Genome-wide association analysis identifies genetic variations in subjects with ME/CFS

[voner]

This is an open acess paper. interesting collaboration of authors. 42 ME/CFS patients and 38 controls ... published in the journal, "Translational Psychiatry".

http://www.nature.com/tp/journal/v6/n2/pdf/tp2015208a.pdf

Genome-wide association analysis identifies genetic variations

in subjects with myalgic encephalomyelitis/chronic fatigue

syndrome

authors:
K A Schlauch1, S F Khaiboullina2,3, K L De Meirleir2, S Rawat2, J Petereit1, A A Rizvanov3, N Blatt3, T Mijatovic4, D Kulick5, A Palotás3,6 and V C Lombardi1,2

abstract

Myalgic encephalomyelitis, also known as chronic fatigue syndrome or ME/CFS, is a multifactorial and debilitating disease that has an impact on over 4 million people in the United States alone. The pathogenesis of ME/CFS remains largely unknown; however, a genetic predisposition has been suggested. In the present study, we used a DNA single-nucleotide polymorphism (SNP) chip representing over 906,600 known SNPs to analyze DNA from ME/CFS subjects and healthy controls. To the best of our knowledge, this study represents the most comprehensive genome-wide association study (GWAS) of an ME/CFS cohort conducted to date. Here 442 SNPs were identified as candidates for association with ME/CFS (adjusted P-value<0.05). Whereas the majority of these SNPs are represented in non-coding regions of the genome, 12 SNPs were identified in the coding region of their respective gene. Among these, two candidate SNPs resulted in missense substitutions, one in a pattern recognition receptor and the other in an uncharacterized coiled-coil domain-containing protein. We also identified five SNPs that cluster in the non-coding regions of T-cell receptor loci. Further examination of these polymorphisms may help identify contributing factors to the pathophysiology of ME/CFS, as well as categorize potential targets for medical intervention strategies.

 

[msf]

I´ve been waiting for this one for a while, particularly as I am one of the patients in the study (well, I gave my blood for it anyway!).

 

[Asa]

Could someone, please, "dumb-down" this info for me? Thank you!

 

[msf]

Could someone, please, "dumb-down" this info for me? Thank you!

They seem to have found some mutations in genes in some people with ME that are not present in controls. Some of these mutations are in the T-cell receptor genes, another is in another part of the immune system, and there are some with possible neurological implications too (one of these is similar to a previous finding by a different group).

 

[Helen]

As far as I can see only four of the significant twenty-three SNP´s listed on page 4 in the article were analyzed in the 23andme test ( the version used 2011) if you would like to check your own data.

rs6757577 KRT18P33

rs41378447 CASC14

rs7849492 --

rs2249954 FBLN5

 

[Valentijn]

The rs479448 missense mutation on CLEC4M is the one that looks the most interesting. The mutation scores -2 on the BLOSUM62 scale, which means there's a pretty big difference in the substituted amino acid. And CLEC4M is a gene involved in the innate immune system.

Data from the study shows 2.6% MAF for controls and 26.2% for the ME/CFS patients.

 

[Helen]

But the 23andMe data I have for 31 patients shows the same prevalence rate as the data from their controls, each group having a minor allele frequency (MAF - G allele) of 12.9%. Though it's a bit odd that it's that frequent in 23andMe data, since dbSNP says it's pretty rare in Europeans. Data from the study shows 2.6% MAF for controls and 26.2% for the ME/CFS patients.

Could it be that the studied patients were more carefully diagnosed than those you have data on, or are they all diagnosed by a ME/CFS specialist?

 

[Valentijn]

Could it be that the studied patients were more carefully diagnosed than those you have data on, or are they all diagnosed by a ME/CFS specialist?

No, I made an error in searching my excel data sheet, and a very similar number (extra 8 on the end) led me astray. It's not actually tested on 23andMe, so I edited my post.

