Development of a prognosis prediction model for Alzheimer's disease using integrative multi-omics data

2023 Fiscal Year Annual Research Report

• Project/Area Number: 21H02470
• Allocation Type: Single-year Grants
• Research Institution: National Center for Geriatrics and Gerontology
• Principal Investigator: 重水 大智 国立研究開発法人国立長寿医療研究センター, 研究所 メディカルゲノムセンター, 部長 (70617464)
• Co-Investigator(Kenkyū-buntansha): 尾崎 浩一 国立研究開発法人国立長寿医療研究センター, 研究所 メディカルゲノムセンター, センター長 (50373288)
• Project Period (FY): 2021-04-01 – 2026-03-31
• Keywords: アルツハイマー病 / HLA

Outline of Annual Research Achievements

国立長寿医療研究センター（NCGG）には、高齢者の高品質な血液試料・ゲノムデータを保有しているバイオバンクがある。その中から少なくとも1年以上フォローアップした軽度認知障害者のゲノムデータ、遺伝子発現データ、臨床情報のマルチオミクス統合解析からアルツハイマー病(AD)への移行に関わるリスク因子を網羅的に探索し、予測診断システムの開発を目指す。
現在報告されているAD発症リスク因子の多くが免疫に関連している。そのため、ADと免疫との関係を、NCGGバイオバンクのAD患者303名、認知機能正常高齢者1717人の全ゲノム配列データ解析から調べた。結果、APOEε4を持たない集団でHLA-DRB1*09:01とHLA-DQB1*03:03のアレル頻度がAD患者で有意に高いことがわかった。この両アレルは、日本人を含む東アジア人特異的に認められるアレルである。
HLA-DRB1*09:01とHLA-DQB1*03:03は連鎖不平衡が強い（r2 = 0.88）。そのため、HLA-DRB1*09:01-DQB1*03:03のハプロタイプがADの発症に強く寄与している可能性が示唆された。実際、このハプロタイプはAPOEε4を持たない集団でAD発症のリスクを有意に高めていることが示された。
本研究で同定されたHLAハプロタイプは、HLAクラスIIに属する。HLAクラスII分子は、細胞表面に抗原を提示し、その抗原をT細胞受容体（TCR）によって認識することで、CD4＋ヘルパーT細胞への分化を促進させる。そこで、本研究で同定されたハプロタイプとTCRの多様性の関連について調べた。その結果、その関連性は示されなかったが、TCRのα鎖の多様性の低下がAD発症に関与することが新たにわかった。今後、さらに症例数を増やして検証する予定である。

Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

大規模な全ゲノムシークエンスデータ解析からAD移行に関わる新規バイオマーカー候補を同定することができたため。

Strategy for Future Research Activity

網羅的な遺伝子発現のデータとゲノムデータ、臨床データの統合解析から、ADへの移行を予測できる最適なバイオマーカーの組み合わせを探索する。ゲノム変異と遺伝子発現の関係を示すeQTLに着目し、eQTLをバイオマーカー候補とし、AD移行予測診断システムの開発を行う。開発した予測システムは、独立した前向きコホートデータを用いてその予測能を検証する。

