Takaoki Kasahara1, Mizuho Ishiwata1, Chihiro Kakiuchi1, Satoshi Fuke1, Nakao Iwata2, Norio Ozaki3, Hiroshi Kunugi4, Yoshio Minabe5, Kazuhiko Nakamura5, Yasuhide Iwata5, Kumiko Fujii1,6, Shigenobu Kanba7, Hiroshi Ujike8, Ichiro Kusumi9, Muneko Kataoka1, Nana Matoba1, Atsushi Takata1, Kazuya Iwamoto10, Takeo Yoshikawa11, Tadafumi Kato1. 1. Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, Wako, Japan. 2. Faculty of Medicine, Department of Psychiatry, Fujita Health University, Japan. 3. Faculty of Medicine, Department of Psychiatry, Nagoya University, Nagoya, Japan. 4. Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Japan. 5. Department of Psychiatry and Neurology, Hamamatsu University School of Medicine, Hamamatsu, Japan. 6. Department of Psychiatry, Dokkyo Medical University School of Medicine, Mibu, Japan. 7. Department of Psychiatry, Kyushu University School of Medicine, Fukuoka, Japan. 8. Department of Psychiatry, Okayama University School of Medicine, Okayama, Japan. 9. Department of Psychiatry, Hokkaido University School of Medicine, Sapporo, Japan. 10. Department of Molecular Brain Science, Graduate School of Medicine, Kumamoto University, Kumamoto, Japan. 11. Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Wako, Japan.
Abstract
AIM: 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. CONCLUSION: Together with mitochondrial dysfunction in bipolar disorder, the present results suggested deleterious POLG1 variants as a credible risk for the multifactorial disease.
AIM: 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. CONCLUSION: Together with mitochondrial dysfunction in bipolar disorder, the present results suggested deleterious POLG1 variants as a credible risk for the multifactorial disease.
Authors: Yeni Kim; Krishna C Vadodaria; Zsolt Lenkei; Tadafumi Kato; Fred H Gage; Maria C Marchetto; Renata Santos Journal: Antioxid Redox Signal Date: 2019-02-01 Impact factor: 8.401
Authors: Vincent A Magnotta; Jia Xu; Jess G Fiedorowicz; Aislinn Williams; Joseph Shaffer; Gary Christensen; Jeffrey D Long; Eric Taylor; Leela Sathyaputri; Jenny Gringer Richards; Gail Harmata; John Wemmie Journal: J Affect Disord Date: 2022-01-12 Impact factor: 4.839