Searching for susceptibility genes for narcolepsy, and their application for precision medicine

• Project/Area Number: 15H04709
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Human genetics
• Research Institution: Tokyo Metropolitan Institute of Medical Science
• Principal Investigator: MIYAGAWA Taku 公益財団法人東京都医学総合研究所, 精神行動医学研究分野, 主席研究員 (20512263)
• Co-Investigator(Kenkyū-buntansha): 徳永 勝士 東京大学, 大学院医学系研究科(医学部), 教授 (40163977) ; 豊田 裕美 東京大学, 大学院医学系研究科(医学部), 客員研究員 (90637448)
• Research Collaborator: SHIMADA mihoko
• Project Period (FY): 2015-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000); Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2017: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2016: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2015: ¥6,630,000 (Direct Cost: ¥5,100,000、Indirect Cost: ¥1,530,000)
• Keywords: ナルコレプシー / ゲノム / ゲノムワイド関連解析 / 睡眠 / 過眠症 / アシルカルニチン / 人類遺伝学 / 中枢性過眠症 / 感受性遺伝子 / 特発性過眠症 / 脂肪酸代謝 / 遺伝学 / 睡眠障害

Outline of Final Research Achievements

We performed genome-wide and epigenome-wide association studies in narcolepsy, identifying that a SNP and a DNA methylation probe in the CCR3 gene region were associated with narcolepsy. meQTL was identified through a significant association between the SNP and the DNA methylation probe. Expression levels of the CCR3 were significantly lower in patients with narcolepsy than in controls. A polygenic analysis using genome-wide SNP data revealed that patients with HLA-DQB1*06:02-positive essential hypersomnia (EHS) were estimated to possess higher shared genetic background to narcoleptic patients. In addition, we found a significant association between HLA-DQB1*06:02-negative EHS and a SNP in the CRAT gene region, and succinylcarnitine as a candidate biomarker for HLA-DQB1*06:02-negative EHS.

Academic Significance and Societal Importance of the Research Achievements

本研究の結果からナルコレプシーにおけるオレキシン産生神経の脱落にはCCR3を介した免疫異常が関わることが示唆された。ナルコレプシーの発症前後に起きている免疫異常を抑えることで、オレキシン産生神経の脱落を防ぐことが可能であると推測される。HLA-DQB1*06:02を遺伝マーカーとして真性過眠症の病態が異なることがわかり、これは個別化医療につながる結果であった。HLA-DQB1*06:02陰性の真性過眠症には代謝異常が関わり、その原因物質の候補としてスクシニルカルニチンを同定できた。これは創薬のターゲットにもなる結果であった。

Research Products

• [Int'l Joint Research] Stanford University(米国)
• [Int'l Joint Research] Stanford University(米国)
• [Int'l Joint Research] Stanford University(米国)
• [Int'l Joint Research] Stanford University(米国)
• [Journal Article] Genetics of narcolepsy (2019)
  • Author(s): Miyagawa Taku, Tokunaga Katsushi
  • Journal Title: Human Genome Variation Volume: 6 Issue: 1 Pages: 4-4
  • DOI: 10.1038/s41439-018-0033-7
  • Peer Reviewed / Open Access
• [Journal Article] A variant at 9q34.11 is associated with HLA-DQB1*06:02 negative essential hypersomnia (2018)
  • Author(s): Miyagawa T, Khor SS, Toyoda H, Kanbayashi T, Imanishi A, Sagawa Y, Kotorii N, Kotorii T, Ariyoshi Y, Hashizume Y, Ogi K, Hiejima H, Kamei Y, Hida A, et al.
