Nature

Pulmonary inflammation drives critical illness in Covid-19, 1;2 creating a clinically homogeneous extreme phenotype, which we have previously shown to be highly efficient for discovery of genetic associations. 3;4 Despite the advanced stage of illness, we have found that immunomodulatory therapies have strong beneficial effects in this group. 1;5 Further genetic discoveries may identify additional therapeutic targets to modulate severe disease. 6 In this new data release from the GenOMICC (Genet...

Severe COVID-19 is characterised by immunopathology and epithelial injury. Proteomic studies have identified circulating proteins that are biomarkers of severe COVID-19, but cannot distinguish correlation from causation. To address this, we performed Mendelian randomisation (MR) to identify proteins that mediate severe COVID-19. Using protein quantitative trait loci (pQTL) data from the SCALLOP consortium, involving meta-analysis of up to 26,494 individuals, and COVID-19 genome-wide association ...

Critical illness in COVID-19 is caused by inflammatory lung injury, mediated by the host immune system. We and others have shown that host genetic variation influences the development of illness requiring critical care1 or hospitalisation2;3;4 following SARS-Co-V2 infection. The GenOMICC (Genetics of Mortality in Critical Care) study recruits critically-ill cases and compares their genomes with population controls in order to find underlying disease mechanisms. Here, we use whole genome sequenc...

Analysis of host genetic components provides insights into the susceptibility and response to viral infection such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19). To reveal genetic determinants of susceptibility to COVID-19 related mortality, we train a deep learning model to identify groups of genetic variants and their interactions that contribute to the COVID-19 related mortality risk using the UK Biobank data. We refer to suc...

In susceptible patients, COVID-19 causes life-threatening disease driven by immune-mediated inflammatory lung injury. We have previously shown that multiple common host genetic variants are significantly associated with susceptibility to critical Covid-19, 1;2;3 and in one case, we demonstrated that such variants can inform development of new, effective drug treatment1;4. Here we report an association analysis of whole-genome sequences (WGS) from 11,423 cases from the GenOMICC study and 60,628 c...

The proteome is fundamental to human biology and health but little is known about ancestral diversity of its genetic determinants. In GWAS of plasma levels of 2,923 proteins in 3,974 Chinese adults, we identified pQTLs for 1,784 proteins, including 1,312 cis-pQTLs for 1,264 proteins. Fine-mapping identified 3,475 credible sets for independent pQTLs, 36% of which were distinct from those identified in European adults as assessed by three different methods. In phenome-wide MR analyses, 59 disease ...

BACKGROUNDEpidemiological studies indicate that as many as 20% of individuals who test positive for COVID-19 develop severe symptoms that can require hospitalization. These symptoms include low platelet count, severe hypoxia, increased inflammatory cytokines and reduced glomerular filtration rate. Additionally, severe COVID-19 is associated with several chronic co-morbidities, including cardiovascular disease, hypertension and type 2 diabetes mellitus. The identification of genetic risk factors...

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes coronavirus disease-19 (COVID-19), a respiratory illness that can result in hospitalization or death. We investigated associations between rare genetic variants and seven COVID-19 outcomes in 543,213 individuals, including 8,248 with COVID-19. After accounting for multiple testing, we did not identify any clear associations with rare variants either exome-wide or when specifically focusing on (i) 14 interferon pathway genes in w...

BackgroundRespiratory failure is a key feature of severe Covid-19 and a critical driver of mortality, but for reasons poorly defined affects less than 10% of SARS-CoV-2 infected patients. MethodsWe included 1,980 patients with Covid-19 respiratory failure at seven centers in the Italian and Spanish epicenters of the SARS-CoV-2 pandemic in Europe (Milan, Monza, Madrid, San Sebastian and Barcelona) for a genome-wide association analysis. After quality control and exclusion of population outliers,...

Here we report results from the Bipolar Exome (BipEx) collaboration analysis of whole exome sequencing of 13,933 individuals diagnosed with bipolar disorder (BD), matched with 14,422 controls. We find an excess of ultra-rare protein-truncating variants (PTVs) in BD patients among genes under strong evolutionary constraint, a signal evident in both major BD subtypes, bipolar 1 disorder (BD1) and bipolar 2 disorder (BD2). We also find an excess of ultra-rare PTVs within genes implicated from a rec...

