| Population name | David |
| Genome | GRCh38 |
| Consortium | Genetics Of Mortality In Critical Care (GenOMICC) and the International Severe Acute Respiratory Infection Consortium (ISARIC) Coronavirus Clinical Characterisation Consortium (4C) (ISARIC 4C) |
| Super population | EUR |
| Population description | Cohort participants were critically ill, hospitalized COVID-19 positive patients from 208 UK ICUs: 2109, patients were recruited as part of the GenOMICC project, and an additional 135 cases as part of ISARIC 4C study. Participants of mixed-ancestry were excluded. Ancestry-matched controls without a positive COVID-19 test were obtained from the UK BioBank population study and validation, 45,875 unrelated individuals of European ancestry from the 100,000 Genomes Project were used as an alternative |
| Population origin | United Kingdom |
| Case population size | 2244 |
| Control population size | 11220 |
| Comorbidities | 19% in GenOMICC and 30% in ISARIC |
| Mean / median age | 57.3 +- 12.1 in GenOMICC, 57.3 +- 2.9 in ISARIC |
| Sex | 30% female GenOMICC, 34% female ISARIC |
| Severity | Critical |
| Sample source | Nasopharyngeal swab |
| Method | DNA extraction, genotyping and quality control was previously described in Pairo-Castineira et al 2020 as part of the GenOMICC consortium.TMPRSS2 variants that are predicted to be loss of function, missense or inframe and indel in the database of population genetic variations GnomAD were extracted and evaluated. The rs12329760 is predicted damaging with a MAF of 0.25 in the human population and the relation between the variant and the critical COVID-19 cohort was assessed. The association was re |
| Bioinformatics | The association between the TMPRSS2 rs12329760 variant and COVID-19 severity was assessed using logistic regression. Logistic regression with additive and recessive models was performed in PLINKv1.9, adjusting for sex, age, mean-centred age-squared, top 10 principal components (PCA performed to adjust for population stratification) and deprivation index decile based on UK postcode. Genetic ancestry was inferred using ADMIXTURE and reference individuals from the 1000 Genomes project. Each major ancestry group alternative in the 100,000 Genomes control group was performed with mixed model association tests in SAIGE (v0.39), including age, sex, age-squared, age-sex interaction and the first 20 principal components as covariates. Trans-ethnic metaanalysis of GenOMICC data for different ancestries was performed by METAL using an inverse-variance weighted method and the P-value for heterogeneity was calculated with Cochran’s Q-test for heterogeneity implemented in the same software. Meta-an |
| Imputation details | Imputation was performed using the TOPMed reference panel |
| Limitations | a. The lack of access to a cohort of asymptomatic/pauci symptomatic COVID-19 patients, meant for comparison the general population was used to compare to COVID-19 severe cases. |