Aquaporin 3 modulates the risk of death conferred by dehydration in COVID-19 (preprint)

Severe COVID-19 has been associated with dehydration. Recently, a genetic variant near the aquaporin 3 (AQP3) water channel was associated with severe COVID-19 (rs60840586:G, Odds Ratio: 1.07, P=2.5*10-9). We show that dehydration is associated COVID-19 mortality (OR = 2.06 [95% CI = 1.62-2.65], P = 9.13*10-9), and is modulated by interaction with rs60840586:G genotype (OR = 1.95 [95% CI = 1.22-3.28], P = 0.0075).

Proteome-wide Mendelian randomization implicates nephronectin as an actionable mediator of the effect of obesity on COVID-19 severity (preprint)

Obesity is a major risk factor for COVID-19 severity; however, the underlying mechanism is not fully understood. Considering that obesity influences the human plasma proteome, we sought to identify circulating proteins mediating the effects of obesity on COVID-19 severity. We first screened 4,907 plasma proteins to identify proteins influenced by body mass index (BMI) using Mendelian randomization (MR). This yielded 1,216 proteins, whose effects on COVID-19 severity were assessed, again using MR. This two-step approach identified nephronectin (NPNT), for which a one standard deviation increase was associated with severe COVID-19 (odds ratio = 1.71, 95% CI: 1.45-2.02, P = 1.63 x 10-10). Colocalization analyses indicated that an NPNT splice isoform drove this effect. Overall, NPNT mediates 3.7% of the total effect of BMI on severe COVID-19. Finally, we found that decreasing body fat mass and increasing fat-free mass can lower NPNT levels and thus may improve COVID-19 outcomes. These findings provide actionable insights into how obesity influences COVID-19 severity.

Exome-wide association study to identify rare variants influencing COVID-19 outcomes: Results from the Host Genetics Initiative (preprint)

Host genetics is a key determinant of COVID-19 outcomes. Previously, the COVID-19 Host Genetics Initiative genome-wide association study used common variants to identify multiple loci associated with COVID-19 outcomes. However, variants with the largest impact on COVID-19 outcomes are expected to be rare in the population. Hence, studying rare variants may provide additional insights into disease susceptibility and pathogenesis, thereby informing therapeutics development. Here, we combined whole-exome and whole-genome sequencing from 21 cohorts across 12 countries and performed rare variant exome-wide burden analyses for COVID-19 outcomes. In an analysis of 5,048 severe disease cases and 571,009 controls, we observed that carrying a rare deleterious variant in the SARS-CoV-2 sensor toll-like receptor TLR7 (on chromosome X) was associated with a 5.3-fold increase in severe disease (95% CI: 2.75-10.05, p=5.41x10-7). These results further support TLR7 as a genetic determinant of severe disease and suggest that larger studies on rare variants influencing COVID-19 outcomes could provide additional insights.

Circulating proteins to predict adverse COVID-19 outcomes (preprint)

Predicting COVID-19 severity is difficult, and the biological pathways involved are not fully understood. To approach this problem, we measured 4,701 circulating human protein abundances in two independent cohorts totaling 986 individuals. We then trained prediction models including protein abundances and clinical risk factors to predict adverse COVID-19 outcomes in 417 subjects and tested these models in a separate cohort of 569 individuals. For severe COVID-19, a baseline model including age and sex provided an area under the receiver operator curve (AUC) of 65% in the test cohort. Selecting 92 proteins from the 4,701 unique protein abundances improved the AUC to 88% in the training cohort, which remained relatively stable in the testing cohort at 86%, suggesting good generalizability. Proteins selected from different adverse COVID-19 outcomes were enriched for cytokine and cytokine receptors, but more than half of the enriched pathways were not immune-related. Taken together, these findings suggest that circulating proteins measured at early stages of disease progression are reasonably accurate predictors of adverse COVID-19 outcomes. Further research is needed to understand how to incorporate protein measurement into clinical care.

