Projects

This page lists projects that are supported by the COVID19 Host Genetics Initiative but they are not part of the centralized efforts because they require specialized approaches or focus on specific patients groups.

As a reminder the centralized analyses are based on this analysis plan.

Clonal Hematopoiesis

The presence of pre-existing cardiovascular and lung disease are known to be associated with severe COVID-19. Beyond medical comorbidities, age is a strong independent predictor of COVID-19 severity and may be related to age-related changes in inflammatory cells. Clonal Hematopoiesis is known to alter the inflammatory profile of healthy individuals and may, in part, be a mediator of its ill-effects including cardiovascular disease. Age-related somatic mutations in circulating inflammatory cells have been shown to predispose to chronic inflammatory dysregulation. In some cases, these involve the same pathways implicated in COVID-19. However, whether CH predisposes to severe COVID-19 or affects the complications of COVID-19 is unknown. Conversely, inflammatory stress may be a critical driver of CH. Therefore, studying the acute effects of SARS-CoV-2 infection on the dynamics of CH would provide insight into the potentiators of CH. We seek to understand how clonal hematopoiesis might influence COVID-19 illness severity and conversely how acute infection with SARS-CoV-2 might promote expansion of CHIP.

Contact Persons:

Philip Awadalla, Pradeep Natarajan, Kelly Bolton.

Slack Channel:

#covid19-hg-clonalhematopoeisis

Chr3-clinical trajectories project

The strongest genetic signal for COVID19 severity is located on chromosome 3 and overlaps several genes. However, it is currently unknown 1) which is the likely causal gene and 2) if patients carrying the risk haplotype have different clinical trajectories than those that do not. In this project, we will focus on patients hospitalized for COVID19 and study the association between the chromosomes 3 signal and several longitudinal clinical measures. In particular, we will focus on longitudinal biomarkers, clinical complications/manifestations, and different subtypes of COVID19 patients. The analysis will benefit from combined individual-level data.

Contact Persons:

Brent Richards, Andrea Ganna, Luca Valenti, Alessandra Renieri, Eva Schulte, Hugo Zeberg, Luis Bujanda, Maria Butti, Manuel Romero Gomez, Migeotte Isabelle, Marta Alarcón, Alexandre Pereira, Andre Franke.

Slack Channel:

#covid19-hg-clinical-values

WES/WGS working group within the HGI

The COVID-19 pandemic represents an enormous challenge to the world's healthcare systems. The disease is characterized by a highly heterogeneous phenotypic response to SARS-CoV-2 infection, with the large majority of infected individuals having only mild or even no symptoms. However, the severe cases can rapidly evolve towards a critical respiratory distress syndrome and multiple organ failure.

We believe that the host genetic background plays an important role in COVID-19 susceptibility and progression. Compared to GWAS, WES and WGS have the advantage to bring out both common and very rare variants pinpointing directly to possible severity/protective genes. Both classical gene burden test and innovative analysis using Artificial Intelligence (such as LASSO Regression and Topological Data Analysis) are planned in order to implement a predictive model explaining COVID-19 susceptibility and severity.

Crucially, we are interested in building an international network of participating cohorts, allowing for larger sample size. Thus, if you would like to join our consortium in order to contribute whole exome or whole genome-sequencing data, please contact us on the ICDA Slack channel below and fill in the cohort description table here.

View previous meeting recordings here.

Contact Persons:

Alessandra Renieri, Francesca Mari, Brent Richards, Guillaume Butler-La Porte.

Slack Channel:

#covid19-hg-wes-wgs

Acute respiratory distress syndrome

The most severe outcome among COVID-19 cases includes acute respiratory distress syndrome (ARDS) and related respiratory failure that may fall outside of the Berlin definition of ARDS (i.e., ARDS-like respiratory illness) but could still share underlying genetic risk factors. Additionally, while many groups are waiting for genotype data on SARS-CoV-2 infected individuals to be generated, it would be prudent to examine existing data on ARDS (and ARDS-like respiratory illness) in the context of other non-SARS-CoV-2 respiratory viruses and in the context of sepsis.

