Development and clinical application of a novel method for identifying genes related to cardiovascular diseases

• Project/Area Number: 16K19404
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Cardiovascular medicine
• Research Institution: Osaka University
• Principal Investigator: Imai-Okazaki Atsuko 大阪大学, 医学系研究科, 特任助教(常勤) (70761691)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2017: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2016: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000)
• Keywords: 遺伝性心疾患 / 遺伝統計解析 / 原因遺伝子同定 / 染色体欠失同定 / エクソーム解析 / 全ゲノム解析 / 臨床 / 心臓 / ゲノム / 遺伝学

Outline of Final Research Achievements

To detect causative genes related to cardiovascular disease, linkage analysis has conventionally been used. However, linkage analysis is underpowered in small families as often seen in clinical settings. We therefore developed a novel method for identifying genes, where DNA differences between a patient and unrelated healthy individuals around candidate genes are measured by the Hamming Distance Ratio (HDR). We further developed the HDR method to detect causative genes with various modes of inheritance and chromosomal deletions and succeeded in releasing software as a novel analysis tool for gene identification. As a clinical application of this tool, novel genes related to cardiovascular diseases have been identified.

Research Products

• [Int'l Joint Research] Rockefeller University/Laboratory of Statistical Genetics(米国)
• [Journal Article] Barth syndrome: Different approaches to diagnosis (2018)
  • Author(s): Imai-Okazaki A, Kishita Y, Kohda M, Yatsuka Y, Hirata T, Mizuno Y, Harashima H, Hirono K, Ichida F, Noguchi A, Yoshida M, Tokorodani C, Nishiuchi R, Takeda A, Nakaya A, Sakata Y, Murayama K, Ohtake A, & Okazaki Y
  • Journal Title: Journal of Pediatrics Volume: 193 Pages: 256-260
  • DOI: 10.1016/j.jpeds.2017.09.075
  • Peer Reviewed / Open Access
• [Journal Article] Genetic Linkage Mapping (2018)
  • Author(s): Imai-Okazaki Atsuko、Ott Jurg
  • Journal Title: eLS. John Wiley & Sons, Ltd: Chichester. Volume: 1 Pages: 1-5
  • DOI: 10.1002/9780470015902.a0005360.pub2
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] HDR-del: A tool based on Hamming distance for prioritizing pathogenic chromosomal deletions in exome sequencing (2017)
  • Author(s): Imai-Okazaki A, Kohda M, Kobayashi K, Hirata T, Sakata Y, Murayama K, Ohtake A, Okazaki Y, Nakaya A, & Ott J
  • Journal Title: Human Mutation Volume: 38 Issue: 12 Pages: 1796-1800
  • DOI: 10.1002/humu.23298
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Analysis of an ADTKD family with a novel frameshift mutation in MUC1 reveals characteristic features of mutant MUC1 protein (2017)
  • Author(s): Yamamoto S, Kaimori J, Yoshimura T, Namba T, Imai A, Kobayashi K, Imamura R, Ichimaru N, Kato K, Nakaya A, Takahara S, & Isaka Y
  • Journal Title: Nephrology Dialysis Transplantation Volume: 32 Issue: 12 Pages: 2010-2007
  • DOI: 10.1093/ndt/gfx083
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Mutation in VPS33A affects metabolism of glycosaminoglycans: a new type of mucopolysaccharidosis with severe systemic symptoms (2017)
  • Author(s): Kondo H, Maksimova N, Otomo T*,Kato H, Imai A, Asano Y, Kobayashi K, Nojima S, Nakaya A, Hamada Y, Irahara K, Gurinova E, Sukhomyasova A, Nogovicina A, Savvina M, Yoshimori T, Ozono K Sakai N*
  • Journal Title: Human Molecular Genetics Volume: 26 Pages: 173-183
  • DOI: 10.1093/hmg/ddw377
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] HDR: a statistical two-step approach successfully identifies disease genes in autosomal recessive families (2016)
  • Author(s): Imai A, Kohda M, Nakaya A, Sakata Y, Murayama K, Ohtake A, Lathrop M, Okazaki Y, Ott J
  • Journal Title: Journal of Human Genetics Volume: 61 Issue: 11 Pages: 959-963
