Bidirectional associations between mental disorders, antidepressants and cardiovascular disease.

BACKGROUND: Mental disorders have a high comorbidity with cardiovascular disease (CVD), but the causality between them has not been fully appreciated. OBJECTIVE: This study aimed to systematically explore the bidirectional causality between the two broad categories of diseases. METHODS: We conducted Mendelian randomisation (MR) and multivariable MR (MVMR) analyses to evaluate potential causal links between 10 mental disorders, the use of antidepressants and 7 CVDs. FINDINGS: We discovered that major depressive disorder (MDD), attention-deficit/hyperactivity disorder (ADHD) and insomnia exhibit connections with elevated risks of two or more CVDs. Moreover, the use of antidepressants is linked to heightened risks of each CVD. Each distinct CVD is correlated with a greater probability of taking antidepressants. Our MVMR analysis demonstrated that the use of antidepressants is correlated with the elevation of respective risks across all cardiovascular conditions. This includes arrhythmias (OR: 1.28), atrial fibrillation (OR: 1.44), coronary artery disease (OR: 1.16), hypertension (OR: 1.16), heart failure (OR: 1.16), stroke (OR: 1.44) and entire CVD group (OR: 1.35). However, MDD itself was not linked to a heightened risk of any CVD. CONCLUSIONS: The findings of our study indicate that MDD, insomnia and ADHD may increase the risk of CVD. Our findings highlight the utilisation of antidepressants as an independent risk factor for CVD, thus explaining the influence of MDD on CVD through the mediating effects of antidepressants. CLINICAL IMPLICATIONS: When treating patients with antidepressants, it is necessary to take into consideration the potential beneficial and detrimental effects of antidepressants.

Exploring the influences of education, intelligence and income on mental disorders.

Background: Previous studies have shown that educational attainment (EA), intelligence and income are key factors associated with mental disorders. However, the direct effects of each factor on major mental disorders are unclear. Aims: We aimed to evaluate the overall and independent causal effects of the three psychosocial factors on common mental disorders. Methods: Using genome-wide association study summary datasets, we performed Mendelian randomisation (MR) and multivariable MR (MVMR) analyses to assess potential associations between the 3 factors (EA, N=766 345; household income, N=392 422; intelligence, N=146 808) and 13 common mental disorders, with sample sizes ranging from 9907 to 807 553. Inverse-variance weighting was employed as the main method in the MR analysis. Results: Our MR analysis showed that (1) higher EA was a protective factor for eight mental disorders but contributed to anorexia nervosa, obsessive-compulsive disorder (OCD), bipolar disorder (BD) and autism spectrum disorder (ASD); (2) higher intelligence was a protective factor for five mental disorders but a risk factor for OCD and ASD; (3) higher household income protected against 10 mental disorders but confers risk for anorexia nervosa. Our MVMR analysis showed that (1) higher EA was a direct protective factor for attention-deficit/hyperactivity disorder (ADHD) and insomnia but a direct risk factor for schizophrenia, BD and ASD; (2) higher intelligence was a direct protective factor for schizophrenia but a direct risk factor for major depressive disorder (MDD) and ASD; (3) higher income was a direct protective factor for seven mental disorders, including schizophrenia, BD, MDD, ASD, post-traumatic stress disorder, ADHD and anxiety disorder. Conclusions: Our study reveals that education, intelligence and income intertwine with each other. For each factor, its independent effects on mental disorders present a more complex picture than its overall effects.

Causal influences of neuropsychiatric disorders on Alzheimer's disease.

