Genomics boosts understanding of Covid-19 severity and susceptibility

The Covid-19 Host Genetics Initiative carried out one of the largest genome-wide association studies ever. It involved meta-analysis of nearly 50,000 Covid-19 patients and two million uninfected controls. Dr Hamdi Mbarek, Lead Analyst of the Qatari dataset explains how the initiative improved knowledge of host-genetic determinants of Covid-19 infection and severity.

In drug development we face a major hurdle when attempting to tackle viruses: people’s immune responses vary significantly. External factors such as one’s environment, socio-economic circumstances and access to clinical treatment all impact how our bodies can tackle viruses such as Covid-19. However, it is ultimately how our DNA interacts with these factors that determines our immune response.

To understand how susceptible people are to different viruses and diseases, as well as how severely they might contract them, we must understand which elements in our genes interact negatively and to what extent. Host-specific genetics holds the key to finding the immune-response mechanisms in our biology that will help us to identify the best therapeutics. We’re all different and the answer is not ‘one size fits all’.

Understanding the varied response

Covid-19 posed an unprecedented and unknown threat to our bodies.

As the pandemic spread, it was clear that an urgent response was needed. Researchers around the world undertook different methods to find a solution, and one of the main areas that came to the fore was genomics. Drug repurposing, informed by genomic research, was thought by many to be the most time-effective response to the accelerating threat of Covid-19, and multiple projects were conducted in this space, including here in Qatar.

But one of the most distinctive and perplexing features of the disease was the wide variation in severity experienced by different people. Even among the same age groups, physiologies, and ethnicities, vastly different responses were noted. These variances posed complex questions.

Why are some patients severely affected by the virus while others escape with mild or no symptoms at all? Who is susceptible to ‘long Covid’? What can we learn to help us predict how each person will react? And how can we find a medical solution if everyone reacts differently to the virus?

Ultimately, these questions resulted in one pressing research priority: which genetic factors influence the variance in severity? From March 2020, thousands of scientists around the world united to try to answer this question.

A global effort

Accelerating genome research on immune responses to Covid-19 required a global effort.

The Covid-19 Host Genetics Initiative – founded in March 2020 by Andrea Ganna and Mark Daly from the Institute for Molecular Medicine Finland, University of Helsinki and the Broad Institute of MIT and Harvard – was set up to meet this need. As an international consortium of researchers, the initiative brings the host genetics community together with the aim of learning the genetic determinants of Covid-19 susceptibility, severity, and outcomes. Today, it includes more than 3,500 researchers from 25 countries and we are proud to be taking part at the Qatar Genome Programme.

Through global collaboration, the Covid-19 Host Genetics Initiative has carried out one of the largest genome-wide association studies ever performed. In total, the study involved meta-analysis of nearly 50,000 Covid-19 patients and two million uninfected controls.

Already it has vastly improved our knowledge of host-genetic determinants of Covid-19 infection and severity. The data pooled and analysed will also be vital to developing further therapeutics, in addition to understanding the protection conferred by vaccines.

Identifying the genome loci associated with Covid-19

The wide-scale genomic research conducted by the initiative helped answer the question: what is within us as individuals that affects our response to the virus?

The research identified 13 loci – the name given to locations in the human genome – that are strongly associated with Covid-19 infection or severe Covid-19. By further analysing these loci, the study was able to identify  specific gene characteristics that can be matched to various levels of the immune response within the patient.

Of the 13 loci, multiple indicated an increased risk of the patient developing severe symptoms and a likelihood of the patient requiring hospitalisation. The team found six genome-wide significant associations for critical illness due to Covid-19. Nine genome-wide significant loci were also detected for moderate to severe hospitalised Covid-19 (including five of the six critical illness loci).

The next phase of the research was to understand whether the 13 loci were associated with increased susceptibility to infection or if they were impacting the progression of symptoms. One locus had a particularly strong association with increased susceptibility to the virus. On a practical level, this helps us to understand that certain people with these genes may need to take precautionary measures to avoid the virus.

However, some loci showed stronger links to progression of the diseases, and ultimately a worse outcome, than to susceptibility. One of the first identified and strongest signals associated with Covid-19 is located in chromosome 3, encompassing a clusters of six genes; it confers a twofold increased risk of respiratory failure. A follow-up study found that this locus is also responsible for over twofold increased risk of mortality for individuals under 60. Additionally, the risk variants at this locus are carried by >60% of individuals with South Asian ancestry, compared with 15% of European ancestry groups, partially explaining the ongoing higher death rate in this population in the UK.