Failure to replicate the association of rare loss-of-function variants in type I IFN immunity genes with severe COVID-19 (preprint)

A recent report found that rare predicted loss-of-function (pLOF) variants across 13 candidate genes in TLR3- and IRF7-dependent type I IFN pathways explain up to 3.5% of severe COVID-19 cases. We performed whole-exome or whole-genome sequencing of 1,934 COVID-19 cases (713 with severe and 1,221 with mild disease) and 15,251 ancestry-matched population controls across four independent COVID-19 biobanks. We then tested if rare pLOF variants in these 13 genes were associated with severe COVID-19. We identified only one rare pLOF mutation across these genes amongst 713 cases with severe COVID-19 and observed no enrichment of pLOFs in severe cases compared to population controls or mild COVID-19 cases. We find no evidence of association of rare loss-of-function variants in the proposed 13 candidate genes with severe COVID-19 outcomes.

Circulating Proteins Influencing COVID-19 Susceptibility and Severity: a Mendelian Randomization Study (preprint)

Proteins detectable in peripheral blood may influence COVID-19 susceptibility or severity. However, understanding which circulating proteins are etiologically involved is difficult because their levels may be influenced by COVID-19 itself and also subject to confounding factors. To identify circulating proteins influencing COVID-19 susceptibility and severity we undertook a large-scale two-sample Mendelian randomization (MR) study, since this study design can rapidly scan hundreds of circulating proteins and reduces bias due to confounding and reverse causation. We began by identifying the genetic determinants of 955 circulating proteins in up to 10,708 SARS-CoV-2 uninfected individuals, retaining only single nucleotide polymorphisms near the gene encoded by the circulating protein. We then undertook an MR study to estimate the effect of these proteins on COVID-19 susceptibility and severity using the Host Genetics Initiative. We found that a standard deviation increase in OAS1 levels was associated with reduced COVID-19 death or ventilation (N = 2,972 cases / 284,472 controls; OR = 0.48, P = 7x10-8), COVID-19 hospitalization (N = 6,492 / 1,012,809; OR = 0.60, P = 2x10-7) and COVID-19 susceptibility (N = 17,607 / 1,345,334; OR = 0.81, P = 6x10-5). Results were consistent despite multiple sensitivity analyses probing MR assumptions. OAS1 is an interferon-stimulated gene that promotes viral RNA degradation. Other potentially implicated proteins included IL10RB. Available medicines, such as interferon-beta-1b, increase OAS1 and could be explored for their effect on COVID-19 susceptibility and severity.

Vitamin D and Covid-19 Susceptibility and Severity: a Mendelian Randomization Study (preprint)

Introduction Increased vitamin D levels, as reflected by 25OHD measurements, has been proposed to protect against Covid-19 disease based on in-vitro, observational, and ecological studies. However, vitamin D levels are associated with many confounding variables and thus associations described to date may not be causal. Vitamin D MR studies have provided results that are concordant with large-scale vitamin D randomized trials. Here, we used two-sample MR to assess the effect of circulating 25OHD levels on Covid-19 susceptibility. Methods Genetic variants strongly associated with 25OHD levels in a 443,734-participant genome-wide association study (GWAS) were used as instrumental variables. GWASs of Covid-19 susceptibility and severity from the Covid-19 Host Genetics Initiative were used to test the effect of 25OHD levels on these outcomes. Cohorts from the Covid-19 Host Genetics Initiative GWAS included up to 966,395 individuals of European ancestry. Results Genetically increased 25OHD levels by one standard deviation on the logarithmic scale had no clear effect on susceptibility but tended to increase the odds ratio of hospitalization (OR = 2.34; 95% CI: 1.33, 4.11) and severe disease (OR = 2.21; 95% CI: 0.87, 5.55). Extensive sensitivity analyses probing the assumptions of MR provided consistent estimates. Conclusion These findings do not support a protective role of increased 25OHD levels on Covid-19 outcomes and may suggest harm. At present, individuals should not use vitamin D supplements to protect against Covid-19 outcomes, and on-going supplementation trials should closely monitor for signals of harm.