Previous studies have observed a significant comorbidity between Alzheimer's disease (AD) and some other neuropsychiatric disorders. However, the mechanistic connections between neuropsychiatric disorders and AD are not well understood. We conducted a Mendelian randomization analysis to appraise the potential influences of 18 neurodegenerative and neuropsychiatric disorders on AD. We found that four disorders are causally associated with increased risk for AD, including bipolar disorder (BD) (OR: 1.09), migraine (OR: 1.09), schizophrenia (OR: 1.05), and Parkinson's disease (PD) (OR: 1.07), while attention-deficit/hyperactivity disorder (ADHD) was associated with a decreased risk for AD (OR: 0.80). In case of amyotrophic lateral sclerosis (OR: 1.04) and Tourette's syndrome (OR: 1.05), there was suggestive evidence of their causal effects of on AD. Our study shows that genetic components predisposing to BD, migraine, schizophrenia, and PD may promote the development of AD, while ADHD may be associated with a reduced risk of AD. The treatments aimed at alleviating neuropsychiatric diseases with earlier onset may also influence the risk of AD-related cognitive decline, which is typically observed later in life.

Causal association of attention-deficit/hyperactivity disorder and autism spectrum disorder with post-traumatic stress disorder.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are two neurodevelopmental disorders that often result in individuals experiencing traumatic events. However, little is known about the connection between ADHD/ASD and post-traumatic stress disorder (PTSD). This study aimed to investigate the genetic associations between these disorders. METHODS: Genetic correlation analysis was used to examine the genetic components shared between ADHD (38 691 cases and 275 986 controls), ASD (18 381 cases and 27 969 controls) and PTSD (23 212 cases and 151 447 controls). Two-sample Mendelian randomization analyses were employed to explore the bidirectional causal relationships between ADHD/ASD and PTSD. RESULTS: The results of the genetic correlation analysis revealed significant positive correlations of PTSD with ADHD(r g = 0.70) and ASD (r g = 0.34). Furthermore, the Mendelian randomization analysis revealed that genetic liabilities to ADHD [odds ratio (OR) = 1.14; 95% confidence interval (CI), 1.06-1.24; P  = 7.88 × 10 -4 ] and ASD (OR = 1.04; CI, 1.01-1.08; P  = 0.014) were associated with an increased risk of developing PTSD later in life. However, no evidence supported that genetic liability to PTSD could elevate the risk of ADHD or ASD. CONCLUSION: The findings of this study supported that ADHD and ASD may increase the risk of PTSD, but not vice versa.

Causal associations between COVID-19 and childhood mental disorders.

BACKGROUND: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can invade both the peripheral and central nervous systems and impact the function of the brain. Therefore, it is necessary to evaluate the mutual influences between COVID-19 outcomes and childhood mental disorders. METHODS: We examined genetic correlations and potential causalities between three childhood mental disorders and three COVID-19 phenotypes by genetically proxied analyses. The three mental disorders included attention-deficit/hyperactivity disorder (ADHD, N = 292,548), Tourette's syndrome (TS, N = 14,307), and autism spectrum disorder (ASD, N = 46,350). The three COVID-19 traits included SARS-CoV-2 infection (N = 2,597,856), hospitalized COVID-19 (N = 2,095,324), and critical COVID-19 (N = 1,086,211). Literature-based analysis was used to build gene-based pathways connecting ADHD and COVID-19. RESULTS: ADHD was positively correlated with the three COVID-19 outcomes (Rg: 0.22 ~ 0.30). Our Mendelian randomization (MR) analyses found that ADHD confers a causal effect on hospitalized COVID-19 (odds ratio (OR): 1.36, 95% confidence interval (CI): 1.10-1.69). TS confers a causal effect on critical COVID-19 (OR: 1.14, 95% CI: 1.04-1.25). Genetic liability to the COVID-19 outcomes may not increase the risk for the childhood mental disorders. Pathway analysis identified several immunity-related genes that may link ADHD to COVID-19, including CRP, OXT, IL6, PON1, AR, TNFSF12, and IL10. CONCLUSIONS: Our study suggests that both ADHD and TS may augment the severity of COVID-19 through immunity-related pathways. However, our results did not support a causal role of COVID-19 in the risk for the childhood mental disorders.

miR-9-5p deficiency contributes to schizophrenia.

