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
N1 - Publisher Copyright:
© The Author 2015.
PY - 2015/5
Y1 - 2015/5
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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U2 - 10.1093/schbul/sbu147
DO - 10.1093/schbul/sbu147
M3 - Article
C2 - 25332407
AN - SCOPUS:84930538918
SN - 0586-7614
VL - 41
SP - 744
EP - 753
JO - Schizophrenia Bulletin
JF - Schizophrenia Bulletin
IS - 3
ER -