Development and Application of Omics Data Integrated Association Analysis Method Using Multi-Hierarchical Tensor Factorization

• Project/Area Number: 17KT0125
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 特設分野
• Research Field: Complex Systems Disease Theory
• Research Institution: Kansai Medical University (2018-2019); Kyoto University (2017)
• Principal Investigator: HIGASA Koichiro 関西医科大学, 医学部, 教授 (10419583)
• Project Period (FY): 2017-07-18 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2019: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: オミックス解析

Outline of Final Research Achievements

Throughout the study, we collected omics data from thousands of complex disease and control samples, and obtained the following results by a multi-omics analysis. (1) Genome wide association study of 857 cases of IgG4-related diseases revealed significant associations in HLA-DRB1 and the FCGR2B loci. (2) Genome-wide quantitative trait locus analysis of plasma free amino acids (PFAA) identified eight loci associated with PFAA levels. (3) Three mutations in ALPL gene are significantly associated with serum ALP activity, which is involved in the severity of hypophosphatemia.

Academic Significance and Societal Importance of the Research Achievements

多因子性疾患に代表される様々な複雑系疾病は、遺伝因子だけでなく環境因子や生活習慣などの複数要因の相互作用により、発症や重症化に至る。本課題の対象疾患は、いずれも発症メカニズムが解明されていない疾患群であり、本研究で得られた知見は、患者の類型化による質の高い診療や新規治療薬の開発、発症と重症化プロセスの解明、疾患特異マーカーや治療後の再発予測、診断や重症度判定、治療反応性の指標となる因子の導出など、複雑系疾病群の病因・病態の解明に役立つことが期待される。

