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Associations between mosaic loss and schizophrenia or bipolar disorder of young age

Molecular Psychiatry (2026)Cite this article

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Abstract

Mosaic chromosomal alterations (mCAs) accumulate in the brain tissues and are associated with psychiatric disorders. The association between mCAs in circulating blood and schizophrenia (SCZ) and bipolar disorders (BD) has not been fully evaluated. We detected mCAs from blood samples in 2470 SCZ, 3732 BD, and 177,773 control subjects. The associations between mCAs and SCZ or BD were evaluated using age-adjusted logistic regression models, further evaluated in age subgroups. We analyzed the associations between high cell fraction (CF) mosaic events (CF-mCAs >5% or CF-mCAs >10%) and SCZ or BD in the same way. Furthermore, we assessed the interaction between mCAs and genetic risk scores for SCZ or BD. Autosomal mCAs, especially mosaic loss events, increased in both SCZ and BD (SCZ; OR = 1.78, P = 4.9×10-6, BD; OR = 1.41, P = 0.0025). These associations were highlighted in the young-age subgroup (SCZ; OR = 7.01, P = 1.7×10-16, BD; OR = 4.01, P = 2.9×10-8). In addition, the effect sizes of losses increased in a CF-dependent manner in both SCZ and BD. Loss events with high cell fraction interacted with polygenic risk score in SCZ (P = 0.0098). SCZ or BD were characterized by the presence of a high burden of mosaic losses in blood, especially in young age, suggesting the common somatic pathophysiological mechanisms between these psychiatric diseases. The possible interaction between losses and PRS for SCZ supports the genetic and environmental cross-talk in SCZ.

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Fig. 1: Schematic view of mosaic calling and study design.
Fig. 2: Frequency of different detectable mosaic events stratified by age.
Fig. 3: Associations between autosomal mCAs or mosaic loss events and SCZ or BD stratified in each age subgroup.
Fig. 4: Associations between autosomal mCAs or mosaic loss events with CF-threshold and SCZ or BD.
Fig. 5: Combinatory associations of PRS and autosomal mCAs or mosaic loss events on SCZ.

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Data availability

Statistical codes are available from Chikashi Terao (ORCID 0000-0002-6452-4095) at any time, only on reasonable request. The Mosaic Chromosomal Alterations (MoChA) pipelines used for mosaic calling (mocha.wdl) are available at (https://github.com/freeseek/mochawdl). The genotype and IDAT data of BBJ used for this research was available at the website of the NBDC Human Database (https://humandbs.dbcls.jp/en/) of the Database Center for Life Science (DBCLS) / the Joint Support-Center for Data Science Research (DS) of the Research Organization of Information and Systems (ROIS). The dataset ID are JGAD000836 and JGAS000114.

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Acknowledgements

This work was supported by the Japan Agency for Medical Research and Development (AMED) grants 21ek0109555 (C.T.), 21tm0424220 (C.T.), 21ck0106642 (C.T.), 23ek0410114 (C.T.), 23tm0424225 (C.T.), JP21wm0425008 (N.I. and M.I.), JP23tm0524001 (M.I.), JP21wm0525024 (M.I.), 21tm0424220 (M.I.) and JP23dk0307123 (M.I.); the Japan Society for the Promotion of Science (JSPS) KAKENHI grant JP20H00462 (C.T.), JP21H02854 (M.I.), 24K02381 (M.I.) and JP22H03003 (N.I.); and Takeda Hosho Grants for Research in Medicine. The cartoons shown in Fig. 1 were created using Bio-Render. com. We thank the staff of BBJ for collecting and managing the samples and clinical information.

Author information

Author notes

  1. These authors contributed equally: Shunsuke Uchiyama, Takeo Saito.

Authors and Affiliations

  1. Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan

    Shunsuke Uchiyama, Xiaoxi Liu, Yuki Ishikawa & Chikashi Terao

  2. Department of Allergy and Rheumatology, Nippon Medical School Graduate School of Medicine, Tokyo, Japan

    Shunsuke Uchiyama

  3. Department of Psychiatry, Fujita Health University School of Medicine, 1-98 Dengakugakubo, Katsukake-cho, Toyoake, Aichi, 470-1191, Japan

    Takeo Saito, Masashi Ikeda & Nakao Iwata

  4. Laboratory for Pharmacogenomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan

    Keiko Hikino

  5. Department of Psychiatry, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8560, Japan

    Masashi Ikeda

  6. Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Giulio Genovese

  7. Department of Genetics, Harvard Medical School, Boston, MA, USA

    Giulio Genovese

  8. Clinical Research Center, Shizuoka General Hospital, Shizuoka, Japan

    Chikashi Terao

  9. Department of Applied Genetics, The School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga Ward, Shizuoka, 422-8526, Japan

    Chikashi Terao

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Contributions

M.I., N.I. and C.T. conceived the project. S.U. and C.T. analysed the data. G.G. developed MoChA pipelines for mosaic calling. T.S collected the detailed clinical information. S.U., T.S., X.L., Y.I., K.H., and C.T. wrote the manuscript. All authors have critically reviewed and approved the final version of the manuscript.

Corresponding authors

Correspondence to Nakao Iwata or Chikashi Terao.

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Competing interests

S.U., T.S., X.L., Y.I., K.H., M.I., N.I. and C.T. have no conflicts of interest. G.G. declared competing interests, and patent application PCT/WO2019/079493 has been filed for the mosaic chromosomal alteration detection method used in this study.

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Uchiyama, S., Saito, T., Liu, X. et al. Associations between mosaic loss and schizophrenia or bipolar disorder of young age. Mol Psychiatry (2026). https://doi.org/10.1038/s41380-025-03397-z

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