Epigenetic regulation of serotonin transporter in bipolar disorder

• Project/Area Number: 23890250
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Single-year Grants
• Research Field: Psychiatric science
• Research Institution: Tokyo Women's Medical University (2012); The Institute of Physical and Chemical Research (2011)
• Principal Investigator: SUGAWARA Hiroko 東京女子医科大学, 医学部, 助教 (90610692)
• Project Period (FY): 2011 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000); Fiscal Year 2012: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2011: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 双極性障害 / 一卵性双生児 / セロトニントランスポーター / DNA メチル化 / 死後脳 / DNAメチル化

Research Abstract

We performed promoter-wide DNA methylation analysis of lymphoblastoid cell lines (LCLs) derived from two pairs of monozygotic twins discordant for bipolar disorder (BD). We found distinct difference of DNA methylation in SLC6A4 encoding serotonin transporter (HTT), which is a target of antidepressants and is one of the strongest candidate molecules of mood disorder. Promoter hypermethylation of SLC6A4 in LCLs of BD patients was confirmed in a case-control analysis. DNA methylation of SLC6A4 was significantly correlated with its mRNA expression level in individuals with the S/S genotype of serotonin transporter-linked promoter region (HTTLPR), and mRNA expression level was lower in BD patients carrying the S/S genotype. DNA methylation of the same site was also higher in the postmortem brains of BD patients.