  • Journal Title: J Hum Genet Volume: 63 Issue: 12 Pages: 1259-1267
  • DOI: 10.1038/s10038-018-0518-8
  • Peer Reviewed / Open Access
• [Journal Article] Epigenome-wide association study of DNA methylation in narcolepsy: an integrated genetic and epigenetic approach (2018)
  • Author(s): Shimada Mihoko、Miyagawa Taku、Toyoda Hiromi、Tokunaga Katsushi、Honda Makoto
  • Journal Title: Sleep Volume: 41 Issue: 4 Pages: 1-9
  • DOI: 10.1093/sleep/zsy019
  • Peer Reviewed
• [Journal Article] An epigenome-wide methylation study of healthy individuals with or without depressive symptoms. (2018)
  • Author(s): Shimada M, Otowa T, Miyagawa T, Umekage T, Kawamura Y, Bundo M, Iwamoto K, Ikegame T, Tochigi M, Kasai K, Kaiya H, Tanii H, Okazaki Y, Tokunaga K, Sasaki T. An epigenome-wide methylation study of healthy individuals with or without depressive symptoms.
  • Journal Title: J Hum Genet Volume: 63 Issue: 3 Pages: 319-326
  • DOI: 10.1038/s10038-017-0382-y
  • Peer Reviewed / Open Access
• [Journal Article] Narcolepsy susceptibility gene CCR3 modulates sleep-wake patterns in mice. (2017)
  • Author(s): Toyoda H, Honda Y, Tanaka S, Miyagawa T, Honda M, Honda K, Tokunaga K, Kodama T.
  • Journal Title: PLOS ONE Volume: 12 Issue: 11 Pages: 1-17
  • DOI: 10.1371/journal.pone.0187888
  • Peer Reviewed / Open Access
• [Journal Article] Epigenome-wide association study of DNA methylation in panic disorder (2017)
  • Author(s): Shimada-Sugimoto, M., T. Otowa, T. Miyagawa, T. Umekage, Y. Kawamura, M. Bundo, K. Iwamoto, M. Tochigi, K. Kasai, H. Kaiya, H. Tanii, Y. Okazaki, K. Tokunaga and T. Sasaki
  • Journal Title: Clinical Epigenetics Volume: 9 Issue: 1 Pages: 6-6
  • DOI: 10.1186/s13148-016-0307-1
  • Peer Reviewed / Open Access
• [Journal Article] Evaluation of polygenic risks for narcolepsy and essential hypersomnia (2016)
  • Author(s): Yamasaki M, Miyagawa T, Toyoda H, Khor SS, Liu X, Kuwabara H, Kano Y, Shimada T, Sugiyama T, Nishida H, Sugaya N, Tochigi M, Otowa T, Okazaki Y, Kaiya H, Kawamura Y, Miyashita A, Kuwano R, Kasai K, Tanii H, Sasaki T, Honda Y, Honda M, Tokunaga K
  • Journal Title: Journal of Human Genetics Volume: 61(10) Issue: 10 Pages: 873-878
  • DOI: 10.1038/jhg.2016.65
  • NAID: 40020966185
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Specific HLA genotypes confer susceptibility to acute necrotizing encephalopathy (2016)
  • Author(s): Hoshino A, Saitoh M, Miyagawa T, Kubota M, Takanashi JI, Miyamoto A, Tokunaga K, Oka A, Mizuguchi M
  • Journal Title: Genes and Immunity Volume: 17(6) Issue: 6 Pages: 367-369
  • DOI: 10.1038/gene.2016.32
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Phenome-wide association study maps new diseases to the human major histocompatibility complex region (2016)
  • Author(s): Liu J, Ye Z, Mayer JG, Hoch BA, Green C, Rolak L, Cold C, Khor SS, Zheng X, Miyagawa T, Tokunaga K, Brilliant MH, Hebbring SJ
  • Journal Title: Journal of Medical Genetics Volume: 53(10) Issue: 10 Pages: 681-689