Research Products

• [Journal Article] Association of ALPL variants with serum alkaline phosphatase and bone traits in the general Japanese population: The Nagahama Study (2019)
  • Author(s): Nagata Miho、Setoh Kazuya、Takahashi Meiko、Higasa Koichiro、Kawaguchi Takahisa、Kawasaki Hidenori、Wada Takahito、Watanabe Atsushi、Sawai Hideaki、Tabara Yasuharu、Yamada Takahiro、Matsuda Fumihiko、Kosugi Shinji
  • Journal Title: Journal of Human Genetics Volume: 65 Issue: 3 Pages: 337-343
  • DOI: 10.1038/s10038-019-0712-3
  • Peer Reviewed
• [Journal Article] IgG4-related disease in the Japanese population: a genome-wide association study (2019)
  • Author(s): Terao, C. et al.
  • Journal Title: The Lancet Rheumatology Volume: 1 Issue: 1 Pages: e14-e22
  • DOI: 10.1016/s2665-9913(19)30006-2
  • Peer Reviewed
• [Journal Article] Genetic basis for plasma amino acid concentrations based on absolute quantification: a genome-wide association study in the Japanese population (2019)
  • Author(s): Imaizumi Akira、Adachi Yusuke、Kawaguchi Takahisa、Higasa Koichiro、Tabara Yasuharu、Sonomura Kazuhiro、Sato Taka-aki、Takahashi Meiko、Mizukoshi Toshimi、Yoshida Hiro-o、Kageyama Naoko、Okamoto Chisato、Takasu Mariko、Mori Maiko、Noguchi Yasushi、Shimba Nobuhisa、Miyano Hiroshi、Yamada Ryo、Matsuda Fumihiko
  • Journal Title: European Journal of Human Genetics Volume: 27 Issue: 4 Pages: 621-630
  • DOI: 10.1038/s41431-018-0296-y
  • Peer Reviewed / Open Access
• [Journal Article] A mutation in transcription factor MAFB causes Focal Segmental Glomerulosclerosis with Duane Retraction Syndrome (2018)
  • Author(s): Sato Yoshinori、Tsukaguchi Hiroyasu、Morita Hiroyuki、略 & Takahashi Satoru、Yoshimura Ashio
  • Journal Title: Kidney International Volume: 94 Issue: 2 Pages: 396-407
  • DOI: 10.1016/j.kint.2018.02.025
  • Peer Reviewed
• [Journal Article] Accurate diagnosis of mismatch repair deficiency in colorectal cancer using high-quality DNA samples from cultured stem cells (2018)
  • Author(s): Yamaura Tadayoshi、Miyoshi Hiroyuki、Maekawa Hisatsugu、Morimoto Tomonori、Yamamoto Takehito、Kakizaki Fumihiko、Higasa Koichiro、Kawada Kenji、Matsuda Fumihiko、Sakai Yoshiharu、Taketo M. Mark
  • Journal Title: Oncotarget Volume: 9 Issue: 101 Pages: 37534-37548
  • DOI: 10.18632/oncotarget.26495
  • NAID: 120006546167
  • Peer Reviewed
• [Journal Article] A burden of rare variants in BMPR2 and KCNK3 contributes to a risk of familial pulmonary arterial hypertension. (2017)
  • Author(s): Higasa K, Ogawa A, Terao C, Shimizu M, Kosugi S, Yamada R, Date H, Matsubara H, Matsuda F.
  • Journal Title: BMC Pulm Med. Volume: 17 Issue: 1 Pages: 57-57
  • DOI: 10.1186/s12890-017-0400-z
  • NAID: 120006305759
  • Peer Reviewed / Open Access
• [Journal Article] Exome Sequencing Landscape Analysis in Ovarian Clear Cell Carcinoma Shed Light on Key Chromosomal Regions and Mutation Gene Networks. (2017)
  • Author(s): Murakami R, Matsumura N, Brown JB, Higasa K, Tsutsumi T, Kamada M, Abou-Taleb H, Hosoe Y, Kitamura S, Yamaguchi K, Abiko K, Hamanishi J, Baba T, Koshiyama M, Okuno Y, Yamada R, Matsuda F, Konishi I, Mandai M.
  • Journal Title: The American Journal of Pathology Volume: 187 Issue: 10 Pages: 2246-2258
  • DOI: 10.1016/j.ajpath.2017.06.012
  • Peer Reviewed / Open Access
• [Presentation] GNEミオパチー p.D207V変異は軽症型変異であり、ホモ接合体では極めて稀にしか発症しない (2019)
  • Author(s): 吉岡 和香子、飯田有俊、岡田随象、大矢寧、大久保真理子、小川恵、 松田文彦、日笠幸一郎、森まどか、中村治雅、林晋一郎、野口悟、 西野一三
  • Organizer: 日本筋学会第5回学術集会
• [Presentation] Visualization of comprehensively changes in whole cell subsets after influenza vaccination (2019)
  • Author(s): Okada D, Nakamura N, Setoh K, Kawaguchi T, Narahara M, Higasa K, Tabara Y, Matsuda F, Yamada R
  • Organizer: VIZBI 2019 - the 10th Visualizing biological data
  • Int'l Joint Research
• [Presentation] Frequency of c.620A>T homozygotes is extremely low in Japanese GNE myopathy patients: What is determining the pathogenicity? (2018)
  • Author(s): Yoshioka W, Okubo M, Ogawa M, Matsuda F, Higasa K, Mori-Yoshimura M, Oya Y, Kimura E, Nakamura H, Hayashi S, Iida A, Noguchi S, Nishino I
  • Organizer: International conference at Institut des Hautes Etudes Scientifiques (IHES)
  • Int'l Joint Research
• [Presentation] 一般地域住民における低ホスファターゼ症の未診断罹患者および非発症キャリアの研究：ながはまスタディ (2018)
  • Author(s): 永田 美保、山田 崇弘、十川 麗美、馬場 遥香、川崎 秀徳、和田 敬仁、澤井 英明、瀬藤 和也、川口 喬久、日笠 幸一郎、中山 健夫、田原 康玄、松田 文彦、小杉 眞司
  • Organizer: 第63回日本人類遺伝学会
  • Int'l Joint Research
• [Presentation] MAFB転写因子変異によるDuan眼球後退症候群を合併する巣状分節性糸球体硬化症発症の分子機序 (2018)
  • Author(s): 佐藤 芳憲、塚口 裕康、小岩 文彦、日笠 幸一郎、松田 文彦、高橋 智
  • Organizer: 第63回日本人類遺伝学会
  • Int'l Joint Research
• [Presentation] 大規模シングルセル発現データを用いた細胞集団プロファイル全体の異同の解析 (2018)
  • Author(s): 岡田 大瑚、中村 直俊、瀬藤 和也、川口 喬久、奈良原 舞子、日笠 幸一郎、田原 康玄、松田 文彦、山田 亮
  • Organizer: 第42回日本分子生物学会年会
  • Int'l Joint Research
• [Remarks] 指定難病IgG4関連疾患とHLA-DRB1、FRGR2B遺伝子との関連を解明
  • URL: http://www.kyoto-u.ac.jp/ja/research/research_results/2019/190806_3.html
• [Remarks] デュアン症候群と巣状糸球体硬化症を合併する 稀少疾患の責任遺伝子MAFBを同定
  • URL: http://www.kmu.ac.jp/news/laaes70000002bvj-att/laaes70000002bw7.pdf