Research Products

• [Journal Article] Epigenetic regulation of serotonin transporter in psychiatric disorders (2012)
  • Author(s): Sugawara H, Bundo M, Ishigooka J, Iwamoto K, Kato T
  • Journal Title: J Genet Genomics Volume: (in press)
  • Peer Reviewed
• [Journal Article] Genome-Wide DNA methylation and gene expression analyses of monozygotic twins discordant for intelligence levels. (2012)
  • Author(s): Yu CC
  • Journal Title: PLoS ONE Volume: 7 Issue: 10 Pages: e47081-e47081
  • DOI: 10.1371/journal.pone.0047081
  • Peer Reviewed
• [Journal Article] Psychiatric consultation after kidney transplantation: a 10-year single-center study including outpatients in Japan (2012)
  • Author(s): Nishimura K, Kobayashi S, Sugawara H, Nakajima I, Ishida H, Fuchinoue S, Tanabe K, Ishigooka J
  • Journal Title: Int J Psychiatr Med Volume: 43 Pages: 197-209
  • Peer Reviewed
• [Journal Article] Hypermethylation of serotonin transporter gene in bipolar disorder detected by epigenome analysis of discordant monozygotic twins (2011)
  • Author(s): Sugawara H, Iwamoto K, Bundo M, Ueda J, Miyauchi T, Komori A, Kazuno A, Adati N, Kusumi I, Okazaki Y, Ishigooka J, Koji-ma T, Kato T
  • Journal Title: Translational Psychiatry Volume: 1 Issue: 7 Pages: e24-e24
  • DOI: 10.1038/tp.2011.26
  • Peer Reviewed
• [Journal Article] Graft loss in a living kidney transplant patient with Munchausen syndrome (2011)
  • Author(s): Nishimura K, Oshibuchi H, Kobayashi S, Sugawara H, Sannomiya A, Nakajima I, Fuchinoue S, Teraoka S, Ishigooka J
  • Journal Title: Psychosomatics Volume: 52(4) Pages: 394-5
  • Peer Reviewed
• [Journal Article] Comprehensive DNA methylation analysis of human peripheral blood leukocytes and lymphoblastoid cell lines (2011)
  • Author(s): Sugawara H, Iwamoto K, Bundo M, Ueda J, Ishigooka J, Kato T
  • Journal Title: Epigenetics Volume: 6(4)
  • Peer Reviewed
• [Journal Article] Predictors of efficacy in lithium augmentation for treatment-resistant depression (2010)
  • Author(s): Sugawara H, Sakamoto K, Harada T, Ishigooka J
  • Journal Title: J Affect Disord Volume: 125(1-3) Pages: 165-8
  • Peer Reviewed
• [Journal Article] Effect of mood stabilizers on gene expression in lymphoblastoid cells (2010)
  • Author(s): Sugawara H, Iwamoto K, Bundo M, Ishiwata M, Ueda J, Kakiuchi C, Ishigooka J, Kato T
  • Journal Title: J Neural Transm Volume: 117(2) Pages: 155-64
  • Peer Reviewed
• [Journal Article] A 3-bp deletion of mitochondrial DNA tRNALys observed in lymphoblastoid cells (2009)
  • Author(s): Sugawara H, Iwamoto K, Bundo M, Kazuno A, Nakano Y, Ishigooka J, Kato T
  • Journal Title: J Hum Genet Volume: 54(10) Pages: 612-3
  • Peer Reviewed
• [Journal Article] Aripiprazole and haloperidol suppress excessive dopamine release in the amygdala in response to conditioned fear stress, but show contrasting effects on basal dopamine release in methamphetamine-sensitized rats (2009)
  • Author(s): Oshibuchi H, Inada K, Sugawara H, Ishigooka J
  • Journal Title: Eur J Pharmacol Volume: 615(1-3) Pages: 83-90
  • NAID: 120002361249
  • Peer Reviewed
• [Journal Article] Paradoxical depression in renal transplant recipients (2008)
  • Author(s): Sugawara H, Nishimura K, Kobayashi S, Ishida H, Tanabe K, Ishigooka J
  • Journal Title: Transplant Proc Volume: 40(10) Pages: 3448-50
  • Peer Reviewed
• [Presentation] Hypermethylation of serotonin transporter gene in bipolar disorder detected by epigenome analysis of discordant twins (2012)
  • Author(s): Hiroko Sugawara, et al
  • Organizer: 5^<th> Biennal Conference of The International Society For Bipolar Disorders
  • Place of Presentation: Istanbul
  • Year and Date: 2012-03-15
• [Presentation] ミトコンドリア機能障害仮説に基づく双極性障害モデルマウスにおけるDNA メチル化解析DNA (2012)
  • Author(s): 菅原裕子、文東美紀、上田順子、宮内妙子、窪田美恵、笠原和起、石郷岡純、岩本和也、加藤忠史
  • Organizer: 第6回エピジェネティクス研究会年回
  • Place of Presentation: 東京
• [Presentation] 卵性双生児不一致例のエピゲノ解析で同定された双極性障害におけるSLC6A4 の高メチル化 (2012)
