Elucidation of disease biology and tissue specificity by trans-layer omics analysis and whole-genome sequencing

• Project/Area Number: 19H01021
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Medium-sized Section 48:Biomedical structure and function and related fields
• Research Institution: Osaka University
• Principal Investigator: Okada Yukinori 大阪大学, 医学系研究科, 教授 (70727411)
• Co-Investigator(Kenkyū-buntansha): 細道 一善 金沢大学, 医学系, 准教授 (50420948) ; 白石 友一 国立研究開発法人国立がん研究センター, 研究所, 分野長 (70516880)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥45,630,000 (Direct Cost: ¥35,100,000、Indirect Cost: ¥10,530,000); Fiscal Year 2021: ¥14,560,000 (Direct Cost: ¥11,200,000、Indirect Cost: ¥3,360,000); Fiscal Year 2020: ¥14,560,000 (Direct Cost: ¥11,200,000、Indirect Cost: ¥3,360,000); Fiscal Year 2019: ¥16,510,000 (Direct Cost: ¥12,700,000、Indirect Cost: ¥3,810,000)
• Keywords: 遺伝統計学 / 全ゲノムシークエンス / 横断的オミクス解析 / バイオインフォマティクス / 細胞組織特異性 / eQTL効果 / バイインフォマティクス

Outline of Research at the Start

本研究は、疾患ゲノム情報を中心にオミクス情報を分野横断的に統合し、疾患病態の解明とその鍵となる細胞組織の同定を行う。横断的オミクス解析とは、異なるサンプルから得られたオミクス情報を分野横断的に統合する手法である。本研究は、①：全ゲノムシークエンスを駆使した疾患感受性遺伝子の同定、②：組織特異的多層的オミクス情報における新規レイヤー構築、③：遺伝的背景の相関関係の検討を主軸とした横断的オミクス解析、④：疾患病態ネットワーク構築と病態解明の鍵となる細胞組織の同定、で構成される。本研究は、「どの遺伝子が、どの細胞で、どの疾患の発症に関わっているか」という問いに答えるものと期待される。

Outline of Final Research Achievements

This project aims elucidation of disease biology and tissue specificity by integrating large-scale human genetics and epigenomics based on multi-layer omics analysis and whole genome sequencing. Multi-layer omics analysis integrated omics information from multiple difference resources. This project consists of; (i) identification of disease risk gene by whole-genome sequencing, (ii) construction of novel tissue-specific omics layer, (iii) multi-layer omics analysis based on genetic correlations of the traits, (iv) identification of disease driving cell types. This project explains “which genes, which cells, which disease are linked”.

Academic Significance and Societal Importance of the Research Achievements

本研究においては、疾患ゲノム情報を中心として多層的なオミクス情報をどのように統合し、疾患病態解明につなげるか、という疾患ゲノム研究の根源的問いに対する研究活動を行った。全ゲノムシークエンス情報を対象とした大規模疾患ゲノム解析のアルゴリズムの整備、国際バイオバンク連携による大規模プロジェクトの遂行など、最新の疾患ゲノムリソースの有効な活用例としての意義が認められた。また、複数の疾患ゲノム解析結果が与えられた際に、細胞組織特異的エピゲノム情報と疾患ゲノム情報の統合により細胞組織特異性に基づく疾患-細胞組織ネットワークの再構成が可能となることも示され、病態解明研究への波及効果が期待される。

