23andme Results. Interesting mutations

[Sea]

That's the bit I don't understand. It is genes that are or are not expressed, regardless of what snps they contain - and epigenetics refers to factors other than the genetic code which influence the expression of genes - again regardless of what snps they contain.

I'm trying to understand how a snp could not be expressed. Do you mean the gene containing it would not be expressed? So in the case of a homozygous snp does this mean there would be no gene product?

It's a cop out phrase used by those who are asked for evidence when correlation between certain snps and certain consequences isn't consistent. I don't know who started it but it has become quite common to hear

 

[Critterina]

It's a cop out phrase used by those who are asked for evidence when correlation between certain snps and certain consequences isn't consistent. I don't know who started it but it has become quite common to hear

@Sea ,
I agree that I often hear it used that way. But my brother has a mutation in rs6025 that is associated with a particular protein. Apparently they can tell how much of the mutated protein is in his blood, because his doctor tested for it and, although obviously half his genes are mutated, there isn't much of the mutated protein, at least not enough for them to be concerned. I would consider this a possible case of a gene "not expressing" but I agree with you that most people don't use it that way. I also have to consider the possibility that he has another gene somewhere that degrades the mutated protein preferentially - total speculation here, but possible.
Critt

 

[alicec]

I would consider this a possible case of a gene "not expressing"

Before you could conclude that you'd need to know a lot more about the mutated protein. The simplest explanation would be that the mutated protein is unstable or alternatively that the mRNA for it is unstable. There's no need to postulate another gene involved in degradation (though of course that could be possible).

If tests exist for the mutated protein presumably there is some research behind it which may well include studies of protein or mRNA stability.

 

[alicec]

Is there another reliable methylation/detox profile website besides Genetic Genie and Nutrahacker? I tried Promethease and didn't understand it at all

Promethease does rank snps based on research and gives links, plus it is searchable for any gene you may be interested in and is very comprehensive. Some people do find it difficult to follow unfortunately.

As @Oci notes, MTHFRsupport is fairly comprehensive and has good diagrams showing where the various genes fit into the relevant metabolic pathways.

You have to realise however that just because a snp is flagged doesn't mean it has much consequence. On the MTHFRsupport website they do provide some links to SNPedia which might help in evaluating what the snp means (sometimes though SNPedia is in error!), but for many snps there is no research at all, or maybe just a single dubious association study.

You really have to do some work of your own in deciding whether or not the flagged snps might have consequences. Some snps are discussed on PR, otherwise it's just googling and trying to find the research behind the claims.

Once you understand a bit about the terminology, common sense is also a help. A single isolated +/- snp is highly unlikely to mean anything at all.

A lot of +/- on a particular gene might be more significant, particularly if they were all on the same DNA strand (so-called compound heterozygous), but there is no way of knowing if this is the case since 23andme doesn't record which strand is associated with which snp. Still several +/- would be worth following up.

A single +/+ on a gene might be more significant than +/- but it entirely depends on the snp. You would need to check it out. Some changes have no effect. Several +/+ should make you thoughtful and would certainly be worth following up, but again, it depends on what the changes are.

As a general rule, a change in the part of the gene coding for protein is more likely to have an effect than changes in other parts of the gene, but not always. An altered protein with altered function (either slower or faster than normal, or perhaps more unstable than normal) could be made and this could have consequences. You would need to look at the research to know how much of an effect this could be.

Some changes in coding region are silent - ie the DNA is changed but no change in protein results. This is the case with the MAOA R297R snp which I discussed above. These types of snps mean nothing in isolation. Possibly in combination with a number of other snps there could be an effect but you would need to read the research.

Sometimes a snp upstream of the coding region in the promoter region (which switches on transcription of the gene) can affect the rate at which the protein is made - ie there could be more or less of it.

Snps in other non-coding regions are highly unlikely to have any effect in isolation, but sometimes a lot of them can make mRNA unstable and so affect the amount of protein made.

