Genetic association and drug target exploration of inflammation-related proteins with risk of major depressive disorder.

BACKGROUND: In numerous observational studies, circulating inflammation-related proteins have been linked with major depressive disorder (MDD), yet the precise causal direction of this relationship remains unclear. This study aims to investigate the potential causal link between inflammation-related proteins and the risk of developing MDD. METHODS: We utilized summary data from a genome-wide association study (GWAS) of 91 circulating inflammation-associated proteins in 14,824 individuals of European descent. Additionally, we incorporated findings from a substantial GWAS on MDD, which included 294,322 cases and 741,438 controls. Our analysis employed a two-sample bidirectional Mendelian randomization (MR) approach, with inverse variance weighting (IVW) as the primary method. We augmented this with two supplementary techniques (MR-Egger and weighted median approaches) to detect and address potential pleiotropy. Furthermore, to identify and evaluate possible drug targets, we conducted a thorough search within the Drug-Gene Interaction Database (DGIdb). RESULTS: Analysis using MR unveiled significant and causative associations between genetically determined CASP-8 (odds ratio (OR): 0.97), CD40 (OR: 0.96), IL-18 (OR: 0.98), SLAMF1 (OR: 0.97), and uPA (OR: 0.98) with MDD. Conversely, reverse MR analysis indicated causal associations between MDD and CCL19 (OR: 1.15), HGF (OR: 1.15), IL-8 (OR: 1.10), IL-18 (OR: 1.11), IL20RA (OR: 1.12), TGFA (OR: 1.12) and TNFSF14 (OR: 1.16). Notably, a significant bidirectional causal link was observed between IL-18 and MDD. Gene-drug analysis identified CD40, HGF, IL-8, IL-18, SLAMF1, and TGFA as potential therapeutic targets. CONCLUSIONS: We've pinpointed causal links between inflammation-related proteins and MDD, offering compelling and innovative evidence to enhance our understanding of the inflammatory mechanisms involved in MDD and to investigate potential targets for anti-MDD medications.

Antidepressants account for the causal effect of major depressive disorder on type 2 diabetes.

BACKGROUND: Patients with major depressive disorder (MDD) face an elevated risk of type 2 diabetes (T2D). However, the contribution of the disease itself versus the side effects of antidepressants to this increased risk remains unclear. OBJECTIVE: This study aimed to investigate the overall and independent effects of MDD and exposure to antidepressants on T2D risk. METHODS: Summary genome-wide association study datasets were utilized for the Mendelian randomization (MR) and multivariable MR (MVMR) analyses, including ones for MDD (N = 500,199), antidepressants (N = 175,161), and T2D (N = 933,970). Bayesian colocalization analysis was used to reveal shared genetic variation between MDD, antidepressants, and T2D. RESULTS: We found that both MDD (OR: 1.15, CI: 1.03-1.30, P = 0.016) and antidepressants (OR: 1.37, CI: 1.22-1.53, P = 2.75E-08) have overall causal effects on T2D. While T2D was associated with the risk of antidepressant use (OR: 1.08, CI: 1.06-1.11, P = 8.80E-10), but not with the risk of MDD (OR: 1.00, CI: 0.98-1.01, P = 0.661). Our MVMR analysis showed that the use of antidepressants is associated with higher risks of T2D (OR: 1.21, CI: 1.07-1.37, P = 7.19E-04), while MDD is not linked to the risk of T2D (OR: 1.01, CI: 0.86-1.18, P = 0.799). Colocalization analysis identified two shared genetic loci between antidepressants and T2D. CONCLUSIONS: The elevated T2D risk in MDD patients is chiefly caused by antidepressant use. These findings emphasize the importance of considering the impact of antidepressants on metabolic health in individuals with MDD.

The causal relationship between immune cell traits and schizophrenia: a Mendelian randomization analysis.