Research Products

• [Journal Article] OMARU: a robust and multifaceted pipeline for metagenome-wide association study (2022)
  • Author(s): Kishikawa Toshihiro、Tomofuji Yoshihiko、Inohara Hidenori、Okada Yukinori
  • Journal Title: NAR Genomics and Bioinformatics Volume: 4 Issue: 1
  • DOI: 10.1093/nargab/lqac019
  • Peer Reviewed / Open Access
• [Journal Article] Decoding the diversity of killer immunoglobulin-like receptors by deep sequencing and a high-resolution imputation method (2022)
  • Author(s): Sakaue S, Hosomichi K, Hirata J, Nakaoka H, Yamazaki K, Yawata M, Yawata N, Naito T, Umeno J, Kawaguchi T, Matsui T, Motoya S, Suzuki Y, Inoko H, Tajima A, Morisaki T, Matsuda K, Kamatani Y, Yamamoto K, Inoue I, Okada Y
  • Journal Title: Cell Genomics Volume: 2 Issue: 3 Pages: 100101-100101
  • DOI: 10.1016/j.xgen.2022.100101
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Genetic architecture of microRNA expression and its link to complex diseases in the Japanese population (2021)
  • Author(s): Sonehara Kyuto、Sakaue Saori、Maeda Yuichi、Hirata Jun、Kishikawa Toshihiro、Yamamoto Kenichi、Matsuoka Hidetoshi、Yoshimura Maiko、Nii Takuro、Ohshima Shiro、Kumanogoh Atsushi、Okada Yukinori
  • Journal Title: Human Molecular Genetics Volume: - Issue: 11 Pages: 1806-1820
  • DOI: 10.1093/hmg/ddab361
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Whole gut virome analysis of 476 Japanese revealed a link between phage and autoimmune disease (2021)
  • Author(s): Tomofuji Yoshihiko et al.
  • Journal Title: Annals of the Rheumatic Diseases Volume: 81 Issue: 2 Pages: 278-288
  • DOI: 10.1136/annrheumdis-2021-221267
  • Peer Reviewed / Open Access
• [Journal Article] Responsible use of polygenic risk scores in the clinic: potential benefits, risks and gaps (2021)
  • Author(s): Polygenic Risk Score Task Force of the International Common Disease Alliance
  • Journal Title: Nature Medicine Volume: 27 Issue: 11 Pages: 1876-1884
  • DOI: 10.1038/s41591-021-01549-6
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A cross-population atlas of genetic associations for 220 human phenotypes (2021)
  • Author(s): Sakaue S, Kanai M, Tanigawa Y, Karjalainen J, Kurki M, Koshiba S, Narita A, Konuma T, Yamamoto K, Akiyama M, Ishigaki K, Suzuki A, Suzuki K, Obara W, Yamaji K, Takahashi K, Asai S, Takahashi Y, Suzuki T, Shinozaki N, Yamaguchi H, Minami S, Murayama S, Yoshimori K, Nagayama S, Obata D, Higashiyama M, Masumoto A, et al.
  • Journal Title: Nature Genetics Volume: 53 Issue: 10 Pages: 1415-1424
  • DOI: 10.1038/s41588-021-00931-x
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Metagenome-wide association study revealed disease-specific landscape of the gut microbiome of systemic lupus erythematosus in Japanese (2021)
  • Author(s): Tomofuji Yoshihiko、Maeda Yuichi、Oguro-Igashira Eri、Kishikawa Toshihiro、Yamamoto Kenichi、Sonehara Kyuto、Motooka Daisuke、Matsumoto Yuki、Matsuoka Hidetoshi、Yoshimura Maiko、Yagita Mayu、Nii Takuro、Ohshima Shiro、Nakamura Shota、Inohara Hidenori、Takeda Kiyoshi、Kumanogoh Atsushi、Okada Yukinori
  • Journal Title: Annals of the Rheumatic Diseases Volume: 80 Issue: 12 Pages: 1575-1583
  • DOI: 10.1136/annrheumdis-2021-220687
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Trans‐Ethnic Fine‐Mapping of the Major Histocompatibility Complex Region Linked to Parkinson's Disease (2021)
  • Author(s): Naito Tatsuhiko、Satake Wataru、Ogawa Kotaro、Suzuki Ken、Hirata Jun、Foo Jia Nee、Tan Eng‐King、Toda Tatsushi、Okada Yukinori
  • Journal Title: Movement Disorders Volume: 36 Issue: 8 Pages: 1805-1814
  • DOI: 10.1002/mds.28583
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A deep learning method for HLA imputation and trans-ethnic MHC fine-mapping of type 1 diabetes (2021)
  • Author(s): Naito Tatsuhiko、Suzuki Ken、Hirata Jun、Kamatani Yoichiro、Matsuda Koichi、Toda Tatsushi、Okada Yukinori
  • Journal Title: Nature Communications Volume: 12 Issue: 1 Pages: 1639-1639
  • DOI: 10.1038/s41467-021-21975-x
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Population-specific causal disease effect sizes in functionally important regions impacted by selection (2021)
  • Author(s): Shi Huwenbo、Gazal Steven、Kanai Masahiro、Koch Evan M.、Schoech Armin P.、Siewert Katherine M.、Kim Samuel S.、Luo Yang、Amariuta Tiffany、Huang Hailiang、Okada Yukinori、Raychaudhuri Soumya、Sunyaev Shamil R.、Price Alkes L.
