Abstract Background To summarize modifiable factors for coronavirus disease 2019 (COVID-19) suggested by Mendelian randomization studies. Methods In this systematic review, we searched PubMed, EMBASE and MEDLINE, from inception to 15 November 2021, for Mendelian randomization studies in English. We selected studies that assessed associations of genetically predicted exposures with COVID-19-related outcomes (severity, hospitalization and susceptibility). Risk of bias of the included studies was evaluated based on the consideration of the three main assumptions for instrumental variable analyses. Results We identified 700 studies through systematic search, of which 50 Mendelian randomization studies were included. Included studies have explored a wide range of socio-demographic factors, lifestyle attributes, anthropometrics and biomarkers, predisposition to diseases and druggable targets in COVID-19 risk. Mendelian randomization studies suggested that increases in smoking, obesity and inflammatory factors were associated with higher risk of COVID-19. Predisposition to ischaemic stroke, combined bipolar disorder and schizophrenia, attention-deficit and hyperactivity disorder, chronic kidney disease and idiopathic pulmonary fibrosis was potentially associated with higher COVID-19 risk. Druggable targets, such as higher protein expression of histo-blood group ABO system transferase (ABO), interleukin (IL)-6 and lower protein expression of 2′-5′ oligoadenylate synthetase 1 (OAS1) were associated with higher risk of COVID-19. There was no strong genetic evidence supporting the role of vitamin D, glycaemic traits and predisposition to cardiometabolic diseases in COVID-19 risk. Conclusion This review summarizes modifiable factors for intervention (e.g. smoking, obesity and inflammatory factors) and proteomic signatures (e.g. OAS1 and IL-6) that could help identify drugs for treating COVID-19.

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Identifying factors contributing to increased susceptibility to COVID-19 risk: a systematic review of Mendelian randomization studies

Previous studies reported associations between obesity measured by body mass index (BMI) and coronavirus disease 2019 (COVID-19). However, BMI is calculated only with height and weight and cannot distinguish between body fat mass and fat-free mass. Thus, it is not clear if one or both of these measures are mediating the relationship between obesity and COVID-19. Here, we used Mendelian randomization (MR) to compare the independent causal relationships of body fat mass and fat-free mass with COVID-19 severity. We identified single nucleotide polymorphisms associated with body fat mass and fat-free mass in 454,137 and 454,850 individuals of European ancestry from the UK Biobank, respectively. We then performed two-sample MR to ascertain their effects on severe COVID-19 (cases: 4,792; controls: 1,054,664) from the COVID-19 Host Genetics Initiative. We found that an increase in body fat mass by one standard deviation was associated with severe COVID-19 (odds ratio (OR)body fat mass = 1.61, 95% confidence interval [CI]: 1.28–2.04, P = 5.51 × 10-5; ORbody fat-free mass = 1.31, 95% CI: 0.99–1.74, P = 5.77 × 10-2). Considering that body fat mass and fat-free mass were genetically correlated with each other (r = 0.64), we further evaluated independent causal effects of body fat mass and fat-free mass using multivariable MR and revealed that only body fat mass was independently associated with severe COVID-19 (ORbody fat mass = 2.91, 95% CI: 1.71–4.96, P = 8.85 × 10-5 and ORbody fat-free mass = 1.02, 95%CI: 0.61–1.67, P = 0.945). In summary, this study demonstrates the causal effects of body fat accumulation on COVID-19 severity and indicates that the biological pathways influencing the relationship between COVID-19 and obesity are likely mediated through body fat mass.

/pdf/causal-associations-between-body-fat-accumulation-and-covid-2058hdnz.pdf

Causal associations between body fat accumulation and COVID-19 severity: A Mendelian randomization study