Introduction: The complex and unresolved pathogenesis of schizophrenia has posed significant challenges to its diagnosis and treatment. While recent research has established a clear association between immune function and schizophrenia, the causal relationship between the two remains elusive. Methods: We employed a bidirectional two-sample Mendelian randomization approach to investigate the causal relationship between schizophrenia and 731 immune cell traits by utilizing public GWAS data. We further validated the causal relationship between schizophrenia and six types of white cell measures. Results: We found the overall causal effects of schizophrenia on immune cell traits were significantly higher than the reverse ones (0.011 ± 0.049 vs 0.001 ± 0.016, p < 0.001), implying that disease may lead to an increase in immune cells by itself. We also identified four immune cell traits that may increase the risk of schizophrenia: CD11c+ monocyte %monocyte (odds ratio (OR): 1.06, 95% confidence interval (CI): 1.03~1.09, FDR = 0.027), CD11c+ CD62L- monocyte %monocyte (OR:1.06, 95% CI: 1.03~1.09, FDR = 0.027), CD25 on IgD+ CD38- naive B cell (OR:1.03, 95% CI:1.01~1.06, FDR = 0.042), and CD86 on monocyte (OR = 1.04, 95% CI:1.01~1.06, FDR = 0.042). However, we did not detect any significant causal effects of schizophrenia on immune cell traits. Using the white blood cell traits data, we identified that schizophrenia increases the lymphocyte counts (OR:1.03, 95%CI: 1.01-1.04, FDR = 0.007), total white blood cell counts (OR:1.02, 95%CI: 1.01-1.04, FDR = 0.021) and monocyte counts (OR:1.02, 95%CI: 1.00-1.03, FDR = 0.034). The lymphocyte counts were nominally associated with the risk of schizophrenia (OR:1.08,95%CI:1.01-1.16, P=0.019). Discussion: Our study found that the causal relationship between schizophrenia and the immune system is complex, enhancing our understanding of the role of immune regulation in the development of this disorder. These findings offer new insights for exploring diagnostic and therapeutic options for schizophrenia.

Gut microbiome and schizophrenia: insights from two-sample Mendelian randomization.

Growing evidence suggests a potential link between the gut microbiome and schizophrenia. However, it is unclear whether the gut microbiome is causally associated with schizophrenia. We performed two-sample bidirectional Mendelian randomization to detect bidirectional causal relationships between gut microbiome and schizophrenia. Summary genome-wide association study (GWAS) datasets of the gut microbiome from the MiBioGen consortium (n = 18,340) and schizophrenia (n = 130,644) were utilized in our study. Then a cohort of sensitive analyses was followed to validate the robustness of MR results. We identified nine taxa that exerted positive causal effects on schizophrenia (OR: 1.08-1.16) and six taxa that conferred negative causal effects on schizophrenia (OR: 0.88-0.94). On the other hand, the reverse MR analysis showed that schizophrenia may increase the abundance of nine taxa (OR: 1.03-1.08) and reduce the abundance of two taxa (OR: 0.94). Our study unveiled mutual causal relationships between gut microbiome and schizophrenia. The findings may provide evidence for the treatment potential of gut microbiomes in schizophrenia.

Gut microbiome and major depressive disorder: insights from two-sample Mendelian randomization.

BACKGROUND: Existing evidence suggests that alterations in the gut microbiome are closely associated with major depressive disorder (MDD). We aimed to reveal the causal relationships between MDD and various microbial taxa in the gut. METHODS: We used the two-sample Mendelian randomization (TSMR) to explore the bidirectional causal effects between gut microbiota and MDD. The genome-wide association studies summary results of gut microbiota were obtained from two large consortia, the MibioGen consortium and the Dutch Microbiome Project, which we analyzed separately. RESULTS: Our TSMR analysis identified 10 gut bacterial taxa that were protective against MDD, including phylum Actinobacteria, order Clostridiales, and family Bifidobacteriaceae (OR: 0.96 ∼ 0.98). Ten taxa were associated with an increased risk of MDD, including phyla Firmicutes and Proteobacteria, class Actinobacteria, and genus Alistipes (OR: 1.01 ∼ 1.09). On the other hand, MDD may decrease the abundance of 12 taxa, including phyla Actinobacteria and Firmicutes, families Bifidobacteriaceae and Defluviitaleaceae (OR: 0.63 ∼ 0.88). MDD may increase the abundance of 8 taxa, including phylum Bacteroidetes, genera Parabacteroides, and Bacteroides (OR: 1.12 ∼ 1.43). CONCLUSIONS: Our study supports that there are mutual causal relationships between certain gut microbiota and the development of MDD suggesting that gut microbiota may be targeted in the treatment of MDD.

Genetic predisposition to milder forms of COVID-19 may provide some resilience to head and neck cancers.

