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Common rarity in 7 out of 7 ME/CFS patients based on 23andMe results

nandixon

nandixon

Senior Member
Messages
1,092
Valentijn said:
I've been sorting through the rare results of ME/CFS patients here with 23andMe results, based on what has been filtered out by the rare gene analyzer at https://sourceforge.net/projects/analyzemygenes/ (10% file is at https://sourceforge.net/projects/analyzemygenes/files/Databases/ ).

There have been some false positives, but something which looked like it was homozygous in only three out of the seven of us turned out to be heterozygous for the rest of us. 10% of the population is heterozygous, and only 1% is homozygous - so this may be very significant.

The rsID is rs952061, which can be viewed in your 23andMe files at https://www.23andme.com/you/explorer/snp/?snp_name=rs952061 . The rare allele is T. Thus far we have homozygous results for allyb, GypsyA, roxie60, and heterozygous results for nandixon, Sea, Valentijn, and presumably for GypsyA's daughter, who must have gotten at least one copy from GypsaA but didn't get flagged as having two copies.

I'd appreciate it if other users with ME/CFS could look up their result for that gene, and let me know if they have CC, CT, or TT.

More info in following posts.
Click to expand...

Hi Valentijn,

The frequency for the homozygous rare allele result for rs952061 is correct at 1%, but the heterozygous frequency, rather than 10%, is 24% according to HapMap CEU data (http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=952061). This is corroborated by the 22% heterozygous frequency OpenSNP gives as well (http://opensnp.org/snps/rs952061).

This is still worth finishing an investigation for this SNP, though. Thanks very much for doing this!
 
snowathlete

snowathlete

Senior Member
Messages
5,374
Location
UK
People with 23andme, who use Firefox browser, may like to download the SNP-Tips plugin, as it saves a lot of effort. Basically you point it to the downloaded 23andme raw datafile once and then everytime an RS number appears on any website, forum (including this one) it is displayed green if you have that SNP in your datafile and you can hover the cursor over it and it will display your specific result. Saves you having to go and look manually.

I am CC.
 
Creekee

Creekee

Senior Member
Messages
143
Location
Arizona
Hubby (completely healthy for our purposes) and I are both CC. I am historically ME-diagnosed but recently confirmed Lyme and co-infections...

Thanks for pursuing this, Valentijn!
 
V

Valentijn

Senior Member
Messages
15,786
nandixon said:
Hi Valentijn,

The frequency for the homozygous rare allele result for rs952061 is correct at 1%, but the heterozygous frequency, rather than 10%, is 24% according to HapMap CEU data (http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=952061). This is corroborated by the 22% heterozygous frequency OpenSNP gives as well (http://opensnp.org/snps/rs952061).
Click to expand...
Yes, but we aren't just interested in a relatively inbred group from Utah here. CEU isn't even likely to be particularly representative of European groups, and it definitely excludes the non-white world.

Basically there's a pretty big chance that uncommon genes are over-represented in such small and homozygous populations. Hence I think it's important to look at the (usually) more diverse results from 1000 Genomes instead, which is also what the NCBI and every other program is doing.
 
V

Valentijn

Senior Member
Messages
15,786
24% = TT (5)
38% = CT (8)
38% = CC (8)

So the results aren't as dramatic as they initially were, but are still quite unusual, especially now that the sample size has grown by a factor of 3 :)

I plan to take a closer look at the nearby genes, to see if some commonality is present.

If anyone wants to send me their rare homozygous results generated using the 10_percent file (or their whole file if it's too complicated), that would be great. The more files we have, the more similarities that will pop up, some of which might hold up.
 
nandixon

nandixon

Senior Member
Messages
1,092
Valentijn said:
Yes, but we aren't just interested in a relatively inbred group from Utah here. CEU isn't even likely to be particularly representative of European groups, and it definitely excludes the non-white world.