  • DOI: 10.1038/jhg.2016.85
  • NAID: 40021000514
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Dried blood spots for newborn screening allows easy determination of a high heteroplasmy rate in severe infantile cardiomyopathy (2016)
  • Author(s): Imai A, Kishita Y, Nakayama Y, Fujita S, Futatani T, Kohda M, Yatsuka Y, Nakaya A, Sakata Y, Murayama K, Ohtake A, Okazaki Y
  • Journal Title: International Journal of Cardiology Volume: 221 Pages: 446-449
  • DOI: 10.1016/j.ijcard.2016.06.287
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Association Test for Rare Variants using the Hamming Distance (2018)
  • Author(s): Suhyun Hwangbo, Jin-Young Jang, Atsuko Imai, Jurg Ott, Taesung Park
  • Organizer: 17th European Conference on Computational Biology
  • Int'l Joint Research
• [Presentation] Genetic analysis of rapidly progressive mitochondrial cardiomyopathy with loss of ATP synthesis (2017)
  • Author(s): Atsuko Imai, Yuko Nakayama, Shuhei Fujita, Yasushi Sakata, Akira Ohtake, Yasushi Okazaki
  • Organizer: 第81回日本循環器学会学術集会
• [Presentation] エクソーム解析基盤を用いた日本人変異解析における解析手法の検証と可視化 (2017)
  • Author(s): 小林 香織, 今井 敦子, 山崎 悟, 菊地 正隆, 足尾 勉, 上條 憲一, 松村 泰志, 中谷 明弘
  • Organizer: 第40回日本分子生物学会年会
• [Presentation] Genetic analysis of mitochondrial disorder (2017)
  • Author(s): Kohda M, Kishita Y, Mizuno Y, Imai A, Nakaya A, Hirata T, Yatsuka Y, Borna NN, Harashima H, Murayama K, Ohtake A, Okazaki Y
  • Organizer: 第5回生命医薬情報学連合大会
• [Presentation] Rapidly progressive infantile cardiomyopathy with mitochondrial respiratory chain complex V deficiency due to loss of ATP synthesis (2017)
  • Author(s): 今井 敦子, 藤田 修平, 中山 祐子, 武田 充人, 坂田 泰史, 大竹 明, 岡崎 康司
  • Organizer: 第52回日本小児循環器学会総会・学術集会
• [Presentation] Rapidly progressive infantile cardiomyopathy with mitochondrial respiratory chain complex V deficiency (2016)
  • Author(s): Atsuko Imai, Yoshihito Kishita, Yuko Nakayama, Shuhei Fujita, Takeshi Futatani, Masakazu Kohda, Yukiko Yatsuka, Akihiro Nakaya, Yasushi Sakata, Kei Murayama, Akira Ohtake, Yasushi Okazaki
  • Organizer: 第13回アジアミトコンドリア学会
  • Place of Presentation: TKPガーデンシティ品川（東京都港区）
  • Year and Date: 2016-10-30
  • Int'l Joint Research
• [Presentation] 進行性の乳児心筋症における ミトコンドリアDNA変異同定およびATP合成酵素欠損の証明 (2016)
  • Author(s): 今井 敦子, 藤田 修平, 木下 善仁, 神田 将和, 八塚 由紀子, 中山 祐子, 二谷 武, 平田 智子, 水野 洋介, 原嶋 宏子, 中谷 明弘, 坂田 泰史, 武田 充人, 森 雅人, 村山 圭, 大竹 明, 岡崎 康司
  • Organizer: 第25回日本小児心筋疾患学会
  • Place of Presentation: 東京都医師会館（東京都千代田区）
  • Year and Date: 2016-10-08
• [Presentation] Rapidly progressive infantile cardiomyopathy with mitochondrial respiratory chain complex V deficiency due to loss of ATP synthesis (2016)
  • Author(s): 今井 敦子, 藤田 修平, 中山 祐子, 武田 充人, 坂田 泰史, 大竹 明, 岡崎 康司
  • Organizer: 第52回日本小児循環器学会総会・学術集会
  • Place of Presentation: 東京ドームホテル（東京都文京区）
  • Year and Date: 2016-07-07
• [Presentation] Family-Control analysis based on Hamming distance for prioritizing candidate pathogenic variants (2016)
  • Author(s): Atsuko Imai, Akihiro Nakaya, Somayyeh Fahiminiya, Martine Tetreault, Jacek Majewski, Yasushi Sakata, Seiji Takashima, Mark Lathrop, Jurg Ott
  • Organizer: The 13th International Congress of Human Genetics
  • Place of Presentation: 国立京都国際会館（京都市左京区）
  • Year and Date: 2016-04-07
  • Int'l Joint Research
• [Book] 代謝ナビゲーション ミトコンドリアを中心とする代謝ネットワーク (2017)
  • Author(s): 代謝ナビゲーション ミトコンドリアを中心とする代謝ネットワーク
  • Total Pages: 256
  • Publisher: メディカルサイエンスインターナショナル
  • ISBN: 9784895929004
• [Book] ミトコンドリア病診療マニュアル2017 (2016)
  • Author(s): ミトコンドリア病診療マニュアル編集委員会, 村山 圭, 小坂 仁, 米田 誠他
  • Total Pages: 172
  • Publisher: 診断と治療社
• [Remarks] HDR (Hamming Distance Ratio)
  • URL: http://www.gi.med.osaka-u.ac.jp/software/hdr
• [Remarks] HDR (Hamming Distance Ratio) 2
  • URL: http://www.gi.med.osaka-u.ac.jp/software/hdr2
• [Remarks] 大阪大学医学系研究科ゲノム情報学ホームページ
  • URL: http://www.gi.med.osaka-u.ac.jp/genome/software