title: Enrichment of deleterious variants of mitochondrial DNA polymerase gene (POLG1) in bipolar disorder.
abstract: OBJECTIVE
  Rare missense variants, which likely account for a substantial portion of the genetic 'dark matter' for a common complex disease, are challenging because the impacts of variants on disease development are difficult to substantiate. This study aimed to examine the impacts of amino acid substitution variants in the POLG1 found in bipolar disorder, as an example and proof of concept, in three different modalities of assessment: in silico predictions, in vitro biochemical assays, and clinical evaluation. We then tested whether deleterious variants in POLG1 contributed to the genetics of bipolar disorder.
  
  
  METHODS
  We searched for variants in the POLG1 gene in 796 Japanese patients with bipolar disorder and 767 controls and comprehensively investigated all 23 identified variants in the three modalities of assessment. POLG1 encodes mitochondrial DNA polymerase and is one of the causative genes for a Mendelian-inheritance mitochondrial disease, which is occasionally accompanied by mood disorders. The healthy control data from the Tohoku Medical Megabank Organization were also employed.
  
  
  RESULTS
  Although the frequency of carriers of deleterious variants varied from one method to another, every assessment achieved the same conclusion that deleterious POLG1 variants were significantly enriched in the variants identified in patients with bipolar disorder compared to those in controls.
  
  
  CONCLUSIONS
  Together with mitochondrial dysfunction in bipolar disorder, the present results suggested deleterious POLG1 variants as a credible risk for the multifactorial disease.
authors.affiliation: Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, Wako, Japan.
authors.forename: Takaoki
authors.initials: T
authors.lastname: Kasahara
authors.affiliation: Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, Wako, Japan.
authors.forename: Mizuho
authors.initials: M
authors.lastname: Ishiwata
authors.affiliation: Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, Wako, Japan.
authors.forename: Chihiro
authors.initials: C
authors.lastname: Kakiuchi
authors.affiliation: Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, Wako, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Fuke
authors.affiliation: Faculty of Medicine, Department of Psychiatry, Fujita Health University, Japan.
authors.forename: Nakao
authors.initials: N
authors.lastname: Iwata
authors.affiliation: Faculty of Medicine, Department of Psychiatry, Nagoya University, Nagoya, Japan.
authors.forename: Norio
authors.initials: N
authors.lastname: Ozaki
authors.affiliation: Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kunugi
authors.affiliation: Department of Psychiatry and Neurology, Hamamatsu University School of Medicine, Hamamatsu, Japan.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Minabe
authors.affiliation: Department of Psychiatry and Neurology, Hamamatsu University School of Medicine, Hamamatsu, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Nakamura
authors.affiliation: Department of Psychiatry and Neurology, Hamamatsu University School of Medicine, Hamamatsu, Japan.
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Iwata
authors.affiliation: Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, Wako, Japan.|Department of Psychiatry, Dokkyo Medical University School of Medicine, Mibu, Japan.
authors.forename: Kumiko
authors.initials: K
authors.lastname: Fujii
authors.affiliation: Department of Psychiatry, Kyushu University School of Medicine, Fukuoka, Japan.
authors.forename: Shigenobu
authors.initials: S
authors.lastname: Kanba
authors.affiliation: Department of Psychiatry, Okayama University School of Medicine, Okayama, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ujike
authors.affiliation: Department of Psychiatry, Hokkaido University School of Medicine, Sapporo, Japan.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Kusumi
authors.affiliation: Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, Wako, Japan.
authors.forename: Muneko
authors.initials: M
authors.lastname: Kataoka
authors.affiliation: Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, Wako, Japan.
authors.forename: Nana
authors.initials: N
authors.lastname: Matoba
authors.affiliation: Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, Wako, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Takata
authors.affiliation: Department of Molecular Brain Science, Graduate School of Medicine, Kumamoto University, Kumamoto, Japan.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Iwamoto
authors.affiliation: Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Wako, Japan.
authors.forename: Takeo
authors.initials: T
authors.lastname: Yoshikawa
authors.affiliation: Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, Wako, Japan.
authors.forename: Tadafumi
authors.initials: T
authors.lastname: Kato
mesh_terms: D001714:Bipolar Disorder / Q000235:genetics*; D016022:Case-Control Studies; D000074002:DNA Polymerase gamma / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D008928:Mitochondria / Q000201:enzymology* / Q000235:genetics*
chemical_list: D000074002:DNA Polymerase gamma; C413027:POLG protein, human
keywords: POLG; POLG1; bipolar disorder; mitochondrial dysfunction; rare variants