Basically there's a pretty big chance that uncommon genes are over-represented in such small and homozygous populations. Hence I think it's important to look at the (usually) more diverse results from 1000 Genomes instead, which is also what the NCBI and every other program is doing.
Click to expand...

You're accidentally mixing up two different frequency measurements. The 10% frequency for rs952061 from 1000 Genomes is the Minor Allele Frequency (MAF). HapMap CEU gives 13% for this value; OpenSNP gives 12%. So they're all very similar.

You're accidentally using the 10% MAF value for heterozygous frequency, ie, a Genotype Frequency. The heterozygous frequency is much higher than the MAF, eg, 22-24%, as I noted.
 
V

Valentijn

Senior Member
Messages
15,786
nandixon said:
You're accidentally using the 10% MAF value for heterozygous frequency, ie, a Genotype Frequency. The heterozygous frequency is much higher than the MAF, eg, 22-24%, as I noted.
Click to expand...
I must admit I've been a bit confused by that. If there are 0 homozygous TT versions in a population, why is the heterozygous frequency twice as high as the T allele prevalence? The HAPMAP-Mex group should be an easy one to make sense of. There's a sample of 100, with T prevalence of 8% but CT genotype prevalence of 16%.

So my understanding (now) is that they're counting for chromosomes - but only for alleles, whereas genotypes must be calculating based on the number of people. So out of 100 chromosomes (2 per person) there are 8 which are T. So out of the 50 people tested, 8 have one T and one C, which makes 16% heterozygous people and 84% of people with the common CC version.

Hence MAF is not reflecting the odds of having that allele for each person, but rather at the odds that each chromosome will have that allele. I think that's the bit I was getting hung up at. So basically the odds of having one minor allele are very approximately twice the MAF.

I think I've got it now - math really isn't my strong suit :p
 
V

Valentijn

Senior Member
Messages
15,786
TT = 22% (5)
CT = 35% (8)
CC = 43% (10)

And if we look at our Minor Allele Frequency (MAF) as a group, we have 18 T alleles out of 46 total alleles. So our MAF of T is 39%, compared to a MAF of 10% for T in the general public.
 
nandixon

nandixon

Senior Member
Messages
1,092
Valentijn said:
I must admit I've been a bit confused by that. If there are 0 homozygous TT versions in a population, why is the heterozygous frequency twice as high as the T allele prevalence? The HAPMAP-Mex group should be an easy one to make sense of. There's a sample of 100, with T prevalence of 8% but CT genotype prevalence of 16%.

So my understanding (now) is that they're counting for chromosomes - but only for alleles, whereas genotypes must be calculating based on the number of people. So out of 100 chromosomes (2 per person) there are 8 which are T. So out of the 50 people tested, 8 have one T and one C, which makes 16% heterozygous people and 84% of people with the common CC version.

Hence MAF is not reflecting the odds of having that allele for each person, but rather at the odds that each chromosome will have that allele. I think that's the bit I was getting hung up at. So basically the odds of having one minor allele are very approximately twice the MAF.

I think I've got it now - math really isn't my strong suit :p
Click to expand...

Yes, I think that's right. In the Mexican group there were 50 people (100 chromosomes), and they found that 16% of those people were heterozygous. So 8 people were CT.

And they found that 8% of the total alleles were the minor allele T (MAF = 8%). So they found 8 out of 100 alleles with T.

Another example is, they might have instead found that 0% were heterozygous and that 8% were homozygous TT. So 4 people would be TT, and the MAF would still be 8%.

Another example is, they might have found that 8% were heterozygous and that 4% were homozygous TT. So 4 people would be CT, 2 people would be TT, and the MAF would still be 8%.
 
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maryb

maryb

iherb code TAK122
Messages
3,602
Location
UK
@Valentijn
much as I would like nay love to understand any of this I can't:(
but if you tell me where to look I will try to find it. also you can have a copy of my results with pleasure.
 
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