MicroRNA-9-5p (miR-9-5p) is highly expressed in the brain and has been implicated in the risk of schizophrenia. We compared the expression levels of miR-9-5p in schizophrenia cases and healthy controls and evaluated whether regulatory targets of miR-9-5p are enriched in schizophrenia genome-wide risk genes. Literature-based analysis was conducted to construct molecular pathways connecting miR-9-5p and schizophrenia. We found that the expression levels of miR-9-5p were down-regulated in the peripheral blood of schizophrenia patients compared with those in healthy controls. miR-9-5p can regulate 24 out of the 1136 genome-wide risk genes of schizophrenia, which was higher than by chance (hypergeometric test P = 4.09E-06). The literature-based analysis showed that quantitative genetic changes driven by miR-9 exert more inhibitory (the IL1B, ABCB1, FGFR1 genes) than promoting (the INS gene) effects on schizophrenia, suggesting that miR-9 may protect against schizophrenia. Our results suggest that miR-9-5p deficiency may contribute to the development of schizophrenia.

Causal influences of osteoarthritis on COVID-19: a Mendelian randomization study.

Objective: Although observational and genetic studies have indicated a correlation between OA and COVID-19, it remains uncertain whether osteoarthritis (OA) contributes to the severity of COVID-19. Here, we aimed to investigate the potential causal links between the two. Methods: In this study, we conducted Mendelian randomization (MR) analysis to investigate whether there is a potential causal connection between OA and COVID-19 outcomes. The analysis utilized publicly available GWAS summary datasets, incorporating data on OA (N = 455,221), SARS-CoV-2 infection (N = 2,597,856), hospitalized COVID-19 (N = 2,095,324), and critical COVID-19 (N = 1,086,211). Additionally, we performed a literature analysis to establish a molecular network connecting OA and COVID-19. Results: The MR analysis showed causal effects of OA on hospitalized COVID-19 (OR: 1.21, 95% CI: 1.02-1.43, p = 0.026) and critical COVID-19 (OR: 1.35, 95% CI: 1.09-1.68, p = 0.006) but not on SARS-CoV-2 infection as such (OR: 1.00, 95% CI: 0.92-1.08, p = 0.969). Moreover, the literature-based pathway analysis uncovered a set of specific genes, such as CALCA, ACE, SIRT1, TNF, IL6, CCL2, and others, that were found to mediate the association between OA and COVID-19. Conclusion: Our findings indicate that OA elevates the risk of severe COVID-19. Therefore, larger efforts should be made in the prevention of COVID-19 in OA patients.

Penta-SiCN monolayer as a well-balanced performance anode material for Li-ion batteries.

Lithium-ion batteries (LIBs) remain irreplaceable for clean energy storage applications. The intrinsic metallic nature of penta-SiCN ensures its promising application in the electrodes of LIBs. Using first-principles calculations, we evaluate the performance of the intrinsic metallic penta-SiCN monolayer as the anode material for LIBs. Penta-SiCN exhibits a low diffusion energy barrier (0.107 eV) for Li atom migration on Si18C18N18, while the diffusion energy barrier for vacancy migration on Li17Si18C18N18 is only 0.006 eV. Additionally, penta-SiCN possesses a high theoretical capacity of 1485.98 mA h g-1, average open-circuit voltage of 0.97 V, and small volume expansion of 1%. Remarkably, penta-SiCN exhibits robust wettability towards the electrolytes (solvent molecules and metal salts) widely used in commercial LIBs, indicating the excellent compatibility in electrode applications. These intriguing theoretical findings make penta-SiCN a high performance anode material for LIBs.

Causal associations and genetic overlap between COVID-19 and intelligence.