You can find out where snps are located in a gene by searching on dsSNPs.

Once you've done these sorts of assessments, then you have to make up your own mind about what to do. As an example, I have several +/+ snps on the gene for the enzyme that converts beta carotene to vitamin A. Some of these are known to adversely affect the function of the enzyme - not dramatically, but an effect. I therefore think it is wise for me to supplement vit A.

Similarly I have a number of +/+ snps on the fatty acid desaturase enzyme which makes longer chain unsaturated fatty acids from linolenic and linoleic acid precursors. Again at least some of them are known to adversely affect enzyme function, so I supplement borage and fish oils.

On the other hand, I have quite a few +/- MAOA snps which I have concluded mean very little and quite a few +/+ COMT snps which I have concluded probably have a minor effect. I don't take any particular action for either of these (though I do supplement their cofactors for other more general reasons), I certainly don't give any credence to the myth that COMT+/+ can't tolerate methyl groups - I have no trouble with them.

Sorry there's no easy answer, you have to work at it.

 

[SuckSmoothie]

Is there any other website

Promethease does rank snps based on research and gives links, plus it is searchable for any gene you may be interested in and is very comprehensive. Some people do find it difficult to follow unfortunately.

As @Oci notes, MTHFRsupport is fairly comprehensive and has good diagrams showing where the various genes fit into the relevant metabolic pathways.

You have to realise however that just because a snp is flagged doesn't mean it has much consequence. On the MTHFRsupport website they do provide some links to SNPedia which might help in evaluating what the snp means (sometimes though SNPedia is in error!), but for many snps there is no research at all, or maybe just a single dubious association study.

You really have to do some work of your own in deciding whether or not the flagged snps might have consequences. Some snps are discussed on PR, otherwise it's just googling and trying to find the research behind the claims.

Once you understand a bit about the terminology, common sense is also a help. A single isolated +/- snp is highly unlikely to mean anything at all.

A lot of +/- on a particular gene might be more significant, particularly if they were all on the same DNA strand (so-called compound heterozygous), but there is no way of knowing if this is the case since 23andme doesn't record which strand is associated with which snp. Still several +/- would be worth following up.

A single +/+ on a gene might be more significant than +/- but it entirely depends on the snp. You would need to check it out. Some changes have no effect. Several +/+ should make you thoughtful and would certainly be worth following up, but again, it depends on what the changes are.

As a general rule, a change in the part of the gene coding for protein is more likely to have an effect than changes in other parts of the gene, but not always. An altered protein with altered function (either slower or faster than normal, or perhaps more unstable than normal) could be made and this could have consequences. You would need to look at the research to know how much of an effect this could be.

Some changes in coding region are silent - ie the DNA is changed but no change in protein results. This is the case with the MAOA R297R snp which I discussed above. These types of snps mean nothing in isolation. Possibly in combination with a number of other snps there could be an effect but you would need to read the research.

Sometimes a snp upstream of the coding region in the promoter region (which switches on transcription of the gene) can affect the rate at which the protein is made - ie there could be more or less of it.

Snps in other non-coding regions are highly unlikely to have any effect in isolation, but sometimes a lot of them can make mRNA unstable and so affect the amount of protein made.

You can find out where snps are located in a gene by searching on dsSNPs.

Sorry there's no easy answer.

i knew there wouldn't be an easy answer lol, but I think I'm understanding things a little better now. Some SNP's alone like MAO-A R297R might not cause a complication, but I also have the COMT and GAD. L-theanine is recommended for GAD1 but it's a methyl donor and I don't react well to methyl donors according to COMT, although L-theanine calms my anxiety I fear that it might affect methylation one way or another and cause an aggressive episode, which im prone to with methyl B12 and methylfolate. Is there a way to find out what supplements are Methyl donors and which ones are methyl receivers?

