Genetic genealogy raw data and Alzheimer's research ...

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J11
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Re: Genetic genealogy raw data and Alzheimer's research ...

Postby J11 » Sun May 15, 2016 9:06 pm

What do you think of the idea of a dbsnp+ site that could link to dbsnp additional affecteds?
It is quite possible that I could round up a whole bunch of relatives with the mutYH variant and perhaps we could
use this as an internal validation study on snpedia.

Waiting for a study to be done that might just sample random CRC patients in clinics seems a hopeless strategy.
Members of our extended family probably have more genetic power to work out the statistics of this than any study that might ever be
done.

Might also be some payola in snpedia's future for this type of research. I would expect that there would be a cost savings in the tens of thousands of dollars for each of these ER surgeries that could be avoided. I am quite sure insurance would be quite happy to finance treatments that are smart, preventative and cheap than dumb, expensive and in the ER.

Perhaps snpedia could move more towards being a primary research site than a secondary compiler of published research.

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Re: Genetic genealogy raw data and Alzheimer's research ...

Postby J11 » Mon May 16, 2016 8:58 am

Starting to wonder whether snpedia could move towards offering haplotyping for phenotypes.
With the mutYH variants, could simply find the gene chip SNPs that are shared with those affecteds with the variant.
Not sure whether this would be specific enough to actually capture the variant, some might have the haplotype though not the variant.
Would save quite a bit in terms of exome scanning costs, though.

Yet, for our family we know that all family members that descend for the one with the mutYH variant who are also on
the strand which has the variant should also have the variant. Additional exome scanning should not be necessary for them.

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Re: Genetic genealogy raw data and Alzheimer's research ...

Postby J11 » Tue Jun 07, 2016 7:09 pm

Just caught a huge break!

I have been building up my family tree on Ancestry.com.
Out of the blue today one of the relatives from the tree made contact.
This relative has done extensive research into our family and knows of other family members with dementia!

It appears that I now have a trail that I might follow to help locate the Alzheimer's variant!
Even one other nearish cousin with AD could greatly reduce the search space on the exome file!

I was starting to wonder if I would ever make contact with any others in the family who had any knowledge of the dementia.
My close relatives were not aware of any others in the near family who had developed dementia.
Finding this new link might finally unlock the mystery!!

circular
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Re: Genetic genealogy raw data and Alzheimer's research ...

Postby circular » Tue Jun 07, 2016 7:25 pm

Great news! What is the genetic distance estimate, i.e. second cousin or ? As you know closer is better because with each generation back to the common ancestor more unrelated genes come to play. But if your loved one is genetically related to all the ones with dementia ... ? BTW, did you test your loved one there or you? You want to test the oldest generation of possible.
ApoE 3/4 > Thanks in advance for any responses made to my posts.

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Re: Genetic genealogy raw data and Alzheimer's research ...

Postby J11 » Tue Jun 07, 2016 7:47 pm

Thanks, circ!

I am fairly stoked about this!

Our relatives had told us that no one descending through our loved one's mother's parents were known to have developed dementia aside
from our loved one and her mother. The trail had seemed fairly cold. In the good ole days the family trees branch out so wide that if you do not know which limb to follow then you can become hopelessly lost fast!

Our newly found relative has personal knowledge of other family members from our loved one's grandfather's generation who also had dementia! Apparently there is also a cousin who is now coping with dementia. I am not sure what the cMs of siblings of grandparents would be, though if we could at least locate the branch where this was originating from it would be amazing! With the cousin it might be even more helpful. From what I understand it is best to find affected relatives that are somewhat distantly related so that the common genomics would be as small as possible. If we had found other close relatives with dementia it might not have been overly helpful as they would have had too much overlapping genetics. If this cousin only has 10-30 cM that would be simply AMAZINMG! I have been bugging hundreds of our relatives on 23andme with really no clear idea how I was going to narrow down the search space. Let's face it if you ask a few hundred people about dementia in their family, a fairly large percentage will have a positive history. Most of them probably would not even have the family variant that we are looking for!

Our loved one genotyped with 23andme. We recently bought the Ancestry.com DNA kit for our loved one. The problem is that the Ancestry.com uses a saliva kit and our loved one does not understand how to give a saliva sample. I think what I will need to do is use one of those dental lollipops to obtain the sample.

The lesson here is to try and find the family genealogist. All you need to do is to go to Ancestry and find out who built out the family tree
near your branch. It sounds like our relative is close to a professional genealogist. Randomly emailing DNA relatives on 23andme was not a good strategy! I should have contacted the family tree builders on Ancestry. The relative who just made contact was actually one of the nearest relatives with an adjacent tree to our family.

