Integrative network analysis of Williams syndrome

• Project/Area Number: 16K09965
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Kyoto University
• Principal Investigator: Kimura Ryo 京都大学, 医学研究科, 助教 (20636641)
• Research Collaborator: Tomiwa Kiyotaka
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2018: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: ウィリアムス症候群 / 7q11.23 / トランスクリプトーム解析 / マイクロRNA / ネットワーク解析 / 自閉スペクトラム障害 / 遺伝子発現 / ネットワーク / 発達障害

Outline of Final Research Achievements

Our results show that the upregulation of multiple co-expression modules containing genes located outside of the standard 7q11.23 deletion region may significantly contribute to the intermediate and highly variable Williams syndrome phenotypes.The effects of the glial cell activation-mediated mRNA/miRNA regulatory network provide novel insight into the biological mechanisms underlying Williams syndrome neuropsychiatric phenotypes.The downregulation of one miRNA module appears to have significant consequences on the transcriptome, leading to the upregulation of three mRNA modules, all of which include genes that are dispersed throughout the genome.
To our knowledge, this is the first time that the dysregulated mRNA and miRNA transcriptomic networks have been broadly evaluated in association with the complex phenotypes observed in Williams syndrome patients.

Academic Significance and Societal Importance of the Research Achievements

ウィリアムス症候群では、7番染色体の片方にある約28個の遺伝子が失われていることが知られている。これまで、これら失われた遺伝子に着目した研究が進められてきましたが、症状と遺伝子との関係については十分に明らかになっていませんでした。
本研究では、多数のウィリアムス症候群の患者検体を用いて、大規模で網羅的遺伝子発現およびマイクロRNA解析を実施することで、失われた遺伝子以外の遺伝子やマイクロRNAが病態に関与しているということを初めて明らかにした。今後、病気に対するさらなる理解と将来的な治療法の開発につながることが期待される。

Research Products

• [Int'l Joint Research] University of California Los Angeles(米国)
• [Int'l Joint Research] University of California Los Angeles(米国)
• [Int'l Joint Research] Maastricht University Medical Centre(Netherlands)
• [Journal Article] Williams-Beuren Syndrome as a Potential Risk Factor for Burkitt Lymphoma (2018)
  • Author(s): Ryo Kimura, Yuko Ishii, Kiyotaka Tomiwa, Tomonari Awaya, Masatoshi Nakata, Takeo Kato, Shin Okazaki, Toshio Heike, Masatoshi Hagiwara
  • Journal Title: Frontiers in Genetics Volume: 9 Pages: 368-368
  • DOI: 10.3389/fgene.2018.00368
  • NAID: 120006533292
  • Peer Reviewed / Open Access
• [Journal Article] Comparative Analyses of Copy-Number Variation in Autism Spectrum Disorder and Schizophrenia Reveal Etiological Overlap and Biological Insights. (2018)
  • Author(s): Kushima I, (27名中略）, Hashimoto R,(80名中29番目) , et al.
  • Journal Title: Cell Rep Volume: 24(11) Issue: 11 Pages: 2838-2856
  • DOI: 10.1016/j.celrep.2018.08.022
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Integrative network analysis reveals biological pathways associated with Williams syndrome (2018)
  • Author(s): Kimura Ryo、Swarup Vivek、Tomiwa Kiyotaka、Gandal Michael J.、Parikshak Neelroop N.、Funabiki Yasuko、Nakata Masatoshi、Awaya Tomonari、Kato Takeo、Iida Kei、Okazaki Shin、Matsushima Kanae、Kato Toshihiro、Murai Toshiya、Heike Toshio、Geschwind Daniel H.、Hagiwara Masatoshi
  • Journal Title: Journal of Child Psychology and Psychiatry Volume: 60 Issue: 5 Pages: 585-598
  • DOI: 10.1111/jcpp.12999
  • NAID: 120006533268
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Epigenome-wide association study of DNA methylation in Williams syndrome (2018)
  • Author(s): 木村亮, 粟屋智就, 中田昌利, 加藤竹雄, 富和清隆, 岡崎伸, 平家俊男, 萩原正敏
  • Organizer: 第63回日本人類遺伝学会
• [Presentation] Epigenome-wide association study of Williams syndrome (2018)
  • Author(s): 木村亮, 粟屋智就, 中田昌利, 加藤竹雄, 富和清隆, 平家俊男, 萩原正敏
  • Organizer: 第123回日本解剖学会総会
• [Presentation] A potential blood-based DNA methylation biomarker for autism spectrum disorder (2018)
  • Author(s): Kimura, R., Awaya, T., Nakata, M., Kato, T., Funabiki, Y., Tomiwa, K., Heike, T., Hagiwara, M
  • Organizer: Neuroscience 2018
  • Int'l Joint Research
• [Presentation] Aberrant expression of microRNAs as specific blood-based biomarkers for autism spectrum disorder (2017)
  • Author(s): 1.Kimura, R., Nakata, M., Awaya, T., Kato, T., Funabiki, F., Murai, T., Heike, T., Hagiwara, M.
  • Organizer: The 13th World Congress of Biological Psychiatry
  • Int'l Joint Research
• [Presentation] Epigenome-wide association study of DNA methylation in Williams syndrome (2017)
  • Author(s): 1.Kimura, R., Awaya, T., Nakata, M., Kato, T., Funabiki, Y., Tomiwa, K., Heike, T., Hagiwara, M.
  • Organizer: SfN's 47th annual meeting, Neuroscience 2017
  • Int'l Joint Research
• [Presentation] An epigenome-wide association study of Williams syndrome (2017)
  • Author(s): 2.Kimura, R., Awaya, T., Nakata, M., Kato, T., Funabiki, Y., Tomiwa, K., Heike, T., Hagiwara, M.
  • Organizer: The American Society of Human Genetics
  • Int'l Joint Research
• [Presentation] Integrated gene co-expression network analysis reveals genotype-phenotype correlations in Williams syndrome (2016)
  • Author(s): Ryo Kimura, Kiyotaka Tomiwa, Tomonari Awaya, Takeo Kato, Masatoshi Nakata, Yasuko Funabiki, Toshio Heike, Masatoshi Hagiwara
  • Organizer: American Society of Human Genetics
  • Place of Presentation: Vancouver, Canada
  • Year and Date: 2016-10-19
  • Int'l Joint Research