Genome-wide Association Study of Long COVID (preprint)

Infections can lead to persistent or long-term symptoms and diseases such as shingles after varicella zoster, cancers after human papillomavirus, or rheumatic fever after streptococcal infections(1,2). Similarly, infection by SARS-CoV-2 can result in Long COVID, a condition characterized by symptoms of fatigue and pulmonary and cognitive dysfunction(3-5). The biological mechanisms that contribute to the development of Long COVID remain to be clarified. We leveraged the COVID-19 Host Genetics Initiative(6,7) to perform a genome-wide association study for Long COVID including up to 6,450 Long COVID cases and 1,093,995 population controls from 24 studies across 16 countries. We identified the first genome-wide significant association for Long COVID at the FOXP4 locus. FOXP4 has been previously associated with COVID-19 severity(6), lung function(8), and cancers(9), suggesting a broader role for lung function in the pathophysiology of Long COVID. While we identify COVID-19 severity as a causal risk factor for Long COVID, the impact of the genetic risk factor located in the FOXP4 locus could not be solely explained by its association to severe COVID-19. Our findings further support the role of pulmonary dysfunction and COVID-19 severity in the development of Long COVID.

Health, socioeconomic and genetic predictors of COVID-19 vaccination uptake: a nationwide machine-learning study (preprint)

Reduced participation in COVID-19 vaccination programs is a key societal concern. Understanding factors associated with vaccination uptake can help in planning effective immunization programs. We considered 2,890 health, socioeconomic, familial, and demographic factors measured on the entire Finnish population aged 30 to 80 (N=3,192,505) and genome-wide information for a subset of 273,765 individuals. Risk factors were further classified into 12 thematic categories and a machine learning model was trained for each category. The main outcome was uptaking the first COVID-19 vaccination dose by 31.10.2021, which has occurred for 90.3% of the individuals. The strongest predictor category was labor income in 2019 (AUC evaluated in a separate test set = 0.710, 95% CI: 0.708-0.712), while drug purchase history, including 376 drug classes, achieved a similar prediction performance (AUC = 0.706, 95% CI: 0.704-0.708). Higher relative risks of being unvaccinated were observed for some mental health diagnoses (e.g. dissocial personality disorder, OR=1.26, 95% CI : 1.24-1.27 ) and when considering vaccination status of first-degree relatives (OR=1.31, 95% CI:1.31-1.32 for unvaccinated mothers) We derived a prediction model for vaccination uptake by combining all the predictors and achieved good discrimination (AUC = 0.801, 95% CI: 0.799-0.803). The 1% of individuals with the highest risk of not vaccinating according to the model predictions had an average observed vaccination rate of only 18.8%. We identified 8 genetic loci associated with vaccination uptake and derived a polygenic score, which was a weak predictor of vaccination status in an independent subset (AUC=0.612, 95% CI: 0.601-0.623). Genetic effects were replicated in an additional 145,615 individuals from Estonia (genetic correlation=0.80, 95% CI: 0.66-0.95) and, similarly to data from Finland, correlated with mental health and propensity to participate in scientific studies. Individuals at higher genetic risk for severe COVID-19 were less likely to get vaccinated (OR=1.03, 95% CI: 1.02-1.05). Our results, while highlighting the importance of harmonized nationwide information, not limited to health, suggest that individuals at higher risk of suffering the worst consequences of COVID-19 are also those less likely to uptake COVID-19 vaccination. The results can support evidence-informed actions for COVID-19 and other areas of national immunization programs.

