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Angiogenic gene networks are dysregulated in opioid use disorder: evidence from multi-omics and imaging of postmortem human brain


Opioid use disorder (OUD) is a public health crisis in the U.S. that causes over 50 thousand deaths annually due to overdose. Using next-generation RNA sequencing and proteomics techniques, we identified 394 differentially expressed (DE) coding and long noncoding (lnc) RNAs as well as 213 DE proteins in Brodmann Area 9 of OUD subjects. The RNA and protein changes converged on pro-angiogenic gene networks and cytokine signaling pathways. Four genes (LGALS3, SLC2A1, PCLD1, and VAMP1) were dysregulated in both RNA and protein. Dissecting these DE genes and networks, we found cell type-specific effects with enrichment in astrocyte, endothelial, and microglia correlated genes. Weighted-genome correlation network analysis (WGCNA) revealed cell-type correlated networks including an astrocytic/endothelial/microglia network involved in angiogenic cytokine signaling as well as a neuronal network involved in synaptic vesicle formation. In addition, using ex vivo magnetic resonance imaging, we identified increased vascularization in postmortem brains from a subset of subjects with OUD. This is the first study integrating dysregulation of angiogenic gene networks in OUD with qualitative imaging evidence of hypervascularization in postmortem brain. Understanding the neurovascular effects of OUD is critical in this time of widespread opioid use.

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Fig. 1: Differential expression of RNAs and proteins in BA9 of OUD subjects.
Fig. 2: Convergent pathways of differentially expressed genes and proteins.
Fig. 3: Cell type deconvolution and WGCNA.
Fig. 4: Ex Vivo MRI of postmortem brain.


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We are grateful for the invaluable donations and participation from families, as well as for the generous collaboration of the medical examiners at the Harris County Institute of Forensic Sciences. This study was supported by R01DA044859 to CWB. ZZ was supported by R01LM012806. The University of Texas System provided funding for the Neuropsychiatric Proteome Database, for which proteomics data from brain tissue was generated by the Mass Spectrometry Core at the University of Texas Medical Branch.

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EM and CWB designed and organized the study, and wrote the manuscript; EM analyzed the data, interpreted the results, and wrote the manuscript; LS, GRF, KN, and KM contributed to data acquisition; HW, RH, ZZ, and JQW contributed to analysis of data; XW, MM, and JQW performed lncRNA validation studies; CML, JK and JX contributed to MRI data acquisition and analysis; KN, TM, SS, and ALT contributed to psychological autopsies and subject diagnosis. All authors revised and approved the final manuscript.

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Correspondence to Consuelo Walss-Bass.

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Mendez, E.F., Wei, H., Hu, R. et al. Angiogenic gene networks are dysregulated in opioid use disorder: evidence from multi-omics and imaging of postmortem human brain. Mol Psychiatry (2021).

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