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Researchers propose deep trawl of DNA to help uncover the causes of ME/CFS (Simon McG blog)

Simon

Senior Member
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3,789
Location
Monmouth, UK
Researchers propose deep trawl of DNA to help uncover the causes of ME/CFS

Analysing the DNA of thousands of patients can help to uncover the genetic roots of diseases and shed light on the underlying biological mechanisms. This can reveal targets for drug development.

A new and very different type of genetic research has emerged this millennium – the genome-wide association study (GWAS, pronounced “gee-was”). By probing small genetic differences between people, such studies can help to uncover the biological roots of disease and have already helped to guide drug development. Researchers including Professor Chris Ponting, an expert in biomedical genomics, are asking the main UK research funders to finance a large GWAS for ME/CFS.

The genome is our complete set of genetic information – all our DNA – and is made up of more than three billion DNA nucleotide base pairs. These nucleotides, usually referred to by their initial letters of A, T, G and C, spell out our genetic content. That includes all our genes, which are the bits of our genome that tell the body how to make all its proteins.

There are roughly ten million places along the human genome where these individual letters can vary from person to person. For example, one person might have a G while another has an A. Each site where the letters vary is called a single nucleotide polymorphism, or SNP (pronounced “snip”) and a GWAS reads out around a million of these SNPs.

SNP-close-up.jpg

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Researchers look for when a particular SNP version is strongly associated with a disease or a characteristic such as intelligence. For example, the “G” version of a particular SNP might be more common in people with ME/CFS than in healthy controls. This demonstrates a genetic influence on the risk of disease or on the characteristic – and what genes are involved, and what those genes do can reveal a great deal about the underlying biology.
read the blog

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As a result of GWAS (confusingly, the same acronym is usually used for both the singular and the plural), we now know that hundreds of genes affect height, but each gene typically increases or decreases height by around 1 mm. (Environmental factors such as childhood nutrition affect height too.) Ponting told me in an email conversation:

“SNPs are like small pieces of paper that – placed under the legs of a pool table – tip the balance of the table so that a ball rolls in one direction more than another.”
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With ME/CFS, scientists have pursued many different hypotheses about its cause over the years but have yet to make a breakthrough. University College London’s emeritus Professor Jonathan Edwards argues that it is time for broad approaches like GWAS with the potential to generate new avenues to explore. He told me in a recent email,

“The success of research into causes of disease hinges on someone suddenly having a brilliant idea… yet for ME/CFS nobody has a strong enough lead to show everyone the way forward. So it makes sense to set up a comprehensive fishing trip to see if we can trawl up some clues. Genetic screening [a GWAS] is probably the best bet for finding such clues.”
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GWAS successes
Despite these limitations, GWAS studies and follow-up work have already thrown light on the mechanisms of several diseases and have helped to identify new or promising drug therapies.
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Other autoimmune disease

Analysing DNA from one patient reveals little, but combining data from thousands of people in a GWAS can reveaal much more.
Researchers have compared GWAS results from different illnesses to see if they have something in common – and autoimmune diseases often do. Findings from these studies have led to the identification of a common pathway for several diseases, one that includes an immune-regulating molecule called IL-23. As a result of this insight, existing drugs that are used to inhibit the IL-23 pathway in other diseases have become a mainstay treatment for several autoimmune conditions, including psoriasis and ankylosing spondylitis.

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GWAS can sweep across the whole of human biology looking for potential mechanisms that might cause ME/CFS, even unsuspected mechanisms. It’s a remarkable technique and this is the ideal time for an ME/CFS study.

UK researchers, including Chris Ponting, colleagues from the CMRC and the CureME team are aiming to put a proposal in for a large GWAS later this year. The study might need as many as 20,000 patients.


But recruiting so many ME/CFS patients would pose an unprecedented challenge for the researchers. The study would be the largest ever conducted in ME/CFS.
DNA-people.jpg


However, recent years have seen rapid growth of an action orientated patient community around the world. MillionsMissing events, for example, have shown what patients can come together to achieve. Chris Ponting says,

“we can get this done, and done fast – but it will be people with ME who make it happen.”
 

Gemini

Senior Member
Messages
1,176
Location
East Coast USA
UK researchers, including Chris Ponting, colleagues from the CMRC and the CureME team are aiming to put a proposal in for a large GWAS later this year. The study might need as many as 20,000 patients.

But recruiting so many ME/CFS patients would pose an unprecedented challenge for the researchers. The study would be the largest ever conducted in ME/CFS.

@Simon excellent blog!

In the US the NIH's Precision Medicine Initiative has set a goal of enrolling 1 Million+ people in their "All Of Us Research Program." It has already achieved about a quarter of that in its first year.

Whole genome sequencing on all who enroll will start by the end of 2019, at no cost to the participants who will receive their test results.

The Program's data will also be available to researchers who can apply to NIH to study it.

Currently 700 ME/CFS patients have enrolled; as far as I can tell US patient advocacy groups have not been involved but that number might be higher in the future if they were. Perhaps @Emily Taylor and @JaimeS can comment?

I believe researchers worldwide can apply to NIH to study the "All Of Us" data. Do you think UK researchers would be interested?

https://forums.phoenixrising.me/thr...-all-of-us-research-study.76309/#post-2205550