Alzheimer's Disease Meta-Analysis Identifies Five New Risk Genes

[Fc1345linville]

This report sounds like progress, even though the findings seem to add to the complexity of treatment or cure.

https://www.genomeweb.com/genetic-resea ... risk-genes

[mike]

Here is a link to an open version https://www.nih.gov/news-events/news-re ... rs-disease

[circular]

Interesting graphic. Mike's link contains this synopsis:

In addition to confirming the known association of 20 genes with risk of Alzheimer’s and identifying five additional Alzheimer’s-associated genes, these genes were analyzed to see what cellular pathways might be implicated in the disease process. The pathway analysis implicated the immune system, lipid metabolism and amyloid precursor protein (APP) metabolism. Mutations in the APP gene have been shown to be directly related to early onset Alzheimer’s. The present study, done in late onset Alzheimer’s subjects, suggests that variants affecting APP and amyloid beta protein processing are associated with both early-onset autosomal dominant Alzheimer’s and with late onset Alzheimer’s. In addition, for the first time, the study implicated a genetic link to tau binding proteins. Taken together, data suggest that therapies developed by studying subjects with early-onset disease could also be applied to the late-onset form of Alzheimer’s. [Emphases added]

[mike]

Here is another link to Tau being key to AD, I think. Along with women having higher incidence of AD, similar to their higher incidence of Tau. I wonder if somehow it is preventing zombie cells from breaking up and instead leaving them spewing out toxins?

[J11]

Thank you very much for posting this!

I am very glad to see that there is a commitment to pursue large GWAS for AD.
It would make no sense to me for this not to happen.
There is still a great deal of the genetics of AD still to be unlocked and it is very well understood that such an unlock
would directly follow from simply increasing the sample sizes which given the current global dementia pandemic are not difficult to access. At the same the return on the research dollars will be considerable.

Here is another large sample AD GWAS.
https://www.biorxiv.org/content/early/2 ... 3.full.pdf

[J11]

BOOM!!!

Just found a ridiculously rare variant in AdamTS1.
Mutation Taster calls it disease causing.
I can now go to my DNA relatives on GEDmatch etc and see if anyone has dementia with this stretch of 21.

[J11]

https://www.biorxiv.org/content/biorxiv ... 9.full.pdf

[aphorist]

Interesting. I thought the importance of ADAM10 was well understood, as it is directly regulated by SIRT1 expression and is required to process APP in a non-amyloidogenic way. Maybe it's that they revealed the SNP that causes mutated ADAM10.

Doesn't seem like a lot of these snps are available on my 23andme data.

[antimatter37]

Looking at this article, it may be possible to “rank” these 25 snp variants that have genome-wide significance based on their respective detrimental or beneficial effects toward AD. This listing would correlate to the odds ratio (OR) as listed in this same study, where OR is the odds of disease for individuals having a specific allele divided by the odds of disease for individuals who do not have that same allele.

For detrimental effects, in descending order (worst first):

Gene Variant OR
APOE rs429358 3.32
TREM2 rs75932628 2.08
ACE rs138190086 1.32
BIN1 rs6733839 1.20
CR1 rs4844610 1.17
WWOX rs62039712 1.16
ABCA7 rs3752246 1.15
FERM2 rs17125924 1.14
HLA rs9271058 1.10
PTK2B rs73223431 1.10
CD2AP rs9473117 1.09
ECHDC3 rs7920721 1.08

For protective effects in descending order (most protective first):

SORL1 rs11218343 0.80
CLU rs9331896 0.88
PICALM rs3851179 0.88
CASS4 rs6024870 0.88
MS4A2 rs7933202 0.89
EPHA1 rs10808026 0.90
INPP5D rs10933431 0.91
NYAP1 rs12539172 0.92
SPI1 rs3740688 0.92
SLC24A4 rs12881735 0.92
IQCK rs7185636 0.92
ADAM10 rs593742 0.93
ADAMTS1 rs2830500 0.93

Note that genes such as BIN1 many have a stronger genome wide significance p-value (see Manhattan plot in same article) than another such as TREM2, but have a significantly lower odds ratio. This rank is based on odds ratio alone.

I’m not entirely sure how to interpret risk variants not on this list that have higher (or lower in the case of protective variants) odds ratios but do not appear on this list because in this study they did not have “genome wide significance”, basically a suitably low p-ratio.

I also wonder if the statistical size of this study (94k cases of LOAD) would allow for a higher level analysis based on persons having various groupings of the above risk or protective variants. For example (made up), if a person had APOE 4/4, but not TREM2 or ACE risk alleles, and has SORL1 but no other protective alleles, what would their “net” LOAD risk be?

[ru442]

So I had some time to check if I have any of these variants, I've got 4 of the protective SNP's (SORL1/CLU/PICALM/SPI1), and 5 of the bad ones (APOE4 being obvious + TREM2/ACE/BIN1/ECHDC3). Of the 4 bad variants, one ends up being good:

TREM2 rs75932628 2.08 - CC is good (which I have), CT and TT are bad repute 3.x AZ risk

ACE is a suggestive risk in SNPedia if you have a G variant (and I do).

BIN1 (TT) is linked to episodic memory in elders with T2D, I am TT, not T2D, and not elderly so hopefully good,

I found nominal information on the others, and since I am not a scientist (except on TV) I was unable to decipher the scientific papers on ECHDC3, but it seems that you also need to have the STARD6 variant (Rs10164112) for the risk to be significant (which I don't have).