Early life adversity and 5HTT mRNA expression and DNA methylation in patients with major depressive disorder

• Project/Area Number: 15K09808
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Psychiatric science
• Research Institution: Ehime University
• Principal Investigator: Iga Jun-ichi 愛媛大学, 医学系研究科, 准教授 (70363140)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: うつ病 / アルツハイマー型認知症 / レビー小体型認知症 / 統合失調症 / 生物学的マーカー / 血液 / セロトニントランスポーター / バイオマーカー / 遺伝子発現 / ＤＮＡメチル化 / 5HTT / TREM2 / SNCA / DRD2 / ABCA7 / biomarker / depression / Alzheimer disease / プロモーター / 遺伝子メチル化 / 遺伝子多型

Outline of Final Research Achievements

5HTT expression using real-time PCR and Taqman probes was increased in unmedicated patients with major depressive disorder compared with controls and then decreased 8 weeks after antidepressant treatment. The 5HTTLPR genotype was significantly associated with mean methylation levels in patients only. The mean methylation level was significantly increased in patients compared with controls. Increased depressive symptoms were related to decreased levels of methylation. The association between these biological markers and early life adversity should be examined in future studies. Interestingly, 5HTT expression was also increased in patients with Alzheimer’s disease compared with controls and its increment was associated with apathy. Furthermore, I examined blood biomarkers for discriminating Alzheimer’s disease from geriatric depression and reported significant changes in gene expression and DNA methylation of TREM2, SNCA, INPP5D, TOMM40, APOE, PINK1, ABCA7, MEF2C and DRD2.

