@Valentijn and
@shoponl
Just a technical note here because I've been researching this gene a fair bit: I think the most up-to-date understanding of how GCH1 is likely working in terms of haplotypes, in a European population, is found in the first reference I gave in
post #20 above, which is from 2014.
You can see in Fig. 1C of
Figure 1 of that article, which I show below, that there appear to be 2 large haploblocks, the first of which can be defined by rs10483639, rs841 and rs3783641; the second of which by rs10137071 and rs8007267.
23andMe no longer tests for rs841 in its latest test (v4), which is a little unfortunate because I think this may well be the most functional common SNP for the first haploblock (and maybe the whole gene). But since it's in tight linkage disequilibrium with rs10483639 and rs3783641 those should work okay as proxies.
23andMe doesn't test for rs10137071 (on either v3 or v4), so that leaves rs8007267.
So from the latest research, as limited by 23andMe, we're left with exactly the same 3 SNPs that comprise what Promethease/SNPedia calls "gs224" (rs10483639; rs3783641; rs8007267).
About rs841, it's actually located in the
3'-UTR region of the gene, so it doesn't affect the function of the resulting protein/enzyme (i.e., GTP cyclohydrolase 1). However, from everything I've read, it does seems to be very significantly affecting how well the gene is expressed (post-transcriptionally) and therefore how much of the enzyme is actually made (and thus ultimately how much BH4 is made and whether the NOS enzymes properly produce nitric oxide versus peroxynitrite). This particular 3'-UTR SNP seems subject to affects from a great variety of different regulators, like cytokines, blood sugar, oxidative stress, AMPK, etc.
(Rs841 is probably the best single proxy not only for the first haploblock, but for the entire gene, and alone might give 90% or more specificity for a person's genotype for GCH1. But it's a moot point now that it's no longer available, and the other two SNPs for the first haploblock in gs224 seem to mostly represent it.)
Just to mention also that a Japanese study looked specifically to see whether there might be a correlation between rs841 and "CFS." They came to the conclusion that there wasn't one (except for, allegedly, "harm avoidance"), but I haven't seen the full text yet to see how the cohort was selected and all the statistics. (
Association of monoamine-synthesizing genes with the depression tendency and personality in chronic fatigue syndrome patients)
Regardless, I do think that rs841 (rs10483639/rs3783641), while not likely a cause of ME/CFS, is very likely to exacerbate/make worse any disease that involves significant oxidative stress, and that includes ME/CFS.