  • DOI: 10.1136/jmedgenet-2016-103867
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Polymorphisms in the TMEM132D region are associated with panic disorder in HLA-DRB1*13:02-negative individuals of a Japanese population. (2016)
  • Author(s): Shimada-Sugimoto M, Otowa T, Miyagawa T, Khor S-S, Omae Y, Toyo-oka L, Sugaya N, Kawamura Y, Umekage T, Miyashita A, Kuwano R, Kaiya H, Kasai K, Tanii H, Okazaki Y, Tokunaga K, Sasaki T
  • Journal Title: Human Genome Variation Volume: 3 Issue: 1 Pages: 16001-16001
  • DOI: 10.1038/hgv.2016.1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Identification of ITPA as a susceptibility gene to young-onset tuberculosis on Chromosome 20 (2016)
  • Author(s): Nakauchi A, Wong JH, Mahasirimongkol S, Yanai H, Yuliwulandari R, Mabuchi A, Liu X, Mushiroda T, Wattanapokayakit S, Miyagawa T, Keicho N, Tokunaga K
  • Journal Title: Human Genome Variation Volume: 3 Issue: 1 Pages: 15067-15067
  • DOI: 10.1038/hgv.2015.67
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] An association analysis of HLA-DQB1 with narcolepsy without cataplexy and idiopathic hypersomnia with/without long sleep time in a Japanese population. (2015)
  • Author(s): Miyagawa T, Toyoda H, Kanbayashi T, Imanishi A, Sagawa Y, Shimizu T, Inoue Y, Honda Y, Mishima K, Honda M, Tokunaga K.
  • Journal Title: Hum Genome Var. Volume: 17(2) Issue: 1 Pages: 15031-15031
  • DOI: 10.1038/hgv.2015.31
  • Peer Reviewed / Open Access
• [Journal Article] A polymorphism in CCR1/CCR3 is associated with narcolepsy. (2015)
  • Author(s): Toyoda H, Miyagawa T, Koike A, Kanbayashi T, Imanishi A, Sagawa Y, Kotorii N, Kotorii T, Hashizume Y, Ogi K, Hiejima H, Kamei Y, Hida A, Miyamoto M, Imai M, Fujimura Y, Tamura Y, Ikegami A, Wada Y, Moriya S, Furuya H, Takeuchi M, Kirino Y, Meguro A, Remmers EF, Kawamura Y, Otowa T, Miyashita A, et al.
  • Journal Title: Brain Behav Immun. Volume: 印刷中 Pages: 148-155
  • DOI: 10.1016/j.bbi.2015.05.003
  • Peer Reviewed
• [Journal Article] Immune-related pathways including HLA-DRB1(*)13:02 are associated with panic disorder. (2015)
  • Author(s): Shimada-Sugimoto M ほか
  • Journal Title: Brain Behav Immun Volume: Epub Pages: 96-103
  • DOI: 10.1016/j.bbi.2015.01.002
  • Peer Reviewed
• [Journal Article] High-accuracy imputation for HLA class I and II genes based on high-resolution SNP data of population-specific references. (2015)
  • Author(s): Khor SS, Yang W, Kawashima M, Kamitsuji S, Zheng X, Nishida N, Sawai H, Toyoda H, Miyagawa T, Honda M, Kamatani N, Tokunaga K.
  • Journal Title: Pharmacogenomics J. Volume: 未定 Issue: 6 Pages: 1-8
  • DOI: 10.1038/tpj.2015.4
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Novel rare variations of the oxytocin receptor (OXTR) gene in autism spectrum disorder individuals. (2015)
  • Author(s): Liu X, Kawashima M, Miyagawa T, Otowa T, Latt KZ, Thiri M, Nishida H, Sugiyama T, Tsurusaki Y, Matsumoto N, Mabuchi A, Tokunaga K, Sasaki T.
