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

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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.
Smith et al. utilized a convergent functional genomics approach by combining the analysis of a large-scale GWAS with an mRNA expression study to identify polymorphisms in two genes of interest in CFS subjects from the Wichita CFS Surveillance Study. Two SNPs were identified 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 identified SNP lies in the NPAS2 gene, which is a putative circadian clock gene. Although the two SNPs identified 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 significantly 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.
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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:
Of the 65 total SNPs identified as nominally associated with CFS (P<0.001) by Smith et al., only 28 were represented on the current SNP Array 6.0, and, of these, only one (rs10509412, ATAD1) was observed to associate within our ME/CFS cohort.
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From GeneCards:
ATAD1: Predicted to enable ATP hydrolysis activity. Involved in extraction of mislocalized protein from mitochondrial outer membrane. Located in mitochondrial outer membrane and peroxisomal membrane. Implicated in hyperekplexia 4.
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And it says to keep an eye on the TCA (T-cell receptor alpha) gene (also called TRAC) in future studies:
The implications of multiple SNPs in the intragenic regions of TCA loci are more obvious. In the thymus, the TCA gene undergoes somatic recombination to give rise to diverse amino-acid sequences in the antigen-binding regions of the alpha chain of T-cell receptors. T-cell receptors recognize antigens bound to major histocompatibility complex class I and class II molecules and, therefore, are critical components of adaptive immunity. Major histocompatibility complex can present antigens from nearly all forms of pathogens; however, T cells that recognize 'self' antigens and have escaped negative selection in the thymus can promote autoimmune disease. Indeed, polymorphisms in the TCA locus have been described in association with autoimmune disease. For example, based on familial associations with the human leukocyte antigen allele DQB1*0602, an autoimmune etiology had long been suggested for the sleep disorder narcolepsy; however, the identification of a polymorphism in the TCA locus provided the convincing evidence. If the association of these SNPs in the TCA locus is confirmed in a larger ME/CFS cohort, this observation may also provide evidence of an autoimmune component in this disease.
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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

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Edit: I think they mean GRIK2 and GRIK3 are "paralogs", not "orthologs".
Orthologs, or orthologous genes, are genes in different species that originated by vertical descent from a single gene of the last common ancestor.

If a gene in an organism is duplicated to occupy two different positions in the same genome, then the two copies are paralogous.
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GeneCards also says these two genes are "paralogs".
 
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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.
 
Kitty said:
So does a non-coding gene mean it doesn't affect protein products etc?
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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.
 
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