“Neanderthal Ancestry Affects COVID-19 Severity, But Only Slightly ”
A new study links Neanderthal ancestry to severe COVID-19. But, before checking your Neanderthal percentage on 23andMe to gauge your COVID-19 risk, consider this…
Multiple studies in the last decade have identified Neanderthal DNA in the modern human genome – the result of interbreeding between the two human lineages in the last 100,000 years. This inherited Neanderthal DNA has shaped modern human diversity, including human resilience and vulnerability to disease.
In a new study from Zeberg and Pääbo, published in the journal Nature via an accelerated peer-review, the two researchers determined that a genetic variant associated with increased risk for severe COVID-19 was introduced into the human genome from Neanderthals.
The variant’s association with severe COVID-19 was first discovered by two separate genome-wide association studies (GWAS). Heterogeneity in COVID-19 susceptibility and severity has led many researchers to believe that a patient’s genes may play a role — in addition to behavioral and clinical features like mask wearing, social distancing, age, sex, and cardiovascular health. In a GWAS of 1,610 patients from Italy and Spain who were hospitalized for COVID-19, Ellinghaus et al. identified two genetic variants associated with severe illness. One of those genetic variants, a single base-pair mutation on chromosome 3, was confirmed by a separate global study of 3,199 COVID-19 patients carried out by the COVID-19 Host Genetics Initiative.
Manhattan plot from COVID-19 Host Genetics Initiative (Release 3). GWAS of “hospitalized COVID v. population”. The significant locus on chromosome 3 is the same region identified in Ellinghaus et al. (2020).
Zeberg and Pääbo — both being experts in Neanderthal genetics and recognizing that inherited Neanderthal DNA has shaped the modern human immune system — compared the genetic variant identified on chromosome 3, along with several others variants close-by, to the genomes of three different Neanderthals. They found the variant on chromosome 3 was part of a 50,000 base-pair genetic chunk that was inherited from Neanderthals, and most closely matched the genome of a Neanderthal from Croatia.
The report by Zeberg and Pääbo has garnered a lot of media interest, including a mention by Trevor Noah on “The Daily Show.” But, before going to check your level of Neanderthal ancestry on 23andMe to gauge your COVID-19 risk, consider the following details.
Most important, the two studies that identified the genetic mutation associated with COVID-19 looked specifically at patients with severe COVID-19 symptoms. The term “severe COVID-19” is strictly defined, meaning a patient tested positive for SARS-CoV-2 virus and was hospitalized with respiratory failure requiring mechanical ventilator assistance. The genetics of these “severe” patients were compared to the genetics of individuals who had not been hospitalized, and only a few dozen of whom were previously infected with mild or no symptoms. Therefore, while the Neanderthal-inherited variant increases an infected individual’s risk of having a severe outcome and requiring ventilator assistance, the results of all three studies say nothing about this variant affecting the likelihood of becoming infected, the duration of the infection, the variability of symptoms aside from severe respiratory distress, or the likelihood of death from infection. Inferences should not be made connecting the Neanderthal-inherited variant to any of these other outcomes.
In addition to the very specific outcome that is linked to this mutation, the mutations also contributes only minimally to the risk of severe COVID-19 when compared to non-genetic factors. In GWAS studies, the level of association between a genetic variant and an outcome — like severe COVID-19 — is by reporting a ratio of the odds that patients with severe COVID-19 have or do not have the genetic variant. When this “odds-ratio” (OR) is greater than 1, it indicates an increased risk for individuals with the Neanderthal-inherited variant. The OR also gives a relative estimate for the magnitude of the genetic contribution to the disease. It is common that GWAS for complex diseases with genetic components, like heart disease or diabetes, will identify many variants associated with the disease, but each may contribute only a small amount, carrying ORs less than 1.5 or even 1.2.
It is surprising that in the GWAS of COVID-19 by Ellinghaus et al., only a single variant was detected as significantly associated with the disease. Furthermore, the OR for the variant was only 1.77 (95% CI 1.48-2.11), indicating a relatively minor increase in risk and a low-level genetic contribution. For comparison, a study by Li et al. of COVID-19 patients in Wuhan, China, looked at the same “severe COVID-19” outcome and found that non-genetic factors had similarly significant effects on whether individuals developed severe COVID-19. These non-genetic factors included age older than 65yrs (OR=2.25, 95%CI 1.46-3.47), hypertension (OR=2.01, 95%CI 1.27-3.17), and biomarkers related to blood clotting (D-dimer) (OR=2.18 95%CI 1.42-3.34). For a complex disease like COVID-19, it is surprising that the GWAS have only revealed a single associated genetic variant, and that this variant seems to have a small genetic contribution. It may be that the size of the GWAS (only approximately 3,500 patients and controls) does not provide enough power to detect the many other weakly contributing genetic variants. Other studies of complex disease regularly require sample sizes of tens-of-thousands of individuals to make significant discoveries.
Odds ratios for non-genetic risk factors for “severe COVID-19” from Li et al. (2020).
I go into this detail to emphasize two points. Yes, there is certainly a genetic variant contributing to COVID-19 severity. And it is exciting that Zeberg and Pääbo were able to trace the origin of this variant to our ancient interbreeding with Neanderthals. Our inherited Neanderthal DNA has shaped our immune response to numerous pathogens, and continues to have an impact on modern human health and disease.
But, the contribution of this genetic variant is not significantly greater than many non-genetic factors like age and cardiovascular health. The presence of this variant also says nothing about an individual’s risk of becoming infected with SARS-CoV-2 virus, the duration of that infection, or risk of death. These outcomes likely depend more on socio-economic factors including race and access to healthcare, as well as personal behaviors like mask-wearing and social-distancing.