 

[ahmo]

As far as I can see only four of the significant twenty-three SNP´s listed on page 4 in the article were analyzed in the 23andme test ( the version used 2011) if you would like to check your own data.

rs6757577 KRT18P33

rs41378447 CASC14

rs7849492 --

rs2249954 FBLN5

I'm homozygous for 3 of these 4.

 

[merylg]

I have one copy of the minor allele C for rs2249954 FBLN5. I am CT.
FBLN5 is interesting.

http://ghr.nlm.nih.gov/gene/FBLN5

I was actually considering taking part in a research study into Cutis Laxa but on enquiry I thought myself not well enough to complete all the required testing. Others may be interested.

http://cutislaxa.pitt.edu/

 

[GreyOwl]

None of those SNPs are in my results (tested in early 2015).

 

[roller]

the study shows 2.6% MAF for controls and 26.2% for the ME/CFS patients.

not that some decimal point...

 

[Helen]

In my opinion this study deserves a lot more of attention from PWME. I think it mediates hope and future treatment possibilities.

Surprisingly a study that indicates genetics as a cause of ME/CFS was published in a well-reputed journal of psychiatry. It´s time for the psychobabblers to change side; ME/CFS IS a disease or a syndrome of physical origin.
From the Journal of Translational Psychiatry
http://www.nature.com/tp/journal/v6/n2/full/tp2015208a.html
http://www.nature.com/tp/journal/v6/n2/suppinfo/tp2015208s1.html

From the abstract- to start with:

"The pathogenesis of ME/CFS remains largely unknown; however, a genetic predisposition has been suggested. In the present study, we used a DNA single-nucleotide polymorphism (SNP) chip representing over 906,600 known SNPs to analyze DNA from ME/CFS subjects and healthy controls. "

"To the best of our knowledge, this study represents the most comprehensive genome-wide association study (GWAS) of an ME/CFS cohort conducted to date."

"Further examination of these polymorphisms may help identify contributing factors to the pathophysiology of ME/CFS, as well as categorize potential targets for medical intervention strategies." (My bolding)

I think we could learn a lot by looking thorough at the 23 significant SNP´s (page 4) and how they can affect us. We might find explanations to our disparate symptoms while waiting for more research and a possibility to get the actual genes, or SNP´s, tested.

 

[Helen]

@voner , I ask you as a TS, could we save this thread for discussions about the research and create another thread for sharing our own data as far as they are known? No blame on you who already have shared yours.

 

[Valentijn]

Surprisingly a study that indicates genetics as a cause of ME/CFS was published in a well-reputed journal of psychiatry. It´s time for the psychobabblers to change side; ME/CFS IS a disease or a syndrome of physical origin.

It's not quite that simple, unfortunately. The first problem is that there's probably been a dozen or more studies involving SNPs in ME/CFS, and there's no consistent results. It's likely that they are not including the same set of SNPs in different studies, but they need to be replicated before they'll be taken seriously.

The other problem is that false positives are a pretty huge problem in genetic studies. For example, most of the "significant" results in this study involve SNPs which aren't even resulting in missense mutations. Even when correcting for multiple comparisons, there still seems to be a lot of positive results which don't hold up.

Correlations found in those non-coding SNPs also tend to have a very small effect size, meaning they aren't very relevant. So many healthy people will have the "risk" genotype for those SNPs, and many (most) patients probably won't have those "risk" genotypes.

The final problem is that similar SNP correlations are frequently found for supposed mental disorders. While it would possible suggest a genetic/biological underlying mechanism (if they results hold up consistently), it has done nothing at all to change the perception or treatment of those disorders. People don't just suddenly say "Oh, I guess it's not your fault for being (supposedly) weak-minded after all, here's a higher rate of disability payments which won't expire after two years." They're still expected to fix themselves with the prescribed counseling and psychotropic drugs.