Research Products

• [Journal Article] TOMM40 and APOE Gene Expression and Cognitive Decline in Japanese Alzheimer’s Disease Subjects (2017)
  • Author(s): Mise Ayano、Yoshino Yuta、Yamazaki Kiyohiro、Ozaki Yuki、Sao Tomoko、Yoshida Taku、Mori Takaaki、Mori Yoko、Ochi Shinichiro、Iga Jun-ichi、Ueno Shu-ichi
  • Journal Title: Journal of Alzheimer's Disease Volume: 60 Issue: 3 Pages: 1107-1117
  • DOI: 10.3233/jad-170361
  • Peer Reviewed
• [Journal Article] INPP5D mRNA Expression and Cognitive Decline in Japanese Alzheimer’s Disease Subjects (2017)
  • Author(s): Yoshino Yuta、Yamazaki Kiyohiro、Ozaki Yuki、Sao Tomoko、Yoshida Taku、Mori Takaaki、Mori Yoko、Ochi Shinichiro、Iga Jun-Ichi、Ueno Shu-Ichi
  • Journal Title: Journal of Alzheimer's Disease Volume: 58 Issue: 3 Pages: 687-694
  • DOI: 10.3233/jad-161211
  • Peer Reviewed
• [Journal Article] Improvement of Visuo-spatial Function Assessed by Raven's Colored Progressive Matrices in Dementia with Lewy Bodies by Donepezil Treatment (2017)
  • Author(s): Yoshino Yuta、Mori Takaaki、Yoshida Taku、Toyota Yasutaka、Shimizu Hideaki、Iga Jun-ichi、Nishitani Shusaku、Ueno Shu-ichi
  • Journal Title: Clinical Psychopharmacology and Neuroscience Volume: 15 Issue: 3 Pages: 243-247
  • DOI: 10.9758/cpn.2017.15.3.243
  • Peer Reviewed
• [Journal Article] Gene expression-based biological test for major depressive disorder; an advanced study (2017)
  • Author(s): Watanabe S, Numata S, Iga J, Kinoshita M, Umehara H, Ishii K, Ohmori T
  • Journal Title: Neuropsychiatr Dis Treat. Volume: 13 Pages: 535-541
  • DOI: 10.2147/ndt.s120038
  • NAID: 120006999399
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Gene Expression and Methylation Analysis of ABCA7 in Patients with Alzheimer's Disease. (2017)
  • Author(s): Yamazaki K, Yoshino Y, Mori T, Yoshida T, Ozaki Y, Sao T, Mori Y, Ochi S, Iga JI, Ueno SI
  • Journal Title: J Alzheimers Dis Volume: 57 Issue: 1 Pages: 171-181
  • DOI: 10.3233/jad-161195
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Endothelial nitric oxide synthase in rat brain is downregulated by sub-chronic antidepressant treatment (2017)
  • Author(s): Yoshino Yuta、Ochi Shinichiro、Yamazaki Kiyohiro、Nakata Shunsuke、Iga Jun-ichi、Ueno Shu-ichi
  • Journal Title: Psychopharmacology Volume: 234 Issue: 11 Pages: 1663-1669
  • DOI: 10.1007/s00213-017-4567-z
  • Peer Reviewed
• [Journal Article] Elevated mRNA expression of CASPR3 in patients with schizophrenia. (2017)
  • Author(s): Okita M, Yoshino Y, Iga JI, Ueno SI
  • Journal Title: Nord J Psychiatry Volume: 71 Issue: 4 Pages: 312-314
  • DOI: 10.1080/08039488.2017.1291720
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] DNA Methylation Changes in Intron 1 of Triggering Receptor Expressed on Myeloid Cell 2 in Japanese Schizophrenia Subjects (2017)
  • Author(s): Yoshino Yuta、Ozaki Yuki、Yamazaki Kiyohiro、Sao Tomoko、Mori Yoko、Ochi Shinichiro、Iga Jun-ichi、Ueno Shu-ichi
  • Journal Title: Frontiers in Neuroscience Volume: 11 Pages: 1-7
  • DOI: 10.3389/fnins.2017.00275
  • Peer Reviewed
• [Journal Article] DNA methylation changes at TREM2 intron 1 and TREM2 mRNA expression in patients with Alzheimer's disease. (2017)
  • Author(s): Ozaki Y, Yoshino Y, Yamazaki K, Sao T, Mori Y, Ochi S, Yoshida T, Mori T, Iga JI, Ueno SI
  • Journal Title: J Psychiatr Res Volume: 92 Pages: 74-80
  • DOI: 10.1016/j.jpsychires.2017.04.003
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] DNA methylation changes at SNCA intron 1 in patients with dementia with Lewy bodies. (2017)
  • Author(s): Funahashi Y, Yoshino Y, Yamazaki K, Mori Y, Mori T, Ozaki Y, Sao T, Ochi S, Iga JI, Ueno SI.
  • Journal Title: Psychiatry Clin Neurosci Volume: 71 Issue: 1 Pages: 28-35
  • DOI: 10.1111/pcn.12462
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] 1H-magnetic resonance spectroscopy study of glutamate-related abnormality in bipolar disorder. (2017)
  • Author(s): Kubo H, Nakataki M, Sumitani S, Iga JI, Numata S, Kameoka N, Watanabe SY, Umehara H, Kinoshita M, Inoshita M, Tamaru M, Ohta M, Nakayama-Yamauchi C, Funakoshi Y, Harada M, Ohmori T.
  • Journal Title: J Affect Disord. Volume: 208 Pages: 139-144
  • DOI: 10.1016/j.jad.2016.08.046
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] MEF2C mRNA expression and cognitive function in Japanese patients with Alzheimer's disease (2017)
  • Author(s): Sao Tomoko、Yoshino Yuta、Yamazaki Kiyohiro、Ozaki Yuki、Mori Yoko、Ochi Shinichiro、Yoshida Taku、Mori Takaaki、Iga Jun-ichi、Ueno Shu-ichi
  • Journal Title: Psychiatry and Clinical Neurosciences Volume: 72 Issue: 3 Pages: 160-167
  • DOI: 10.1111/pcn.12618
  • Peer Reviewed
• [Journal Article] Endothelial nitric oxide synthase in rat brain is downregulated by sub-chronic antidepressant treatment. (2017)
  • Author(s): Yoshino Y, Ochi S, Yamazaki K, Nakata S, Iga JI, Ueno SI
  • Journal Title: Psychopharmacology (Berl) Volume: -
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Neural basis of visual perception and reasoning ability in Alzheimer's disease: correlation between Raven's Colored Progressive Matrices test and ¹²³ I-IMP SPECT imaging results. (2017)
