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Disrupted long-range gene regulations elucidate shared tissue-specific mechanisms of neuropsychiatric disorders

Molecular Psychiatry volume 27, pages 2720–2730 (2022)Cite this article

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Abstract

Neurological and psychiatric disorders have overlapped phenotypic profiles, but the underlying tissue-specific functional processes remain largely unknown. In this study, we explore the shared tissue-specificity among 14 neuropsychiatric disorders through the disrupted long-range gene regulations by GWAS-identified regulatory SNPs. Through Hi-C interactions, averagely 38.0% and 17.2% of the intergenic regulatory SNPs can be linked to target protein-coding genes in brain and non-brain tissues, respectively. Interestingly, while the regulatory target genes in the brain tend to enrich in nervous system development related processes, those in the non-brain tissues are inclined to interfere with synapse and neuroinflammation related processes. Compared to psychiatric disorders, neurological disorders present more prominently the neuroinflammatory processes in both brain and non-brain tissues, indicating an intrinsic difference in mechanisms. Through tissue-specific gene regulatory networks, we then constructed disorder similarity networks in two brain and three non-brain tissues, highlighting both known disorder clusters (e.g. the neurodevelopmental disorders) and unexpected disorder clusters (e.g. Parkinson’s disease is consistently grouped with psychiatric disorders). We showcase the potential pharmaceutical applications of the small bowel and its disorder clusters, illustrated by the known drug targets NR1I3 and NFACT1, and their small bowel-specific regulatory modules. In conclusion, disrupted long-range gene regulations in both brain and non-brain tissues contribute to the similarity among distinct clusters of neuropsychiatric disorders, and the tissue-specifically shared functions and regulators for disease clusters may provide insights for future therapeutic investigations.

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Fig. 1: Flowchart and overview of the regulatory potential of intergenic daSNPs.
Fig. 2: Regulatory target genes of intergenic daSNPs across different tissue types.
Fig. 3: The disorder similarity network and potentially shared regulators.

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Data availability

The original public datasets were downloaded as described in “Materials and Methods”. The processed datasets supporting the conclusions of this article are included within the article and its supplementary files (supplementary information is available at MP’s website). All codes for the analyses are available upon request, and essential codes are available at https://github.com/JChen-GitHub/daSNP_interpretation_np.

Code availability

The codes are publicly available at https://github.com/JChen-GitHub/daSNP_interpretation_np.

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Acknowledgements

This work is supported by the National Key R&D Program of China (2019YFA0709502, 2020YFA0712403), the National Natural Science Foundation of China (61932008), the 111 Project (B18015) of China, the Shanghai Municipal Science and Technology Major Project (No. 2018SHZDZX01), Natural Science Foundation of Shanghai (21ZR1403200), ZJ Lab, and Shanghai Center for Brain Science and Brain-Inspired Technology. The authors also want to thank all the original data sources.

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Authors and Affiliations

  1. Institute of Science and Technology for Brain-Inspired Intelligence, Fudan University, Shanghai, 200433, China

    Jingqi Chen, Liting Song, Anyi Yang, Guiying Dong & Xing-Ming Zhao

  2. MOE Key Laboratory of Computational Neuroscience and Brain-Inspired Intelligence, and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, 200433, China

    Jingqi Chen, Liting Song, Anyi Yang, Guiying Dong & Xing-Ming Zhao

  3. Zhangjiang Fudan International Innovation Center, Shanghai, China

    Jingqi Chen & Xing-Ming Zhao

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  1. Jingqi Chen
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Contributions

XZ conceived the project. XZ and JC designed the project. JC performed most of the analyses, and wrote the manuscript. XZ helped revise the manuscript. LS constructed GCN modules and TRN, wrote relevant parts in methods, and constructed Supplementary Fig. 2. AY computed genes by MAGMA (and its derivitives) and TWAS. GD constructed Fig. 4A.

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Correspondence to Jingqi Chen or Xing-Ming Zhao.

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Chen, J., Song, L., Yang, A. et al. Disrupted long-range gene regulations elucidate shared tissue-specific mechanisms of neuropsychiatric disorders. Mol Psychiatry 27, 2720–2730 (2022). https://doi.org/10.1038/s41380-022-01529-3

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