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Mitochondrial DNA variants correlate with symptoms in ME/CFS

Simon

Senior Member
Messages
3,789
Location
Monmouth, UK
Thanks, @Bob

As it's under a CC licence I will quote here almost completely - reallly interesting stuff, and very good of Maureen Hanson to arrange for an accessible report.

The main point that grabbed me in this thorough study, after reading this report, is the idea that "much of the diversity of the manifestation of the illness [could] results from genetic diversity rather than the existence of multiple fundamental causes". Don't know how easily you can distinguish between the possibities but it's an intersting idea..

Mitochondria and ME/CFS A Guide to the Hanson Lab's 2016 JTM Publication

Patients with ME/CFS experience a profound lack of energy, severe fatigue, along with a variety of other symptoms, including one or more of the following:... Mitochondria, sub-cellular organelles are responsible for producing ATP, the energy coinage of the cell, through conversion of glucose. Therefore, a logical approach to learn more about a disease affecting energy is probing of the function of mitochondria.

Mitochondria are made up of molecules encoded by the nuclear genome--DNA located in the nucleus--as well as the mitochondrial genome—a small amount of DNA present within each organelle. Defects in mitochondrial DNA lead to devastating genetic diseases, with such symptoms as brain abnormalities, severe fatigue, blindness or defective heart function—and can be fatal.

The mitochondrial genome of healthy humans also exhibits some natural variation—a single component of the mitochondrial DNA sometimes differs between one human and another—this is known as a SNP (single nucleotide polymorphism, "snip").

Often more than one SNP differs between one population of humans and another—for example, mitochondrial genomes whose origin can be traced to France differ in a number of SNPs from those in people in Central Asia. These different types of mitochondrial genomes, based on a specific set of SNPs, are referred to as haplogroups. Even people whose mitochondrial DNA belongs to the same haplogroup can differ among one another because of some variation in additional SNPs. Some mitochondrial SNPs have been... implicated in susceptibility to diabetes and various inflammatory diseases...

A further complexity of mitochondrial genetics is that there are many individual mitochondria within the same cell, and thus many copies of mitochondrial DNA in each cell. Sometimes new mutations arise so that some of the copies of DNA within the same cell, and therefore within the same person, differ from one another. This situation is called “heteroplasmy”. As cells grow and multiply, by chance there can be uneven distribution of normal vs. abnormal DNA to different cells. If mitochondrial DNA with a harmful mutation becomes the predominant type in a particular tissue, serious symptoms will emerge.

In our recent paper, work that was primarily supported by the Chronic Fatigue Initiative, we sequenced the mitochondrial DNA from a cohort of ME/CFS patients and healthy individuals, using DNA extracted from white blood cells stored in the biobank developed by the Chronic Fatigue Initiative.

We asked four primary questions:

  • Were any of the ME/CFS patients identified by 6 well-known ME/CFS experts misdiagnosed and are actually victims of a mitochondrial genetic disease?
  • Do people with ME/CFS carry more copies of mitochondrial DNA with harmful mutations than healthy people (heteroplasmy)?
  • Are people belonging to one haplogroup more likely to fall victim to ME/CFS than another?
  • Are people who have particular SNPs more likely to experience particular symptoms or have increased severity of symptoms?
Our work showed that
  • none of the blood samples obtained from 193 patients identified by the CFI’s 6 expert M.D.s gave any indication of a mitochondrial genetic disease.
  • Furthermore, we found no difference in the degree of heteroplasmy between patients and healthy individuals.
  • We also observed no increased susceptibility to ME/CFS among individuals carrying particular haplogroups or SNPs within a haplogroup.

However, we did detect associations of particular SNPs with certain symptoms and/or their severity. For example, we did find that individuals with particular SNPs were more likely to have gastrointestinal distress, chemical or light sensitivity, disrupted sleep, or flu-like symptoms. This finding does NOT mean that if your mitochondrial DNA carries one of these SNPs, you will inevitably experience a particular symptom or have higher severity of some symptoms. Instead, because a particular SNP was seen more often in ME/CFS patients with certain characteristics, individuals that carry that SNP are predicted to be at greater risk of experiencing particular types of symptoms once they become ill.

This study demonstrates the importance of a well-characterized cohort of patients and controls along with detailed clinical information about their experience of illness. Without the data from the lengthy patient questionnaires collected along with the subject’s blood, we could not have correlated SNPs with patient characteristics.

While the materials from the CFI subjects are extremely valuable and our results are statistically significant, greater numbers of subjects must be analyzed to determine whether the correlations we detected continue to hold up when more patients are studied, and whether such correlations exist within people carrying other haplogroups. Due to the European origin of most of the ancestors of the CFI subjects, most belong to haplogroup H, the most common European haplogroup.

A much larger number of haplogroup H subjects, as well as large cohorts of individuals with other haplogroups, will be necessary to analyze to dissect out other possible correlations or to determine whether or not any of the correlations we detected with a relatively small population are spurious. With more subjects, we might also be able to detect additional correlations that were not obvious from our initial study.

Whether or not the genetic correlations we have observed are verified or not through further work, our study indicates an important hypothesis that should be tested in ME/CFS. How much of the variation in symptoms between different individuals results from their different nuclear and/or mitochondrial genetic makeup, rather than variation in the inciting cause?

A puzzling aspect of ME/CFS has been the diversity of symptoms and the variation of their severity among different individuals. These differences should not be taken as proof that more than one insult was the initiating factor, nor that different patients have different underlying problems. It remains possible that much of the diversity of the manifestation of the illness results from genetic diversity rather than the existence of multiple fundamental causes.