OBJECTIVE: COVID-19 might cause neuroinflammation in the brain, which could decrease neurocognitive function. We aimed to evaluate the causal associations and genetic overlap between COVID-19 and intelligence. METHODS: We performed Mendelian randomization (MR) analyses to assess potential associations between three COVID-19 outcomes and intelligence (N = 269 867). The COVID phenotypes included severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (N = 2 501 486), hospitalized COVID-19 (N = 1 965 329) and critical COVID-19 (N = 743 167). Genome-wide risk genes were compared between the genome-wide association study (GWAS) datasets on hospitalized COVID-19 and intelligence. In addition, functional pathways were constructed to explore molecular connections between COVID-19 and intelligence. RESULTS: The MR analyses indicated that genetic liabilities to SARS-CoV-2 infection (odds ratio [OR]: 0.965, 95% confidence interval [CI]: 0.939-0.993) and critical COVID-19 (OR: 0.989, 95% CI: 0.979-0.999) confer causal effects on intelligence. There was suggestive evidence supporting the causal effect of hospitalized COVID-19 on intelligence (OR: 0.988, 95% CI: 0.972-1.003). Hospitalized COVID-19 and intelligence share 10 risk genes within 2 genomic loci, including MAPT and WNT3. Enrichment analysis showed that these genes are functionally connected within distinct subnetworks of 30 phenotypes linked to cognitive decline. The functional pathway revealed that COVID-19-driven pathological changes within the brain and multiple peripheral systems may lead to cognitive impairment. CONCLUSIONS: Our study suggests that COVID-19 may exert a detrimental effect on intelligence. The tau protein and Wnt signaling may mediate the influence of COVID-19 on intelligence.

Causal associations between major depressive disorder and COVID-19.

Background: We aimed to evaluate whether major depressive disorder (MDD) could aggravate the outcomes of coronavirus disease 2019 (COVID-19) or whether the genetic liability to COVID-19 could trigger MDD. Aims: We aimed to assess bidirectional causal associations between MDD and COVID-19. Methods: We performed genetic correlation and Mendelian randomisation (MR) analyses to assess potential associations between MDD and three COVID-19 outcomes. Literature-based network analysis was conducted to construct molecular pathways connecting MDD and COVID-19. Results: We found that MDD has positive genetic correlations with COVID-19 outcomes (rg: 0.10-0.15). Our MR analysis indicated that genetic liability to MDD is associated with increased risks of COVID-19 infection (odds ratio (OR)=1.05, 95% confidence interval (CI): 1.00 to 1.10, p=0.039). However, genetic liability to the three COVID-19 outcomes did not confer any causal effects on MDD. Pathway analysis identified a panel of immunity-related genes that may mediate the links between MDD and COVID-19. Conclusions: Our study suggests that MDD may increase the susceptibility to COVID-19. Our findings emphasise the need to increase social support and improve mental health intervention networks for people with mood disorders during the pandemic.

Causal associations and shared genetics between hypertension and COVID-19.

To evaluate the genetic relationship between hypertension and COVID-19 and explore the molecular pathways linking hypertension to COVID-19. We performed genetic correlation and Mendelian randomization (MR) analyses to assess potential associations between hypertension and hospitalized COVID-19. We compared genome-wide association signals to reveal shared genetic variation between hypertension and hospitalized COVID-19. Moreover, hypertension-driven molecular pathways were constructed based on large-scale literature data to understand the influence of hypertension on COVID-19 at the molecular level. Hypertension has a positive genetic correlation with COVID-19 (rg = 0.19). The MR analyses indicate that genetic liability to hypertension confers a causal effect on hospitalized COVID-19 (odds ratio [OR]: 1.05, confidence interval [CI]: 1.00-1.09, p = 0.030). Hypertension and hospitalized COVID-19 have three overlapping loci and share eight protein-coding risk genes, including ABO, CSF2, FUT2, IZUMO1, MAMSTR, NPNT, RASIP1, and WNT3. Molecular pathway analysis suggests that hypertension may promote the development of COVID-19 through the induction of inflammatory pathways. Our study suggests that genetically determined hypertension may increase the risk for severe COVID-19. The shared genetic variation and the connecting molecular pathways may underline causal links between hypertension and COVID-19.

Shared genetics and bidirectional causal relationships between type 2 diabetes and attention-deficit/hyperactivity disorder.