Multiple loci identified were also associated with other diseases. For example, one locus which correlated to patients with the most severe Covid-19 cases, was located near the FOXP4 gene. The FOXP4 variant was found to increase the gene’s expression, suggesting that inhibiting the gene could be a potential therapeutic strategy. Other loci associated with severe Covid-19 included DPP9, a gene also involved in lung cancer and pulmonary fibrosis, and TYK2, which is implicated in some autoimmune diseases. Interestingly, the study showed that there was a positive correlation between people who are genetically vulnerable to ischemic stroke and critical illness or hospitalisation due to Covid-19 – but there was not an increased likelihood of infection.

Although the treatment of Covid-19 is still in clinical trials phases, genomics research like this is providing promising direction towards drug repurposing and tailored treatments. The research can help guide the allocation of existing medical treatments to those suffering from a range of Covid-19 severity levels.

Based on these results of the study, genetic tests are now being developed to predict potential targeted therapies, and drug repurposing candidates are being evaluated. The research will hopefully indicate multiple drugs that could be repurposed, according to severity levels and symptoms.

The researchers are also examining further what differentiates ‘long-haulers’, or those patients whose Covid-19 symptoms persist for months, from others genetically. More research is also being conducted to continue to identify additional loci associated with infection and severe disease.

Harnessing diversity in genomic research

The research conducted by this initiative is playing an important role in creating a representative picture of Covid-19 immune responses.

As ethnicity is a driver of genetic makeup, it can be a significant factor in how different people respond to viruses. When we analyse viruses, it is therefore essential to build an extensive dataset across various populations – rather than just focusing on one group – to understand how the virus affects them differently. Without an inclusive data set, it can be too easy to make global assumptions on issues like virus susceptibility, severity and appropriate therapeutics, potentially leading to ineffective actions being taken as a result of incomplete knowledge.

To date, genome research has largely portrayed an incomplete picture of the world, skewed by the majority of projects being conducted using European or American datasets. The genomes of populations from the Middle East, Africa and some parts of Asia have been significantly underrepresented. This hinders our overall understanding of health in these regions and, in the case of a pandemic, can also hinder the implementation of quick and effective treatments for a large proportion of the world’s population.

Thanks to the collaborative nature of the Covid-19 Host Genetics Initiative, the study benefited from a large amount of data pouring in from around the world, representing diverse populations. We contributed the data of 13,000 genomes from Qatar as part of the project, ensuring that Arab genomes were represented in the findings.

The initiative also bridged the gap between academic researchers and companies working in the field of genomics. The data analysed for this study came not just from biobanks and clinical studies but also from direct-to-consumer genetic companies such as 23andMe.

The expansive dataset revealed several interesting findings about how different populations react to Covid-19. For example, two of the 13 loci identified by the team had higher frequencies among patients of Asian or Middle Eastern ancestry than in those of European ancestry, indicating that people of Asian or Middle Eastern descent are more likely to experience severe symptoms of Covid-19 if they have the virus.

Care must be taken when drawing conclusions from these correlations but the findings do indicate the importance of diverse genomic research in understanding the spread and management of Covid-19 across the globe.

Overall, the initiative enabled us to produce statistically robust analyses far more quickly, and from a greater diversity of populations, than any one group could have done on its own. Studies like this typically take three to five years to deliver, but significant results were instead achieved over a much shorter period of time.

Long-term, the research will serve to create a much fuller picture of Covid-19 responses, to inform drug repurposing and ensure appropriate treatments are accessible to all.

The success of this initiative embodies what can be achieved when researchers around the world work together to analyse genomics on a larger scale and proves how critical international collaboration is in addressing global health issues. Multiple countries have already implemented their own genomics projects and have access to a wealth of information that can inform the treatment of the people in their country. But through knowledge-sharing across organisations and borders, far more can be achieved, ultimately ensuring that the right treatments are offered to people in accordance with their genetic makeup and associated needs. Qatar’s contribution will promote the correct treatment of Arab patients not only in the Middle East but elsewhere around the globe too.