Introduction: The impact of the COVID-19 pandemic on head and neck cancer (HNC) has been suggested, but the causal relationship remains unclear. Methods: We explore this connection by utilizing the Mendelian randomization (MR) approach applied to publicly available genome-wide association study (GWAS) summary datasets for COVID-19 and HNC. The datasets included critical COVID-19 (13,769 cases, 1,072,442 controls), hospitalized COVID-19 (32,519 cases, 2,062,805 controls), SARS-CoV-2 infection (122,616 cases, 2,475,240 controls), and HNC (2,131 cases, 287,137 controls). Mechanistic underpinnings of the causal relationships identified by MR analysis were explored through functional annotation augmented by AI-based literature data mining. Results: Surprisingly, a genetic predisposition to contracting a milder form of COVID-19 substantially reduced the risks of developing HNC (OR: 0.52, 95% CI: 0.35-0.78, p = 1.42E-03), with no significant association between genetic liability to severe COVID-19 and the risk of HNC detected. Additionally, our findings highlighted 14 genes linked to SARS-CoV-2 infection, potentially playing a protective role in the context of HNC. These genes include OAS1, LOC107985887, BCL11A, DPP9, LOC107984685, LINC02326, MUC4, NXPE3, IFNAR2, LZTFL1, LOC105372437, NAPSA, LOC105376622, LOC107986082, and SLC6A20. Conclusion: Our study emphasizes the protective role of the genetic liability to milder COVID-19 in reducing the risk of HNC while refuting a causal relationship between severe COVID-19 and HNC.

Exploring the causal effects of depression and antidepressants on COVID-19.

BACKGROUND: While existing studies have suggested an increased risk of COVID-19 in patients with depression, the causal impact of MDD on the severity of COVID-19 remains to be validated. Additionally, the potential impact of antidepressant medication on the risk of COVID-19 is not known. METHODS: In our study, we applied a Mendelian Randomization (MR) method, leveraging summary data from GWAS, to evaluate the potential causal effects of depression on three COVID-19 outcomes. Furthermore, we investigated the causal effects of antidepressants on COVID-19 outcomes. The COVID-19 datasets contain information on various stages of the disease, including SARS-CoV-2 infection (N = 2,597,856), hospitalized COVID-19 (N = 2,095,324), and critical COVID-19 (N = 1,086,211). Datasets for depression and antidepressants were comprised of 1,349,887 and 106,785 participants, respectively. RESULTS: Employing the inverse variance-weighted (IVW) method, we show a causal association between depression and three COVID-19 outcomes. Specifically, we found that genetic liability to depression is linked to critical COVID-19 (OR: 1.28, 95 % CI: 1.13-1.46), hospitalized COVID-19 (OR: 1.23, 95 % CI: 1.13-1.34), and SARS-CoV-2 infection (OR: 1.06, 95 % CI: 1.02-1.10). Interestingly, the use of antidepressants was not associated with COVID-19, with the odds ratios for critical COVID-19 (OR: 1.05, 95 % CI: 0.88-1.26), hospitalization (OR: 1.01, 95 % CI: 0.90-1.13), and SARS-CoV-2 infection (OR: 1.03, 95 % CI: 0.99-1.08) indicating no causal impact. CONCLUSION: Our study indicates that genetic liability to depression may increase the susceptibility to COVID-19 and its severe forms. The lack of causal effect of antidepressant use on COVID-19 implies antidepressant medication may counteract the detrimental effect of depression on COVID-19.

Causal Associations between Posttraumatic Stress Disorder and COVID-19.

OBJECTIVE: We aimed to evaluate bidirectional genetic relationships between posttraumatic stress disorder (PTSD) and COVID-19. METHODS: We investigated potential causal associations between PTSD and two COVID-19 conditions (COVID-19 hospitalization and SARS-CoV-2 infection) via Mendelian randomization (MR) analyses. Three genome-wide association study (GWAS) summary datasets were used in the study, including PTSD (N = 174,659), SARS-CoV-2 infection (N = 2,597,856), and COVID-19 hospitalization (N = 2,095,324). We performed a literature-based analysis to uncover molecular pathways connecting PTSD and COVID-19. RESULTS: We found that PTSD exerts a causal effect on SARS-CoV-2 infection (odds ratio (OR): 1.10, 95% confidence interval (CI): 1.00-1.21, p = 0.048) and hospitalized COVID-19 (OR: 1.34, 95% CI: 1.07-1.67, p = 0.001). However, both SARS-CoV-2 infection and hospitalized COVID-19 were not associated with the risk of PTSD. Pathway analysis revealed that several immunity-related genes may link PTSD to COVID-19. CONCLUSIONS: Our study suggests that PTSD was associated with increased risks for COVID-19 susceptibility and severity. Early diagnosis and effective treatment of PTSD in individuals infected with the coronavirus may improve the management of the outcomes of COVID-19.

