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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.
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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 â¼ 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 â¼ 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 â¼ 0.88). MDD may increase the abundance of 8 taxa, including phylum Bacteroidetes, genera Parabacteroides, and Bacteroides (OR: 1.12 â¼ 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.
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Transtorno Depressivo Maior , Microbioma Gastrointestinal , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Humanos , Microbioma Gastrointestinal/genética , Transtorno Depressivo Maior/microbiologia , Transtorno Depressivo Maior/genéticaRESUMO
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.
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Antidepressivos , COVID-19 , Análise da Randomização Mendeliana , SARS-CoV-2 , Humanos , COVID-19/psicologia , COVID-19/epidemiologia , Antidepressivos/uso terapêutico , Antidepressivos/efeitos adversos , Depressão/epidemiologia , Estudo de Associação Genômica Ampla , Causalidade , Hospitalização/estatística & dados numéricos , Transtorno Depressivo Maior/epidemiologia , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/genéticaRESUMO
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.
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COVID-19 , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Transtornos de Estresse Pós-Traumáticos , Transtornos de Estresse Pós-Traumáticos/genética , Humanos , COVID-19/complicações , Hospitalização , CausalidadeRESUMO
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.
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Transtorno do Deficit de Atenção com Hiperatividade , Doenças Cardiovasculares , Transtorno Depressivo Maior , Distúrbios do Início e da Manutenção do Sono , Humanos , Transtorno Depressivo Maior/tratamento farmacológico , Distúrbios do Início e da Manutenção do Sono/complicações , Doenças Cardiovasculares/epidemiologia , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Antidepressivos/efeitos adversosRESUMO
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.
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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.
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Doença de Alzheimer , Transtorno do Deficit de Atenção com Hiperatividade , Transtornos de Enxaqueca , Doença de Parkinson , Esquizofrenia , Humanos , Doença de Alzheimer/genética , Esquizofrenia/epidemiologia , Esquizofrenia/genética , Doença de Parkinson/genética , Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtornos de Enxaqueca/genética , Estudo de Associação Genômica AmplaRESUMO
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)â =â 1.14; 95% confidence interval (CI), 1.06-1.24; P â =â 7.88â ×â 10 -4 ] and ASD (ORâ =â 1.04; CI, 1.01-1.08; P â =â 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.
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Transtorno do Deficit de Atenção com Hiperatividade , Transtorno do Espectro Autista , Transtornos de Estresse Pós-Traumáticos , Humanos , Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno do Espectro Autista/genética , Transtornos de Estresse Pós-Traumáticos/genética , Transtornos de Estresse Pós-Traumáticos/complicações , Razão de ChancesRESUMO
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.
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Transtorno do Deficit de Atenção com Hiperatividade , Transtorno do Espectro Autista , COVID-19 , Humanos , Criança , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/complicações , SARS-CoV-2 , Transtorno do Deficit de Atenção com Hiperatividade/complicações , Causalidade , Estudo de Associação Genômica Ampla , ArildialquilfosfataseRESUMO
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.
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MicroRNAs , Esquizofrenia , Humanos , Esquizofrenia/genética , MicroRNAs/genética , MicroRNAs/metabolismoRESUMO
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.
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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.
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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.
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COVID-19 , Humanos , COVID-19/genética , SARS-CoV-2/genética , Estudo de Associação Genômica Ampla , Encéfalo , Inteligência/genética , Polimorfismo de Nucleotídeo ÚnicoRESUMO
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.
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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.
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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.
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COVID-19 , Hipertensão , Humanos , COVID-19/complicações , COVID-19/genética , Estudo de Associação Genômica Ampla , Hipertensão/complicações , Hipertensão/genética , Razão de Chances , Polimorfismo de Nucleotídeo ÚnicoRESUMO
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.
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COVID-19 , Esclerose Múltipla , Humanos , COVID-19/complicações , COVID-19/epidemiologia , COVID-19/genética , Proteína 1 Associada a ECH Semelhante a Kelch , Estudo de Associação Genômica Ampla , Esclerose Múltipla/complicações , Esclerose Múltipla/genética , SARS-CoV-2/genética , Fator 2 Relacionado a NF-E2 , Polimorfismo de Nucleotídeo ÚnicoRESUMO
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.
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Doença de Alzheimer , COVID-19 , Humanos , COVID-19/genética , SARS-CoV-2/genética , Doença de Alzheimer/epidemiologia , Doença de Alzheimer/genética , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo ÚnicoRESUMO
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.