Wider applications

Without a doubt, genomic research will continue to play a pivotal role in medical treatment and healthcare, thanks to its ability to inform precision medicine. Continuously facilitated by advances in technology, increasingly extensive databases will provide researchers with in-depth and diverse data at their fingertips. The more we can encourage collaboration between organisations, the more all researchers will be able to benefit from accessing the type of information that would only traditionally be available through drawn-out data collection processes that would take years to collate.

While the Covid-19 Host Genetics Initiative was founded with the specific aim of aiding research to tackle the pandemic, the data it has produced on immune responses can vastly increase our understanding of responses to other diseases too.

Applying genomics to cancer detection and treatment is likely to become a rapidly growing field. The severity of many cancers can largely be reduced by early diagnosis. Yet, modern healthcare too often relies on people noticing physical symptoms of cancer before diagnosis and, for those not fortunate enough to have routine health check-ups, this process can prove dangerous. Genomics research may very well provide the answer to early diagnosis and prevention. At the Qatar Biomedical Research Institute, for example, a team recently used the genomic data we have for the Qatari population to uncover findings around individuals’ susceptibility to developing breast cancer. Research such as this, focusing on identifying trends that can enhance prevention and early detection of cancer, could have major benefits for the local population, and worldwide if conducted using other datasets.

Another example of applying genomics to advance prevention and personalised treatment comes from a study led by researchers at Hamad Bin Khalifa University (HBKU) and Qatar Genome Programme. It highlighted that 2.3% of the Qatari individuals with whole genome sequence data carried a pathogenic (meaning disease-causing) or likely pathogenic variant in one of the 59 genes identified as medically actionable. Many of these genes are related to inherited forms of cancer and heart conditions.

Studies such as these will advance personalised healthcare exponentially. The ability to identify and to return secondary findings with potentially lifesaving interventions is indispensable to help patients, family members, and clinicians to identify the best interventions and medical follow-up strategies.

Research challenges

Conducting the genomics research that can make the greatest difference to our global healthcare systems is not without its challenges.

The lack of global standardisation across methodology, analysis tools and the databases holding findings, can make it difficult for researchers to apply the results of other organisations in their own research. However, efforts to increase standardisation can be seen. The Global Alliance for Genomics and Health (GA4GH) is a good framework for collaboration on these topics, and the Qatar Genome Programme is taking part.

The development of Artificial Intelligence (AI) solutions is also aiding data analysis by making sense of extensive sets and drawing user-friendly conclusions. AI can facilitate a far quicker approach to analysing genomes and can also help us in identifying solutions, effectively matching needs with the compounds of existing drugs.

Another challenge still to be addressed is that questions of privacy come hand-in-hand with wide-scale genomic research. Due to the potential for large-scale access to the datasets, patients must be fully briefed on how their information will be used, and on the measures in place to ensure their anonymity is upheld. AI can again help in this area, processing anonymised data and reducing human access to specific information about an individual’s health, but it is also part of the challenge. However, trusted bodies such as the World Health Organisation are now developing a global digital health strategy to govern data handling in medical research and such formal regulation is promising.

The future of genomic research

Overall, genomic research and precision medicine hold a wealth of potential in addressing major threats to modern health. By establishing large-scale databases on human genomics, critical global trends can be identified, and valuable conclusions can be drawn in areas that have previously been left uncovered. Biobanks hold great potential for precision medicine, especially when it comes to achieve time-efficient drug repurposing.

As we continuously tackle the challenges to health that Covid-19 poses, global collaboration must remain at the centre of our efforts in genomic research. The necessity of transparency and open data sharing in research has become far more prevalent in the medical industry in light of this crisis – and rightly so. It is via collaboration that we can accelerate research and reach the discoveries we need in order to live with this world-changing virus.

There is scope to extend this collaboration far beyond Covid-19 research. As we look to overcome other major viruses and diseases, research bodies should not be competing with one another to find solutions; where possible, they should seek to work together. While the concept of working in large consortia is familiar to many geneticists – now more than ever, following the various initiatives launched to tackle the pandemic – it is still a relatively unusual phenomenon in other areas of healthcare, where collaboration could likewise achieve great success.

Volume 23, Issue 1 – Winter 2021/22

About the author

Dr. Hamdi Mbarek is Research Partnerships Manager at Qatar Genome Programme and lead analyst of the Qatari dataset for the Covid-19 Host Genetics Initiative.

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