 

[Sea]

@Sea ,
I agree that I often hear it used that way. But my brother has a mutation in rs6025 that is associated with a particular protein. Apparently they can tell how much of the mutated protein is in his blood, because his doctor tested for it and, although obviously half his genes are mutated, there isn't much of the mutated protein, at least not enough for them to be concerned. I would consider this a possible case of a gene "not expressing" but I agree with you that most people don't use it that way. I also have to consider the possibility that he has another gene somewhere that degrades the mutated protein preferentially - total speculation here, but possible.
Critt

2 of my girls have this. The blood test is not looking for the mutated protein, it tests how much resistance there is against another substance. (Activated protein C, the substance responsible in this instance for 'turning off' clotting) The more resistance there is the more likely it is that the mutated protein is an issue. There are a number of factors that can determine how much of a problem this mutation is because there are multiple genes involved in the clotting process and other risk factors as well eg medications, smoking etc. This doesn't have anything to do with expressing or not. If you have this mutation you make protein Q instead of protein R. How much that effects you depends on whether it is heterozygous, homozygous, other mutations in the pathway etc.

 

[SuckSmoothie]

I'm assembling a shopping list to work on my SNPs and im stuck on wether I should pick up taurine or not. On one hand it helps with the GAD1 mutation but a usual symptom of the CBS mutation is high taurine content in the blood. would supplementing taurine be a smart choice? Currently buying a multi mineral with iron and copper, active B2 and snake root for MAO-A, and watching my amine intake.

Side note: I found out MAO-A breaks down tyramine in our body, so reduced MAO-A activity might mean more anxiety and fatigue from cheese, fish, processed meats etc

 

[alicec]

im stuck on wether I should pick up taurine or not. On one hand it helps with the GAD1 mutation but a usual symptom of the CBS mutation is high taurine content in the blood. would supplementing taurine be a smart choice?

First start with some critical thinking. Why do you think CBS is an issue - or are you just swallowing Yasko's erroneous claim about upregulated CBS.

I don't know which GAD1 snps you have but even if they are known to have adverse effects, they would at best be contributors to a complex condition like anxiety. You could be disappointed if you think that "fixing" GAD1 will "fix" your anxiety.

so reduced MAO-A activity

Why do you think you have reduced MAOA activity?

 

[SuckSmoothie]

First start with some critical thinking. Why do you think CBS is an issue - or are you just swallowing Yasko's erroneous claim about upregulated CBS.

I don't know which GAD1 snps you have but even if they are known to have adverse effects, they would at best be contributors to a complex condition like anxiety. You could be disappointed if you think that "fixing" GAD1 will "fix" your anxiety.



Why do you think you have reduced MAOA activity?

I'm new to SNPs and methylation so I have no clue what I should be looking out for and what's ignorable, but I've noticed that eating onions gives me a bad reflux so maybe I have an issue with my CBS gene.

In regards to GAD1, im homozygous for both rs3749034 (GG) and rs3828275 (TT). Whenever im stressed out my thoughts get scattered and I start slutting my speech, this isn't just an anxiety or panic attack, this is something more specific and im thinking its glutamate neurotoxicity. I know I have other complications that lead to anxiety but I don't know where to start with fixing myself

 

[alicec]

I'm new to SNPs and methylation so I have no clue what I should be looking out for and what's ignorable

Various people have been trying to give you clues about this but you have to help yourself also.

but I've noticed that eating onions gives me a bad reflux so maybe I have an issue with my CBS gene.

Why assume CBS? Problems with sulfur don't mean problems with CBS - this is one of Yasko's errors. There has been a lot of discussion about this on PR - just search for it. Also problems with onions may have nothing to do with sulfur.

I quickly googled those GAD snps. The first one is reported wrongly - GG is wildtype (normal) and is extremely common so there's nothing of concern there. With the second one, TT is correctly reported as the minor allele. The snp is located in an intron - not the protein coding part of the gene. In itself it is highly unlikely to do anything. Two association studies were reported. One found no association with alcohol dependence, the other found some association with post-traumatic seizures following traumatic brain injury. It may or may not mean anything.

