GG rs9472817 annuls APOE epsilon 4 risk? Wo Hoo!

Insights and discussion from the cutting edge with reference to journal articles and other research papers.
Matisse
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Re: GG rs9472817 annuls APOE epsilon 4 risk? Wo Hoo!

Postby Matisse » Sat Mar 05, 2016 9:10 pm

It's not genotyped on mine which is V4. My brother was tested on V3 and he's GG. 23 says it's plus orientation so the results shown should be correct but CG and AT can sometimes be ambiguous.

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Re: GG rs9472817 annuls APOE epsilon 4 risk? Wo Hoo!

Postby J11 » Sat Mar 05, 2016 9:13 pm

Yes, there are caveats.

Yet, this initial report is a fair size study.
There are n = 465 sporadic and familial cases versus n = 442 controls.

It is true that the fine grained homozygote genotypes would be moving to smallish numbers, though it does
not appear that they have done an excessive amount of comparisons. They were already hitting into
low p values. (p about 10-3 -- 10-4)

On a Promethease report the user would only see a 2.1 magnitude result which might not even be investigated.

With snpedia I often like seeing the initial report at least reported with a minimal magnitude. One of the frequent problems
that occurs is legacy studies in Alzheimer's will be on the system that simply cannot be correct (for example, SNPs that increase risk by 6x) based on small sample sizes. The same argument might be applied to this new result, though with the combinations it is not as obviously incorrect. IGAP had 100,000 people, so it has been proven that there are no outstanding common AD SNPs that increase risk by greater than 10%. We should already have the statistical power to make similar statements about combos, though as we have seen recently on this forum: This is not correct!

It is difficult to believe that this new SNP could possibly have this much power to change AD risk.
Why would it not have already been found?
All the same keeping it under the radar with a minimal magnitude allows it to be seen be those interested and ignored by others.
Last edited by J11 on Sun Mar 06, 2016 6:25 pm, edited 1 time in total.

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Re: GG rs9472817 annuls APOE epsilon 4 risk? Wo Hoo!

Postby J11 » Sat Mar 05, 2016 10:02 pm

Hmm, these UCPs have a certain face credibility in being involved in neurodegenerative illness.

"Uncoupling proteins (UCPs) are a group of five mitochondrial inner membrane transporters with a tissue specific expression that uncouple biofuel oxidation from ATP synthesis and function as regulators of energy homeostasis and antioxidants Previous data suggested that neuronal UCPs (UCP2, UCP4, and UCP5) can directly influence synaptic plasticity, neurotransmission, and neurodegenerative processes, and have a crucial role in the function and protection of the central nervous system. In fact, it has been observed that the expression of neuronal UCPs significantly decreases in Alzheimer's disease (AD) patients."

These UCPs are giving me a bad feeling with respect to dementia risk.

http://www.ncbi.nlm.nih.gov/pubmed/2692 ... t=Abstract
{original article cited}

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Re: GG rs9472817 annuls APOE epsilon 4 risk? Wo Hoo!

Postby J11 » Sat Mar 05, 2016 10:19 pm

The more one reads the more one dreads UCPs:

"... As mentioned above, once the expression levels of UCP 2, 4, 5 were significantly decreased, the ability of neurons from AD brain to be protected from oxidative stress damage was impaired. ... Tangles and plaques are found predominantly in areas of AD brain that regulate learning, memory and emotional behaviours, including the hippocampus, cortex, basal forebrain and brain stem. Interestingly, these brain regions also express neuronal UCPs. ... Furthermore, dietary restriction, which protects neurons from dysfunction and death in models of Alzheimer’s disease [36], also enhances UCP4 expression in the cortex and hippocampus "

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2872223/

Anyone have an idea what the functional consequence of rs9472817 might be?

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Re: GG rs9472817 annuls APOE epsilon 4 risk? Wo Hoo!

Postby J11 » Sat Mar 05, 2016 10:37 pm

Mutation Taster does not show anything out of the ordinary here with rs9472817.

Ensembl is calling it an intron variant.
It seems a little tricky what allele to consider for different transcripts.
Some of the transcripts call it antisense, some call it nonsense.

http://uswest.ensembl.org/Homo_sapiens/ ... edirect=no

The 23andme genechip picked it up, though our exome scan did not.

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Re: GG rs9472817 annuls APOE epsilon 4 risk? Wo Hoo!

Postby J11 » Sat Mar 05, 2016 11:21 pm

UCP-4 (aka SLC25A27) does give one the willies.

