Project description:The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-191,2, host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases3-7. They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.
Project description:Genetic variants that are associated with common human diseases do not lead directly to disease, but instead act on intermediate, molecular phenotypes that in turn induce changes in higher-order disease traits. Therefore, identifying the molecular phenotypes that vary in response to changes in DNA and that also associate with changes in disease traits has the potential to provide the functional information required to not only identify and validate the susceptibility genes that are directly affected by changes in DNA, but also to understand the molecular networks in which such genes operate and how changes in these networks lead to changes in disease traits. Toward that end, we profiled more than 39,000 transcripts and we genotyped 782,476 unique single nucleotide polymorphisms (SNPs) in more than 400 human liver samples to characterize the genetic architecture of gene expression in the human liver, a metabolically active tissue that is important in a number of common human diseases, including obesity, diabetes, and atherosclerosis. This genome-wide association study of gene expression resulted in the detection of more than 6,000 associations between SNP genotypes and liver gene expression traits, where many of the corresponding genes identified have already been implicated in a number of human diseases. The utility of these data for elucidating the causes of common human diseases is demonstrated by integrating them with genotypic and expression data from other human and mouse populations. This provides much-needed functional support for the candidate susceptibility genes being identified at a growing number of genetic loci that have been identified as key drivers of disease from genome-wide association studies of disease. By using an integrative genomics approach, we highlight how the gene RPS26 and not ERBB3 is supported by our data as the most likely susceptibility gene for a novel type 1 diabetes locus recently identified in a large-scale, genome-wide association study. We also identify SORT1 and CELSR2 as candidate susceptibility genes for a locus recently associated with coronary artery disease and plasma low-density lipoprotein cholesterol levels in the process.
Project description:The severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) and the сoronavirus disease 2019 (COVID-19) have become a global health threat. At the height of the pandemic, major efforts were focused on reducing COVID-19-associated morbidity and mortality. Now is the time to study the long-term effects of the pandemic, particularly cognitive impairment associated with long COVID. In recent years much attention has been paid to the possible relationship between COVID-19 and Alzheimer's disease, which is considered a main cause of age-related cognitive impairment. Genetic predisposition was shown for both COVID-19 and Alzheimer's disease. However, the analysis of the similarity of the genetic architecture of these diseases is usually limited to indicating a positive genetic correlation between them. In this review, we have described intrinsic linkages between COVID-19 and Alzheimer's disease, pointed out shared susceptibility genes that were previously identified in genome-wide association studies of both COVID-19 and Alzheimer's disease, and highlighted a panel of SNPs that includes candidate genetic risk markers of the long COVID-associated cognitive impairment.
Project description:BackgroundThe coronavirus disease 2019 (COVID-19) has resulted in an unprecedented research response, demonstrating exceptional examples of rapid research and collaboration. There has however been an ongoing need for greater coordination, with limited resources for research and the shifting global pandemic.MethodsThe UK Collaborative on Development Research (UKCDR) and Global Research Collaboration for Infectious Disease Preparedness (GloPID-R), two funder coordination groups have collaborated to develop a live database of funded research projects across the world relating to COVID-19. Drawing data continually from their members and further global funding bodies, as of 15th October 2022 the database contains 20,006 projects, funded by 351 funders, taking place across 157 countries representing an investment of at least $7.4 billion. To our knowledge it is one of the most comprehensive databases. The database is aligned to the World Health Organisation and GloPID-R Global Research Roadmap: 2019 Novel Coronavirus and the UN Research Roadmap for the COVID-19 Recovery. It is being used by the WHO, governments and further policy makers, research funders and researchers. This living mapping review aims to supplement the database by providing an open, accessible, and frequently updated resource summarising the characteristics of the COVID-19 funded research portfolio. Both descriptive and thematic analyses are presented and updated frequently to aid interpretation of the global COVID-19 funded research portfolio.ResultsIn this final version ten analysis, we provide an updated detailed descriptive analysis of the database (on data from three months after version nine) and focus our thematic analysis on research gaps, research areas in need of coordination, study populations, and research locations (with a focus on resource-limited countries).ConclusionsAs the global research response to COVID-19 plateaus, this living mapping review has helped both funders and researchers to prioritise resources and review investments.
Project description:At the end of December 2019 many cases of severe pulmonary inflammation were reported in Hubei Province, China. Nearly all of the affected individuals had had contact to the wet fish market, which was believed to be the source of the novel infection and was closed on 1 January 2020. Subsequently, the Chinese health authorities confirmed that the pathogen was a previously unknown severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which belongs to the Coronaviridae family. The disease was then designated as coronavirus disease 2019 (COVID-19) and rapidly spread initially in Asia and later worldwide. In March 2020 the COVID-19 outbreak was declared a global pandemic by the World Health Organization. At the time of manuscript submission, more than 20 million people were affected by COVID-19, with more than 500,000 deaths worldwide. The article gives a general overview on the novel COVID-19 with a specific clinical focus on vascular involvement. The article is essentially based on the currently available evidence and the experiences of the authors.
Project description:To uncover the genetic determinants affecting expression in a metabolically active tissue relevant to the study of obesity, diabetes, atherosclerosis, and other common human diseases, we profiled 427 human liver samples on a comprehensive gene expression microarray targeting greater than 40,000 transcripts and genotyped DNA from each of these samples at greater than 1,000,000 SNPs. The relatively large sample size of this study and the large number of SNPs genotyped provided the means to assess the relationship between genetic variants and gene expression and it provided this look for the first time in a non-blood derived, metabolically active tissue. A comprehensive analysis of the liver gene expression traits revealed that thousands of these traits are under the control of well defined genetic loci, with many of the genes having already been implicated in a number of human diseases. Clincal data was requested, but not provided by submitter. Keywords: eQTL Liver samples (1-2 g) were acquired from Caucasian individuals from three independent liver collections at tissue resource centers at Vanderbilt University, University of Pittsburg, and Merck Research Laboratories. All individuals were compared to a common pool created from equal portions of RNA from 191 (111 from Vanderbilt University and 80 from University of Pittsburg) samples.