Imaging epigenome-wide association study to identify biomarkers for child maltreatment

• Project/Area Number: 20K02700
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 09030:Childhood and nursery/pre-school education-related
• Research Institution: University of Fukui
• Principal Investigator: Nishitani Shota 福井大学, 子どものこころの発達研究センター, 特命講師 (50448495)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2022: ¥520,000 (Direct Cost: ¥400,000、Indirect Cost: ¥120,000); Fiscal Year 2021: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2020: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 虐待 / マルトリートメント / エピゲノム / MRI / 子ども / DNAメチル化 / 脳 / 遺伝子 / トラウマ / エピジェネティクス / ゲノムワイド解析

Outline of Research at the Start

マルトリートメントの早期介入・治療が望まれていながらも、Mal児当事者を対象とした研究は、未成年である当事者の親権者からの研究同意が得られない等、研究実施が極めて困難なことから、治療の根幹をなす標的分子機序も定まっていない。近年、マルトリートメントがDNAメチル化のエピジェネティックな変化を刻み、それが生涯に渡る脳の脆弱性に関連することを示唆する研究が行われてきた。しかし、かつてマルトリートメントを受けた成人研究が主で、Mal児当事者を対象としたものはごく僅かである。そこで、本研究では、エピジェネティクス、脳MRI、両者を組み合わせた脳画像エピゲノムから、Mal児のバイオマーカー開発を行う。

Outline of Final Research Achievements

In addition to the existing data, additional samples and data were consolidated and cleaned, resulting in a data set (brain MRI and saliva methylation microarray) of 61 maltreatment children and 62 typically developed children. The epigenome-wide analysis identified 16 genome-wide significant DMPs, but no significant DMRs were detected. We also conducted a GAMuT analysis, a genome-wide comparison of each gene unit, and found that the gene containing one location in the DMP was significantly associated. In relation to brain MRI, this methylation was found to correlate negatively with the fusiform gyrus of the occipital lobe.

Academic Significance and Societal Importance of the Research Achievements

マルトリートメント児、及び同年代の定型発達児の脳MRI、唾液メチル化アレイデータの両者が揃った、世界有数かつ本邦一の規模となるデータセットが構築された。これは今後、多くの研究者らに活用される二次データとしての学術的な利用価値も高い。代表者の一次解析の結果では、マルトリートメントに関連した複数のメチル化部位が明らかにされた。それらメチル化部位や遺伝子と、幼少期のマルトリートメントとを、データ駆動型解析から結びつけた功績は、学術的に貢献度が高い。今後、マルトリートメントに曝された子どもの早期発見に資するバイオマーカーとなる視点についての検討も行うことで、社会的意義にも多大な貢献をする可能性が高い。

