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

Publisher Copyright: Copyright: © 2022 Butler-Laporte et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.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 5,085 severe disease cases and 571,737 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). This association was consistent across sexes. 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.Peer reviewe

Gene Variants Related to Cardiovascular and Pulmonary Diseases May Correlate with Severe Outcome of COVID-19

Background: Severe outcomes of COVID-19 account for up to 15% of all cases. The study aims to check if any gene variants related to cardiovascular (CVD) and pulmonary diseases (PD) are correlated with a severe outcome of COVID-19 in a Polish cohort of COVID-19 patients. Methods: In this study, a subset of 747 samples from unrelated individuals collected across Poland in 2020 and 2021 was used and whole-genome sequencing was performed. Results: The GWAS analysis of SNPs and short indels located in genes related to CVD identified one variant significant in COVID-19 severe outcome in the HADHA gene, while for the PD gene panel, we found two significant variants in the DRC1 gene. In this study, both potentially protective and risk variants were identified, of which variants in the HADHA gene deserve the most attention. Conclusions: This is the first study reporting the association between the HADHA and DRC1 genetic variants and COVID-19 severe outcome based on the cohort WGS analysis. Although all the identified variants are localised in introns, they may be correlated and therefore inherited along with other risk variants, potentially causative to severe outcome of COVID-19 but not discovered yet

A Study of 41 Canine Orthologues of Human Genes Involved in Monogenic Obesity Reveals Marker in the <i>ADCY3</i> for Body Weight in Labrador Retrievers

Obesity and overweight are common conditions in dogs, but individual susceptibility varies with numerous risk factors, including diet, age, sterilization, and gender. In addition to environmental and biological factors, genetic and epigenetic risk factors can influence predisposition to canine obesity, however, they remain unknown. Labrador Retrievers are one of the breeds that are prone to obesity. The purpose of this study was to analyse 41 canine orthologues of human genes linked to monogenic obesity in humans to identify genes associated with body weight in Labrador Retriever dogs. We analysed 11,520 variants from 50 dogs using a linear mixed model with sex, age, and sterilization as covariates and population structure as a random effect. Estimates obtained from the model were subjected to a maxT permutation procedure to adjust p-values for FWER ADCY3 gene showed statistically significant association: TA>T deletion located at 17:19,222,459 in 1/20 intron (per allele effect of 5.56 kg, SE 0.018, p-value = 5.83 × 10−5, TA/TA: 11 dogs; TA/T: 32 dogs; T/T: 7 dogs). Mutations in the ADCY3 gene have already been associated with obesity in mice and humans, making it a promising marker for canine obesity research. Our results provide further evidence that the genetic makeup of obesity in Labrador Retriever dogs contains genes with large effect sizes

Genetic Variability of Methane Production and Concentration Measured in the Breath of Polish Holstein-Friesian Cattle

The genetic architecture of methane (CH4) production remains largely unknown. We aimed to estimate its heritability and to perform genome-wide association studies (GWAS) for the identification of candidate genes associated with two phenotypes: CH4 in parts per million/day (CH4 ppm/d) and CH4 in grams/day (CH4 g/d). We studied 483 Polish Holstein-Friesian cows kept on two commercial farms in Poland. Measurements of CH4 and carbon dioxide (CO2) concentrations exhaled by cows during milking were obtained using gas analyzers installed in the automated milking system on the farms. Genomic analyses were performed using a single-step BLUP approach. The percentage of genetic variance explained by SNPs was calculated for each SNP separately and then for the windows of neighbouring SNPs. The heritability of CH4 ppm/d ranged from 0 to 0.14, with an average of 0.085. The heritability of CH4 g/d ranged from 0.13 to 0.26, with an average of 0.22. The GWAS detected potential candidate SNPs on BTA 14 which explained ~0.9% of genetic variance for CH4 ppm/d and ~1% of genetic variance for CH4 g/d. All identified SNPs were located in the TRPS1 gene. We showed that methane traits are partially controlled by genes; however, the detected SNPs explained only a small part of genetic variation—implying that both CH4 ppm/d and CH4 g/d are highly polygenic traits

Beyond GWAS—Could Genetic Differentiation within the Allograft Rejection Pathway Shape Natural Immunity to COVID-19?

