An epigenome-wide methylation study of healthy individuals with or without depressive symptoms

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Major depressive disorder is a common psychiatric disorder that is thought to be triggered by both genetic and environmental factors. Depressive symptoms are an important public health problem and contribute to vulnerability to major depression. Although a substantial number of genetic and epigenetic studies have been performed to date, the detailed etiology of depression remains unclear and there are no validated biomarkers. DNA methylation is one of the major epigenetic modifications that play diverse roles in the etiology of complex diseases. In this study, we performed an epigenome-wide association study (EWAS) of DNA methylation on subjects with (N = 20) or without (N = 27) depressive symptoms in order to examine whether different levels of DNA methylation were associated with depressive tendencies. Employing methylation-array technology, a total of 363,887 methylation sites across the genomes were investigated and several candidate CpG sites associated with depressive symptoms were identified, especially annotated to genes linked to a G-protein coupled receptor protein signaling pathway. These data provide a strong impetus for validation studies using a larger cohort and support the possibility that G-protein coupled receptor protein signaling pathways are involved in the pathogenesis of depression.

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We thank all the participants of this study. This study was supported by JSPS (JSPS KAKENHI Grant Number 15J04964, 26461712, and 25461723) and the Takeda Science Foundation in Japan.

Author information


  1. Department of Psychiatry and Behavioral Sciences, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

    • Mihoko Shimada
    •  & Taku Miyagawa
  2. Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

    • Mihoko Shimada
    • , Taku Miyagawa
    •  & Katsushi Tokunaga
  3. Graduate School of Clinical Psychology, Professional Degree Program in Clinical Psychology, Teikyo Heisei University, Tokyo, Japan

    • Takeshi Otowa
  4. Division for Environment, Health and Safety, The University of Tokyo, Tokyo, Japan

    • Tadashi Umekage
  5. Department of Psychiatry, Shonan Kamakura General Hospital, Kanagawa, Japan

    • Yoshiya Kawamura
  6. Department of Molecular Brain Science, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan

    • Miki Bundo
    •  & Kazuya Iwamoto
  7. Department of Neuropsychiatry, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

    • Tempei Ikegame
    •  & Kiyoto Kasai
  8. Department of Neuropsychiatry, Teikyo University School of Medicine, Tokyo, Japan

    • Mamoru Tochigi
  9. Panic Disorder Research Center, Warakukai Med. Corp., Tokyo, Japan

    • Hisanobu Kaiya
  10. Department of Psychiatry, Institute of Medical Life Science, Graduate School of Medicine, Mie University, Mie, Japan

    • Hisashi Tanii
  11. Department of Psychiatry, Koseikai Michinoo Hospital, Nagasaki, Japan

    • Yuji Okazaki
  12. Department of Physical and Health Education, Graduate School of Education, The University of Tokyo, Tokyo, Japan

    • Tsukasa Sasaki


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Conflict of interest

The authors declare that they have no competing interests.

Corresponding author

Correspondence to Takeshi Otowa.

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