Variants near rs9472817
"... of mitochondrial uncoupling protein 4 in the development of vascular demyelinization of the white matter of the brain, referred to as leukoaraiosis (LA). The mUCPs are presumed to be of great importance in the regulation of the mitochondrial membrane potential (MMP) and the cellular energy metabolism."

https://www.ncbi.nlm.nih.gov/pubmed/20545631


Same variant near rs9472817 for Multiple sclerosis:
"...of mitochondrial uncoupling protein 4 (mUCP4) can give rise to the development of MS, since mUCP4 is presumed to be of great importance in the regulation of the MMP and cellular energy metabolism. The clinical and genetic data on 120 relapsing-remitting MS patients and 250 neuroimaging alteration-free subjects were analyzed. The rs10807344 CC genotype proved to exert a protective effect against the occurrence of MS (neuroimaging alteration-free controls, 58%; MS group, 33%; P < 0.0000089; OR, 0.32; 95% CI: 0.2-0.56, P < 0.005).

https://www.ncbi.nlm.nih.gov/pubmed/19536655

Also schizophrenia

"...These neuronal UCPs are expressed in various brain tissues and may exert a neuroprotective effect against increased oxidative stress. We found modest associations between schizophrenia and the four tag SNPs, rs660339 (odds ratio (OR) = 1.330; P = 0.0043) and rs649446 (OR = 0.739; P = 0.0069) in UCP2, and rs10807344 (OR = 0.622; P = 0.0029) and rs2270450 (OR = 0.704; P = 0.0043) in UCP4, all of which were statistically significant even after correcting for multiple comparisons."

https://www.ncbi.nlm.nih.gov/pubmed/17066476

None of these were recent large scale GWAS, though it does show that the AD result would not be a throw of the dart.
Modern GWAS are agnostic about what the genes involved might be, so they need huge samples to overcome the multiple
comparisons.

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Re: GG rs9472817 annuls APOE epsilon 4 risk? Wo Hoo!

Postby Silverlining » Sun Mar 06, 2016 3:53 am

Agreed, preliminary results. I checked rs9472817 for myself and family members. For myself as a 4/4, I am GG. My mother and daughter both 3/4 are CG. My husband 3/3 is CG. My father, a 4/4, was genotyped on a later 23andme chip and rs 9472817 does not appear to be on that chip.

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Re: GG rs9472817 annuls APOE epsilon 4 risk? Wo Hoo!

Postby Tincup » Sun Mar 06, 2016 7:25 am

Full:
Genetic Variability of UCP4.pdf

Moderator note - I deleted the attached paper (DOI 10.3233/JAD-150993) because our copyright infringement policy prohibits it. Members in jurisdictions for which access to Sci-Hub is legal may want to search for the paper there.
Tincup
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Re: GG rs9472817 annuls APOE epsilon 4 risk? Wo Hoo!

Postby Kathleen1 » Sun Mar 06, 2016 9:09 am

So as a CG I guess I keep working the program. Thanks for the text of the article, lots of learning there.

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Re: GG rs9472817 annuls APOE epsilon 4 risk? Wo Hoo!

Postby J11 » Sun Mar 06, 2016 11:38 am

Thank you very much for posting the article GeorgeN!
So much better to have the full details on hand.

I was very glad to see that they only used a limited SNP set of 16.
If this had been a typical GWAS lottery, then the result would have been nearly meaningless.

I was taken aback when they noted
"Our results support the role of UCP4 rs9472817 as one of the most relevant genetic modifiers
of the risk conferred by APOE-epsilon 4 reported to date."
This is a strong claim, though considering how murky AD genetics has been to date it would be welcome
if it were shown to be true.

It was also surprising to me that they included only 4 SNPs from the UCP4 gene.
In the SNP selection section "The selection was based on the following criteria: Minor
169 allele frequency (MAF) >5% in Caucasians, putative functional significance
(non-synonymous SNPs, SNPs located in the 5’ - and 3’ –UTR regions), SNPs
previously investigated in association studies." Are they truly only 4 SNPs in the UCP4 gene that
met these conditions?

To the question of risk by allele carriage especially heterozygotes:
"In fact, in familial LOAD patients, with respect to subjects with the GG genotype (no risk allele), the estimated risk of developing the disease for subjects with the CG genotype (1 copy of the risk allele C) was increased about 1.50-fold, while subjects with two copies of the some allele (homozygous CC) had an almost 2.24–fold increased risk

This gene-dosage dependent effect was evident also in sporadic LOAD patients, where subjects with the CG and CC genotypes showed, respectively, a 1.53-fold and 2.36-fold risk of developing the disease when compared to subjects
with the GG genotype.

As would seem reasonable the heterozygotes had intermediate risk.

They lumped epsilon 4 carriers into one bin so it is not clear whether the interaction with the rs9472817 genotype changes with the number of epsilon 4 alleles. For many 44s on the forum this is clearly a pivotal unanswered question from this study.

I would have liked to see the p-value for the combined sporadic and familial groups. It might not have totally made sense to do this, though seeing a nice, very low p-value would have added some sense of confidence (real or otherwise). Also would have liked to have seen the p-value for the entire genotype result GG-CG-CC in Table 3.

I would still want to hedge a bit on this overall result, though it would be a great step forward for AD research if they have truly hit on the major APOE epsilon 4 interaction.

"Epistatic interactions may account for much of the unexplained variance in AD status"

It is still difficult for me to understand how we are still at the point, 20 years into AD genetic research, where APOE epsilon 4 genetic interactions are still so granular. As I noted before, if this result had been for a single SNP it could have been immediately discarded as invalid. IGAP showed conclusively that there are no outstanding common AD risk increasing variants of much more than 10% still left to be discovered. Now that the single SNP AD variants have largely been worked through, one can only wish that we will not have to spend the next 20 years, working through hundreds of erroneous epsilon 4 interacting variants.


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