  • Author(s): 菅原裕子、岩本和也、文東美紀、足立直樹、久住一郎、岡崎祐士、石郷岡純、小島俊男、加藤忠史
  • Organizer: 第6回エピジェネティクス研究会年回
  • Place of Presentation: 東京
• [Presentation] Hypermethylation of serotonin transporter gene in bipolar disorder detected by epigenome analysis of discordant monozygotic twins (2012)
  • Author(s): Sugawara H, Iwamoto K, Bundo M, Ueda J, Miyauchi T, Komori A, Kazuno A, Adati N, Kusuni I, Okazaki Y, Ishigooka J, Kojima T, Kato T
  • Organizer: 5th Biennial Conference of ISBD
  • Place of Presentation: Istanbul
• [Presentation] Hypermethylation of serotonin transporter gene in bipolar disorder detected by epigenome analysis of discordant monozygotic twins (2012)
  • Author(s): Hiroko Sugawara
  • Organizer: 28th CINP Congress
  • Place of Presentation: Stockhorm
• [Presentation] Hypermethylation of serotonin transporter gene in bipolar disorder detected by epigenome analysis of discordant monozygotic twins (2012)
  • Author(s): Hiroko Sugawara
  • Organizer: The 2nd meeting of EABF
  • Place of Presentation: 福岡
  • Invited
• [Presentation] 一卵性双生児双極性障害不一致例におけるゲノム差異およびエピゲノム差異の探索 (2011)
  • Author(s): 菅原裕子、岩本和也、文東美紀、上田順子、宮内妙子、小森敦子、数野杏亜、足立直樹、久住一郎、岡崎祐士、石郷岡純、小島俊男、加藤忠史
  • Organizer: 第33回日本生物学的精神医学会
  • Place of Presentation: 東京
• [Presentation] Hypermethylation of serotonin transporter gene in bipolar disorder detected by epigenome analysis of discordant monozygotic twins
  • Author(s): Sugawara H, Iwamoto K, Bundo M, Ueda J, Miyauchi T, Komori A, Kazuno A, Adati N, Kusuni I, Okazaki Y, Ishigooka J, Kojima T, Kato T
  • Organizer: 2EABF
  • Place of Presentation: Fukuoka
• [Presentation] Hypermethylation of serotonin transporter gene in bipolar disorder detected by epigenome analysis of discordant monozygotic twins
  • Author(s): Sugawara H, Iwamoto K, Bundo M, Ueda J, Miyauchi T, Komori A, Kazuno A, Adati N, Kusuni I, Okazaki Y, Ishigooka J, Kojima T, Kato T
  • Organizer: XXVIIIth CINP Congress
  • Place of Presentation: Stockholm
• [Book] 【精神疾患の薬理学的理解を薬物治療や心理教育にどう生かすか】 うつ病の生物学的・薬理学的理解と臨床への活用, 臨床精神薬理 (2012)
  • Author(s): 菅原裕子, 坂元薫
• [Book] 【双極性障害の治療】 うつ状態, 精神科 (2012)
  • Author(s): 菅原裕子, 加藤忠史
• [Book] うつ病治療の実際 再び大うつ病治療におけるリチウムの意義を考える, Depression Frontier (2012)
  • Author(s): 菅原裕子, 石郷岡純
• [Book] 【最新の精神科薬物治療ガイドライン】 うつ病の最新薬物治療ガイドライン, 臨床精神薬理 (2011)
  • Author(s): 原田豪人, 菅原裕子, 坂元薫
• [Book] 【双極性障害の新たな展開】 薬物療法の副作用モニタリングで必要なこと, 臨床精神医学 (2011)
  • Author(s): 菅原裕子, 石郷岡純
• [Book] 【社交不安障害(SAD)を再考する】 社交不安障害(SAD)治療における paroxetine の可能性, 臨床精神薬理 (2010)
  • Author(s): 菅原 裕子, 坂元 薫
• [Book] 【内科医が知っておきたいうつ病診療】 プライマリケアでのうつ病治療の進め方, Mebio27 (2010)
  • Author(s): 菅原裕子, 坂元薫
• [Book] 【Clozapine 症例集】 Clozapine 投与により脳波異常 てんかん発作が出現した 1 例, 臨床精神薬理 (2010)
  • Author(s): 菅原裕子, 大下隆司, 奥井賢一郎, 馬場美穂, 瀧村剛, 石郷岡純
• [Book] 精神医学臨床研究ガイドブック, 臨床精神医学 (2009)
  • Author(s): 菅原裕子, 坂元薫
• [Book] 【精神科薬物療法の本音と実際】 治療抵抗性うつ病の lithium 増強療法の理論と実際, 臨床精神薬理 (2009)
  • Author(s): 菅原裕子, 坂元薫, 石郷岡純
• [Book] 【抗うつ薬治療における増強療法と併用療法】 治療抵抗性うつ病に対する第二世代抗精神病薬増強療法, 臨床精神薬理 (2009)
  • Author(s): 菅原裕子, 坂元薫
• [Book] 【新薬展望 2009】 注目の新薬 抗精神病薬 一般名 ブロナンセリン 「ロナセン」, 医薬ジャーナル (2009)
  • Author(s): 菅原裕子, 石郷岡純
• [Book] 【向精神薬の効果・副作用の予測因子】Benzodiazepine の有効性・安全性の予測因子, 臨床精神薬理 (2009)
  • Author(s): 菅原裕子, 石郷岡純
• [Book] 【気分障害】 非定型うつ病(解説/特集), 精神科 (2008)
  • Author(s): 菅原裕子, 坂元薫
• [Book] 「軽いうつ」「軽い躁」 どう対応するか】 双極 II 型の治療 気分安定薬と抗うつ薬, 精神科治療学 (2008)
  • Author(s): 鈴木枝里子, 菅原裕子, 坂元薫
• [Book] 【ライフステージに応じたサービスを考える】 疾患ごとに見たライフステージ ライフステージから見た双極 I 型障害, 精神科臨床サービス (2008)
  • Author(s): 菅原裕子, 坂元薫
• [Book] 【臨床睡眠学 睡眠障害の基礎と臨床】治療法 薬物療法 ベンゾジアゼピン系睡眠薬、非ベンゾジアゼピン系睡眠薬, 日本臨床, 臨床睡眠学 (2008)
  • Author(s): 菅原裕子, 稲田健, 石郷岡純
• [Book] 【精神科治療過程で有用な臨床検査】 うつ病治療における臨床検査, 精神科治療学 (2008)
  • Author(s): 菅原裕子, 長谷川大輔, 坂元薫
• [Book] 【プライマリケアにおけるうつ病診療の実際】 うつ病の治療 その他の治療 気分安定薬、非薬物療法, Progress in Medicine (2007)
  • Author(s): 菅原裕子, 坂元薫
• [Book] 【双極性障害の薬物療法】 双極性障害に対する第二世代抗精神病薬の有効性, 臨床精神薬理 (2007)
  • Author(s): 菅原裕子, 坂元薫
• [Book] 統合失調症に対する治療薬の使い分けと服薬指導の実際, 日本薬剤師会雑誌 (2007)
  • Author(s): 菅原裕子, 石郷岡純