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 IidakaToshiya Inada, Michio Suzuki, Hiroshi Ujike, Hiroshi Kunugi, Tadafumi Kato, Takeo Yoshikawa, Nakao Iwata, Kozo Kaibuchi, Norio Ozaki

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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

All Science Journal Classification (ASJC) codes

  • Psychiatry and Mental health

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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., ... Ozaki, N. (2015). Identification of rare, single-nucleotide mutations in NDE1 and their contributions to schizophrenia susceptibility. Schizophrenia Bulletin, 41(3), 744-753. https://doi.org/10.1093/schbul/sbu147