Multi-ancestry GWAS of [LC] identifies immune-related loci and etiological links to [CFS], fibromyalgia and depression, 2024, Chaudhary et al

Multi-ancestry GWAS of Long COVID identifies‬ ‭immune-related loci and etiological links to chronic fatigue‬ syndrome, fibromyalgia and depression‬ ‭

Abstract
The etiology of Long COVID is poorly understood despite its estimated global burden of 65 million cases. There exists a paucity of genetic studies that can shed light on potential mechanisms leading to Long COVID. Using consented and genotyped data from 23andMe adult research participants, we conducted the largest multi-ancestry meta-analysis of genome-wide association studies of Long COVID across European (42,899 cases, 94,721 controls), Latinx (8,631 cases, 20,351 controls), and African-American (2,234 cases, 5,596 controls) genetic ancestry groups. GWAS of Long COVID identified three genome-wide significant loci (HLA-DQA1 and HLA-DQB, ABO, BPTF:KPAN2:C17orf58). Functional analysis of these genes points to underlying immune and thrombo-inflammatory mechanisms. We present evidence of shared genetic architecture (genetic correlation p-value < 0.001) of Long COVID with thirteen phenotypes of similar symptomatology or pathophysiology. We identified potential causal roles from liability to chronic fatigue (Mendelian randomization OR=1.59, 95% CI[1.51,1.66]), fibromyalgia (OR=1.54, 95% CI[1.49,1.60]), and depression (OR=1.53, 95% CI[1.46,1.61]) with Long COVID, which replicated in the COVID-19 Host Genetics Initiative data, and which are unlikely to originate from collider bias. These findings can help identify populations vulnerable to Long COVID and inform future therapeutic approaches.

Link | PDF (23andMe research preprint, October 2024, open access)

 

A previous Long Covid GWAS (with only 6,450 cases) highlighted FOXP4 with with one SNP having an OR of 1.63 [1.40-1.89] but this wasn't replicated in this 23andME GWAS (p=0.57). They say that the previous GWAS found the same effect sizes for the genes they identified but that these were not picked up as significant because of the smaller sample size.

 

In the second part of the paper they looked at whether several conditions including chronic fatigue increased the risk of Long Covid.

Unfortunately, they used the term 'chronic fatigue/myalgic encephalitis' which does not give a lot of confidence that they defined ME/CFS accurately. Table 1 shows that 1.5% of the controls had it - did anyone find how they defined it?

 

As part of an ongoing experiment here is a summary of the paper (AI generated and read). I often find these more useful than the Abstracts but feedback welcome

https://u.pcloud.link/publink/show?code=XZ7bjv0ZGbw7qqyhtlYym4OQ1XuaYyuR1l77

 

Yes it’s an audio summary, sorry if that wasn’t clear. I can easily post the text too if people prefer? (quoted below)

So I don’t completely derail discussions of the papers maybe people can post feedback to this thread
https://www.s4me.info/threads/enhan...h-technology-feedback-and-ideas-wanted.40207/

 

Thread from Prof Akiko Iwasaki

https://threadreaderapp.com/thread/1844801167722709000.html?utm_campaign=topunroll

 

Yes, this is likely an extremely broad self-defined LC definition.

It may be worthy of note that HLA-DQA1 was once potentially implicated in CFS; there was a small (n=49) genotyping study - defined by the old CDC/Fukuda criteria - from 2005 (J Clin Pathol 2005;58:860–863). The result did not survive full correction for multiple comparisons but this is worth mentioning:

 

I can appreciate the good that can come from GWAS research. Validation leaps to the front. Possible therapeutics as well.

I worry, I think, even more about the potential for harm.

What if we find people that get fibro or ME/CFS or LC or late stage Lyme etc, all share common gene traits that people who rarely if ever get those diseases, do not?

Would that breed resentment and prejudice?

Would we be blamed for higher health care costs? Higher insurance premiums? Higher taxes? Could we be DENIED health care or be forced to pay much higher premium/taxes?

Would health politics assume a new vitriol? Normal people vs those - like us - with inferior or corrupted genes? Would life for us devolve into a Darwinian dystopia where eugenics becomes typical dinner table discussion?

I suppose I read one too many Asimov novels back in the 60's.

 

No , not at all. Here ACEs ( Adverse Childhood Experiences" are a thing, even though the research base is a bit dodgy.
It was being used as a predictive tool in cases - an application so far removed from its initial questionnaire basis - truly disturbing.
A little humanity would surely let you appreciate that a childhood full of multiple crap experiences can impact some, and perhaps there are more supportive routes that could be adopted, but then humanity can be sadly lacking, particularly for already marginalized groups

 

Eugenics never went anywhere. So yeah absolutely, there would be a new different type of prejudice to deal with.