In other words, the GAD snps are not likely to be contributing to your problems.

Supplements may well be helpful for various of your problems but it won't be because they are fixing your GAD or CBS snps.

 

[caledonia]

Thanks Caledonia, I do have COMT++. Can you tell me what might help with it?

Check out Youtube videos like:

COMT and MAO How Diet Influences Dopamine and Adrenalin (Beyond MTHFR, Dr. Rostenberg)
Genetic Roots of Pain and Anxiety - COMT MAO and MTHFR (Beyond MTHFR)
COMT What's the Big Deal - Ben Lynch

Rostenberg focuses a lot on the gut to help COMT. Such as eating often, betaine HCl, a gut protocol to fix candida/inflammation. Also, as you said, no coffee.

Ben Lynch says possibly SAMe + magnesium to speed up the enzyme, works for some people.

 

[caledonia]

I have heterozygous MTHFR C677T. There was no indication on the Great Plains OAT test that I was low in folate or B12. Would you trust this test to show up a deficiency?

I don't know enough about it to say for sure. You may be able to interpret it using Rich Vank's Interpretation for the Nutreval Test (there is some overlap). Check to see if you have a partial methylation block or not. If so, then consider supplementation.

 

[SuckSmoothie]

Is there a list of methyl and lipid donors that those with the COMT++ mutation should avoid? I don't know if I should stay away from lipid donors, but it was suggested by Nutrahacker. Although I am skeptical about Nutrahacker suggestions I can give it a shot, but I definitely have to steer clear from methyl donors for my own mental safety. I am very sensitive to methyl b-12 and as of yesterday I discovered taurine was also bad for me. I know coffee is a methyl donor too and im looking to cut down my intake (easily 800mg in a day, don't judge me)

 

[Flo]

Promethease does rank snps based on research and gives links, plus it is searchable for any gene you may be interested in and is very comprehensive. Some people do find it difficult to follow unfortunately.

As @Oci notes, MTHFRsupport is fairly comprehensive and has good diagrams showing where the various genes fit into the relevant metabolic pathways.

You have to realise however that just because a snp is flagged doesn't mean it has much consequence. On the MTHFRsupport website they do provide some links to SNPedia which might help in evaluating what the snp means (sometimes though SNPedia is in error!), but for many snps there is no research at all, or maybe just a single dubious association study.

You really have to do some work of your own in deciding whether or not the flagged snps might have consequences. Some snps are discussed on PR, otherwise it's just googling and trying to find the research behind the claims.

Once you understand a bit about the terminology, common sense is also a help. A single isolated +/- snp is highly unlikely to mean anything at all.

A lot of +/- on a particular gene might be more significant, particularly if they were all on the same DNA strand (so-called compound heterozygous), but there is no way of knowing if this is the case since 23andme doesn't record which strand is associated with which snp. Still several +/- would be worth following up.

A single +/+ on a gene might be more significant than +/- but it entirely depends on the snp. You would need to check it out. Some changes have no effect. Several +/+ should make you thoughtful and would certainly be worth following up, but again, it depends on what the changes are.

As a general rule, a change in the part of the gene coding for protein is more likely to have an effect than changes in other parts of the gene, but not always. An altered protein with altered function (either slower or faster than normal, or perhaps more unstable than normal) could be made and this could have consequences. You would need to look at the research to know how much of an effect this could be.

Some changes in coding region are silent - ie the DNA is changed but no change in protein results. This is the case with the MAOA R297R snp which I discussed above. These types of snps mean nothing in isolation. Possibly in combination with a number of other snps there could be an effect but you would need to read the research.

Sometimes a snp upstream of the coding region in the promoter region (which switches on transcription of the gene) can affect the rate at which the protein is made - ie there could be more or less of it.