Background: Type 2 diabetes (T2D) is a chronic metabolic disorder with high comorbidity with mental disorders. The genetic links between attention-deficit/hyperactivity disorder (ADHD) and T2D have yet to be elucidated. Aims: We aim to assess shared genetics and potential associations between ADHD and T2D. Methods: We performed genetic correlation, two-sample Mendelian randomisation and polygenic overlap analyses between ADHD and T2D. The genome-wide association study (GWAS) summary results of T2D (80 154 cases and 853 816 controls), ADHD2019 (20 183 cases and 35 191 controls from the 2019 GWAS ADHD dataset) and ADHD2022 (38 691 cases and 275 986 controls from the 2022 GWAS ADHD dataset) were used for the analyses. The T2D dataset was obtained from the DIAGRAM Consortium. The ADHD datasets were obtained from the Psychiatric Genomics Consortium. We compared genome-wide association signals to reveal shared genetic variation between T2D and ADHD using the larger ADHD2022 dataset. Moreover, molecular pathways were constructed based on large-scale literature data to understand the connection between ADHD and T2D. Results: T2D has positive genetic correlations with ADHD2019 (rg=0.33) and ADHD2022 (rg=0.31). Genetic liability to ADHD2019 was associated with an increased risk for T2D (odds ratio (OR): 1.30, p<0.001), while genetic liability to ADHD2022 had a suggestive causal effect on T2D (OR: 1.30, p=0.086). Genetic liability to T2D was associated with a higher risk for ADHD2019 (OR: 1.05, p=0.001) and ADHD2022 (OR: 1.03, p<0.001). The polygenic overlap analysis showed that most causal variants of T2D are shared with ADHD2022. T2D and ADHD2022 have three overlapping loci. Molecular pathway analysis suggests that ADHD and T2D could promote the risk of each other through inflammatory pathways. Conclusions: Our study demonstrates substantial shared genetics and bidirectional causal associations between ADHD and T2D.

A phenome-wide investigation of risk factors for severe COVID-19.

With the continued spread of COVID-19 globally, it is crucial to identify the potential risk or protective factors associated with COVID-19. Here, we performed genetic correlation analysis and Mendelian randomization analysis to examine genetic relationships between COVID-19 hospitalization and 405 health conditions and lifestyle factors in 456 422 participants from the UK Biobank. The genetic correlation analysis revealed 134 positive and 65 negative correlations, including those with intakes of a variety of dietary components. The MR analysis indicates that a set of body fat-related traits, maternal smoking around birth, basal metabolic rate, lymphocyte count, peripheral enthesopathies and allied syndromes, blood clots in the leg, and arthropathy are causal risk factors for severe COVID-19, while higher education attainment, physical activity, asthma, and never smoking status protect against the illness. Our findings have implications for risk stratification in patients with COVID-19 and the prevention of its severe outcomes.

Bidirectional causal associations between type 2 diabetes and COVID-19.

Observational studies have reported high comorbidity between type 2 diabetes (T2D) and severe COVID-19. However, the causality between T2D and COVID-19 has yet to be validated. We performed genetic correlation and Mendelian randomization (MR) analyses to assess genetic relationships and potential causal associations between T2D and three COVID-19 outcomes (severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] infection, COVID-19 hospitalization, and critical COVID-19). Molecular pathways connecting SARS-CoV-2 and COVID-19 were reconstructed to extract insights into the potential mechanisms underlying the connection. We identified a high genetic overlap between T2D and each COVID-19 outcome (genetic correlations 0.21-0.28). The MR analyses indicated that genetic liability to T2D confers a causal effect on hospitalized COVID-19 (odds ratio 1.08, 95% confidence interval [CI] 1.04-1.12) and critical COVID-19 (1.09, 1.03-1.16), while genetic liability to SARS-CoV-2 infection exerts a causal effect on T2D (1.25, 1.00-1.56). There was suggestive evidence that T2D was associated with an increased risk for SARS-CoV-2 infection (1.02, 1.00-1.03), while critical COVID-19 (1.06, 1.00-1.13) and hospitalized COVID-19 (1.09, 0.99-1.19) were associated with an increased risk for T2D. Pathway analysis identified a panel of immunity-related genes that may mediate the links between T2D and COVID-19 at the molecular level. Our study provides robust support for the bidirectional causal associations between T2D and COVID-19. T2D may contribute to amplifying the severity of COVID-19, while the liability to COVID-19 may increase the risk for T2D.