Background Obesity has been associated with more severe clinical manifestations of coronavirus disease 2019 (COVID-19). However, this association can be affected by many correlates of these traits. Due to its large impact on human health, socioeconomic status (SES) could at least partially influence the association between obesity and COVID-19 severity. To estimate the independent effect of traits related to body size and SES on the clinical manifestations of COVID-19, we conducted a Mendelian randomization (MR) study analyzing the effect of obesity-related anthropometric traits on COVID-19 outcomes. Methods Applying two-sample MR approaches, we evaluated the effects of body mass index (BMI), waist circumference (WC), hip circumference, (HIP) and waist-hip ratio (WHR) studied in up to 234,069 participants from the Genetic Investigation of ANthropometric Traits (GIANT) consortium with respect to three COVID-19 outcomes: severe respiratory COVID-19 (5,101 cases vs. 1,383,241 controls), hospitalized COVID-19 (9,986 cases vs. 1,877,672 controls), and COVID-19 infection (38,984 cases vs. 1,644,784 controls) obtained from the COVID-19 Host Genetics Initiative (HGI). Finally, to test the effect of SES using multivariable MR methods, we analyzed genetic data related to self-reported household income (HI) information from 286,301 UK Biobank (UKB) participants. Results BMI and WC were associated with severe respiratory COVID-19 (BMI: OR⍰=⍰1.68 p⍰=⍰0.0004; WC: OR⍰=⍰1.72, p⍰=⍰0.007) and COVID-19 hospitalization (BMI: OR=⍰1.62, p⍰=⍰1.35e-06; WC: OR⍰=⍰1.62, p⍰=⍰0.0001). Also, HIP influenced hospitalized COVID-19 (OR⍰=⍰1.31, p⍰=⍰0.012) and COVID-19 infection (OR⍰=⍰1.18, p⍰=⍰0.002). Conversely, HI was associated with lower odds of severe respiratory COVID-19 (OR⍰=⍰0.57, p⍰=⍰0.011) and hospitalized COVID-19 (OR⍰=⍰0.71, p⍰=⍰0.045). Testing these effects in multivariable MR models, we observed that the effect of these obesity-related anthropometric traits on COVID-19 outcomes is not independent of SES effect assessed as HI. Conclusions Our findings indicate that low SES is a contributor to the observed association between body size and COVID-19 outcomes.

https://medrxiv.org/content/10.1101/2021.06.08.21258587v1.full.pdf

The effect of obesity-related traits on COVID-19 severe respiratory symptoms is mediated by socioeconomic status: a multivariable Mendelian randomization study

Background Transthyretin (TTR) is a multi-function protein involved in the systemic transport of retinol and thyroxine. It also participates in the neuronal response to stress and proteolysis of few specific substrates. TTR is also the precursor of the fibrils that compromise organ function in the familial and sporadic systemic amyloidoses (ATTR). RNA-interference and anti-sense therapeutics targeting TTR hepatic transcription have been shown to reduce TTR amyloid formation. The goal of our study was to investigate the role of genetic regulation of TTR transcriptomic variation in human traits and diseases. Methods and Findings We leveraged genetic and phenotypic information from the UK Biobank and transcriptomic profiles from the GTEx (Genotype-Tissue Expression) project to test the association of genetically regulated TTR gene expression with 7,149 traits assessed in 420,531 individuals. We conducted a joint multi-tissue analysis of TTR transcription regulation and identified an association with a specific operational procedure related to secondary open reduction of fracture of bone (p=5.46×10−6, false discovery rate q=0.039). Using tissue-specific TTR cis expression quantitative trait loci, we demonstrated that the association is driven by the genetic regulation of TTR hepatic expression (odds ratio [OR] = 3.46, 95% confidence interval [CI] = 1.85-6.44, p = 9.51×10−5). Although there is an established relationship of retinol and thyroxine abnormalities with bone loss and the risk of bone fracture, this is the first evidence of a possible effect of TTR transcriptomic regulation. Investigating the UK Biobank electronic health records available, we investigated the comorbidities affecting individuals undergoing the specific surgical procedure. Excluding medical codes related to bone fracture events, we identified a pattern of health outcomes that have been previously associated with ATTR manifestations. These included osteoarthritis (OR=3.18, 95%CI=1.93-4.25, p=9.18×10−8), carpal tunnel syndrome (OR=2.15, 95%CI=1.33-3.48, p=0.002), and a history of gastrointestinal diseases (OR=2.01, 95%CI=1.33-3.01, p=8.07×10−4). Conclusions The present study supports the notion that TTR hepatic expression can affect health outcomes linked to physiological and pathological processes presumably related to the encoded protein. Our findings highlight how the integration of omics information and electronic health records can successfully dissect the complexity of multi-function proteins such as TTR.

https://medrxiv.org/content/10.1101/2021.07.14.21260525v1.full.pdf

The integration of genetically-regulated transcriptomics and electronic health records highlights a pattern of medical outcomes related to increased hepatic Transthyretin expression

Brenda Cabrera Mendoza

Papers

The effect of obesity-related traits on COVID-19 severe respiratory symptoms is mediated by socioeconomic status: a multivariable Mendelian randomization study

The integration of genetically-regulated transcriptomics and electronic health records highlights a pattern of medical outcomes related to increased hepatic Transthyretin expression