  • Journal Title: Human Genome Variation Volume: 2 Issue: 1 Pages: 15024-15024
  • DOI: 10.1038/hgv.2015.24
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] A variant affecting levels of succinylcarnitine is associated with HLA-DQB1*06:02-negative essential hypersomnia (2018)
  • Author(s): Miyagawa T, Khor SS, Toyoda H, Shimada M, Kojima H, Futagami T, Yamasaki M, Saji H, Mishima K, Honda Y, Honda M, Tokunaga K
  • Organizer: The American Society of Human Genetics Annual Meeting 2018
  • Int'l Joint Research
• [Presentation] 血中スクシニルカルニチン濃度に影響を与える多型と真性過眠症との関連 (2018)
  • Author(s): 宮川卓, 許昔舜, 嶋多美穂子, 豊田裕美, 三島和夫, 本多真, 徳永勝士
  • Organizer: 日本人類遺伝学会第63回大会
• [Presentation] A variant in CRAT is associated with HLA-DQB1*06:02-negative essential hypersomnia (2018)
  • Author(s): Miyagawa T, Khor SS, Toyoda H, Shimada M, Mishima K, Honda Y, Honda M, Tokunaga K
  • Organizer: The 9th Congress of Asian Sleep Research Society
  • Int'l Joint Research
• [Presentation] ナルコレプシーの感受性遺伝子の探索 (2018)
  • Author(s): 宮川卓
  • Organizer: 日本睡眠学会第43回定期学術集会
  • Invited
• [Presentation] A missense variant in PER2 is associated with delayed sleep-wake phase disorder (2018)
  • Author(s): Miyagawa T, Shimada M, Hida A, Honda Y, Mishima K, Tokunaga K, Honda M
  • Organizer: The European Conference of Human Genetics 2018
  • Int'l Joint Research
• [Presentation] PER2遺伝子上のミスセンス変異と睡眠相後退症候群との関連 (2017)
  • Author(s): 1.宮川 卓、嶋多 美穂子、肥田 昌子、本多 裕、三島 和夫、徳永 勝士、本多 真
  • Organizer: 日本人類遺伝学会第62回大会
• [Presentation] A missense variant in PER2 is associated with delayed sleep phase disorder (2017)
  • Author(s): Miyagawa T, Shimada M, Hida A, Honda Y, Mishima K, Tokunaga K, Honda M
  • Organizer: The American Society of Human Genetics Annual Meeting 2017
  • Int'l Joint Research
• [Presentation] A genetic variant in CRAT is associated with HLA-DQB1*06:02 negative essential hypersomnia (2017)
  • Author(s): Miyagawa T, Khor SS, Toyoda H, Shimada M, Kojima H, Futagami T, Yamasaki M, Saji H, Mishima K, Honda Y, Honda M, Tokunaga K
  • Organizer: World Sleep 2017
  • Int'l Joint Research
• [Presentation] 真性過眠症の新規疾患関連遺伝子 (2017)
  • Author(s): 宮川 卓
  • Organizer: 日本睡眠学会第42回定期学術集会
  • Invited
• [Presentation] ゲノム解析によって見出された過眠症とカルニチンとの関連 (2017)
  • Author(s): 宮川 卓
  • Organizer: 第17回日本抗加齢医学会総会
  • Invited
• [Presentation] 特発性過眠症の感受性遺伝子の探索 (2016)
  • Author(s): 宮川卓、豊田裕美、小島裕人、二神貴臣、佐治博夫、三島和夫、本多裕、徳永勝士、本多真
  • Organizer: 第25回日本組織適合性学会大会
  • Place of Presentation: 北海道大学学術交流会館（札幌市北区）
• [Presentation] A polymorphism in CRAT is associated with HLA-DQB1*06:02 negative essential hypersomnia (2016)