Research Products

• [Int'l Joint Research] Stanford University(米国)
• [Int'l Joint Research] Emory University(米国)
• [Int'l Joint Research] Korea Brain Research Institute(韓国)
• [Int'l Joint Research] University of Malaya(マレーシア)
• [Int'l Joint Research] Emory University/University of Georgia/The University of Toledo(米国)
• [Journal Article] Cross-tissue correlations of genome-wide DNA methylation in Japanese live human brain and blood, saliva, and buccal epithelial tissues. (2023)
  • Author(s): Nishitani S, Isozaki M, Yao A, Higashino Y, Yamauchi T, Kidoguchi M, Kawajiri S, Tsunetoshi K, Neish H, Imoto H, Arishima H, Kodera T, Fujisawa TX, Nomura S, Kikuta K, Shinozaki G, Tomoda A.
  • Journal Title: Transl Psychiatry Volume: 13 Issue: 1 Pages: 72-72
  • DOI: 10.1038/s41398-023-02370-0
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Effects of intranasal oxytocin on neural reward processing in children and adolescents with reactive attachment disorder: A randomized controlled trial (2023)
  • Author(s): Takiguchi Shinichiro、Makita Kai、Fujisawa Takashi X.、Nishitani Shota、Tomoda Akemi
  • Journal Title: Frontiers in Child and Adolescent Psychiatry Volume: 1 Pages: 1-16
  • DOI: 10.3389/frcha.2022.1056115
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Association of Epigenetic Differences Screened in a Few Cases of Monozygotic Twins Discordant for Attention-Deficit Hyperactivity Disorder With Brain Structures (2022)
  • Author(s): Fujisawa Takashi X.、Nishitani Shota、Makita Kai、Yao Akiko、Takiguchi Shinichiro、Hamamura Shoko、Shimada Koji、Okazawa Hidehiko、Matsuzaki Hideo、Tomoda Akemi
  • Journal Title: Frontiers in Neuroscience Volume: 15 Pages: 1-12
  • DOI: 10.3389/fnins.2021.799761
  • Peer Reviewed / Open Access
• [Journal Article] The effects of epigenetic age and its acceleration on surface area, cortical thickness and volume in young adults. (2022)
  • Author(s): Cheong Y, Nishitani S, Yu J, Habata K, Kamiya T, Shiotsu D, Omori IM, Okazawa H, Tomoda A, Kosaka H, Jung M.
  • Journal Title: Cereb Corte Volume: in press Issue: 24 Pages: 043-043
  • DOI: 10.1093/cercor/bhac043
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Epigenetic Clock Deceleration and Maternal Reproductive Efforts: Associations With Increasing Gray Matter Volume of the Precuneus. (2022)
  • Author(s): Nishitani S, Kasaba R, Hiraoka D, Shimada K, Fujisawa TX, Okazawa H, Tomoda A.
  • Journal Title: Front Genet. Volume: 12 Pages: 803584-803584
  • DOI: 10.3389/fgene.2022.803584
  • Peer Reviewed / Open Access
• [Journal Article] A multi-modal MRI analysis of brain structure and function in relation to OXT methylation in maltreated children and adolescents (2021)
  • Author(s): Nishitani Shota、Fujisawa Takashi X.、Hiraoka Daiki、Makita Kai、Takiguchi Shinichiro、Hamamura Shoko、Yao Akiko、Shimada Koji、Smith Alicia K.、Tomoda Akemi
  • Journal Title: Translational Psychiatry Volume: 11 Issue: 1 Pages: 1-9
  • DOI: 10.1038/s41398-021-01714-y
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Influence of the COVID-19 Pandemic on Parenting Stress Across Asian Countries: A Cross-National Study. (2021)
  • Author(s): Kurata S, Hiraoka D, Ahmad Adlan AS, Jayanath S, Hamzah N, Ahmad-Fauzi A, Fujisawa TX, Nishitani S, Tomoda A.
  • Journal Title: Front Psychol. Volume: 12 Pages: 782298-782298
  • DOI: 10.3389/fpsyg.2021.782298
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Altered epigenetic clock in children exposed to maltreatment. (2021)
  • Author(s): Nishitani S, Suzuki S, Ochiai K, Yao A, Fujioka T, Fujisawa TX, Tomoda A.
  • Journal Title: Psychiatry Clin Neurosci. Volume: 75 Issue: 3 Pages: 110-112
  • DOI: 10.1111/pcn.13183
  • Peer Reviewed / Open Access
• [Journal Article] Epigenetic modification of the oxytocin gene is associated with gray matter volume and trait empathy in mothers (2021)
  • Author(s): Hiraoka D, Nishitani S, Shimada K, Kasaba R, Fujisawa TX, Tomoda A.
  • Journal Title: Psychoneuroendocrinology. Volume: 123 Pages: 105026-105026
  • DOI: 10.1016/j.psyneuen.2020.105026
  • Peer Reviewed / Open Access
• [Journal Article] Epigenetic prediction of 17β-estradiol and relationship to trauma-related outcomes in women (2021)
  • Author(s): Hack LM, Nishitani S, Knight AK, Kilaru V, Maddox SA, Seligowski AV, Jovanovic T, Ressler KJ, Smith AK, Michopoulos V
  • Journal Title: Comprehensive Psychoneuroendocrinology Volume: 6 Pages: 100045-100045
  • DOI: 10.1016/j.cpnec.2021.100045
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Mismatch negativity of preschool children at risk of developing mental health problems (2021)
  • Author(s): Aoi T, Fujisawa TX, Nishitani S, Tomoda A.
  • Journal Title: Neuropsychopharmacol Rep. Volume: - Issue: 2 Pages: 1-7
  • DOI: 10.1002/npr2.12168
  • Peer Reviewed / Open Access
• [Journal Article] Epigenetic modification of the oxytocin receptor gene: implications for autism symptom severity and brain functional connectivity (2020)
  • Author(s): Andari E, Nishitani S, Kaundinya G, Caceres GA, Morrier MJ, Ousley O, Smith AK, Cubells JF, Young LJ
  • Journal Title: Neuropsychopharmacology Volume: 45(7) Issue: 7 Pages: 1150-1158
  • DOI: 10.1038/s41386-020-0610-6
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Pathways linking adverse environments to emerging adults' substance abuse and depressive symptoms: A prospective analysis of rural African American men (2020)
  • Author(s): Kogan SM, Bae D, Cho J, Smith AK, Nishitani S
  • Journal Title: Developmental Psychopathology Volume: なし Issue: 4 Pages: 1-11
  • DOI: 10.1017/s0954579420000632
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Methylation of OXT and OXTR genes, central oxytocin, and social behavior in female macaques (2020)
  • Author(s): De Leon D, Nishitani S, Walum H, McCormack KM, Wilson ME, Smith AK, Young LJ, Sanchez MM
  • Journal Title: Hormones and Behavior Volume: 126 Pages: 104856-104856
  • DOI: 10.1016/j.yhbeh.2020.104856
  • Peer Reviewed / Int'l Joint Research
• [Presentation] 社会性とエピジェネティクス (2022)
  • Author(s): 西谷正太
  • Organizer: 日本社会心理学会第63回大会
• [Presentation] A cross-national study of the influences of COVID-19 pandemic on parenting stress across Asian countries (2021)
  • Author(s): Shota Nishitani
  • Organizer: The 2nd International Symposium for CRNACDD
  • Int'l Joint Research
• [Presentation] Epigenetic modulation of OXT and OXTR genes in humans (2021)
  • Author(s): Shota Nishitani
  • Organizer: The 33rd Meeting of the Japanese Society for Behavioral Neuroendocrinology
  • Invited
• [Presentation] Oxytocin and oxytocin receptor DNA methylation modulates social behaviors in humans (2020)
  • Author(s): Shota Nishitani
  • Organizer: The 43rd Annual Meeting of the Japan Neuroscience Society
• [Presentation] 被虐待児のOXTR遺伝子DNAメチル化の脳画像エピゲノム解析 (2020)
  • Author(s): 西谷正太, 友田明美
  • Organizer: 第116回日本精神神経学会学術総会
• [Presentation] 社会環境による ヒトの社会性への影響 (2020)
  • Author(s): 西谷正太
  • Organizer: 日本社会心理学会第61回大会
• [Book] Chapter 16 - Capturing the epigenome: Differences among blood, saliva, and brain samples, Epigenetics of Stress and Stress Disorders (2022)
  • Author(s): Nishitani Shota
  • Total Pages: 420
  • Publisher: Elsevier (Academic Press)
  • ISBN: 9780128230398
• [Remarks] AMAZE-CpG
  • URL: https://snishit-amaze-cpg.web.app/
• [Remarks] meVBM
  • URL: https://snishit-mevbm.web.app/