Research Products

• [Journal Article] The HLA-DRB1*09:01-DQB1*03:03 haplotype is associated with the risk for late-onset Alzheimer’s disease in APOE4 negative Japanese adults (2024)
  • Author(s): Shigemizu Daichi、Fukunaga Koya、Yamakawa Akiko、Suganuma Mutsumi、Fujita Kosuke、Kimura Tetsuaki、Watanabe Ken、Mushiroda Taisei、Sakurai Takashi、Niida Shumpei、Ozaki Kouichi
  • Journal Title: npj Aging Volume: 10 Pages: 3~3
  • DOI: 10.1038/s41514-023-00131-3
  • Peer Reviewed / Open Access
• [Journal Article] CRISPR/Cas9-mediated knock-in cells of the late-onset Alzheimer’s disease-risk variant, SHARPIN G186R, reveal reduced NF-κB pathway and accelerated Aβ secretion (2024)
  • Author(s): Asanomi Yuya、Kimura Tetsuaki、Shimoda Nobuyoshi、Shigemizu Daichi、Niida Shumpei、Ozaki Kouichi
  • Journal Title: Journal of Human Genetics Volume: 69 Pages: 171～176
  • DOI: 10.1038/s10038-024-01224-x
  • Peer Reviewed / Open Access
• [Journal Article] Identification of Potential Blood-Based Biomarkers for Frailty by Using an Integrative Approach (2024)
  • Author(s): Suganuma Mutsumi、Furutani Motoki、Hosoyama Tohru、Mitsumori Risa、Otsuka Rei、Takemura Marie、Matsui Yasumoto、Nakano Yukiko、Niida Shumpei、Ozaki Kouichi、Satake Shosuke、Shigemizu Daichi
  • Journal Title: Gerontology Volume: Mar 14 Pages: 1～9
  • DOI: 10.1159/000538313
  • Peer Reviewed
• [Journal Article] RNA-Sequencing Analysis Identification of Potential Biomarkers for Diagnosis of Sarcopenia (2023)
  • Author(s): Furutani Motoki、Suganuma Mutsumi、Akiyama Shintaro、Mitsumori Risa、Takemura Marie、Matsui Yasumoto、Satake Shosuke、Nakano Yukiko、Niida Shumpei、Ozaki Kouichi、Hosoyama Tohru、Shigemizu Daichi
  • Journal Title: The Journals of Gerontology: Series A Volume: 78 Pages: 1991～1998
  • DOI: 10.1093/gerona/glad150
  • Peer Reviewed
• [Journal Article] Classification and deep-learning-based prediction of Alzheimer disease subtypes by using genomic data (2023)
  • Author(s): Shigemizu Daichi、Akiyama Shintaro、Suganuma Mutsumi、Furutani Motoki、Yamakawa Akiko、Nakano Yukiko、Ozaki Kouichi、Niida Shumpei
  • Journal Title: Translational Psychiatry Volume: 13 Pages: 1-8
  • DOI: 10.1038/s41398-023-02531-1
  • Peer Reviewed / Open Access
• [Journal Article] Association between Circulating Levels of CXCL9 and CXCL10 and Physical Frailty in Older Adults (2023)
  • Author(s): Li Jiaqi、Hosoyama Tohru、Shigemizu Daichi、Yasuoka Mikako、Kinoshita Kaori、Maeda Keisuke、Takemura Marie、Matsui Yasumoto、Arai Hidenori、Satake Shosuke
  • Journal Title: Gerontology Volume: 70 Pages: 279～289
  • DOI: 10.1159/000535109
  • Peer Reviewed
• [Presentation] 日本人集団で見つかったレビー小体型認知症に関連する MFSD3 多型の機能解析 (2023)
  • Author(s): 木村 哲晃、菅沼 睦美、澤村 嘉代子、浅海 裕也、細山 徹、下田 修義、小木曽 昇、新飯田 俊平、尾崎 浩一、重水 大智
  • Organizer: 第42回日本認知症学会学術集会
• [Presentation] 遺伝子発現データに基づくアルツハイマー病移行予測診断システムの開発 (2023)
  • Author(s): 山川 明子、光森 理紗、菅沼 睦美、秋山 真太郎、新飯田 俊平、尾崎 浩一、重水 大智
  • Organizer: 第42回日本認知症学会学術集会
• [Presentation] An integrative approach to detect potential blood-based biomarkers for frailty (2023)
  • Author(s): Suganuma M, Furutani M, Hosoyama T, Akiyama S, Mitsumori R, Otsuka R, Takemura M, Matsui Y, Nakano Y, Niida S, Ozaki K, Satake S, and Shigemizu D.
  • Organizer: The American Society of Human Genetics
  • Int'l Joint Research
• [Presentation] Identification of an East Asian-specific variant associated with Lewy bodies dementia by genome-wide association study in Japanese subjects (2023)
