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Several novel classes of small regulatory RNAs show widespread changes in schizophrenia and bipolar disorder and extensive linkages to critical brain processes
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  • Published: 04 February 2026

Several novel classes of small regulatory RNAs show widespread changes in schizophrenia and bipolar disorder and extensive linkages to critical brain processes

  • Stepan Nersisyan  ORCID: orcid.org/0000-0002-8830-46791 nAff8,
  • Phillipe Loher1,
  • Iliza Nazeraj1,
  • Zhiping Shao2,3,4,5,
  • John F. Fullard  ORCID: orcid.org/0000-0001-9874-29072,3,4,5,
  • Georgios Voloudakis  ORCID: orcid.org/0000-0002-5729-632X2,3,4,5,6,7,
  • Kiran Girdhar  ORCID: orcid.org/0000-0002-5622-042X2,4,5,
  • Panos Roussos  ORCID: orcid.org/0000-0002-4640-62392,3,4,5,6,7 na1 &
  • …
  • Isidore Rigoutsos1 na1 

Translational Psychiatry , Article number:  (2026) Cite this article

We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply.

Subjects

  • Human behaviour
  • Molecular neuroscience

Abstract

Transcriptomic studies of post-mortem brain samples in schizophrenia (SCZ) and bipolar disorder (BD) have primarily focused on messenger RNAs (mRNAs) but have given limited attention to small non-coding RNAs (sncRNAs). In this study, we present our analyses of sncRNA profiles from the prefrontal cortex of SCZ and BD cases and controls (53 SCZ cases, 40 BD cases, 77 controls), which we sourced from the Icahn School of Medicine at Mount Sinai and the NIMH Human Brain Collection Core brain banks. Corresponding mRNA-seq data were obtained from the CommonMind Consortium. Using a state-of-the-art pipeline, we mapped reads and determined differentially abundant and co-expressed sncRNAs and mRNAs, adjusting for known and hidden confounders. Across samples, 98% of all sncRNAs comprised miRNA isoforms (60.6%), tRNA-derived fragments (17.8%), rRNA-derived fragments (11.4%), and Y RNA-derived fragments (8.3%). In SCZ, 15% of the identified sncRNAs exhibited significant fold changes (FCs), with many also altered in BD, albeit to a lesser extent. For miRNAs, the FCs correlated strongly with the presence of non-templated nucleotides to their 3′-ends, independently of miRNA identity or locus of origin. Disease- and age-associated sncRNAs and mRNAs revealed accelerated aging in both SCZ and BD. Co-expression analyses also revealed, for the first time, disease-independent associations of many isomiRs, tRFs, rRFs, and yRFs with critical brain processes. These findings suggest complex and previously uncharacterized roles for novel classes of regulatory sncRNAs in synaptic signaling, neurogenesis, memory, behavior, and cognition.

Data availability

Raw data (FASTQ files) and processed data (read count matrices, metadata) are available in Synapse under synID syn63862703.

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Acknowledgements

The work of the Thomas Jefferson University team was supported by University funds (IR) and NIH grant R01HG012784 (IR). The work of the Mount Sinai School of Medicine team was supported by NIH grants R01MH109677, U01MH116442, R01MH110921, R01MH125246, R01MH109897, R01AG067025, R01AG065582, R01AG050986 (PR). We also acknowledge the use of the Cancer Genomics Shared Resource at the Sidney Kimmel Cancer Center (SKCC) of Thomas Jefferson University: SKCC is supported by an NIH Cancer Center Support Grant P30CA056036. We also thank Dr. Gerhard Schratt for providing us with the raw small RNA sequencing data of rat neurons from his earlier study [50].

Author information

Author notes

  1. Stepan Nersisyan

    Present address: ZS Associates, 201 Washington St, Floor 28, Boston, 02108, MA, USA

  2. These authors jointly supervised the work: Panos Roussos, Isidore Rigoutsos.

Authors and Affiliations

  1. Computational Medicine Center, Thomas Jefferson University, Philadelphia, PA, USA

    Stepan Nersisyan, Phillipe Loher, Iliza Nazeraj & Isidore Rigoutsos

  2. Center for Disease Neurogenomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Zhiping Shao, John F. Fullard, Georgios Voloudakis, Kiran Girdhar & Panos Roussos

  3. Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Zhiping Shao, John F. Fullard, Georgios Voloudakis & Panos Roussos

  4. Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Zhiping Shao, John F. Fullard, Georgios Voloudakis, Kiran Girdhar & Panos Roussos

  5. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Zhiping Shao, John F. Fullard, Georgios Voloudakis, Kiran Girdhar & Panos Roussos

  6. Center for Precision Medicine and Translational Therapeutics, JJ Peters VA Medical Center, Bronx, NY, USA

    Georgios Voloudakis & Panos Roussos

  7. Mental Illness Research Education and Clinical Center (MIRECC), JJ Peters VA Medical Center, Bronx, NY, USA

    Georgios Voloudakis & Panos Roussos

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Contributions

IR and PR designed and supervised the study. IN, PL, and SN developed the small RNA-seq mapping pipeline. ZS, JFF, and GV participated in the selection of samples and isolation of RNA. SN, PL, and IR analyzed the data and interpreted the results with contributions from PR and KG. SN and IR prepared the figures and tables. SN and IR wrote the manuscript with contributions from PR and KG. All authors approved the final version of the manuscript.

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Correspondence to Panos Roussos or Isidore Rigoutsos.

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Nersisyan, S., Loher, P., Nazeraj, I. et al. Several novel classes of small regulatory RNAs show widespread changes in schizophrenia and bipolar disorder and extensive linkages to critical brain processes. Transl Psychiatry (2026). https://doi.org/10.1038/s41398-026-03808-x

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  • Received: 23 September 2025

  • Revised: 22 December 2025

  • Accepted: 15 January 2026

  • Published: 04 February 2026

  • DOI: https://doi.org/10.1038/s41398-026-03808-x

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