title: Identification of Rare, Single-Nucleotide Mutations in NDE1 and Their Contributions to Schizophrenia Susceptibility.
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.
  
  
  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.
authors.affiliation: Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan;
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kimura
authors.affiliation: Department of Cell Pharmacology, Nagoya University Graduate School of Medicine, Nagoya, Japan;
authors.forename: Daisuke
authors.initials: D
authors.lastname: Tsuboi
authors.affiliation: Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan;
authors.forename: Chenyao
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan;
authors.forename: Itaru
authors.initials: I
authors.lastname: Kushima
authors.affiliation: Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan;
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Koide
authors.affiliation: Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Aichi, Japan;
authors.forename: Masashi
authors.initials: M
authors.lastname: Ikeda
authors.affiliation: Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Wako, Saitama, Japan;
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Iwayama
authors.affiliation: Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Wako, Saitama, Japan;
authors.forename: Tomoko
authors.initials: T
authors.lastname: Toyota
authors.affiliation: Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan;
authors.forename: Noriko
authors.initials: N
authors.lastname: Yamamoto
authors.affiliation: Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan;
authors.forename: Shohko
authors.initials: S
authors.lastname: Kunimoto
authors.affiliation: Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan;
authors.forename: Yukako
authors.initials: Y
authors.lastname: Nakamura
authors.affiliation: Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan;
authors.forename: Akira
authors.initials: A
authors.lastname: Yoshimi
authors.affiliation: Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan;
authors.forename: Masahiro
authors.initials: M
authors.lastname: Banno
authors.affiliation: Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan;
authors.forename: Jingrui
authors.initials: J
authors.lastname: Xing
authors.affiliation: Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan;
authors.forename: Yuto
authors.initials: Y
authors.lastname: Takasaki
authors.affiliation: Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan;
authors.forename: Mami
authors.initials: M
authors.lastname: Yoshida
authors.affiliation: Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan; branko@med.nagoya-u.ac.jp.
authors.forename: Branko
authors.initials: B
authors.lastname: Aleksic
authors.affiliation: Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan;
authors.forename: Yota
authors.initials: Y
authors.lastname: Uno
authors.affiliation: Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan;
authors.forename: Takashi
authors.initials: T
authors.lastname: Okada
authors.affiliation: Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan;
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Iidaka
authors.affiliation: Department of Psychiatry, Seiwa Hospital, Institute of Neuropsychiatry, Shinjuku, Tokyo, Japan;
authors.forename: Toshiya
authors.initials: T
authors.lastname: Inada
authors.affiliation: Department of Neuropsychiatry, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan;
authors.forename: Michio
authors.initials: M
authors.lastname: Suzuki
authors.affiliation: Department of Psychiatry, Ujike Nishiguchi Clinic (HU), Okayama, Japan;
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ujike
authors.affiliation: Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan;
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kunugi
authors.affiliation: Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, Wako, Saitama, Japan.
authors.forename: Tadafumi
authors.initials: T
authors.lastname: Kato
authors.affiliation: Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Wako, Saitama, Japan;
authors.forename: Takeo
authors.initials: T
authors.lastname: Yoshikawa
authors.affiliation: Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Aichi, Japan;
authors.forename: Nakao
authors.initials: N
authors.lastname: Iwata
authors.affiliation: Department of Cell Pharmacology, Nagoya University Graduate School of Medicine, Nagoya, Japan;
authors.forename: Kozo
authors.initials: K
authors.lastname: Kaibuchi
authors.affiliation: Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan;
authors.forename: Norio
authors.initials: N
authors.lastname: Ozaki
mesh_terms: D000328:Adult; D001714:Bipolar Disorder / Q000235:genetics*; D002659:Child Development Disorders, Pervasive / Q000235:genetics*; D005091:Exons; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012559:Schizophrenia / Q000235:genetics*
chemical_list: D008869:Microtubule-Associated Proteins; C525094:Nde1 protein, human
keywords: DISC1; SNV; YWHAE; protein-protein interaction; rare variants; target resequencing