare single-nucleotide variants (SNVs) discovered by deep sequencing of candidate genes, because such SNVs may have large effect sizes and their functional analysis may clarify etiopathology. Methods and Results: We conducted mutation screening of NDE1 coding exons using 433 SCZ and 145 pervasive developmental disorders samples in order to identify rare single nucleotide variants with a minor allele frequency =5{\%}. We then performed genetic association analysis using a large number of unrelated individuals (3554 SCZ, 1041 bipolar disorder [BD], and 4746 controls). Among the discovered novel rare variants, we detected significant associations between SCZ and S214F (P = .039), and between BD and R234C (P = .032). Furthermore, functional assays showed that S214F affected axonal outgrowth and the interaction between NDE1 and YWHAE (14-3-3 epsilon; a neurodevelopmental regulator). Conclusions: This study strengthens the evidence for association between rare variants within NDE1 and SCZ, and may shed light into the molecular mechanisms underlying this severe psychiatric disorder.",
author = "Hiroki Kimura and Daisuke Tsuboi and Chenyao Wang and Itaru Kushima and Takayoshi Koide and Masashi Ikeda and Yoshimi Iwayama and Tomoko Toyota and Noriko Yamamoto and Shohko Kunimoto and Yukako Nakamura and Akira Yoshimi and Masahiro Banno and Jingrui Xing and Yuto Takasaki and Mami Yoshida and Branko Aleksic and Yota Uno and Takashi Okada and Tetsuya Iidaka and Toshiya Inada and Michio Suzuki and Hiroshi Ujike and Hiroshi Kunugi and Tadafumi Kato and Takeo Yoshikawa and Nakao Iwata and Kozo Kaibuchi and Norio Ozaki",
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Kimura, H, Tsuboi, D, Wang, C, Kushima, I, Koide, T, Ikeda, M, Iwayama, Y, Toyota, T, Yamamoto, N, Kunimoto, S, Nakamura, Y, Yoshimi, A, Banno, M, Xing, J, Takasaki, Y, Yoshida, M, Aleksic, B, Uno, Y, Okada, T, Iidaka, T, Inada, T, Suzuki, M, Ujike, H, Kunugi, H, Kato, T, Yoshikawa, T, Iwata, N, Kaibuchi, K & Ozaki, N 2015, 'Identification of rare, single-nucleotide mutations in NDE1 and their contributions to schizophrenia susceptibility', Schizophrenia Bulletin, vol. 41, no. 3, pp. 744-753. https://doi.org/10.1093/schbul/sbu147

Identification of rare, single-nucleotide mutations in NDE1 and their contributions to schizophrenia susceptibility. / Kimura, Hiroki; Tsuboi, Daisuke; Wang, Chenyao; Kushima, Itaru; Koide, Takayoshi; Ikeda, Masashi; Iwayama, Yoshimi; Toyota, Tomoko; Yamamoto, Noriko; Kunimoto, Shohko; Nakamura, Yukako; Yoshimi, Akira; Banno, Masahiro; Xing, Jingrui; Takasaki, Yuto; Yoshida, Mami; Aleksic, Branko; Uno, Yota; Okada, Takashi; Iidaka, Tetsuya; Inada, Toshiya; Suzuki, Michio; Ujike, Hiroshi; Kunugi, Hiroshi; Kato, Tadafumi; Yoshikawa, Takeo; Iwata, Nakao; Kaibuchi, Kozo; Ozaki, Norio.

In: Schizophrenia Bulletin, Vol. 41, No. 3, 01.01.2015, p. 744-753.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Identification of rare, single-nucleotide mutations in NDE1 and their contributions to schizophrenia susceptibility

AU - Kimura, Hiroki

AU - Tsuboi, Daisuke

AU - Wang, Chenyao

AU - Kushima, Itaru

AU - Koide, Takayoshi

AU - Ikeda, Masashi

AU - Iwayama, Yoshimi

AU - Toyota, Tomoko

AU - Yamamoto, Noriko

AU - Kunimoto, Shohko

AU - Nakamura, Yukako

AU - Yoshimi, Akira

AU - Banno, Masahiro

AU - Xing, Jingrui

AU - Takasaki, Yuto

AU - Yoshida, Mami

AU - Aleksic, Branko

AU - Uno, Yota

AU - Okada, Takashi

AU - Iidaka, Tetsuya

AU - Inada, Toshiya

AU - Suzuki, Michio

AU - Ujike, Hiroshi

AU - Kunugi, Hiroshi

AU - Kato, Tadafumi

AU - Yoshikawa, Takeo

AU - Iwata, Nakao

AU - Kaibuchi, Kozo

AU - Ozaki, Norio

PY - 2015/1/1

Y1 - 2015/1/1

N2 - Background: Nuclear distribution E homolog 1 (NDE1), located within chromosome 16p13.11, plays an essential role in microtubule organization, mitosis, and neuronal migration and has been suggested by several studies of rare copy number variants to be a promising schizophrenia (SCZ) candidate gene. Recently, increasing attention has been paid to rare single-nucleotide variants (SNVs) discovered by deep sequencing of candidate genes, because such SNVs may have large effect sizes and their functional analysis may clarify etiopathology. Methods and Results: We conducted mutation screening of NDE1 coding exons using 433 SCZ and 145 pervasive developmental disorders samples in order to identify rare single nucleotide variants with a minor allele frequency =5%. We then performed genetic association analysis using a large number of unrelated individuals (3554 SCZ, 1041 bipolar disorder [BD], and 4746 controls). Among the discovered novel rare variants, we detected significant associations between SCZ and S214F (P = .039), and between BD and R234C (P = .032). Furthermore, functional assays showed that S214F affected axonal outgrowth and the interaction between NDE1 and YWHAE (14-3-3 epsilon; a neurodevelopmental regulator). Conclusions: This study strengthens the evidence for association between rare variants within NDE1 and SCZ, and may shed light into the molecular mechanisms underlying this severe psychiatric disorder.

AB - Background: Nuclear distribution E homolog 1 (NDE1), located within chromosome 16p13.11, plays an essential role in microtubule organization, mitosis, and neuronal migration and has been suggested by several studies of rare copy number variants to be a promising schizophrenia (SCZ) candidate gene. Recently, increasing attention has been paid to rare single-nucleotide variants (SNVs) discovered by deep sequencing of candidate genes, because such SNVs may have large effect sizes and their functional analysis may clarify etiopathology. Methods and Results: We conducted mutation screening of NDE1 coding exons using 433 SCZ and 145 pervasive developmental disorders samples in order to identify rare single nucleotide variants with a minor allele frequency =5%. We then performed genetic association analysis using a large number of unrelated individuals (3554 SCZ, 1041 bipolar disorder [BD], and 4746 controls). Among the discovered novel rare variants, we detected significant associations between SCZ and S214F (P = .039), and between BD and R234C (P = .032). Furthermore, functional assays showed that S214F affected axonal outgrowth and the interaction between NDE1 and YWHAE (14-3-3 epsilon; a neurodevelopmental regulator). Conclusions: This study strengthens the evidence for association between rare variants within NDE1 and SCZ, and may shed light into the molecular mechanisms underlying this severe psychiatric disorder.

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DO - 10.1093/schbul/sbu147

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