The public health impact of poor sleep on severe COVID-19, influenza and upper respiratory infections (preprint)

BackgroundPoor sleep is associated with an increased risk of infections and all-cause mortality, and acute sleep loss and disruption have been linked with inflammation and poorer immune control. Previous studies, however, have been unable to evidence causality between the chronic effects of poor sleep and respiratory infection risk. In light of the ongoing COVID-19 pandemic and potential future disease outbreaks, understanding the risk factors for these infections is of great importance. AimOur goal was to understand if chronic poor sleep could be identified as a causal risk factor for respiratory infections including influenza, upper respiratory infections and COVID-19. MethodsWe used population cohorts from the UK Biobank (N {approx} 231,000) and FinnGen (N {approx} 327,000) with ICD-10 based electronic health records and obtained diagnoses of insomnia, influenza and upper respiratory infections (URIs) from primary care and hospital settings. We computed logistic regression to assess association between poor sleep and infections, disease free survival hazard ratios, and used summary statistics from genome-wide association studies of insomnia, influenza, URI and COVID-19 to perform Mendelian randomization analyses and assess causality. FindingsUtilizing 23 years of registry data and follow-up, we saw that insomnia diagnosis associated with increased risk for infections in FinnGen and in UK Biobank (FinnGen influenza HR = 5.32 [4.09, 6.92], P = 1.02x10-35, UK Biobank influenza HR = 1.54 [1.37, 1.73], P = 2.49x10-13). Mendelian randomization indicated that insomnia causally predisposed to influenza (OR = 1.59, P = 6.23x10-4), upper respiratory infections (OR = 1.71, P = 7.60x10-13), COVID-19 infection (OR = 1.08, P = 0.037) and risk of hospitalization from COVID-19 (OR = 1.47, P = 4.96x10-5). ConclusionsOur findings indicate that chronic poor sleep is a causal risk factor for contracting respiratory infections, and in addition contributes to the severity of respiratory infections. These findings highlight the role of sleep in maintaining sufficient immune response against pathogens as suggested by earlier work. As the current COVID-19 pandemic has increased the number of people suffering from poor sleep, safe interventions such as sleep management and treating individuals with insomnia could be promoted to reduce infections and save lives.

Age-dependent impact of the major common genetic risk factor for COVID-19 on severity and mortality (preprint)

Background: There is considerable variability in COVID-19 outcomes amongst younger adults and some of this variation may be due to genetic predisposition. We characterized the clinical implications of the major genetic risk factor for COVID-19 severity, and its age-dependent effect, using individual-level data in a large international multi-centre consortium. Method: The major common COVID-19 genetic risk factor is a chromosome 3 locus, tagged by the marker rs10490770. We combined individual level data for 13,424 COVID-19 positive patients (N=6,689 hospitalized) from 17 cohorts in nine countries to assess the association of this genetic marker with mortality, COVID-19-related complications and laboratory values. We next examined if the magnitude of these associations varied by age and were independent from known clinical COVID-19 risk factors. Findings: We found that rs10490770 risk allele carriers experienced an increased risk of all-cause mortality (hazard ratio [HR] 1.4, 95% confidence interval [CI] 1.2-1.6) and COVID-19 related mortality (HR 1.5, 95%CI 1.3-1.8). Risk allele carriers had increased odds of several COVID-19 complications: severe respiratory failure (odds ratio [OR] 2.0, 95%CI 1.6-2.6), venous thromboembolism (OR 1.7, 95%CI 1.2-2.4), and hepatic injury (OR 1.6, 95%CI 1.2-2.0). Risk allele carriers [≤] 60 years had higher odds of death or severe respiratory failure (OR 2.6, 95%CI 1.8-3.9) compared to those > 60 years OR 1.5 (95%CI 1.3-1.9, interaction p-value=0.04). Amongst individuals [≤] 60 years who died or experienced severe respiratory COVID-19 outcome, we found that 31.8% (95%CI 27.6-36.2) were risk variant carriers, compared to 13.9% (95%CI 12.6-15.2%) of those not experiencing these outcomes. Prediction of death or severe respiratory failure among those [≤] 60 years improved when including the risk allele (AUC 0.82 vs 0.84, p=0.016) and the prediction ability of rs10490770 risk allele was similar to, or better than, most established clinical risk factors. Interpretation: The major common COVID-19 risk locus on chromosome 3 is associated with increased risks of morbidity and mortality and these are more pronounced amongst individuals [≤] 60 years. The effect on COVID-19 severity was similar to, or larger than most established risk factors, suggesting potential implications for clinical risk management. Funding: Funding was obtained by each of the participating cohorts individually.