  • Author(s): Mitsumori R, Asanomi Y, Shigemizu D, Akiyama S, Morizono T, Niida S, and Ozaki K.
  • Organizer: The American Society of Human Genetics
  • Int'l Joint Research
• [Presentation] Functional analysis of MFSD3 associated with dementia with Lewy bodies (2023)
  • Author(s): Kimura T, Suganuma M, Hosoyama T, Sawamura K, Shimoda N, Ogiso N, Niida S, Ozaki K, and Shigemizu D.
  • Organizer: The American Society of Human Genetics
  • Int'l Joint Research
• [Presentation] CRISPR/Cas9-mediated knock-in of late-onset Alzheimer’s disease-risk variant, SHARPIN G186R, lessens the NF-κB pathway and accelerates Aβ secretion (2023)
  • Author(s): Asanomi Y, Kimura T, Shimoda N, Shigemizu D, Niida S, and Ozaki K.
  • Organizer: The American Society of Human Genetics
  • Int'l Joint Research
• [Presentation] RNA-seq data analysis identifies blood-based biomarkers for diagnosis and disease progression of Alzheimer's disease (2023)
  • Author(s): Yamakawa A., Mitsumori R., Suganuma M., Akiyama S., Niida S., Ozaki K., and Shigemizu D.
  • Organizer: The American Society of Human Genetics
  • Int'l Joint Research
• [Presentation] Genome-wide association study for non-specific chronic pain in Japanese elderly (2023)
  • Author(s): Shigemizu D., Sakai Y., Honjo K., Wakao N., Matsui H., Shimada H., Mitsumori R., Ozaki K., and Watanabe K.
  • Organizer: Human Genetics Asia 2023
  • Int'l Joint Research
• [Presentation] Identification of potential blood-based biomarkers for frailty by using an integrative approach (2023)
  • Author(s): Suganuma M, Furutani M, Hosoyama T, Akiyama S, Mitsumori R, Otsuka R, Takemura M, Matsui Y, Nakano Y, Niida S, Ozaki K, Satake S, and Shigemizu D.
  • Organizer: Human Genetics Asia 2023
  • Int'l Joint Research
• [Presentation] Functional analysis of MFSD3 associated with dementia with Lewy bodies (2023)
  • Author(s): Kimura T, Suganuma M, Hosoyama T, Sawamura K, Shimoda N, Ogiso N, Niida S, Ozaki K, and Shigemizu D.
  • Organizer: Human Genetics Asia 2023
  • Int'l Joint Research
• [Presentation] A genome wide association study identifies an East Asian-specific risk variant for Lewy bodies dementia in Japanese (2023)
  • Author(s): Mitsumori R, Asanomi Y, Shigemizu D, Akiyama S, Morizono T, Niida S, and Ozaki K.
  • Organizer: Human Genetics Asia 2023
  • Int'l Joint Research
• [Presentation] Knock-in of late-onset Alzheimer’s disease-risk variant SHARPIN G186R lessens NF-κB pathway and accelerates Aβ secretion (2023)
  • Author(s): Asanomi Y, Kimura T, Shimoda N, Shigemizu D, Niida S, and Ozaki K.
  • Organizer: Human Genetics Asia 2023
  • Int'l Joint Research
• [Presentation] Exploration of blood-based biomarkers to predict the progression of Alzheimer's disease by RNA-sequencing data analysis (2023)
  • Author(s): Yamakawa A., Mitsumori R., Suganuma M., Akiyama S., Niida S., Ozaki K., and Shigemizu D.
  • Organizer: Human Genetics Asia 2023
  • Int'l Joint Research
• [Presentation] 日本人集団で見つかったレビー小体型認知症に関連するMFSD3多型の機能解析 (2023)
  • Author(s): 木村 哲晃、菅沼 睦美、澤村 嘉代子、細山 徹、下田 修義、小木曽 昇、新飯田 俊平、尾崎 浩一、重水 大智
  • Organizer: 第12回日本認知症予防学会学術集会
• [Presentation] RNA-seq データ解析に基づく軽度認知機能障害からアルツハイマー型認知症への移行に関与する血液バイオマーカーの探索 (2023)
  • Author(s): 山川 明子、光森 理紗、菅沼 睦美、秋山 真太郎、新飯田 俊平、尾崎 浩一、重水 大智
  • Organizer: 第12回日本認知症予防学会学術集会
• [Presentation] Identification of blood-based biomarkers associated with conversion from mild cognitive impairment to Alzheimer’s disease by RNA-sequencing data analysis (2023)