Future Studies

Whether mitochondria are impaired in ME/CFS has not been definitely determined. Mitochondria could be affected either directly or indirectly in the disease. For example, some disturbance in metabolism or regulation of genes could prevent mitochondria from functioning properly. Theoretically, mitochondria could be affected through an unknown autoimmune mechanism. We have begun to investigate the properties of mitochondria in ME/CFS further by examining how well they function in white blood cells, relative to healthy individuals.

Donate to Support the Hanson Lab's ME/CFS Research
 

valentinelynx

Senior Member
Messages
1,310
Location
Tucson
Interesting stuff
JTM | Full text | Mitochondrial DNA variants correlate with symptoms in myalgic encephalomyelitis/chronic fatigue syndrome

I suspect I annoy some people with how often I bang on about problems of not correcting for multiple comparisons (p<0.05 only works for one comparison: the more comparisons you make, the more chance of a false positive with p<0.05). So I wanted to say how much I appreciate the authors taking the trouble to correct their data for false positives:


Just to show what a difference it makes:

Note how that exciting p value of 0.03 becomes an altogether irrelevant corrected p-value [aka q-value] of 0.6 (=nothing doing). That shows just how big a difference correction for multiple comparisons can make.

In this case they were looking at 21 haplotypes ie 21 comparisons. I've seen many paper that make similar numbers of comparisons with NO correcction for many comparisons. I suspect this is a big issue in mecfs research.


Yes, interesting given they did correct for multiple comparisons. Though worth noting that the results aren't hugely significant: the lowest one was p=0.023, and the other five p=0.039 or higher. (Table 3)

Thank you for answering my question - I was wondering if they had succumbed to the error you mentioned. Glad to see some people are finally getting this.
 

barbc56

Senior Member
Messages
3,657
I suspect I annoy some people with how often I bang on about problems of not correcting for multiple comparisons (p<0.05 only works for one comparison: the more comparisons you make, the more chance of a false positive with p<0.05). So I wanted to say how much I appreciate the authors taking the trouble to correct their data for false positives

Not annoying at all.

A valuable statistics lesson and a researcher who seems to have ethics! :thumbsup:

I can't say about the research as it's way over my head.

Thanks.
Barb
 

Mary

Moderator Resource
Messages
17,335
Location
Southern California
@Marky90 - I started a new thread before I learned that this one existed. But there's a link from a blogger which might be of interest which compared their SNPs to the ones found in the study.

from the thread I started:

https://cfsremission.wordpress.com/2016/01/23/new-study-found-snps-for-some-symptoms/

The original study the above article is based on is here: http://www.translational-medicine.com/content/14/1/19

And I compared my SNPs to those of the person who wrote the wordpress article above, and mine were a match with him or her, except for nucleotide position 16519, where I had a C instead of a T (for more gastro symptoms). Though I didn't get a result from 23andme for 16223.

And Adreno responded, and he was match for the blogger's SNPs.
 

shannah

Senior Member
Messages
1,429
@Marky90 - I started a new thread before I learned that this one existed. But there's a link from a blogger which might be of interest which compared their SNPs to the ones found in the study.

from the thread I started:

https://cfsremission.wordpress.com/2016/01/23/new-study-found-snps-for-some-symptoms/

The original study the above article is based on is here: http://www.translational-medicine.com/content/14/1/19

And I compared my SNPs to those of the person who wrote the wordpress article above, and mine were a match with him or her, except for nucleotide position 16519, where I had a C instead of a T (for more gastro symptoms). Though I didn't get a result from 23andme for 16223.

And Adreno responded, and he was match for the blogger's SNPs.

Nice chart associating SNPs with symptoms. I tried copying the table from the research paper. Thought it might be informative to have it appear on this thread but alas, it won't copy for me in chart form.
 

Mary

Moderator Resource
Messages
17,335
Location
Southern California

Wow - that's really interesting! e.g., this statement:

What this means is that 1) ME/CFS is not genetic, 2) ME/CFS patients do not have pre-dispositions for getting the disease, and 3) there may be a single pathogen causing the disease.

and this:

"A puzzling aspect of ME/CFS has been the diversity of symptoms and the variation of their severity among different individuals. These differences should not be taken as proof that more than one insult was the initiating factor, nor that different patients have different underlying problems. It remains possible that much of the diversity of the manifestation of the illness results from genetic diversity rather than the existence of multiple fundamental causes.

"This study provides a rationale for outbreaks and clusters. It also accounts for both the discrepancies in Fukuda, CCC, and ICC clinical case definitions as well as the large number of possible combinations of symptoms. These case definitions may be describing the same illness, caused by the same pathogen, as it is experienced by people with distinct genetic variations.
 
Messages
15,786
Some Blog said:
What this means is that 1) ME/CFS is not genetic, 2) ME/CFS patients do not have pre-dispositions for getting the disease, and 3) there may be a single pathogen causing the disease.
They are completely wrong to reach any such conclusion on all three points.

1)The authors of the study looked at mitochondrial DNA. This is a tiny, tiny piece of the human genome. MTDNA consists of about 16,000 SNPs, whereas all DNA consists of about 3 billion SNPs. That means they looked at 0.00053% of the human genome. That leaves 99.99947% that could potentially still be harboring mutations causing serious problems.

And science is an ongoing process. One study does not close the book on the subject.

2) Even if genetics were completely ruled out (they aren't, see #1), there are other types of predispositions. Environmental, behavioral, earlier infections, etc etc.

3) It's unlikely that there is a single pathogen, and nothing in this study supports that conclusion, even if genetics contributions were ruled out (they aren't, see #1). There have been several prospective studies following people after they become ill with various infections, and a small percentage of them go on to develop ME/CFS. This includes EBV, Q-fever, ross-river virus, and probably a few others found thus far.

So please ... don't believe everything you read on a random blog :p