Causal effect of COVID-19 on Alzheimer's disease: A Mendelian randomization study.

It was reported that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may cause brain size reduction and cognitive decline. Whether COVID-19 may contribute to the development of Alzheimer's disease (AD) is not known. We conducted genetic correlation and Mendelian randomization (MR) analyses to assess genetic relationships and potential causal associations between AD and three COVID-19 outcomes (SARS-CoV-2 infection, COVID-19 hospitalization, and critical COVID-19) by utilizing genome-wide association study datasets on these traits. A map of COVID-19-driven molecular pathways was constructed to investigate potential mechanisms underlying the COVID-19 and AD connection. Genetic correlation analyses indicated that AD had a significant positive genetic correlation with hospitalized COVID-19 (rg = 0.271). The MR analysis from the inverse-variance-weighted model showed that genetic liabilities to hospitalized COVID-19 (odds ratio: 1.02, 95% confidence interval: 1.01-1.03) and critical COVID-19 (1.01, 1.00-1.02) were associated with an increased risk for AD. However, no causal effect of genetic liability to SARS-CoV-2 infection on AD was detected (1.03, 0.97-1.09). A total of 60 functionally interconnected genes were reported to mediate the COVID-19-AD connection, which showed functional enrichment in immunity-related pathways and tissue enrichment in the lung and brain. Our study suggests that severe COVID-19 may contribute to the development of AD, while suffering a mild case of COVID-19 may not increase the risk for AD. The influence of COVID-19 on AD may be mediated by immunity-related pathways acting predominantly in the lung and brain.

Causal Associations Between Basal Metabolic Rate and COVID-19.

Many coronavirus disease 2019 (COVID-19) risk factors, including obesity and diabetes, are associated with an abnormal basal metabolic rate (BMR). We aimed to evaluate whether BMR could impact the susceptibility to or severity of COVID-19. We performed genetic correlation and Mendelian randomization (MR) analyses to assess genetic correlations and potential causal associations between BMR (n = 448,348) and three COVID-19 outcomes: severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, COVID-19 hospitalization, and critical COVID-19 (n = 1,086,211-2,597,856). A multivariable MR (MVMR) analysis was used to estimate the direct effect of BMR on COVID-19 independent of BMI and type 2 diabetes. BMR has positive genetic correlations with the COVID-19 outcomes (genetic correlations 0.213-0.266). The MR analyses indicated that genetic liability to BMR confers causal effects on SARS-CoV-2 infection (odds ratio 1.14, 95% CI 1.09-1.20, P = 1.65E-07), hospitalized COVID-19 (1.31, 1.18-1.46, P = 8.69E-07), and critical COVID-19 (1.04, 1.19-1.64, P = 4.89E-05). Sensitivity analysis of MR showed no evidence of directional pleiotropy or heterogeneity, indicating the robustness of its results. The MVMR analysis showed that the causal effects of BMR on hospitalized COVID-19 and critical COVID-19 were dependent on BMI and type 2 diabetes but that BMR may affect the SARS-CoV-2 infection risk independently of BMI and type 2 diabetes (odds ratio 1.09, 95% CI 1.03-1.15, P = 4.82E-03). Our study indicates that a higher BMR contributes to amplifying the susceptibility to and severity of COVID-19. The causal effect of BMR on the severity of COVID-19 may be mediated by BMI and type 2 diabetes.

Shared genetics and causal associations between COVID-19 and multiple sclerosis.

