Locus for severity implicates CNS resilience in progression of multiple sclerosis, 2023, MS consortia

[Jacob Richter]

Post copied from the DecodeME thread:

I agree the 85% response rate is fantastic - unheard of really. Decode ME is such a brilliant study.

On a related note, I found the following UCSF and University of Cambridge study on MS, published yesterday, interesting:

Scientists identify first genetic marker for MS severity | University of Cambridge

"A study of more than 22,000 people with multiple sclerosis has discovered the first genetic variant associated with faster disease progression, which can rob patients of their mobility and independence over time [...] This gives us a new opportunity to develop new drugs that may help preserve the health of all who suffer from MS.”

Are there lines of communication open between the Decode ME team and researchers collecting DNA sample sets to search for for susceptibility genes and causal mechanisms for diseases like MS? Hopefully there will opportunities over the long term to share lessons etc


Edit: Published paper abstract added:
https://www.nature.com/articles/s41586-023-06250-xLocus for severity implicates CNS resilience in progression of multiple sclerosis

• International Multiple Sclerosis Genetics Consortium &
• MultipleMS Consortium

Abstract

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) that results in significant neurodegeneration in the majority of those affected and is a common cause of chronic neurological disability in young adults1,2. Here, to provide insight into the potential mechanisms involved in progression, we conducted a genome-wide association study of the age-related MS severity score in 12,584 cases and replicated our findings in a further 9,805 cases.

We identified a significant association with rs10191329 in the DYSF–ZNF638 locus, the risk allele of which is associated with a shortening in the median time to requiring a walking aid of a median of 3.7 years in homozygous carriers and with increased brainstem and cortical pathology in brain tissue. We also identified suggestive association with rs149097173 in the DNM3–PIGC locus and significant heritability enrichment in CNS tissues.

Mendelian randomization analyses suggested a potential protective role for higher educational attainment. In contrast to immune-driven susceptibility3, these findings suggest a key role for CNS resilience and potentially neurocognitive reserve in determining outcome in MS.

 

[Hutan]

Copied post

From @Jacob Richter's link on MS genes:
Interesting, and it really underlines how important it is to set up patient registries that track patients over the course of their illness.

In findings published today in Nature, an international collaboration of researchers report a genetic variant that increases disease severity, providing the first real progress in understanding and eventually fighting this aspect of MS.

The work was the result of a large international collaboration of more than 70 institutions from around the world, led by researchers from UCSF (USA) and the University of Cambridge (UK).

“Inheriting this genetic variant from both parents accelerates the time to needing a walking aid by almost four years,” said Professor Sergio Baranzini at UCSF, co-senior author of the study.

“Understanding how the variant exerts its effects on MS severity will hopefully pave the way to a new generation of treatments that are able to prevent disease progression,” said Professor Stephen Sawcer from the University of Cambridge and Cambridge University Hospitals NHS Foundation Trust, the other co-senior author of the study.

To address the mystery of MS severity, two large MS research consortia joined forces: The International Multiple Sclerosis Genetics Consortium (IMSGC) and The MultipleMS Consortium. This enabled MS researchers from around the world to pool the resources needed to begin to identify the genetic factors influencing MS outcomes.

Previous studies have shown that MS susceptibility, or risk, stems in large part from dysfunction in the immune system, and some of this dysfunction can be treated, slowing down the disease. But, explained Baranzini, “these risk factors don’t explain why, ten years after diagnosis, some MS patients are in wheelchairs while others continue to run marathons.”

The two consortia combined data from over 12,000 people with MS to complete a genome-wide association study (GWAS), which uses statistics to carefully link genetic variants to particular traits. In this case, the traits of interest were related to MS severity, including the years it took for each individual to advance from diagnosis to a certain level of disability.

After sifting through more than seven million genetic variants, the scientists found one that was associated with faster disease progression. The variant sits between two genes with no prior connection to MS, called DYSF and ZNF638. The first is involved in repairing damaged cells, and the second helps to control viral infections. The variant’s proximity to these genes suggests that they may be involved in disease progression.

To confirm their findings, the scientists investigated the genetics of nearly 10,000 additional MS patients. Those with two copies of the variant became disabled faster.

@Andy or @Chris Ponting, if you have a spare moment, perhaps you could remind us what might happen after the initial DecodeME project? I guess you'd need a whole lot more funding to create an ongoing very large patient registry?

Professor Alastair Compston from the University of Cambridge and a founding member of the IMSGC added: “Having been personally involved with the identification of susceptibility genes for multiple sclerosis since the 1970s, it is a tribute to those within IMSGC who led this project that fully independent risk variants for progression have now been discovered.

Hopefully it won't take 50 years for the genetics of ME/CFS to be unravelled.