  • Author(s): 山川 明子、光森 理紗、菅沼 睦美、秋山 真太郎、新飯田 俊平、尾崎 浩一、重水 大智
  • Organizer: IIBMP2023
• [Presentation] Association between spatio-temporal gait parameters and the risk of falls in older adults (2023)
  • Author(s): Li J., Yasuoka M., Kinoshita K., Hirano Y., Maeda K., Takemura M., Matsui Y., Hosoyama T., Shigemizu D., Arai H., and Satake S.
  • Organizer: IAGG Asia/Oceania Regional Congress 2023
  • Int'l Joint Research
• [Presentation] Circulating CXCL9 levels, but not CXCL10 levels, were associated with frailty in older adults (2023)
  • Author(s): Li J., Hosoyama T., Shigemizu D., Yasuoka M., Kinoshita K., Maeda K., Takemura M., Matsui Y., Arai H., Satake S.
  • Organizer: IAGG Asia/Oceania Regional Congress 2023
  • Int'l Joint Research
• [Presentation] Ferroptotic aspects of cartilage degeneration in mouse osteoarthritis (2023)
  • Author(s): Ishii K., Ma L., Shigemizu D., Asanomi Y., Nakamura H., Ozaki K., and Watanabe K.
  • Organizer: IAGG Asia/Oceania Regional Congress 2023
  • Int'l Joint Research
• [Presentation] MFSD3 loss of function with dementia with Lewy bodies causes an increase of butyrylcholinesterase activity in the brain (2023)
  • Author(s): Kimura T., Suganuma M., Sawamura K., Hosoyama T., Ogiso N., Niida S., Ozaki K., and Shigemizu D.
  • Organizer: IAGG Asia/Oceania Regional Congress 2023
  • Int'l Joint Research
• [Presentation] Genome wide association study identifies new genetic risk loci for dementia with Lewy body in Japanese (2023)
  • Author(s): Mitsumori R., Asanomi Y., Shigemizu D., Akiyama S., Morizono T., Niida S., and Ozaki K.
  • Organizer: IAGG Asia/Oceania Regional Congress 2023
  • Int'l Joint Research
• [Presentation] East Asian-specific late-onset Alzheimer's disease risk variant alters the endogenous SHARPIN function (2023)
  • Author(s): Asanomi Y., Shigemizu D., Akiyama S., Mitsumori R., Niida S., Ozaki K.
  • Organizer: IAGG Asia/Oceania Regional Congress 2023
  • Int'l Joint Research
• [Presentation] Identification of blood-based biomarkers associated with conversion from mild cognitive impairment to Alzheimer’s disease by RNA-sequencing data analysis. (2023)
  • Author(s): Yamakawa A., Mitsumori R., Akiyama S., Niida S., Ozaki K., and Shigemizu D.
  • Organizer: IAGG Asia/Oceania Regional Congress 2023
  • Int'l Joint Research
• [Presentation] Identification of blood-based biomarkers for early diagnosis of frailty through a combined analysis of the clinical data, gene-expression data, and aging-related factors (2023)
  • Author(s): Suganuma M., Furutani M., Hosoyama T., Akiyama S., Mitsumori R., Otsuka R., Takemura M., Matsui Y., Nakano Y., Niida S., Ozaki K., Satake S., and Shigemizu D.
  • Organizer: IAGG Asia/Oceania Regional Congress 2023
  • Int'l Joint Research
• [Presentation] 日本人および民族間横断的ゲノムワイド関連解析によるレビー小体認知症感受性座位の探索 (2023)
  • Author(s): 光森 理紗, 浅海 裕也, 重水 大智, 秋山 真太郎, 森園 隆, 新飯田 俊平, 尾崎 浩一
  • Organizer: 第31回日本医学会総会2023東京
• [Presentation] Genomic research on dementia in the Japanese population (2023)
  • Author(s): Shigemizu D.
  • Organizer: NCGG ICAH TMIG Joint Symposium 2023 IAGG-AOR Sattelite
  • Int'l Joint Research / Invited
• [Presentation] Genomic research on dementia in the Japanese population (2023)
  • Author(s): Shigemizu D., and Ozaki K.
  • Organizer: Human Genetics Asia 2023
  • Int'l Joint Research / Invited