Preprint Human genetics implicate thromboembolism in the pathogenesis of long COVID in individuals of European ancestry, 2024, Schuermans et al

Human genetics implicate thromboembolism in the pathogenesis of long COVID in individuals of European ancestry

Art Schuermans, Andreas Verstraete, Vilma Lammi, Tomoko Nakanishi, Maddalena Ardissino, Jef Van den Eynde, Benjamin B. Sun, Marios K. Georgakis, Beatriz Guillen-Guio, Louise V. Wain, Christopher E. Brightling, PHOSP-COVID Collaborative Group, Johan Van Weyenbergh, Adam J. Lewandowski, Betty Raman, Hugo Zeberg, Hanna M. Ollila, Stephen Burgess, Pradeep Natarajan, Michael C. Honigberg, Kathleen Freson, Thomas Vanassche, Peter Verhamme

[Preprint]

Abstract
SARS-CoV-2 infection can result in long COVID, characterized by post-acute symptoms from multiple organs. Current hypotheses on mechanisms underlying long COVID include persistent inflammation and thromboembolism; however, compelling evidence from humans is limited and causal associations remain unclear.

Here, we tested the association of thromboembolism-related genetic variants with long COVID in the Long COVID Host Genetics Initiative (ncases=3,018; ncontrols=994,582). Primary analyses revealed that each unit increase in the log-odds of genetically predicted venous thromboembolism risk was associated with 1.21-fold odds of long COVID (95%CI: 1.08-1.35; P=1.2×10-3). This association was independent of acute COVID-19 severity, robust across genetic instruments and methods, and replicated in external datasets for both venous thromboembolism and long COVID.

Downstream analyses using gene-specific instruments, along with protein and gene expression data, suggested the protease-activated receptor 1 (PAR-1) as a potential molecular contributor to long COVID. These findings provide human genetic evidence implicating thromboembolism in long COVID pathogenesis.

Link | PDF (Preprint)

 

What irks me about this selection is it is completely unclear what happens to people that develop post COVID cases of ME/CFS, POTS, or other common labels often included in long COVID subtypes.

Does that count as an “alternative diagnosis” which means they aren’t in the study cohort. If so it might end up being a weird exclusion of more severe ME and POTS cases resulting from COVID because they are more likely to be separately diagnosed, while including mild ones under the long COVID label? This makes the data quite messy, and it worries me the long COVID label is doing more harm than good at this point. Studying a heterogeneous set of conditions resulting from a viral infection, perhaps through different mechanisms, as a single entity, will likely dilute useful subtype level findings.

The data seems to be coming from this previous long COVID GWAS. Who’s major finding was an association with FOXP4 Locus

This suggests the signals they are picking up are likely related to susceptibility to lung damage from COVID, Post-ICU syndrome and the such. In this context, this study’s association with clotting genes makes more sense, and perhaps points to the fact even if there is a buildup of evidence behind the microclot data, it likely isn’t going to be relevant for post-COVID ME/CFS.

 

I emailed the corresponding author and received a prompt and interesting response.

Interestingly, POTS and ME were not considered as alternative diagnoses. So people with both Long COVID and POTS and Long COVID and ME were included in the study. (This raises the question of us needing a steady definition of what illness to include and exclude under the long COVID umbrella term.)

Responding to my questions about if this finding applied to ME/CFS they said that it applies to a general long COVID cohort, and suggested further research seeing if these findings hold in specific subtypes like POTS and ME/CFS. Their findings were also independent of acute COVID-19 infection severity, suggesting the signal they picked up is not simply from post-ICU syndrome cases.

Quote from the study:

 

That at least does implicate that there could be more to this finding. But I suspect the LC diagnosis is still far to noisy by itself. Accounting for severity of acute infection is necessary but there's probably an abundance of other things you have to take into account as well which might not have occured. If the GWAS data is based on a nonsensical diagnosis of LC (I don't think anybody has an idea what LC within this cohort is supposed to mean) you could be picking up all kinds of noise not having to do much with LC. It does also still seem like a largely elderly and to a larger degree hospitalized cohort. For example it could be possible that a genetic difference results in one group being more likely to catch Covid more often which by itself leads to a higher LC rate, without the effect being very direct.

Perhaps once DecodeME is done one can look back at these findings. Interesting to see Van Weyenbergh's name on this, after he's made a bit of a splash in the viral persistence field. Someone from the MRC is also on board as well as many other names. Perhaps enough motivation to get more genetic studies of LC where more attention is placed on what the diagnosis is supposed to entail.

 

In my email correspondence, I did indeed slip in a link to the researcher applications for decode ME data.