The primary research question includes: Which host genetic susceptibility factors are associated with ARDS or ARDS-like phenotypes in the context of respiratory viruses OR sepsis?

Discovery of these variants will then enable further comparisons with other consortium or investigator-led analyses. For example: Which host genetic susceptibility factors for COVID-19 ARDS are unique to SARS-CoV-2 infection and which ones are shared with ARDS subsequent to other respiratory viruses OR sepsis?

Contact Persons:

Lea Davis, Eric Kerchberger.

Slack Channel:

#ardsgwas

Post COVID-19 lung fibrosis project

Early reports based on radiologic evidence suggest that lung fibrosis might be a short-term sequelae of COVID-19 but the extent to which this is progressive over time, and how this relates to interventions during the acute phase of COVID-19 infection are yet to be understood. As many countries move beyond the first wave of the pandemic, studies are being established to define and understand COVID-19 sequelae. Even if only a small proportion of individuals go on to develop progressive pulmonary fibrosis after COVID-19, the scale of the pandemic means that those individuals will still represent a substantial patient population. This project aims to understand the genetic determinants of post-COVID-19 fibrosis and to use this to yield valuable knowledge about the genes and pathways that promote fibrotic processes during infection and recovery from coronavirus infection. This information could also enable identification of individuals who might be at highest risk of progressive fibrosis for whom earlier intervention with anti-fibrotic medicines would be of benefit.

Contact Persons:

Tomoko Nakanishi, Brent Richards, Louise Wain.

Slack Channel:

#covid19-hg-postcovid-fibrosis

COVID19 vascular complications

Recent publications suggest that vascular complications are common in COVID19 patients, especially complications of the ischemic / thrombotic type, and that they may be associated with unfavorable outcomes. In a series of 184 ICU patients admitted in 3 Dutch hospitals with proven COVID-19 pneumonia, 31% developed thrombotic complications, including of imaging-confirmed venous thromboembolism (VTE) in 27% and arterial thrombotic events in 3.7%.

Two recent French studies have underlined an unexpected high number of VTE (mainly pulmonary embolism - PE) with a prevalence of 16% (64/150) in Strasbourg (3) and 21% (22/107) in Lille despite a conventional thromboprophylaxis in COVID19 patients admitted in ICU. This high increase in PE prevalence which is twice higher than the frequency of PE in the influenza ICU patients may worsen the respiratory prognosis of COVID-19 patients. The low number of associated deep vein thrombosis (DVT)in COVID-19 patients may suggest that they have pulmonary thrombosis rather than embolism. In another recent series of 221 patients with COVID-19 hospitalized in Union hospital, Wuhan, 5% developed acute ischemic stroke (5 large-vessel occlusion, 3 small vessel occlusion, and 3 cardioembolic strokes), 0.5% cerebral venous sinus thrombosis, 0.5% intracerebral hemorrhage.

While in this and other series COVID19 patients with cerebrovascular complications were significantly older than those without, recent reports from New-York hospitals have described large-vessel strokes as a presenting feature in several young patients. The mechanisms underlying these vascular complications is unclear and could involve excessive inflammation, hypoxia, immobilization and obesity (for VTE), hypercoagulability diffuse intravascular coagulation, cardio-embolism from COVID-19-related cardiac injury and arrhythmia, and possibly invasion of the central nervous system by SARS-CoV-2 leading to encephalopathy. Stroke and VTE genetic predisposition in the general population has been confirmed by recent waves of Genome Wide Association (GWAs) and genetic factors may also modulate the risk of such complications in COVID19 patients. Better understanding the mechanisms underlying the risk of vascular / thrombotic complications in COVID19 patients has important implications for prevention strategies. We aim to identify genetic risk factors associated with the risk of vascular complications (stroke and VTE) in COVID-19 patients, using both an agnostic approach and focusing on known genetic risk factors for these vascular diseases.

Contact Persons:

Israel Fernández Cadenas, Stéphanie Debette, David Alexandre Tregouet.

Slack Channel:

#covid19-hg-stroke-vte