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Convergence of the dysregulated regulome in schizophrenia with polygenic risk and evolutionarily constrained enhancers

Molecular Psychiatry (2023)Cite this article

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Abstract

Enhancers play an essential role in the etiology of schizophrenia; however, the dysregulation of enhancer activity and its impact on the regulome in schizophrenia remains understudied. To address this gap in our knowledge, we assessed enhancer and gene expression in 1,382 brain samples comprising cases with schizophrenia and unaffected controls. Dysregulation of enhancer expression was concordant with changes in gene expression, and was more closely associated with schizophrenia polygenic risk, suggesting that enhancer dysregulation is proximal to the genetic etiology of the disease. Modeling the shared variance of cis-coordinated genes and enhancers revealed a gene regulatory program that was highly associated with genetic vulnerability to schizophrenia. By integrating coordinated factors with evolutionary constraints, we found that enhancers acquired during human evolution are more likely to regulate genes that are implicated in neuropsychiatric disorders and, thus, hold potential as therapeutic targets. Our analysis provides a systematic view of regulome dysregulation in schizophrenia and highlights its convergence with schizophrenia polygenic risk and human-gained enhancers.

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Fig. 1: Robust enhancer dysregulation in SCZ.
Fig. 2: Concordant perturbation in SCZ between enhancers and gene expression.
Fig. 3: Association between gene/enhancer expression and PRS.
Fig. 4: MOFA decomposition of EP-linked genes and enhancers.
Fig. 5: Evolutionary nonconserved enhancers associated with neuropsychiatric disorders.

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Data availability

CMC human and macaque RNA-seq data are available through the CMC Knowledge Portal. The CMC investigators are committed to the release of data and analysis results, with the anticipation that data sharing in a rapid and transparent manner will speed the pace of research to the benefit of the greater research community. Data are available for general research use according to following requirements for data access and data attribution detailed at https://www.synapse.org//#!Synapse:syn2759792/wiki/197282.

Code availability

Supporting code for the analysis is available at https://zenodo.org/records/10149932. Further information and requests may be directed to the corresponding author, Pengfei Dong (pengfei.dong@mssm.edu), or Panos Roussos (panagiotis.roussos@mssm.edu).

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Acknowledgements

We thank the computational resources and staff expertise provided by the Scientific Computing of the Icahn School of Medicine at Mount Sinai. This study was supported by NIH awards R01MH125246, R01AG065582, R01AG067025, R01AG050986, U01MH116442, R01MH109677 to P.R. P.D. was supported in part by NARSAD Young Investigator Grant 29683 from the Brain & Behavior Research Foundation.

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Authors and Affiliations

  1. Center for Disease Neurogenomics, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA

    Pengfei Dong, Georgios Voloudakis, John F. Fullard, Gabriel E. Hoffman & Panos Roussos

  2. Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA

    Pengfei Dong, Georgios Voloudakis, John F. Fullard & Panos Roussos

  3. Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA

    Pengfei Dong, Georgios Voloudakis, John F. Fullard, Gabriel E. Hoffman & Panos Roussos

  4. Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA

    Pengfei Dong, Georgios Voloudakis, John F. Fullard, Gabriel E. Hoffman & Panos Roussos

  5. Mental Illness Research Education and Clinical Center (MIRECC), James J. Peters VA Medical Center, Bronx, NY, 10468, USA

    Georgios Voloudakis & Panos Roussos

  6. Center for Precision Medicine and Translational Therapeutics, James J. Peters VA Medical Center, Bronx, NY, 10468, USA

    Georgios Voloudakis & Panos Roussos

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Contributions

PD and PR conceived and designed the project. PD designed analytical strategies, performed all downstream omics data analyses, and interpreted results. GV conducted the PRS analysis. GEH, JFF, and PR supervised data analysis. PD and PR wrote the manuscript with input from all authors.

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Correspondence to Pengfei Dong or Panos Roussos.

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Dong, P., Voloudakis, G., Fullard, J.F. et al. Convergence of the dysregulated regulome in schizophrenia with polygenic risk and evolutionarily constrained enhancers. Mol Psychiatry (2023). https://doi.org/10.1038/s41380-023-02370-y

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