COVID-19 infections pose a serious global health concern so it is crucial to identify the biomarkers for the susceptibility to and resistance against this disease that could help in a rapid risk assessment and reliable decisions being made on patients’ treatment and their potential hospitalisation. Several studies investigated the factors associated with severe COVID-19 outcomes that can be either environmental, population based, or genetic. It was demonstrated that the genetics of the host plays an important role in the various immune responses and, therefore, there are different clinical presentations of COVID-19 infection. In this study, we aimed to use variant descriptive statistics from GWAS (Genome-Wide Association Study) and variant genomic annotations to identify metabolic pathways that are associated with a severe COVID-19 infection as well as pathways related to resistance to COVID-19. For this purpose, we applied a custom-designed mixed linear model implemented into custom-written software. Our analysis of more than 12.5 million SNPs did not indicate any pathway that was significant for a severe COVID-19 infection. However, the Allograft rejection pathway (hsa05330) was significant (p = 0.01087) for resistance to the infection. The majority of the 27 SNP marking genes constituting the Allograft rejection pathway were located on chromosome 6 (19 SNPs) and the remainder were mapped to chromosomes 2, 3, 10, 12, 20, and X. This pathway comprises several immune system components crucial for the self versus non-self recognition, but also the components of antiviral immunity. Our study demonstrated that not only single variants are important for resistance to COVID-19, but also the cumulative impact of several SNPs within the same pathway matters

Better safe than sorry-Whole-genome sequencing indicates that missense variants are significant in susceptibility to COVID-19.

Undoubtedly, genetic factors play an important role in susceptibility and resistance to COVID-19. In this study, we conducted the GWAS analysis. Out of 15,489,173 SNPs, we identified 18,191 significant SNPs for severe and 11,799 SNPs for resistant phenotype, showing that a great number of loci were significant in different COVID-19 representations. The majority of variants were synonymous (60.56% for severe, 58.46% for resistant phenotype) or located in introns (55.77% for severe, 59.83% for resistant phenotype). We identified the most significant SNPs for a severe outcome (in AJAP1 intron) and for COVID resistance (in FIG4 intron). We found no missense variants with a potential causal function on resistance to COVID-19; however, two missense variants were determined as significant a severe phenotype (in PM20D1 and LRP4 exons). None of the aforementioned SNPs and missense variants found in this study have been previously associated with COVID-19

Fig 4 -

Genomic regions that correspond to the location of two missense SNPs with a potential causal function on a severe outcome of COVID–19, with green dots representing the missense SNPs in severe (A) and resistant (B) phenotypes.</p

Gene Variants Related to Cardiovascular and Pulmonary Diseases May Correlate with Severe Outcome of COVID-19

Background: Severe outcomes of COVID-19 account for up to 15% of all cases. The study aims to check if any gene variants related to cardiovascular (CVD) and pulmonary diseases (PD) are correlated with a severe outcome of COVID-19 in a Polish cohort of COVID-19 patients. Methods: In this study, a subset of 747 samples from unrelated individuals collected across Poland in 2020 and 2021 was used and whole-genome sequencing was performed. Results: The GWAS analysis of SNPs and short indels located in genes related to CVD identified one variant significant in COVID-19 severe outcome in the HADHA gene, while for the PD gene panel, we found two significant variants in the DRC1 gene. In this study, both potentially protective and risk variants were identified, of which variants in the HADHA gene deserve the most attention. Conclusions: This is the first study reporting the association between the HADHA and DRC1 genetic variants and COVID-19 severe outcome based on the cohort WGS analysis. Although all the identified variants are localised in introns, they may be correlated and therefore inherited along with other risk variants, potentially causative to severe outcome of COVID-19 but not discovered yet