Investigation of genome and epigenome factors in elderly patients with mood disorders

• Project/Area Number: 18K15486
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 52030:Psychiatry-related
• Research Institution: Osaka University (2020-2021); Kumamoto University (2018-2019)
• Principal Investigator: Sugawara Hiroko 大阪大学, 医学系研究科, 招へい教員 (90610692)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2019: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 双極性障害 / 高齢者 / SLC6A4 / 5HTTLPR / DNAメチル化 / 気分障害 / エピゲノム / HTTLPR / うつ病

Outline of Final Research Achievements

In this study, I aimed to investigate the genomic and epigenomic factors in elderly patients with mood disorders, focusing on the serotonin transporter gene, which has been suggested to be associated with the gene-environmental interaction in bipolar disorder. Furthermore, I tried to develop a biomarker for detecting underdiagnosed patients with bipolar disorder. I performed high throughput genotyping of 5HTTLPR using DNA derived from peripheral blood of about 1500 healthy elderly subjects. As a result, there was no association between 5HTTLPR and depressive symptoms. Then, I performed comprehensive DNA methylation analysis using DNA derived from peripheral blood of 3 elderly healthy subjects and 4 bipolar disorder patients, and identified the differences of DNA methylation in 56453 genes.

Academic Significance and Societal Importance of the Research Achievements

本研究では、大規模なコホートサンプルを用いて詳細なgenotypingを行うことで、高齢健常者における5HTTLPRと抑うつ症状の関連についての知見を得ることができた。今後はセロトニントランスポーター（SLC6A4）遺伝子のDNAメチル化レベルを測定し、高齢健常者における抑うつ症状とSLC6A4のゲノム・エピゲノム状態の関連を明らかにし、高齢発症の気分障害患者との比較を行うことで、高齢発症の気分障害におけるゲノム・エピゲノム要因について検討する。また、高齢の双極性障害患者におけるエピゲノムバイオマーカーの開発を試みることで、高齢発症の気分障害における分子病態の異種性について検討を行う。

Research Products

• [Journal Article] Cell-type-specific DNA methylation analysis of the frontal cortices of mutant Polg1 transgenic mice with neuronal accumulation of deleted mitochondrial DNA (2021)
  • Author(s): Sugawara H, Bundo M, Kasahara T, Nakachi Y, Ueda J, Kubota-Sakashita M, Iwamoto K, Kato T
  • Journal Title: Molecular Brain Volume: 15 Issue: 1 Pages: 9-9
  • DOI: 10.1186/s13041-021-00894-4
  • Peer Reviewed / Open Access
• [Journal Article] Identification and functional characterization of the extremely long allele of the serotonin transporter-linked polymorphic region. (2021)
  • Author(s): 1.Ikegame T, Hidaka Y, Nakachi Y, Murata Y, Watanabe R, Sugawara H, Asai T, Kiyota E, Saito T, Ikeda M, Sasaki T, Hashimoto M, Ishikawa T, Takebayashi M, Iwata N, Kakiuchi C, Kato T, Kasai K, Bundo M, Iwamoto K
  • Journal Title: Transl Psychiatry. Volume: 11;11(1) Issue: 1 Pages: 119-119
  • DOI: 10.1038/s41398-021-01242-9
  • Peer Reviewed / Open Access
• [Journal Article] Promoter Activity-Based Case-Control Association Study on SLC6A4 Highlighting Hypermethylation and Altered Amygdala Volume in Male Patients With Schizophrenia (2020)
  • Author(s): Ikegame T, Bundo M, Okada N, Murata Y, Koike S, Sugawara H, Saito T, Ikeda M, Owada K, Fukunaga M, Yamashita F, Koshiyama D, Natsubori T, Iwashiro N, Asai T, Yoshikawa A, Nishimura F, Kawamura Y, Ishigooka J, Kakiuchi C, Sasaki T, Abe O, Hashimoto R, Iwata N, Yamasue H, Kato T, Kasai K, Iwamoto K
  • Journal Title: Schizophrenia Bulletin Volume: 46 Issue: 6 Pages: 1577-1586
  • DOI: 10.1093/schbul/sbaa075
  • Peer Reviewed / Open Access