Neuroinflammation caused by COVID-19 negatively impacts brain metabolism and function, while pre-existing brain pathology may contribute to individuals' vulnerability to the adverse consequences of COVID-19. We used summary statistics from genome-wide association studies (GWAS) to perform Mendelian randomization (MR) analyses, thus assessing potential associations between multiple sclerosis (MS) and two COVID-19 outcomes (severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] infection and COVID-19 hospitalization). Genome-wide risk genes were compared between the GWAS datasets on hospitalized COVID-19 and MS. Literature-based analysis was conducted to construct molecular pathways connecting MS and COVID-19. We found that genetic liability to MS confers a causal effect on hospitalized COVID-19 (odd ratio [OR]: 1.09, 95% confidence interval: 1.03-1.16) but not on SARS-CoV-2 infection (1.03, 1.00-1.05). Genetic liability to hospitalized COVID-19 confers a causal effect on MS (1.15, 1.02-1.30). Hospitalized COVID-19 and MS share five risk genes within two loci, including TNFAIP8, HSD17B4, CDC37, PDE4A, and KEAP1. Pathway analysis identified a panel of immunity-related genes that may mediate the links between MS and COVID-19. Our study suggests that MS was associated with a 9% increased risk for COVID-19 hospitalization, while hospitalized COVID-19 was associated with a 15% increased risk for MS. Immunity-related pathways may underlie the link between MS on COVID-19.

Old drugs, new tricks: leveraging known compounds to disrupt coronavirus-induced cytokine storm.

A major complication in COVID-19 infection consists in the onset of acute respiratory distress fueled by a dysregulation of the host immune network that leads to a run-away cytokine storm. Here, we present an in silico approach that captures the host immune system's complex regulatory dynamics, allowing us to identify and rank candidate drugs and drug pairs that engage with minimal subsets of immune mediators such that their downstream interactions effectively disrupt the signaling cascades driving cytokine storm. Drug-target regulatory interactions are extracted from peer-reviewed literature using automated text-mining for over 5000 compounds associated with COVID-induced cytokine storm and elements of the underlying biology. The targets and mode of action of each compound, as well as combinations of compounds, were scored against their functional alignment with sets of competing model-predicted optimal intervention strategies, as well as the availability of like-acting compounds and known off-target effects. Top-ranking individual compounds identified included a number of known immune suppressors such as calcineurin and mTOR inhibitors as well as compounds less frequently associated for their immune-modulatory effects, including antimicrobials, statins, and cholinergic agonists. Pairwise combinations of drugs targeting distinct biological pathways tended to perform significantly better than single drugs with dexamethasone emerging as a frequent high-ranking companion. While these predicted drug combinations aim to disrupt COVID-induced acute respiratory distress syndrome, the approach itself can be applied more broadly to other diseases and may provide a standard tool for drug discovery initiatives in evaluating alternative targets and repurposing approved drugs.

In-silico investigation of systematic missense mutations of middle east respiratory coronavirus spike protein.

Middle East Respiratory Syndrome Coronavirus (MERS-CoV) causes severe pneumonia-like symptoms and is still pose a significant threat to global public health. A key component in the virulence of MERS-CoV is the Spike (S) protein, which binds with the host membrane receptor dipeptidyl peptidase 4 (DPP4). The goal of the present investigation is to examine the effects of missense mutations in the MERS-CoV S protein on protein stability and binding affinity with DPP4 to provide insight that is useful in developing vaccines to prevent coronavirus infection. We utilized a saturation mutagenesis approach to simulate all possible mutations in the MERS-CoV full-length S, S Receptor Binding Domain (RBD) and DPP4. We found the mutations in MERS-CoV S protein residues, G552, C503, C526, N468, G570, S532, S451, S419, S465, and S435, affect protein stability. We identified key residues, G538, E513, V555, S557, L506, L507, R511, M452, D537, and S454 in the S protein RBD region are important in the binding of MERS-CoV S protein to the DPP4 receptor. We investigated the effects of MERS-CoV S protein viral mutations on protein stability and binding affinity. In addition, we studied all DPP4 mutations and found the functional substitution R336T weakens both DPP4 protein stability and S-DPP4 binding affinity. We compared the S protein structures of MERS-CoV, SARS-CoV, and SARS-CoV-2 viruses and identified the residues like C526, C383, and N468 located in equivalent positions of these viruses have effects on S protein structure. These findings provide further information on how mutations in coronavirus S proteins effect protein function.