Snps in other non-coding regions are highly unlikely to have any effect in isolation, but sometimes a lot of them can make mRNA unstable and so affect the amount of protein made.

You can find out where snps are located in a gene by searching on dsSNPs.

Once you've done these sorts of assessments, then you have to make up your own mind about what to do. As an example, I have several +/+ snps on the gene for the enzyme that converts beta carotene to vitamin A. Some of these are known to adversely affect the function of the enzyme - not dramatically, but an effect. I therefore think it is wise for me to supplement vit A.

Similarly I have a number of +/+ snps on the fatty acid desaturase enzyme which makes longer chain unsaturated fatty acids from linolenic and linoleic acid precursors. Again at least some of them are known to adversely affect enzyme function, so I supplement borage and fish oils.

On the other hand, I have quite a few +/- MAOA snps which I have concluded mean very little and quite a few +/+ COMT snps which I have concluded probably have a minor effect. I don't take any particular action for either of these (though I do supplement their cofactors for other more general reasons), I certainly don't give any credence to the myth that COMT+/+ can't tolerate methyl groups - I have no trouble with them.

Sorry there's no easy answer, you have to work at it.

Great to have you here @alicec .

This:
"I certainly don't give any credence to the myth that COMT+/+ can't tolerate methyl groups - I have no trouble with them."

That has been something that has been driving me crazy and it is so ingrained in peoples imagination that it is a notion that is hard for them to get past. It started because it is a very marketable pitch; "over and under methylators".

Speaking of MAOA, I have found three people with anxiety/panic disorders with the minor allele in rs5905418 and in the more common rs2072743, rs1800659, rs3027397.

rs5905418 has a very low frequency (1%). The incidence of anxiety seems to be worse in the men (who only have one allele since it is on the x chromosome).

 

[Oci]

....On the other hand, I have quite a few +/- MAOA snps which I have concluded mean very little and quite a few +/+ COMT snps which I have concluded probably have a minor effect. I don't take any particular action for either of these (though I do supplement their cofactors for other more general reasons), I certainly don't give any credence to the myth that COMT+/+ can't tolerate methyl groups - I have no trouble with them.

Many thanks, as always, Alicec for shedding light on a very complicated subject. I learn so much from you!
I am interested in what the cofactors are for COMT++? How does one find out the cofactors?
I am COMT++ but also VDR taq++. I had the Great Plains OAT test done recently and it indicated a somewhat low dopamine level. I wonder why.
Would taking COMT++ cofactors push my dopamine levels lower?

 

[alicec]

I am interested in what the cofactors are for COMT++? How does one find out the cofactors?

Magnesium is the COMT cofactor. Just go to [URL='http://www.uniprot.org']www.uniprot.org, type in the gene you are interested in at the top (accepted abbreviation eg COMT, or full name) and you will get a list of entries for various species. Human usually at top. Just click on the identifying number at the beginning of the entry and you will get a lot of info, including cofactor used by the gene product. Here is the result for COMT.

I am COMT++ but also VDR taq++.

Some COMT SNPs certainly do something - eg the quite common V158M (rs4680) but many of them in themselves do nothing. Groups of them may form haploblocks but you have to have just the right combination.

VDR taq is not significant.

I had the Great Plains OAT test done recently and it indicated a somewhat low dopamine level. I wonder why.

Interpretation of the neurotransmitter breakdown products in urine is a bit tricky. Low values could mean there is decreased turnover in the pathways.

Often it is the ratio that it interesting - it may indicate problems in one part of the pathways.

However what is showing up in urine might not reflect what is going on in the brain - ie neurotransmitter activity in CNS, periphery and gut is compartmentalised.

Would taking COMT++ cofactors push my dopamine levels lower

Well taking magnesium is a good idea for lots of reasons and it may be helpful in nudging a sluggish COMT. How much of a difference it will make to dopamine levels is impossible to say.

