Genome Wide Associations

Seanko

Well-Known Member
ME Research UK have reported on a new paper on genome wide associations & ME/CFS published in Nature's Translational Psychiatry by an international team including Dr Meirleir of the University of Nevada.

MERUK on Genome wide Associations
Source Paper in Nature's Translational Psychiatry

Genome-wide association studies involve the rapid scanning of participants’ DNA (their genome) to hunt for genetic variations. A comprehensive genome-wide association study in ME/CFS was published this month.
In human beings, a very small number of DNA gene sequences differ between individuals, and these consist largely of single nucleotide polymorphisms (SNPs, pronounced “snips”). While most SNPs are silent, others have important consequences; for instance, an HLA-DRB1 gene SNP is associated with a 3–6 fold higher risk of multiple sclerosis, and a SNP mutation in the APOE gene with an increased risk of Alzheimer’s disease. At present, scientists in many countries are working to identify particular SNPs and link them with particular diseases.
The most comprehensive GWAS of an ME/CFS cohort yet conducted has just been published by a consortium of researchers from Nevada, USA, Hungary and Russia (read more) . They recruited 42 people with a confirmed diagnosis of ME/CFS (Fukuda 1994 and ICC 2011) and 38 healthy controls; in each, genomic DNA was extracted from white blood cells and loaded onto a Genome-Wide SNP Array (‘SNP chip’) representing over 906,600 known SNPs. In total, 659,094 SNPs passed quality control, and 442 (407 autosomal and 35 on the X chromosome) were found to be associated with ME/CFS, though most of these were in non-coding regions of the genome and believed (at the present time) to have no functional significance.

Overall, 23 SNPs had a strong statistical association with ME/CFS, and the most significant SNP was in an intragenic region of the RECKgene which is thought to have a role in slowing or preventing secondary tumours. Two of the 23 SNPs were in locations associated with T-cell receptors, and another was observed in the area ofGRIK3, a gene involved in neurotransmission and also identified in a previous SNP study of ME/CFS (read more).

Twelve SNPs were located within the coding region of a gene, so could ‘linked’ to a particular gene. Two of these were in the immunoglobulin lambda locus, involved in antibody production, and another was in the CLEC4M gene locus involved in the recognition of pathogens. In addition, there were three regions with multiple statistically significant SNPs in proximity to specific genes (the MAP7gene on chromosome 6; the CCDC7 gene on chromosome 10; and the T-cell receptor loci). Very little is known about the first two, but T-cell receptors are critical components of adaptive immunity, and many believe ME/CFS to have an an autoimmune component.

Like all genome-wide association studies, this was essentially a fishing expedition – a dense and comprehensive survey of the entire genome to find SNPs that differ between ME/CFS patients and healthy people. The authors identified 23 interesting candidates – which are passed on from generation to generation, like all SNPs – but whether they predispose or cause ME/CFS remains unknown. Essentially, the importance of this study lies in showing other researchers where to concentrate their efforts, while recognising that a genetic predisposition to ME/CFS, if one exists at all, is most likely to involve multiple genes acting in concert and the influence of environmental factors.
 

Seanko

Well-Known Member
Original paper: http://www.nature.com/tp/journal/v6/n2/full/tp2015208a.html
Genome-wide association analysis identifies genetic variations in subjects with myalgic encephalomyelitis/chronic fatigue syndrome

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 (adjustedP-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.

Source: http://www.nature.com/tp/journal/v6/n2/full/tp2015208a.html
 

Seanko

Well-Known Member
They were looking for specific genetic traits in patients with ME/CFS, they have identified 23 possible areas...They did not use the phrase but imply "further study is needed." :)
 

bobby

Well-Known Member
thanks @Seanko ! I remember Ron Davis saying in The Forgotten Plague that the possibilities are pretty much endless when it comes to unravelling the human genome. So it's probably gonna take a while until they find any real clues... Good to know they're searching for it though!

btw I hate that sentence 'further study is needed'...
 

Croatoan

Well-Known Member
OK, one gene they look at is RECK, which regulates metalloproteinase, and of course it is sensitive to oxidative stress:
http://www.ncbi.nlm.nih.gov/pubmed/11121376
https://eurheartj.oxfordjournals.org/content/ehj/24/24/2180.full.pdf

Also they found associations between CFS and SNPs in T Cell receptor genes (TRA) and glutamate receptors, (GRIk2 and GRIK3)

To me the glutamate receptors can tell a lot of the story since they seem to have a connection with serotinin:
http://onlinelibrary.wiley.com/doi/10.1046/j.1460-9568.1998.00248.x/abstract?userIsAuthenticated=false&deniedAccessCustomisedMessage=

But again, since they did not look on the X chromosome they will be missing a big part of the story in my opinion.
Looks like the chip that used could look at the X chromosome, but they might not have looked there regardless.
 
Last edited:

Cort

Founder of Health Rising and Phoenix Rising
Staff member
OK, one gene they look at is RECK, which regulates metalloproteinase, and of course it is sensitive to oxidative stress:
http://www.ncbi.nlm.nih.gov/pubmed/11121376
https://eurheartj.oxfordjournals.org/content/ehj/24/24/2180.full.pdf

Also they found associations between CFS and SNPs in T Cell receptor genes (TRA) and glutamate receptors, (GRIk2 and GRIK3)

To me the glutamate receptors can tell a lot of the story since they seem to have a connection with serotinin:
http://onlinelibrary.wiley.com/doi/10.1046/j.1460-9568.1998.00248.x/abstract?userIsAuthenticated=false&deniedAccessCustomisedMessage=

But again, since they did not look on the X chromosome they will be missing a big part of the story in my opinion.
Looks like the chip that used could look at the X chromosome, but they might not have looked there regardless.
Interesting that GRIK2 gene showed up again! The last one was in what looked like a pretty strong CDC study. Both gene expression and gene polymorphisms had to show up in that study. Finding a GRIK gene again in another group might be pretty significant.

The convergence is also interesting because the CDC study used a population based patients derived from random sampling using the Empirical definition - and some general similarities showed up in with the post-infectious group. Who would have thought?
From the CDC study
RESULTS:

Sixty-five SNPs were nominally associated with CFS (p<0.001), and 165 genes were differentially expressed (≥4-fold; p≤0.05) in peripheral blood mononuclear cells of CFS subjects. Two genes, glutamate receptor, ionotropic, kinase 2 (GRIK2) and neuronal PAS domain protein 2 (NPAS2), were identified by both SNP and gene expression analyses. Subjects with the G allele of rs2247215 (GRIK2) were more likely to have CFS (p=0.0005), and CFS subjects showed decreased GRIK2 expression (10-fold; p=0.015). Subjects with the T allele of rs356653 (NPAS2) were more likely to have CFS (p=0.0007), and NPAS2 expression was increased (10-fold; p=0.027) in those with CFS.
CONCLUSION:

Using an integrated genomic strategy, this study suggests a possible role for genes involved in glutamatergic neurotransmission and circadian rhythm in CFS and supports further study of novel candidate genes in independent populations of CFS subjects.
 

Cort

Founder of Health Rising and Phoenix Rising
Staff member
thanks @Seanko ! I remember Ron Davis saying in The Forgotten Plague that the possibilities are pretty much endless when it comes to unravelling the human genome. So it's probably gonna take a while until they find any real clues... Good to know they're searching for it though!

btw I hate that sentence 'further study is needed'...
It does get a little tiring...:)
Getting at the genome is not easy. We need REALLY big studies.
 

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