  • Author(s): Yoshida T, Mori T, Shimizu H, Yoshino Y, Sonobe N, Matsumoto T, Kikuchi K, Miyagawa M, Iga J, Mochizuki T, Ueno SI.
  • Journal Title: Int J Geriatr Psychiatry Volume: 32 Issue: 4 Pages: 407-413
  • DOI: 10.1002/gps.4481
  • Peer Reviewed
• [Journal Article] Elevated mRNA Expression and Low Methylation of SNCA in Japanese Alzheimer's Disease Subjects (2016)
  • Author(s): Yoshino Y, Mori T, Yoshida T, Yamazaki K, Ozaki Y, Sao T, Funahashi Y, Iga JI, Ueno SI.
  • Journal Title: J Alzheimers Dis Volume: 54 Issue: 4 Pages: 1349-1357
  • DOI: 10.3233/jad-160430
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Low methylation rates of dopamine receptor D2 gene promoter sites in Japanese schizophrenia subjects. (2016)
  • Author(s): Yoshino Y, Kawabe K, Mori T, Mori Y, Yamazaki K, Numata S, Nakata S, Yoshida T, Iga J, Ohmori T, Ueno S.
  • Journal Title: World J Biol Psychiatry Volume: 17 Issue: 6 Pages: 449-456
  • DOI: 10.1080/15622975.2016.1197424
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Elevated TREM2 mRNA expression in leukocytes in schizophrenia but not major depressive disorder. (2016)
  • Author(s): Yoshino Y, Kawabe K, Yamazaki K, Watanabe S, Numata S, Mori Y, Yoshida T, Iga J, Ohmori T, Ueno S
  • Journal Title: J Neural Transm (Vienna) Volume: 123 Issue: 6 Pages: 637-641
  • DOI: 10.1007/s00702-016-1560-3
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Association study of polymorphism in the serotonin transporter gene promoter, methylation profiles, and expression in patients with major depressive disorder. (2016)
  • Author(s): Iga J, Watanabe SY, Numata S, Umehara H, Nishi A, Kinoshita M, Inoshita M, Shimodera S, Fujita H, Ohmori T.
  • Journal Title: Hum Psychopharmacol. Volume: 31(3) Issue: 3 Pages: 193-199
  • DOI: 10.1002/hup.2527
  • Peer Reviewed / Open Access
• [Journal Article] Association Study and Meta-Analysis of Polymorphisms, Methylation Profiles, and Peripheral mRNA Expression of the Serotonin Transporter Gene in Patients with Alzheimer's Disease. (2016)
  • Author(s): Yamazaki K, Yoshino Y, Mori T, Okita M, Yoshida T, Mori Y, Ozaki Y, Sao T, Iga J, Ueno S
  • Journal Title: Dement Geriatr Cogn Disord Volume: 41 Issue: 5-6 Pages: 334-347
  • DOI: 10.1159/000447324
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Polymorphism in the promoter of the gene for the serotonin transporter affects the age of onset of major depressive disorder in the Japanese population. (2015)
  • Author(s): Watanabe SY, Iga J, Numata S, Umehara H, Nishi A, Kinoshita M, Inoshita M, Ohmori T.
  • Journal Title: J Affect Disord Volume: 183 Pages: 156-158
  • DOI: 10.1016/j.jad.2015.05.009
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] Low methylation rates of SNCA gene intron 1 in dementia with Lewy bodies patients (2017)
  • Author(s): Jun-ichi Iga, Yuta Yoshino, Yu Funahashi, Kiyohiro Yamazaki, Yoko Mori, Takaaki Mori, Shu-ichi Ueno
  • Organizer: Neuroscience 2017
  • Int'l Joint Research
• [Presentation] うつ病・双極性障害から認知症移行 (2017)
  • Author(s): 伊賀淳一
  • Organizer: 日本うつ病学会
• [Presentation] 老年期うつ病と認知症 (2017)
  • Author(s): 伊賀淳一
  • Organizer: 中国四国精神神経学会
• [Presentation] 統合失調症薬物治療ガイドラインの特徴とアセナピンの位置づけ (2016)
  • Author(s): 伊賀淳一
  • Organizer: 第57回中国・四国精神神経学会
  • Place of Presentation: 愛媛
  • Year and Date: 2016-11-10
  • Invited
• [Presentation] うつ病治療ガイドラインと生物学的マーカー研究 (2016)
  • Author(s): 伊賀淳一
  • Organizer: 第38回日本生物学的精神医学会
  • Place of Presentation: 福岡
  • Year and Date: 2016-09-08
  • Invited
• [Presentation] 白血球を用いたTranslational Neuropsychopharmacology (2016)
  • Author(s): 伊賀淳一
  • Organizer: 第4回Translational Neuropsychopharmacology Conference
  • Place of Presentation: 兵庫
  • Year and Date: 2016-09-03
  • Invited
• [Presentation] 白血球mRNA発現を用いたバイオマーカー (2016)
  • Author(s): 伊賀淳一
  • Organizer: 第13回日本うつ病学会
  • Place of Presentation: 愛知
  • Year and Date: 2016-08-05
• [Presentation] Association study of polymorphism in the serotonin transporter gene promoter, methylation profiles, and expression in patients with major depressive disorder (2016)
  • Author(s): Jun-ichi Iga, Shin-ya Watanabe, Shusuke Numata, Hidehiro Umehara, Akira Nishi, Makoto Kinoshita, Masatoshi Inoshita, Shinji Shimodera, Hirokazu Fujita, and Tetsuro Ohmori
  • Organizer: 30th CINP world congress
  • Place of Presentation: Seoul
  • Year and Date: 2016-07-03
  • Int'l Joint Research
• [Presentation] 薬物投与計画－薬物相互作用と妊婦、老人における投与計画－ (2016)
  • Author(s): 伊賀淳一
  • Organizer: 臨床精神薬理教育セミナー
  • Place of Presentation: 大阪
  • Invited
• [Presentation] うつ病患者における5HTTLPR, DNAメチル化, 遺伝子発現の関連研究 (2015)
  • Author(s): 伊賀淳一、渡部真也、沼田周助、梅原英裕、西晃、木下誠、井下真利、下寺信次、藤田博一、大森哲郎
  • Organizer: 第２５回日本臨床精神神経薬理学会
  • Place of Presentation: 東京都新宿区
  • Year and Date: 2015-10-29
• [Presentation] 遺伝子を用いたうつ病診断について (2015)
  • Author(s): 伊賀淳一
  • Organizer: 第１２回日本うつ病学会総会
  • Place of Presentation: 東京都新宿区
  • Year and Date: 2015-07-17
• [Remarks] 愛媛大学大学院医学系研究科 精神神経科学
  • URL: https://www.m.ehime-u.ac.jp/school/neuropsychiatry/
• [Remarks] 愛媛大学大学院医学系研究科精神神経科学
  • URL: http://www.m.ehime-u.ac.jp/school/neuropsychiatry/