The subset of patients who develop critical illness in Covid-19 have extensive inflammation affecting the lungs1 and are strikingly different from other patients: immunosuppressive therapy benefits critically-ill patients, but may harm some non-critical cases.2 Since susceptibility to life-threatening infections and immune-mediated diseases are both strongly heritable traits, we reasoned that host genetic variation may identify mechanistic targets for therapeutic development in Covid-19.3 GenOM...

BackgroundDespite recent development of vaccines and monoclonal antibodies to prevent SARS-CoV-2 infection, treatment of critically ill COVID-19 patients remains an important goal. In principle, genome-wide association studies (GWAS) could shortcut the clinical evidence needed to repurpose drugs - the use of an existing drug for a new indication. However, it has been shown that the genes found in GWA studies usually do not encode an established drug target and the causal role for disease, a key ...

We present here genetic risk factors for survivability from infection by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) responsible for coronavirus disease 19 (COVID-19). At the time of writing it is too early to determine comprehensively and without doubt all risk factors, but there is an urgency due to the global pandemic crisis that merits this early analysis. We have nonetheless discovered 5 novel risk variants in 4 genes, discovered by examining 193 deaths from 1,412 confi...

BackgroundThe advent of genetic biobanking has powered gene-environment interaction (GxE) studies in various disease contexts. Therefore, we aimed to discover novel GxE effects that address hot spring residency as a risk to inconspicuous disease association. MethodsA complete genetic and demographic registry comprising 129,451 individuals was obtained from Taiwan Biobank (TWB). Geographical disease prevalence was analyzed to identify putative disease association with hot-spring residency, multi...

The cost of acquiring participants for genome-wide association studies (GWAS) can limit sample sizes and inhibit discovery of genetic variants. We introduce the surrogate functional false discovery rate (sfFDR) framework which integrates summary statistics of related traits to increase power. The sfFDR framework provides estimates of FDR quantities such as the functional local FDR and q-value, and uses these estimates to derive a functional p-value for type I error rate control and a functional ...

Host genetic susceptibility is a key risk factor for severe illness associated with COVID-19. Despite numerous studies of COVID-19 host genetics, our knowledge of COVID-19-associated variants is still limited, and there is no resource comprising all the published variants and categorizing them based on their confidence level. Also, there are currently no computational tools available to predict novel COVID-19 severity variants. Therefore, we collated 820 host genetic variants reported to affect ...

The role of the circadian clock is becoming apparent in many aspects of human health and disease. Large scale GWAS studies have delivered high numbers of genetic markers for chronotype, which can be used to find links to Mendelian disorders. We used the variants in the 1,000 genomes study to estimate linkage disequilibrium for these chronotype markers. We analysed genes in high linkage disequilibrium with the chronotype markers for enrichment of disease-causing genes, and looked for enrichment o...

Studies of genetic factors associated with severe COVID-19 in young adults have been limited in non-Caucasian populations. Here, we use whole exome sequencing to characterize the genetic landscape of severe COVID-19 in a well phenotyped cohort of otherwise healthy, young adults (N=55; mean age 34.1 {+/-} SD 5.0 years) representing 16 countries in Asia, the Middle East, and North Africa. Our findings show enrichment of rare, likely deleterious missense and truncating variants in interferon-mediat...

It is plausible that variants in the ACE2 and TMPRSS2 genes might contribute to variation in COVID-19 severity and that these could explain why some people become very unwell whereas most do not. Exome sequence data was obtained for 49,953 UK Biobank subjects of whom 74 had tested positive for SARS-CoV-2 and could be presumed to have severe disease. A weighted burden analysis was carried out using SCOREASSOC to determine whether there were differences between these cases and the other sequenced ...

One in ten SARS-CoV-2 infections result in prolonged symptoms termed long COVID, yet disease phenotypes and mechanisms are poorly understood. We studied the blood proteome of 719 adults, grouped by long COVID symptoms. Elevated markers of monocytic inflammation and complement activation were associated with increased likelihood of all symptoms. Elevated IL1R2, MATN2 and COLEC12 associated with cardiorespiratory symptoms, fatigue, and anxiety/depression, while elevated MATN2 and DPP10 associated...