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New blog at ME/CFS Research Review
Guest blog by Professor Chris Ponting and colleagues.
Summary
A new analysis using data from UK Biobank indicates that one version of a particular gene increases the risk of ME/CFS in women. The gene codes for a transporter protein in the mitochondrial membrane and plays a critical role in the urea cycle, which is important for removing ammonia from the body. Reduced levels of the transporter protein, which are expected for the gene variant associated with ME/CFS, are likely to impair mitochondrial function. If replicated later, this finding would provide the first evidence that a person’s risk for ME/CFS is caused by changes to mitochondrial function.
Background
On June 11 2018 we posted a blog describing an analysis of the UK Biobank’s data, drawn from half-a-million individuals from around the UK. The data implied that there is a genetic contribution to an individual’s risk of ME/CFS but it did not provide strong evidence that change in any one section of DNA explained this risk.
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We are blogging again because a new analysis has revealed a promising finding.
This new analysis is again of the UK Biobank data and has been posted by Ben Neale’s lab. After discarding data that they considered lower quality, they were left with data from 194,174 females and 167,020 males and kindly made their results freely available to all.
Female-only GWAS
Considering males and females together they identified no specific region of the human genome whose DNA variants were significantly associated with self-reported CFS/ME. (One variant, rs148723539, is possibly indicated [p = 2.3x10-9] but this is not supported by adjacent variants.)
However, the female-only analysis revealed a single region, on chromosome 13. Ten DNA variants (single nucleotide variants, SNVs) were significantly associated [SNVs with minor allele frequency <0.001 or that were "low confidence” were filtered out] using a probability threshold of p < 5x10-8.
These 10 SNVs are inherited down the generations together (they are in “linkage disequilibrium” [LD]) and so this looks like just one association, rather than ten different ones. The 10 SNVs all lie in a 51,000 base region that surrounds the SLC25A15 gene (Figure 1 below).
Their conclusion is that DNA variation in this part of the genome slightly changes a woman’s risk of having a ME/CFS diagnosis. This must mean that one or more DNA differences in this part of the genome cause this risk change. But because all 10 differences are inherited together, it is not clear which one or ones are causing the increase in disease risk. Pinning down the causal DNA changes will require detailed experimental research.
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Ornithine Transporter type 1
Figure 1 shows that the GWAS genetic associations are for DNA differences that lie in-or-around a particular gene called SLC25A15.
So what do we know about SLC25A15? Interestingly, it encodes a protein called Ornithine Transporter type 1 (ORNT1). This transports ornithine (as well as lysine and arginine) across the inner membrane of mitochondria to the mitochondrial matrix.
Ornithine is an amino acid (but not incorporated into proteins) that plays a role in the urea cycle. This cycle plays an essential part in removing ammonia from the body (see point iv below).
This analysis predicts that if you have a letter G at this position then (Figure 2):
(i) if you are female, then you have a greater risk of ME/CFS;
(ii) many of your cells (for example in the heart or hippocampus, but not in muscle or liver) would tend to produce less ORNT1 RNA and less ORNT1 protein; and,
(iii) if so, then ornithine would build up in these cells and mitochondrial function overall would be impaired; and,
(iv) ammonia would accumulate in the blood.
... read the full blog