  • Journal Title: Nature Communications Volume: 12 Issue: 1 Pages: 1098-1098
  • DOI: 10.1038/s41467-021-21286-1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Tractor uses local ancestry to enable the inclusion of admixed individuals in GWAS and to boost power (2021)
  • Author(s): Atkinson Elizabeth G.、Maihofer Adam X.、Kanai Masahiro、Martin Alicia R.、Karczewski Konrad J.、Santoro Marcos L.、Ulirsch Jacob C.、Kamatani Yoichiro、Okada Yukinori、Finucane Hilary K.、Koenen Karestan C.、Nievergelt Caroline M.、Daly Mark J.、Neale Benjamin M.
  • Journal Title: Nature Genetics Volume: 53 Issue: 2 Pages: 195-204
  • DOI: 10.1038/s41588-020-00766-y
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A Mendelian randomization study identified obesity as a causal risk factor of uterine endometrial cancer in Japanese (2020)
  • Author(s): Masuda Tatsuo、Ogawa Kotaro、Kamatani Yoichiro、Murakami Yoshinori、Kimura Tadashi、Okada Yukinori
  • Journal Title: Cancer Science Volume: 111 Issue: 12 Pages: 4646-4651
  • DOI: 10.1111/cas.14667
  • Peer Reviewed
• [Journal Article] Fine Mapping of the Major Histocompatibility Complex Region and Association of the HLA-B*52:01 Allele With Cervical Cancer in Japanese Women (2020)
  • Author(s): Masuda Tatsuo、Ito Hidemi、Hirata Jun、Sakaue Saori、Ueda Yutaka、Kimura Tadashi、Takeuchi Fumihiko、Murakami Yoshinori、Matsuda Koichi、Matsuo Keitaro、Okada Yukinori
  • Journal Title: JAMA Network Open Volume: 3 Issue: 10 Pages: e2023248-e2023248
  • DOI: 10.1001/jamanetworkopen.2020.23248
  • Peer Reviewed / Open Access
• [Journal Article] Obelisc: an identical-by-descent mapping tool based on SNP streak (2020)
  • Author(s): Sonehara Kyuto、Okada Yukinori
  • Journal Title: Bioinformatics Volume: 36 Issue: 24 Pages: 5567-5570
  • DOI: 10.1093/bioinformatics/btaa940
  • Peer Reviewed / Open Access
• [Journal Article] Trans-biobank analysis with 676,000 individuals elucidates the association of polygenic risk scores of complex traits with human lifespan (2020)
  • Author(s): Sakaue S, Kanai M, Karjalainen J, Akiyama M, Kurki M, Matoba N, Takahashi A, Hirata M, Kubo M, Matsuda K, Murakami Y; FinnGen, Daly MJ, Kamatani Y, Okada Y
  • Journal Title: Nat Med Volume: 26 Issue: 4 Pages: 542-548
  • DOI: 10.1038/s41591-020-0785-8
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Dimensionality reduction reveals fine-scale structure in the Japanese population with consequences for polygenic risk prediction (2020)
  • Author(s): Sakaue S, Hirata J, Kanai M, Suzuki K, Akiyama M, Lai Too C, Arayssi T, Hammoudeh M, Al Emadi S, Masri BK, Halabi H, Badsha H, Uthman IW, Saxena R, Padyukov L, Hirata M, Matsuda K, Murakami Y, Kamatani Y, Okada Y
  • Journal Title: Nat Commun Volume: 11 Issue: 1 Pages: 1569-1569
  • DOI: 10.1038/s41467-020-15194-z
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] GWAS of 165,084 Japanese individuals identified nine loci associated with dietary habits. (2020)
  • Author(s): Matoba N, Akiyama M, Ishigaki K, Kanai M, Takahashi A, Momozawa Y, Ikegawa S, Ikeda M, Iwata N, Hirata M, Matsuda K, Murakami Y, Kubo M, Kamatani Y, Okada Y
  • Journal Title: Nat Hum Behav Volume: 4 Issue: 3 Pages: 308-346
  • DOI: 10.1038/s41562-019-0805-1
  • Peer Reviewed
• [Journal Article] Metagenome-wide association study of gut microbiome revealed novel aetiology of rheumatoid arthritis in the Japanese population (2020)
  • Author(s): Kishikawa T, Maeda Y, Nii T, Motooka D, Matsumoto Y, Matsushita M, Matsuoka H, Yoshimura M, Kawada S, Teshigawara S, Oguro E, Okita Y, Kawamoto K, Higa S, Hirano T, Narazaki M, Ogata A, Saeki Y, Nakamura S, Inohara H, Kumanogoh A, Takeda K, Okada Y.
  • Journal Title: Annals of the Rheumatic Diseases Volume: 79(1) Issue: 1 Pages: 103-111
  • DOI: 10.1136/annrheumdis-2019-215743
  • Peer Reviewed / Open Access
• [Journal Article] Biological characterization of expression quantitative trait loci (eQTLs) showing tissue-specific opposite directional effects. (2019)
  • Author(s): Mizuno A, Okada Y
  • Journal Title: Eur J Hum Genet Volume: 27 Issue: 11 Pages: 1745-1756
  • DOI: 10.1038/s41431-019-0468-4
  • Peer Reviewed / Open Access
• [Book] ゼロから実践する 遺伝統計学セミナー (2020)
  • Author(s): 岡田 随象
  • Total Pages: 247
  • Publisher: 羊土社
  • ISBN: 9784758120920