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Thanks. The reason that it doesn't show up in the UK Biobank (UKBB) is that this UKBB project was not focused on a particular disease (e.g. schizophrenia) but instead recruited 500,000 people from across the UK of whom relatively few had a schizophrenia diagnosis. The power of a GWAS comes from...

This is not a Genome-Wide Association Study (GWAS). It is not genome-wide, it has no appropriate control group, it is not well-powered for its intended aims, and its statistics are inappropriate. So, yes, I agree with your assessment.

Sorry, hadn't seen this until now. I agree with you, re: P4HA1. About chromosome 1 and LPGAT1: There is a risk of reading too much into 'peaks' that are not significant overall (over the entire genome). Yes, these *could* be true, but the statistics imply that most of them are false. In GWAS of...

Yes, the statistically significant association is to the DNA variant (SNP) and not to the gene. But having said that, the DNA variant does also predict the activity of SLC25A15 (ORNT1) - in other words the amount of the protein made by cells - so it is a good candidate for the gene that is...

Whole genome genotyping, probably using the Affymetrix UK Biobank Axiom® array. This will survey ~850,000 DNA variants in every person. Yes, it will not survey every one of our 3 billion DNA letters but the ~850,000 variants actually allow many other variants to be guessed accurately ("imputed")...

Unfortunately not likely. Participants were chosen according to different diagnoses, but I think it's highly unlikely that pwME were included. Personally, I think whole genome sequence (WGS) data is currently too expensive to do at scale. So the "SNP-chip" genotyping approach (that Nancy Klimas...

Thanks. A q-value is the expected fraction of 'false discoveries' in the full set of statistical tests used. https://en.wikipedia.org/wiki/Q-value_(statistics) As Wikipedia puts it: "Just as the p-value gives the expected false positive rate obtained by rejecting the null hypothesis for any...

@RDP It might be interesting to apply for the 50k exomes' data from UK Biobank. ~200 people with self-reported ME/CFS are expected to have had their exomes sequenced. The preliminary analysis (https://www.biorxiv.org/content/biorxiv/early/2019/03/09/572347.full.pdf) does not report an...

Thank you @RDP. This is very helpful indeed. I am only now left with a couple of questions: (1) What is the probability that your analysis would have alighted upon *any* gene with this burden of damaging mutations among all that you considered? (In other words, after correcting for multiple...

RE: "So if it is only two individuals that have this MNV I think we can say that for most people the STOP is valid. Am I right?" Yes, you're correct: only two individuals, I hadn't spotted this. Thank you. So for nearly all people that have the variant it does, indeed, truncate the protein...

Great questions. (1) Until the experiment is done we will not know for sure. But because natural selection is good at weeding out "bad" mutations over 100s/1000s of generations, we must have a strong expectation that the combined variants (cancelling each other) produce a "good", functioning...

Thanks. If we think - conservatively - that half of this cohort of people have one disease (with a genetic contribution) and the other half has another disease (with a genetic contribution) then - if the GWAS/genetics study is sufficiently powered - the *sum* of genetic signals for both would be...

Very few. MAF = minor allele frequency = 0.0001062. This number times 450247 is ~47 who would have *one* of their two copies of this gene with this DNA variant and predicted to be no people with both copies of this gene with this variant.

I needed some time to look into this. By reading the Broad investigators' manuscript on MNVs (here: https://www.biorxiv.org/content/biorxiv/early/2019/03/10/573378.1.full.pdf) and looking at the Supplemental Data for this paper this is the conclusion: the annotation of Tyr359Ter/Stop appears to...

There are mutations in the protein-coding parts of IDO2. You can see what and where they are here: https://gnomad.broadinstitute.org/gene/ENSG00000188676. Probably most importantly, the Y359X variant on this website has a warning flag MNV: "Multinucleotide variant: Variant annotation dubious"...

Sorry: the y-axis is the negative logarithm (base 10) of the p-value. In other words if p=0.01 then -log10p is 2; if p=0.0001, it is 4; etc. Because hundreds of thousands of DNA variants are tested, the p-value has to be very small (-log10 p > 8) before being deemed significant. The IDO2...

The UK Biobank results were generated entirely blinded without prejudice with respect to genes or traits/diseases. It was designed to determine whether common DNA variants can help predict an anthropometric trait or disease (e.g. whether someone is a ME/CFS case or else a control). In this case...

"Deemed significant" - this is the conventional genome-wide threshold, i.e. an industry standard. See https://www.ncbi.nlm.nih.gov/pubmed/30349118 or https://www.biorxiv.org/content/10.1101/176834v2 if the former is behind a paywall. The UK Biobank data has been acquired and analysed to very...

Just read the genetics part of this paper (https://www.mdpi.com/2075-4418/9/3/82/htm) and because Kashi et al. propose that "any predisposing genetic mutation must be common" I turned once again to the huge UK Biobank study with 2017 individuals with self-reported diagnosis of ME/CFS. UK Biobank...

Yes, there are tests for the burden of rare variants, for example: (1) https://www.cell.com/ajhg/fulltext/S0002-9297(08)00408-4 (2) https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1000384 These work best when most rare variants alter trait (ME/CFS risk) which is not...