Genome-wide association analysis identifies genetic variations in subjects with [ME/CFS], 2016, Schlauch et al

Genome-wide association analysis identifies genetic variations in subjects with myalgic encephalomyelitis/chronic fatigue syndrome

K A Schlauch, S F Khaiboullina, K L De Meirleir, S Rawat, J Petereit, A A Rizvanov, N Blatt, T Mijatovic, D Kulick, A Palotás, V C Lombardi

(Line breaks added)

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.

Link | PDF (Translational Psychiatry) [Open Access]

 

2016 study, but posting because there was a semi-replication of a gene from an even older GWAS [27]. Both small studies, but just some genes to watch in any future genetic studies.

The older study, Smith et al, used Fukuda. It reported the genes significant in both DNA and in mRNA expression levels. The thread's study required both Fukuda and CCC. GRIK2 was reported in the older study and GRIK3 in this one, and these are apparently orthologs with similar functions.

----

And I think this is saying a SNP on ATAD1 was significant in Smith just in the DNA, and the same SNP was significant in this study:

From GeneCards:

----

And it says to keep an eye on the TCA (T-cell receptor alpha) gene (also called TRAC) in future studies:

27. Smith AK, Fang H, Whistler T, Unger ER, Rajeevan MS. Convergent genomic studies identify association of GRIK2 and NPAS2 with chronic fatigue syndrome.
Neuropsychobiology 2011; 64: 183–194

----

Edit: I think they mean GRIK2 and GRIK3 are "paralogs", not "orthologs".

GeneCards also says these two genes are "paralogs".

 

So does a non-coding gene mean it doesn't affect protein products etc?

Don't seem to have the Ladybird Book of Genetics, though I'm pretty sorted for Stamp Collecting, Levers Pulleys & Engines, Making a Transistor Radio, and Pond & River Birds.

 

It means that that particular variant of the DNA base sequence (the single nucleotide (SN) change or 'polymorphism' (SNP)) does not do anything directly to a protein sequence. But that does not mean the SNP link is not important. The SN change might affect protein production if it is part of a binding site for a protein X that regulates the production of another protein Y (X being a transcription factor, whose own amino acid sequence is coded somewhere else completely).

But more generally SNPs are used just to indicate that there has been a mutation or variant formation in a domain that may include perhaps 10 genes. DNA gets inherited in chunks, partly as whole chromosomes but there is also a process of swapping over chunks of genes from one chromosome to another (translocation - I think in this case it is called sister chromatid exchange but I forget the jargon).

If a disease is caused by a mutation or variant in gene U then that variation will spread to offspring along with a chunk or domain that might contain genes RSTUVWX etc. An SNP between genes S and T in the same ancestry can be quite a good tag for a mutation in gene U over many generations. So when an SNP link is found geneticists tend to look to see what genes are nearby, as well as what gene the SNP is in or next to.

This is roughly my level of understanding and things are more complicated. But the bottom line is that if an SNP produces a protein mistake directly then it is likely to indicate that protein is important but if not the linkage may be just as important but the culprit gene may be nearby but not at the SNP site.

 

Thanks, that really helps!

 

Just noting that there was a fairly large 2022 study that tried to confirm this team's TCA (or TRA, T cell receptor alpha) gene finding, and they found no association.

"large Norwegian ME/CFS cohort (409 cases and 810 controls) and data from the UK biobank (2105 cases and 4786 controls)"

No replication of previously reported association with genetic variants in the T cell receptor alpha (TRA) locus for (ME/CFS), 2022, Ueland et al