Most people experience only mild symptoms when they have COVID-19 but a minority will have a severe or life-threatening response. Whilst some of the difference can be explained by older age or underlying health conditions, the reasons why some fit, young people become so ill is one of the puzzles of the COVID-19 pandemic.
Some answers could lie in the human genome. The genome is the body’s instruction manual containing all the information needed to make, maintain and repair an individual. There is a copy of it in almost all cells of the human body. It is made of DNA, which we inherit from our parents. Genes within the genome can work singly, but much more commonly act together, rather like players in an orchestra. They also interact with the environment. For example, in sunshine, the activity of genes involved in the protection of skin from UV light damage increases.
Any two people have genomes that are roughly 99.9% the same; it is the remaining 0.1% that makes them different. This variation may be important in determining how different people respond to particular infections. For example, when people are infected with coronavirus, fragments of the virus will be seen by the immune system in a way that may differ from one person to another. The outcome could be a variation in the response to infection.
Human genes involved in the response to infection are numerous and highly diverse within the genome. Some are located on the X chromosome and this could be one reason why males (who have only one copy of X) are more severely affected by COVID-19 infection than females (who have two copies). Variations in human genomes, both of immune system genes and others, could explain at least some of the differences in responses to coronavirus infection. They might also help to explain differences in how patients respond to treatments for COVID-19.
Although family or twin studies are useful in establishing whether there is likely to be an inherited element driving a severe response to infection, finding a few, or even a few hundred sets of letters that might be responsible among the genome’s six billion letters of code has, until recently, been time-consuming and expensive. It has meant that previous attempts to investigate the genomes of those with severe responses to an infection such as influenza during the last pandemic in 2009 were difficult.
However, since the flu pandemic in 2009, there has been a revolution both in sequencing (‘reading’ each letter of the genetic code) and in the tools for genome analysis. This has made it easier to compare large numbers of genomes quickly. High speed computing has also made it easier to work out a response to infection that involves many genes acting together or, to use the orchestra analogy, which members of an orchestra are responsible for playing the tune.
Large collaborations maximize the chance of discovering genes that affect the severity of disease. The COVID-19 Host Genetics Initiative brings together the human genetics community worldwide to generate, share, and analyze data to find out about the genetic determinants of COVID-19. The data compiled by this consortium could help to identify individuals at high or low risk of disease, generate ideas for drug repurposing, and contribute to global knowledge of the biology of SARS-CoV-2 infection and disease. The UK BioBank, a long established resource for studying human genetics, is one of the UK contributors to that consortium.
In addition, a £28 million sequencing study involving 20,000 people currently or previously in intensive care with COVID-19, plus 15,000 people with mild or moderate symptoms, has just been launched by Genomics England, partnering with the GenOMICC consortium, Illumina, the NHS and UK Research and Innovation, among others. The study, reaching patients in 170 intensive care units throughout the UK, will explore the varied effects coronavirus has on patients, and support the search for treatments by identifying those most at risk and helping to fast-track new therapies into clinical trials.
Genetic factors are well-known to play a role in human susceptibility to infectious diseases – for instance severe forms of malaria – and they could be important for COVID-19 too. Whether genes turn out to play a major or minor part in determining the response to coronavirus infection, tracking them down is important because they could provide clues about the biological pathways involved in COVID-19 disease. If these pathways are affected by drugs already used to treat other diseases, these drugs might be repurposed to treat COVID-19 too.
One promising place to look for genetic factors controlling COVID-19 is within the HLA (human leukocyte antigen) complex, which plays a key role in regulating immunity. There are many different HLA types, controlled by multiple genes, and it is possible that one of these types is involved in the severe response to coronavirus infection. We do not yet know whether there is a link between genes, immunity and the severity of COVID-19. But the studies now being carried out around the world should begin to provide some answers.