COVID-19 patient transcriptomic and genomic profiling reveals comorbidity interactions with psychiatric disorders

Abstract

Psychiatric symptoms are seen in some COVID-19 patients, as direct or indirect sequelae, but it is unclear whether SARS-CoV-2 infection interacts with underlying neuronal or psychiatric susceptibilities. Such interactions might arise from COVID-19 immune responses, from infection of neurons themselves or may reflect social-psychological causes. To clarify this we sought the key gene expression pathways altered in COVID-19 also affected in bipolar disorder, post-traumatic stress disorder (PTSD) and schizophrenia, since this may identify pathways of interaction that could be treatment targets. We performed large scale comparisons of whole transcriptome data and immune factor transcript data in peripheral blood mononuclear cells (PBMC) from COVID-19 patients and patients with psychiatric disorders. We also analysed genome-wide association study (GWAS) data for symptomatic COVID-19 patients, comparing GWAS and whole-genome sequence data from patients with bipolar disorder, PTSD and schizophrenia patients. These studies revealed altered signalling and ontology pathways shared by COVID-19 patients and the three psychiatric disorders. Finally, co-expression and network analyses identified gene clusters common to the conditions. COVID-19 patients had peripheral blood immune system profiles that overlapped with those of patients with psychiatric conditions. From the pathways identified, PTSD profiles were the most highly correlated with COVID-19, perhaps consistent with stress-immune system interactions seen in PTSD. We also revealed common inflammatory pathways that may exacerbate psychiatric disorders, which may support the usage of anti-inflammatory medications in these patients. It also highlights the potential clinical application of multi-level dataset studies in difficult-to-treat psychiatric disorders in this COVID-19 pandemic.

Fig. 1. Flow diagram of the study.

RNA-Seq, GWAS and WGS analyses define genomic relationships and infection responses between the novel coronavirus SARS-CoV-2, and Bipolar, PTSD and Schizophrenia psychiatric disorders. A RNA-Seq gene expression profiling of human peripheral blood mononuclear cells infected with SARS-CoV-2. B RNA-Seq gene expression profiling of human peripheral blood mononuclear cells for the bipolar disorder, PTSD and schizophrenia. C Sparse overlapping gene expression signature between the SARS-CoV-2 and bipolar disorder, PTSD and schizophrenia. D WGS and GWAS data from the different curated data sources and filtered for the bipolar, PTSD and schizophrenia and identified concordant genes with the COVID-19 GWAS biomarker. E–G A similar conclusion was reached using the functional enrichment, pathways and co-expression analyses of the concordant genes.

Fig. 2. Comparison of RNA-Seq analyses of SARS Cov-2 infected patient whole blood PBMC reveals shared common genes with the Bipolar disorder, PTSD and Schizophrenia PBMC transcriptomic genes.

A Venn diagram shows the number of common significant genes of SARS Cov-2 with the bipolar disorder, PTSD and schizophrenia. B Heat map of the log fold changes for the shared common genes between SARS-CoV-2 and either of the bipolar disorder, PTSD and schizophrenia. C Heat map of the adjusted p-values for the shared common genes between SARS-CoV-2 and either of the bipolar disorder, PTSD and schizophrenia. D Bubble plot shows the combined log fold changes and adjusted p-values for the shared common genes between SARS-CoV-2 and either of the bipolar disorder, PTSD and schizophrenia.

Fig. 3. Targeted immune profiling of SARS Cov-2 infected patient blood using a Nanostring targeted immunology reveals systemic immune responses genes to infection, and shared common genes with the Bipolar disorder, PTSD and Schizophrenia.

A Volcano plot of the Nanostring RNA-seq SARS-CoV-2 data shows genes with their threshold log fold changes and adjusted p-values to consider as significant genes. B Venn diagram shows the number of common significant genes of SARS Cov-2 in the immune panel with the bipolar disorder, PTSD and schizophrenia PBMC transcriptomic genes. C Bubble plot shows the combined log fold changes and adjusted p-values for the shared common genes between SARS-CoV-2 in the immune panel and either of the bipolar disorder, PTSD and schizophrenia PBMC transcriptomic genes. D Heat map of the log fold changes for the shared common genes between SARS-CoV-2 in the immune panel and either of the bipolar disorder, PTSD and schizophrenia. E Heat map of the adjusted p-values for the shared common genes between SARS-CoV-2 in the immune panel and either of the bipolar disorder, PTSD and schizophrenia, respectively, based on the PBMC transcriptomic analysis.

Fig. 4. GWAS of SARS-CoV-2 infected patients reveal shared common significant genes with the bipolar disorder, PTSD and schizophrenia in GWAS and WGS datasets.

A Venn diagram shows the number of common significant genes of SARS Cov-2 with the bipolar disorder, PTSD and schizophrenia genes. B Barchart shows the significant shared genes of SARS-CoV-2 and schizophrenia, and their corresponding 10 based −log p-values. C Barchart shows the significant shared genes of SARS-CoV-2 and bipolar disorder, and their corresponding 10 based −log p-values. D Barchart shows the significant shared genes of SARS-CoV-2 and PTSD, and their corresponding 10 based −log p-values. E Association network of the common significant genes identified in SARS-CoV-2 infected patients with the bipolar disorder, PTSD and schizophrenia in GWAS and WGS.

Fig. 5. Coexpression and clustering analyses.

A Coexpression and clustering analyses of the significant shared genes of SARS-CoV-2 with the bipolar disorder, PTSD and schizophrenia, reveal that SARS-CoV-2 infection could perturb some genes that are also affected in bipolar disorder, PTSD, and schizophrenia. Two clusters were selected based on the co-expression values in all the transcriptome samples used in this study. B One cluster is explored based on the correlation values>0.8 and it contains 43 genes that are coexpressed together. C The second cluster is also explored based on the correlation values>0.8 and it contains 32 genes that are coexpressed together. D The network of the genes of these two co-expressed clusters that shows some genes influenced by the SARS-CoV-2 are concordant in bipolar, PTSD, and schizophrenia.