Genome-wide Association Study of Long COVID, 2023, Lammi et al.

[chillier]

Genome-wide Association Study of Long COVID, Lammi, Ollila et al 2023


Abstract
Infections can lead to persistent or long-term symptoms and diseases such as shingles after varicella zoster, cancers after human papillomavirus, or rheumatic fever after streptococcal infections(1,2). Similarly, infection by SARS-CoV-2 can result in Long COVID, a condition characterized by symptoms of fatigue and pulmonary and cognitive dysfunction(3-5). The biological mechanisms that contribute to the development of Long COVID remain to be clarified.

We leveraged the COVID-19 Host Genetics Initiative(6,7) to perform a genome-wide association study for Long COVID including up to 6,450 Long COVID cases and 1,093,995 population controls from 24 studies across 16 countries. We identified the first genome-wide significant association for Long COVID at the FOXP4 locus. FOXP4 has been previously associated with COVID-19 severity(6), lung function(8), and cancers(9), suggesting a broader role for lung function in the pathophysiology of Long COVID. While we identify COVID-19 severity as a causal risk factor for Long COVID, the impact of the genetic risk factor located in the FOXP4 locus could not be solely explained by its association to severe COVID-19. Our findings further support the role of pulmonary dysfunction and COVID-19 severity in the development of Long COVID.

https://www.medrxiv.org/content/10.1101/2023.06.29.23292056v1

 

[chillier]

Some commentary here

 

[Hoopoe]

If you're curious what FOXP4 does: it's a transcription factor. That means it controls the expression of other genes. Little seems to be known about the exact genes regulated by FOXP4. It is known to play a role in the nervous system, and to also be expressed in the gut and lungs.

I get the impression that it's related to cell adhesion.

PS: the paper has some discussion about the role of FOXP4 in the human body. They emphasize the expressed on FOXP4 in the lung and also say it's also expressed in some immune cells.

 

[Hoopoe]

Interestingly FOXP4 is mentioned in one study on the genetic overlap between Ehlers-Danlos syndrome and long covid: https://www.medrxiv.org/content/10.1101/2023.03.24.23287706v1.full

(the EDS in that study appears to be a clinical diagnosis with dysautonomia plus hypermobility, not the well defined monogenetic disorder type. The genetics data on EDS predates the pandemic)

 

[ahimsa]

Some commentary here

Can't read that thread without logging in. And I think there are forum members who don't have twitter accounts.

I can't do it today, but if anyone thinks it's useful I can login and transcribe the twitter thread in a day or two.

EDIT: Forgot to mention, please send me a direct message if you want me to transcribe that twitter thread.

 

[Kalliope]

Nature
Gene linked to long COVID found in analysis of thousands of patients

quotes:

It’s very important that this type of study is being done,” says Chris Ponting, who studies medical bioinformatics at the University of Edinburgh, UK. “It will gain momentum and greater power as the case number increases.”

...


“It won’t just be a single answer, there will be a whole variety of people’s vulnerabilities contributing to why they haven’t recovered from COVID,” says Ponting. He and his colleagues proposed a study that would have included DNA from 15,000 people with long COVID. But grant reviewers rejected the proposal, he says, because they thought the condition too complex to be dissected in the way Ponting's team suggested.

“I disagree,” he says. “It is very complicated, but also very important to pick apart. The health and socio-economic costs of long COVID are enormous.”

 

[wastwater]

I’m familiar with FOXC1 as a developmental gene involving the eye

 

[Hubris]

He and his colleagues proposed a study that would have included DNA from 15,000 people with long COVID. But grant reviewers rejected the proposal, he says, because they thought the condition too complex to be dissected in the way Ponting's team suggested.

What a load of bullshit. The condition is too complex to be studied with GWAS, really? But psychologists telling you to think happy thoughts and ignore your symptoms, those are fine eh? And those unblinded clinical trials with unlikely drugs and subjective measures, those are fine too. What a joke.

By the way, @Jonathan Edwards what do you think of this result? FOXP4?

 

[Jonathan Edwards]

By the way, @Jonathan Edwards what do you think of this result? FOXP4?

A very interesting finding.
It is sufficiently close to known immune regulators (such as FOXP3) to seem maybe relevant but also suitably obscure - maybe responsible for some control mechanism we don't yet know. much about.

 

[RedFox]

What a load of bullshit. The condition is too complex to be studied with GWAS, really? But psychologists telling you to think happy thoughts and ignore your symptoms, those are fine eh? And those unblinded clinical trials with unlikely drugs and subjective measures, those are fine too. What a joke

Agreed. If anything, very poorly understood diseases might be the best candidates for a GWAS, because when studying the whole genome, we don't need to know where to look.

 

[Ariel]

Are there any similar studies happening so that this result could be replicated; does anyone know? I was really disappointed that the Ponting-led GWAS study was not funded. I know they were hoping someone else would do the study? Is anything else happening?

 

[ahimsa]

Some news coverage of this study, by NPR's "Goats and Soda" series:

A new clue to the reason some people come down with long COVID

https://www.npr.org/sections/goatsa...-reason-some-people-come-down-with-long-covid

 

[FMMM1]

Perhaps someone has posted this - https://www.genomicseducation.hee.n...d-for-asymptomatic-and-long-covid-conditions/

 

[SNT Gatchaman]

See also Absence of Association between a Long COVID and Severe COVID-19 Risk Variant of FOXP4 and Lung Cancer (2023, Frontiers in Genetics)

 

[SNT Gatchaman]

Discussed in the Nov 2023 NIH ME/CFS Genetics/Genomics Webinar from 1:24:23 to 1:35:46

 

[SNT Gatchaman]

Replicated across countries —



Important to evaluate non-European populations who have higher FOXP4 mutations —



FOXP4 overlaps with lung pathology including asthma / airways hypersensitivity —



Is expressed in multiple tissues: lung, hypothalamus, immune cells —



Is a standout risk factor for Covid hospitalisation —



But also stands out independently of hospitalisation as a long Covid risk factor —

 

[Sid]

But grant reviewers rejected the proposal, he says, because they thought the condition too complex to be dissected in the way Ponting's team suggested.

How do they know it’s complex? It could be very simple. No one knows anything about long covid, this blanket pronouncement is inappropriate.

 

[V.R.T.]

If Decode ME has a postive result, should we anticipate the Ponting decode long covid study being revived? Or a similar project

 

[wastwater]

This shows a few interactions between FOXP genes
https://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-019-1110-3

There is a string of genes including PITX2 FOXC1 PAX6 and COL4A1 that all create the same eye condition and wondered is FOX also a collagen gene
https://www.ncbi.nlm.nih.gov/books/NBK7046/

 

[wigglethemouse]

Discussed in the Nov 2023 NIH ME/CFS Genetics/Genomics Webinar from 1:24:23 to 1:35:46

From the video presentation of unpublished data they had a large replication cohort of 4,400 across additional diverse cohorts that highlighted the same gene. Each cohort showed a positive association which further strengthened the finding.

The video gives details for two variants. The actual gene for these two variants is FOXP4-AS1, FOXP4 antisense RNA 1. Wikipedia doesn't have any other info for it.
rs12660421, 6-41520640-G-A, gnomad link
rs9367106, 6-41515652-G-C, gnomad link

GeneCards Summary for FOXP4-AS1 Gene (link): FOXP4-AS1 (FOXP4 Antisense RNA 1) is an RNA Gene, and is affiliated with the lncRNA class.