 

[ME/CFS Skeptic]

Moved posts

This is the MS paper in question: Locus for severity implicates CNS resilience in progression of multiple sclerosis | Nature

Unfortunately, I do not have access to it. Does anyone have an effect size or p-value for the association because they don't seem to report any in the abstract.

 

[Chris Ponting]

This is the MS paper in question: Locus for severity implicates CNS resilience in progression of multiple sclerosis | Nature

Unfortunately, I do not have access to it. Does anyone have an effect size or p-value for the association because they don't seem to report any in the abstract.

Variant rs10191329 (minor allele frequency 17%) near to genes DYSF and ZNF638: p = 9.7x10-9 (whereas the usual significance threshold is p<5x10-8). This was then replicated (p=3.6x10-9). Effect size = 0.89 (0.015 standard error). Probably acts on dysferlin (DYSF) but could [also] be on ZNF638. No effect of Vitamin D on MS severity.

 

[duncan]

Variant rs10191329 (minor allele frequency 17%) near to genes DYSF and ZNF638: p = 9.7x10-9 (whereas the usual significance threshold is p<5x10-8). This was then replicated (p=3.6x10-9). Effect size = 0.89 (0.015 standard error). Probably acts on dysferlin (DYSF) but could [also] be on ZNF638. No effect of Vitamin D on MS severity.

Seems more prudent to focus on determining the cause(s) of any disease or syndrome, rather than some purported innate deficiency that may or may not be responsible for the disease presenting faster or worse in a portion of the patient population.

 

[Mij]

Merged

Genetic Variant Linked to Faster Progression of Multiple Sclerosis Found

Source: Yale

A study of more than 22,000 people with multiple sclerosis (MS) has for the first time identified a genetic variant associated with faster progression of the disease, an accumulation of disability that can rob patients of their mobility and independence over time.

Summary: A new study involving over 22,000 people with Multiple Sclerosis (MS) has identified a genetic variant associated with the disease’s faster progression.

The research discovered a genetic variant that significantly affects disease severity. This development brings us closer to understanding and combatting the progressive form of MS. The identified genetic variant accelerates disability, undermining patient mobility and independence over time.

Key Facts:

1. This is the first study that identifies a genetic variant that significantly increases the severity of MS.
2. The variant is located between two genes, DYSF and ZNF638, which have no prior connection to MS, hinting at a possible mechanism for faster progression.
3. MS patients inheriting this genetic variant from both parents see the time to needing a walking aid accelerated by nearly four years.

https://neurosciencenews.com/genetics-progressive-ms-23546/

 

[Hutan]

Regarding the funding:

This work was supported in part by funding from the National Institutes of Health/National Institute of Neurological Disorders and Stroke, the European Union’s Horizon 2020 Research and Innovation Funding Programme, and the Multiple Sclerosis Society of Canada.

I wondered about whether there was a US government funded ME patient registry.

There's this one:
The Multiple Sclerosis Surveillance Registry: A Novel Interactive Database Within the Veterans Health Administration, 2020

Objective
To demonstrate the infrastructure and utility of an interactive health system database for multiple sclerosis (MS), we present the MS Surveillance Registry (MSSR) within the US Department of Veterans Affairs (VA).

Background
Disease specific databases can be helpful in the management of neurologic conditions but few are fully integrated into the electronic health record and linked to health system data. Creating a consistent information technology (IT) architecture and with ongoing support within disease specific registries has been a challenge.

Methods
Building the MSSR was initiated by an iterative process with an IT team and MS health care providers. A common registry platform shared by other VA disease specific registries (eg, traumatic brain injury and cancer) was used to develop the IT infrastructure. MS cases were entered online into the MS Assessment Tool at selected MS Centers of Excellence (MSCoE) clinics in the US. Other large VA databases linked to MSSR are reviewed. Patient demographic and clinical characteristics were compared and contrasted with the broader VA population and other US registry populations.

Results
We have enrolled 1,743 patients with MS in the MSSR through fiscal year 2019 from selected MS regional programs in the VA MSCoE network. The mean age of patients was 56.0 years, with a 2.7 male:female ratio. Among those with definite MS, the mean European Database for MS Disability Score was 4.7 and 75% had ever used an MS disease modifying therapy. A summary electronic dashboard was developed for health care providers to easily access demographic and clinical data for individuals and groups of patients. Data on comorbid conditions, pharmacy and prosthetics utilization, outpatient clinic visits, and inpatient admission were documented for each patient.

Conclusions
The MSSR is a unique electronic database that has enhanced clinical management of MS and serves as a national source for clinical outcomes.


It could be worth pushing NIH to have a similar ME/CFS database established, perhaps within the Veterans Health Administration. I'm not sure what patient registry facility they have for Gulf War Illness.

(minor edit)