 

The day is young.

I have faith in humanity's penchant to economize at the expense of society's fringes, and to somehow shoe-horn in "Science" for justification.

 

From 23andMe blog:

Genetic Associations with Long COVID

"In the largest genetic study of its kind to date, 23andMe scientists have identified variants associated with an increased risk of developing Long COVID and also established a genetic link between the potentially debilitating condition and other chronic conditions such as depression, chronic fatigue syndrome, and fibromyalgia.

Published in the preprint server for health scientists known as MedRxiv, the study suggests that genetic differences in how the body’s immune system recognizes and responds to the virus likely influence the chances of developing Long COVID. Among the strongest genetic associations was in the region of the HLA-DRB1 gene, which plays a critical role in the body’s immune response."

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"In addition to the HLA finding, 23andMe scientists also focused on the role of the ABO gene, which determines a person’s blood type. The role of the ABO gene has been previously identified by 23andMe scientists and others for its role in the severity of COVID-19 in some individuals. In this study, the scientists suggest that blood type or ABO variation may also influence the likelihood of developing Long COVID.

The ABO blood group also has a role in immune response as well as influences the factors that affect the coagulation of blood. This, in turn, may explain why it is associated with both acute COVID-19 and Long COVID cases. The blood types determined by the ABO gene are also linked to blood clotting and inflammation, both hallmarks of Long COVID.

The scientists working on this study also identified several new associations in or near the genes BPTF, C17orf58, and KPNA2. Researchers believe these genes’ role in susceptibility to Long COVID is also related to the defense system against viruses."

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"This study is part of a series of studies being conducted by 23andMe scientists since the beginning of the pandemic in 2020, and made possible by 23andMe customers who consented to participate in research."

Link

 

No. There are loads of diseases like that already and nobody takes any notice of the genes.

The one gene allele that might have got near problematic is HLA-B27, which greatly increases the risk of ankylosing spondylitis. However, it was subsequently found that it makes you almost immune from AIDS or at least staves it off for years. Moreover, the real problem arose for people for whom the diagnosis of ank spond was questionable and a B27 test was done to 'confirm'. The insurance weighting was on the ank spond. We learnt to guide patients through the issues raised. In the end we hardly ever did B27 tests because they didn't alter care.

 

I read a little about this, and it's not as straightforward as I had thought.

There are two similar stats: relative risk (RR) and odds ratio (OR).

• RR deals with change of risk - risk being (# people with disease)/(total people).
• OR deals with change in odds - odds being (# with disease)/(# without disease).

As an example, assume a study looked at a random cohort of 200 people.

• 20/100 people without a SNP have MS (0.2% risk)
• 25/100 with the SNP have MS (0.25% risk)

Relative risk would be calculated using the ratio of risk of having MS in each group: 0.25/0.2. RR would be 1.25. The person is 25% more likely to have MS if they have the SNP.

RR is pretty easy to understand. Odds ratio is less intuitive:

• Using the above example numbers, odds of people without the SNP having MS is 20/80 = 0.25. It's the ratio of people with to without MS.
• Odds of people with the SNP having MS is 25/75 = 0.33

The odds ratio is these two odds divided: 0.33/0.25 = 1.32.

Meaning the ratio of MS to not MS is 32% higher in a group of people that have the SNP.

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Given an RR of 1.25. Assume the prevalence of MS in people without the SNP in the real world is 100/1,000,000. In people with the SNP, it'd be 125/1,000,000.

Given an OR of 1.25 and the same prevalence without the SNP. The prevalence with the SNP is 124.996/1,000,000.

They are very similar if real world prevalence is very low, but they trend apart as prevalence increases or RR/OR increases. Assume prevalence of MS without SNP is 100/1000.

RR=1.25: Prevalence with SNP is 125/1000.

OR=1.25: Prevalence with SNP is 122/1000.

The following chart shows how different the two metrics become when the prevalence (or incidence) is very high:


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When to use the odds ratio or the relative risk?

 

In Immunometabolic changes and potential biomarkers in CFS peripheral immune cells revealed by single-cell RNA sequencing (2024, Journal of Translational Medicine) —

HLA-DQB1 was also highlighted in Fine mapping of the major histocompatibility complex MHC in myalgic encephalomyelitis/chronic fatigue syndrome ME/CFS suggests involvement of both HLA class I and class II loci (2021, Brain, Behavior, and Immunity) —