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New ApoE4 protective SNPs

Posted: Sat Jun 15, 2019 8:21 am
by Jgreg80
Hi all, came across this and figured I’d post it here

https://www.alzforum.org/news/research-news/sliced-apoe-genotype-whole-exome-data-yield-new-ad-variants

https://jamanetwork.com/journals/jamaneurology/article-abstract/2735123

The top ApoE4 protective SNP (ISYNA1, rs2303697) is genotyped by AncestryDNA and isn’t rare (minor allele frequency 0.35 in Europeans). Now just have to find someone with JAMA access to see how substantial the odds ratio is...

Re: New ApoE4 protective SNPs

Posted: Sun Jun 16, 2019 2:42 am
by SamNZ
Hi Jgreg80, Thanks so much for sharing this information, I feel that I am learning all the time and it is people like you who allow us all to be at the cutting edge of advances in the disease. For this I warmly welcome you joining our community, I am sure you have found the primer and such like by now but please carry on contributing. I hope you find someone with JAMA access who can help you. Thanks again SamNZ

Re: New ApoE4 protective SNPs

Posted: Sun Jun 16, 2019 2:04 pm
by NF52
Jgreg80 wrote:Hi all, came across this and figured I’d post it here

https://www.alzforum.org/news/research-news/sliced-apoe-genotype-whole-exome-data-yield-new-ad-variants

https://jamanetwork.com/journals/jamaneurology/article-abstract/2735123

The top ApoE4 protective SNP (ISYNA1, rs2303697) is genotyped by AncestryDNA and isn’t rare (minor allele frequency 0.35 in Europeans). Now just have to find someone with JAMA access to see how substantial the odds ratio is...
Welcome, jgreg80!

It's always great to have someone join who likes to dive into the latest research abstracts for clues as to the cutting edge of discovery! I've taken the first article and included a quote from it below. It seems to be finding something that has been widely assumed to be lurking in whole genome analysis: that while ApoE 4 stands out like the steeple of a church as a risk factor, there are likely many other genes that are the equivalent of roofs rising above the skyline which can be protective or, in some case, additive to risk. Those other genes, as well as lifestyle factors, seem to be the invisible "X" factor that explains the wide variation in risk even among people with ApoE 4/4.

I've added the title of the articles you cited, so interested readers can decide to delve deeper. Analysis of Whole-Exome Sequencing Data for Alzheimer Disease Stratified by APOE Genotype

I checked the one allele which was mentioned as protective here:
Among ApoE4 carriers, the top SNP in ISYNA1, rs2303697, protected in all cohorts except CHARGE.
Unfortunately, it's not part of the 23&me analysis I had done.
Sliced by ApoE Genotype, Whole Exome Data Yield New AD Variants

[John Hardy of University College, London] added that the error rate of AD diagnoses, upon which the AD risk associations rely, further complicates the findings.
Farrer said that all variants identified in ADSP will be put to the test in larger, whole genome sequencing cohorts. The Alzheimer’s Disease Genomic Consortium aims to sequence the whole genomes of at least quadruple the number of people included in the current ADSP WES analysis, Farrer said. “We are in the middle of an ongoing saga of filling in the genetic architecture of AD, which clearly is not accounted for by common variants.”
[Emphasis added.]

As an aside, you may want to check out our How-To guide, which can aid in searching for citations of articles, quoting members when you reply to them, subscribing to topics of interest and other tips to save time.

I hope you continue to flag new articles for us to check out!

Re: New ApoE4 protective SNPs

Posted: Thu Jun 27, 2019 8:40 am
by xactly
I cannot find the rs2303697 SNP in the SNPedia, but my 23andme data shows I have C/T at that point. From other posts, I see that the T allele is protective (i.e., reduces the accumulation of myoinositol in the brain). Does anyone know if the wild type is T/T? I'm not well versed in this, but looking at the dbSNP data, it looks like the variation is from T to C. If I'm interpreting this correctly, and the wild type is T/T, T/T allele would provide greater protection for APOE4 carriers than C/T.

Re: New ApoE4 protective SNPs

Posted: Thu Jun 27, 2019 10:08 pm
by Matisse
xactly wrote:I cannot find the rs2303697 SNP in the SNPedia, but my 23andme data shows I have C/T at that point. From other posts, I see that the T allele is protective (i.e., reduces the accumulation of myoinositol in the brain). Does anyone know if the wild type is T/T? I'm not well versed in this, but looking at the dbSNP data, it looks like the variation is from T to C. If I'm interpreting this correctly, and the wild type is T/T, T/T allele would provide greater protection for APOE4 carriers than C/T.


That's how I read it also. T is the wild type. I don't see this on the V3, V4 or V5 platform of 23andme. How did you find it?

Re: New ApoE4 protective SNPs

Posted: Fri Jun 28, 2019 12:48 pm
by xactly
Matisse wrote:I don't see this on the V3, V4 or V5 platform of 23andme. How did you find it?

I was genotyped with the V3 chip. When I searched for the SNP in Raw Data, it showed up.

Re: New ApoE4 protective SNPs

Posted: Fri Jun 28, 2019 2:02 pm
by Matisse
xactly wrote:
Matisse wrote:I don't see this on the V3, V4 or V5 platform of 23andme. How did you find it?

I was genotyped with the V3 chip. When I searched for the SNP in Raw Data, it showed up.


Thank you. I looked again and found it for a family member with V3 chip but not for any of us with V4 or V5.

Re: New ApoE4 protective SNPs

Posted: Fri Aug 09, 2019 7:30 am
by Jgreg80
Found the full article -
https://www.researchgate.net/publication/333684488_Analysis_of_Whole-Exome_Sequencing_Data_for_Alzheimer_Disease_Stratified_by_APOE_Genotype

The odds ratio for the minor T allele of rs2303697 is O.73. A 27% reduction in AD for us ApoE4’s, I’ll take it.

Btw, It’s genotyped by AncestryDNA v2.

Re: New ApoE4 protective SNPs

Posted: Tue Aug 27, 2019 7:20 am
by LG1
Jgreg80 wrote:Found the full article -
https://www.researchgate.net/publication/333684488_Analysis_of_Whole-Exome_Sequencing_Data_for_Alzheimer_Disease_Stratified_by_APOE_Genotype

The odds ratio for the minor T allele of rs2303697 is O.73. A 27% reduction in AD for us ApoE4’s, I’ll take it.

Btw, It’s genotyped by AncestryDNA v2.


I am T, C. So the study found that to reduce the odds by 27% for one T allele?

I'll take it too!!