Supposedly people with COMT+/+ have plenty of dopamine but I certainly don't feel it is the case with me. I'd like to have more dopamine.

My theory is that our negative inhibition pathways are trigger happy or over vigilant. As soon as dopamine starts to rise they kick in and turn off the pathway. Most of the time I feel like I'm in shut down rather then having too much.[/URL]

 

[Oci]

Magnesium is the COMT cofactor....Here is the result for COMT.
Many thanks, Alice, for all the amazing information. I will try to understand it now!!!

I seem to have a huge need for magnesium. Very tight muscles in neck/shoulders. It seems I can't get enough! I am using some mag lotion now as well as oral magnesium (threonate and glycinate mainly)


Some COMT SNPs certainly do something - eg the quite common V158M (rs4680) but many of them in themselves do nothing. Groups of them may form haploblocks but you have to have just the right combination.
I think you posted about these haploblocks and I did not quite fit into one of the categories.

VDR taq is not significant.
Good to know. There is so much misinformation out there.

Interpretation of the neurotransmitter breakdown products in urine is a bit tricky. Low values could mean there is decreased turnover in the pathways.
I also imagine that it can vary from day to day and even moment to moment. My motivation sure does!

Often it is the ratio that it interesting - it may indicate problems in one part of the pathways.
How/where would I figure out the ratio? Ratio of what? Dopamine to serotonin or what?

However what is showing up in urine might not reflect what is going on in the brain - ie neurotransmitter activity in CNS, periphery and gut is compartmentalised.
Good to know.

Well taking magnesium is a good idea for lots of reasons and it may be helpful in nudging a sluggish COMT. How much of a difference it will make to dopamine levels is impossible to say.
After learning my dopamine was low rather than high, I searched for substances that could raise it. I found this site http://bebrainfit.com/increase-dopamine/ Not a learned site, I am sure. I think I read that green tea is contraindicated for those with COMT++ as it is a methyl donor. However, I am trying a little. I drink coffee and it is a methyl donor.

My new naturopath suggested I try tyrosine as my thyroid is a bit sluggish. However, I have not done so yet as I get migraines and are therefore nervous of tyrosine.

Supposedly people with COMT+/+ have plenty of dopamine but I certainly don't feel it is the case with me. I'd like to have more dopamine.
Me too. In the past I have used a lot of caffeine and mental stimulants to increase dopamine, I think. Oh, also diet coke - caffeine + aspartame. I believe it increases dopamine. Not good for me however. I still have some on occasion to give me a boost. I have been cutting way back on caffeine as I have the CYP1A2*1F C164A++ and have had breast cancer.

My theory is that our negative inhibition pathways are trigger happy or over vigilant. As soon as dopamine starts to rise they kick in and turn off the pathway. Most of the time I feel like I'm in shut down rather then having too much.
Me too.

Many thanks again!

 

[Subcosmos]

Hey guys,

I built this site as an alternative SNP interpretation platform. I give literature search results, including figures from pubmed.

Heres what the pages look like for COMT, and its most famous variant. Id love feedback on whether this is useful to you.

https://www.infino.me/gene/COMT/
https://www.infino.me/snp/rs4680/

 

[alicec]

I built this site as an alternative SNP interpretation platform

I've looked at the site, including the links you give to COMT. It looks pretty impressive though I quickly ran into problems. Maybe there are still teething problems with the site.

I uploaded my 23andme results to the site and was quite interested in viewing your analysis of my various risk genes in different health conditions. I had only a short time available so thought I would come back at another time.

There was no way of saving my results so I could view the reports again at a later time. I really don't want to have to upload 23andme results every time I want to look at the site.

Also there was no contact info on the site so I could ask directly about this problem. Still I imagine these glitches will be fixed with time.

I really had only a short time to explore but what I did look at was, as I say, impressive.

Thank you.