If a genetic finding is going to be an impressive breakthrough for any disease, it won't be due to someone finding dozens of non-coding SNPs which are weakly correlated with a tiny increase of risk in developing a disease. It'll be from missense mutations, nonsense mutations, splicing errors, or similar drastic mutations which fundamentally alter how a gene (or a group of genes) functions.

To some extent, I think these typical SNP comparison studies are not suitable for finding such drastic changes. When pathological mutations are found in other diseases, it's not like 100% of those patients have the same mutation. Some mutations may be more common in causing that particular disease, but there also may be 20+ mutations on the gene which cause the disease (often presenting with different features and severity), with just a few patients having each mutation. And then there may be more genes, with more mutations, which also cause the same disease.

In that case, significance may be artificially lost, because none of the actually relevant individual mutations are prevalent enough in the patients to be statistically significant, even if none of the controls have those same mutations.

So I think genetic studies need to take a much more systematic approach, by focusing on the historically more relevant sections of DNA, such as exons and splice sites. It can also focus more specifically on genes likely to be relevant, such as those in the immune system, since genetic differences in the immune system could conceivable cause problems in a lot of other systems, whereas it's harder to imagine how genetic flaws with the nervous system or muscular system might cause problems with the immune system.

 

[msf]

They found some missense mutations in the study, and one was in a gene related to the immune system.

 

[Valentijn]

They found some missense mutations in the study, and one was in a gene related to the immune system.

12 coding mutations, and 430 non-coding It doesn't inspire a lot of faith.

 

[msf]

From the study:

Twelve of the 442 candidate SNPs associated with the ME/CFS
cohort were identi*ed in the coding region (exon) of their
respective gene: *ve of these were synonymous substitutions
(rs16973831, rs2274515, rs3732196, rs7613828 and rs17722227),
two were missense substitutions (rs2015035 and rs479448) and
the remainder were within T-cell receptor or immunoglobulin loci.
With respect to the missense substitutions, the observed SNP in
the gene CCDC157 (rs2015035), which codes for the coiled-coil
domain-containing 157 protein, results in a non-conservative
substitution of the amino acid Serine (S) to Alanine (A). The SNP in
the coding region of the CLEC4M gene, which codes for the C-type
lectin domain family 4, member M, results in a non-conservative
substitution of the amino acid tyrosine (Y) to cysteine (C). Whereas
the function of CCDC157 has not been fully characterized, coiledcoil
domains are common motifs and function as oligomerization
domains for a wide range of proteins such as structural proteins,
motor proteins and transcription factors.
43
CLEC4M, also know as
L-SIGN or CD299, is a mannose-binding C-type lectin receptor, a
component of the innate immune system that recognizes a broad
range of pathogens.

 

[msf]

12 coding mutations, and 430 non-coding It doesn't inspire a lot of faith.

Well, the way I see it is one is better than none. Did you want them to find all the genetic contributions to ME in a single study? They seem to have found more than the last group to attempt this, and also made a similar finding with a GRIK gene:

Two SNPs were identi*ed in the GRIK2 gene, which codes
for an excitatory neurotransmitter receptor that is primarily
expressed in the brain. A number of neurological maladies,
including autism and schizophrenia, are associated with GRIK2.
The second identi*ed SNP lies in the NPAS2 gene, which is a
putative circadian clock gene. Although the two SNPs identi*ed
for GRIK2 in the Smith et al. study were not represented on the
SNP Array 6.0, an ortholog of this gene (GRIK3) was observed to
signi*cantly associate with our ME/CFS cohort. Both GRIK2 and
GRIK3 code for transmembrane subunits of neuroexcitatory
receptors, belonging to the kainate family of glutamate receptors.
These receptors are composed of four subunits and function as
ligand-activated ion channels on presynaptic and postsynaptic
neurons.

 

[Helen]

@Valentijn , apparently I have more trust in our doctor, KDM. Do I get you right that you dismiss this study, or is there anything of value in it, in your opinion?