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.

Evaluating the effects of circulating inflammatory proteins as drivers and therapeutic targets for severe COVID-19.

Objective: The relationships between circulating inflammatory proteins and COVID-19 have been observed in previous cohorts. However, it is not unclear which circulating inflammatory proteins may boost the risk of or protect against COVID-19. Methods: We performed Mendelian randomization (MR) analysis using GWAS summary result of 91 circulating inflammation-related proteins (N = 14,824) to assess their causal impact on severe COVID-19. The COVID-19 phenotypes encompassed both hospitalized (N = 2,095,324) and critical COVID-19 (N = 1,086,211). Moreover, sensitivity analyses were conducted to evaluate the robustness and reliability. Results: We found that seven circulating inflammatory proteins confer positive causal effects on severe COVID-19. Among them, serum levels of IL-10RB, FGF-19, and CCL-2 positively contributed to both hospitalized and critical COVID-19 conditions (OR: 1.10~1.16), while the other 4 proteins conferred risk on critical COVID-19 only (OR: 1.07~1.16), including EIF4EBP1, IL-7, NTF3, and LIF. Meanwhile, five proteins exert protective effects against hospitalization and progression to critical COVID-19 (OR: 0.85~0.95), including CXCL11, CDCP1, CCL4/MIP, IFNG, and LIFR. Sensitivity analyses did not support the presence of heterogeneity in the majority of MR analyses. Conclusions: Our study revealed risk and protective inflammatory proteins for severe COVID-19, which may have vital implications for the treatment of the disease.

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.

The signature of SARS-CoV-2 evolution reflects selective pressures within human guts.

In somatic cells, microRNAs (miRNAs) bind to the genomes of RNA viruses and influence their translation and replication. In London and Berlin samples represented in GISAID database, we traced severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lineages and divided these sequenced in two groups, "Ancestral variants" and "Omicrons," and analyzed them through the prism of the tissue-specific binding between host miRNAs and viral messenger RNAs. We demonstrate a significant number of miRNA-binding sites in the NSP4 region of the SARS-CoV-2 genome, with evidence of evolutionary pressure within this region exerted by human intestinal miRNAs. Notably, in infected cells, NSP4 promotes the formation of double-membrane vesicles, which serve as the scaffolds for replication-transcriptional complexes and protect viral RNA from intracellular destruction. In 3 years of selection, the loss of many miRNA-binding sites in general and those within the NSP4 in particular has shaped the SARS-CoV-2 genomes. With that, the descendants of the BA.2 variants were promoted as dominant strains, which define current momentum of the pandemics.

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.

Curtailing virus-induced inflammation in respiratory infections: emerging strategies for therapeutic interventions.

Acute respiratory viral infections (ARVI) are the most common illnesses worldwide. In some instances, mild cases of ARVI progress to hyperinflammatory responses, which are damaging to pulmonary tissue and requiring intensive care. Here we summarize available information on preclinical and clinical effects of XC221GI (1-[2-(1-methyl imidazole-4-yl)-ethyl]perhydroazin-2,6-dione), an oral drug with a favorable safety profile that has been tested in animal models of influenza, respiratory syncytial virus, highly pathogenic coronavirus strains and other acute viral upper respiratory infections. XC221GI is capable of controlling IFN-gamma-driven inflammation as it is evident from the suppression of the production of soluble cytokines and chemokines, including IL-6, IL-8, CXCL10, CXCL9 and CXCL11 as well as a decrease in migration of neutrophils into the pulmonary tissue. An excellent safety profile of XC221GI, which is not metabolized by the liver, and its significant anti-inflammatory effects indicate utility of this compound in abating conversion of ambulatory cases of respiratory infections into the cases with aggravated presentation that require hospitalization. This drug is especially useful when rapid molecular assays determining viral species are impractical, or when direct antiviral drugs are not available. Moreover, XC221GI may be combined with direct antiviral drugs to enhance their therapeutic effects.