  • Author(s): Miyagawa T, Khor SS, Toyoda H, Kojima H, Futagami T, Yamasaki M, Saji H, Mishima K, Honda Y, Honda M, Tokunaga K
  • Organizer: The European Human Genetics Conference 2016
  • Place of Presentation: バルセロナ（スペイン）
  • Int'l Joint Research
• [Presentation] A polymorphism in CRAT is associated with HLA-DQB1*06:02 negative essential hypersomnia (2016)
  • Author(s): Miyagawa T, Khor SS, Toyoda H, Kojima H, Futagami T, Yamasaki M, Saji H, Mishima K, Honda Y, Honda M, Tokunaga K
  • 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）
  • Int'l Joint Research
• [Presentation] HLA-DQB1*06:02 陰性の真性過眠症候群の感受性遺伝子の探索 (2015)
  • Author(s): 宮川卓、Khor SS、豊田裕美、三島和夫、本多裕、本多真、徳永勝士
  • Organizer: 第48回 精神神経系薬物治療研究報告会
  • Place of Presentation: 千里ライフサイエンスセンター（大阪府豊中市）
• [Presentation] HLA-DQB1*06:02陰性の真性過眠症候群を対象としたゲノムワイド関連解析 (2015)
  • Author(s): 宮川卓、Khor SS、豊田裕美、小島裕人、二神貴臣、山崎茉莉亜、佐治博夫、三島和夫、本多裕、本多真、徳永勝士
  • Organizer: 日本人類遺伝学会第60回大会
  • Place of Presentation: 京王プラザホテル（東京都新宿区）
• [Presentation] A polymorphism in CRAT is associated with HLA-DQB1*06:02 negative essential hypersomnia (2015)
  • Author(s): Miyagawa T, Khor SS, Toyoda H, Kojima H, Futagami T, Yamasaki M, Saji H, Mishima K, Honda Y, Honda M, Tokunaga K
  • Organizer: American Society of Human Genetics Annual Meeting 2015
  • Place of Presentation: ボルチモア（アメリカ）
  • Int'l Joint Research
• [Presentation] HLA-DQB1*06:02陰性の真性過眠症候群を対象としたゲノムワイド関連解析 (2015)
  • Author(s): 宮川卓、Khor SS、豊田裕美、小島裕人、二神貴臣、山崎茉莉亜、佐治博夫、三島和夫、本多裕、本多真、徳永勝士
  • Organizer: 第24回日本組織適合性学会大会
  • Place of Presentation: ホテルレイクビュー水戸（茨城県水戸市）
• [Presentation] Association analysis of narcolepsy without cataplexy and idiopathic hypersomnia (2015)
  • Author(s): Miyagawa T, Khor SS, Toyoda H, Kojima H, Futagami T, Yamasaki M, Saji H, Mishima K, Honda Y, Honda M, Tokunaga K
  • Organizer: The European Human Genetics Conference 2015
  • Place of Presentation: グラスゴー（イギリス）
  • Int'l Joint Research
• [Book] 社会を変える健康のサイエンス 健康総合科学への21の扉 (2016)
  • Author(s): 宮川卓、徳永勝士
  • Total Pages: 6
  • Publisher: 東京大学出版会
• [Book] 臨床精神医学、睡眠の遺伝学 : ナルコレプシーの感受性遺伝子 (特集 精神神経疾患のゲノム研究 : 失われた遺伝率の謎を求めて) Genetic studies in sleep disorders : susceptibility genes for narcolepsy (2015)
  • Author(s): 宮川 卓
  • Total Pages: 6
  • Publisher: 株式会社アークメディア
• [Book] 医学のあゆみ、HLA領域におけるHLA-DQB1*06:02以外のナルコレプシー関連遺伝子 (2015)
  • Author(s): 宮川 卓
  • Total Pages: 2
  • Publisher: 医歯薬出版株式会社
• [Remarks] 東京都医学総合研究所精神行動医学研究分野睡眠プロジェクト
  • URL: http://www.igakuken.or.jp/sleep/
• [Remarks] 東京大学大学院医学系研究科国際保健学専攻人類遺伝学分野
  • URL: http://www.humgenet.m.u-tokyo.ac.jp/
• [Remarks] 東京大学大学院医学系研究科人類遺伝学教室
  • URL: http://www.humgenet.m.u-tokyo.ac.jp/