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Re: Genetic genealogy raw data and Alzheimer's research ...

Postby Silverlining » Wed Jun 08, 2016 3:55 am

Big round of applause for you and your unwavering perseverance J11!! Hope this new lead provides the hidden link you've been searching for.

circular
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Re: Genetic genealogy raw data and Alzheimer's research ...

Postby circular » Wed Jun 08, 2016 8:57 am

Keep us posted. I'm still wrapping my brain around the ideal relative distance for this. I see your point about how a rare variant from further back verified through more distant cousin(s), where both branches have dementia is a target. At the same time, to be clear, you'll need to rule out other explanations for both families having common dementia too? I'm thinking this could make a great case study, the more people in both families that can be tested at all genetic distances for high resolution family gene mapping. For example what if your loved one's and her mother's AD is caused by synergy between a pair of genes, that didn't get passed down the sibling or cousin lines? It's my guess that looking at the genetic files of as many close and distant relatives as possible the better?

Can you try emailing with the researchers studying the south american family with high rates of early onset AD, or the ones studying the US family with high rates of late onset AD (I think mostly in the SE).

Is your new cousin willing to test more family members to help? Is s/he aware of any e4s yet in his or her family?

Have you also transferred your loved one's files to FTDNA to compare against their database too, and GedMatch (free third party)?

No surprise you're not getting many responses on such a loaded issue: serious family illness, privacy concerns, and simply having no interest. Hopefully you share the genealogical interest. It can be best to initially establish trust in the context of family history research and later ask about health. I've done this with some cousin matches myself.

Since, when looking for a rare variant, you'll also want to try to rule out more common causes of the family dementia, you and your 'new' cousin can try to obtain death certificates for key people on the family tree whose health you don't know, constructing a medical family tree. These might show 1) if they had dementia, and 2) if there's a pattern of disease(s) strongly associated with e4. Death certificates aren't always accurate as to cause of death but may wave a flag at you. In my grandmother's case, not sooooo long ago, the dx was atherosclerosis, but in hindsight it was clearly AD. I also found confirmation of my mother's account that her maternal grandfather died of something related to his gall bladder. Gall stone disease has been associated with e4 among men, so I feel somewhat sure the 4 came from him. By photos he also appears to have the inflammatory/rheumatic/EDS type phenotype that my mother and I have. However, I've not confirmed my mother is where my 4 came from. Just makes the most sense.

Look forward to hearing how this evolves. Hope it's revealing.
ApoE 3/4 > Thanks in advance for any responses made to my posts.

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Re: Genetic genealogy raw data and Alzheimer's research ...

Postby J11 » Wed Jun 08, 2016 9:00 pm

I am so happy about this latest development!

It doesn't really put me in the best light, though.
It is almost as if people were on a quest and their leader slipped on a banana peel and fell over the hidden treasure.

The relative contacted me because I had made a mistake on my family tree on Ancestry!
Not exactly heroic!
I should have simply contacted all the users on Ancestry that had included my near relatives in their trees.
This would have let me find this relative months ago!

The information that I have gotten from this relative is already paying dividends.
For example, since there are two branches of the family involved now it is clear to see that mtDNA and the X chromosome can be ruled out.
The mt DNA from my loved one runs out through the non-AD carrying branch of the family.
Also the new found AD affected relatives ran through the male line so the X chromosome can also be tossed.

Though, yes, circ, you are quite right, it would be best not to assume anything here.
It is quite possible that dementia is entering into our family tree from multiple sources.

We already made a mistake when we assumed that our loved one carried an epsilon 4. That was not true.
It appears that basics of genetics have been widely understood in the community for centuries.
It is amazing how many very weird traits pop up in our family.

This gave me the shivers the other day when I was reading one of the threads on the forum.
I remembered what had happened in our family.

Our loved one an APOE4 non-carrier married an APOE4 carrier.
Our loved one's fraternal twin married someone with a family history of motor neuron disease.

A match made in match makers heaven!
Yet, it all ended up in match makers hell.

The APOE4 never developed dementia, while the non-APOE4 did.
The fraternal twin did not develop dementia, though the spouse did develop motor neuron disease.
This twin never remarried nor had children.

What this speaks to me about is that the community has made fairly deliberate attempts to match up
families at risk for various illnesses. Yet, I shuddered when I thought what will now happen with the current
genetic knowledge. In the modern age, we will know what the future holds. We will know that the
APOE4 carrier has protective variants and will avoid clinical AD and we will know which of the fraternal twins will
develop AD and which will not. The match maker in the modern world would match the APOE4 carrier to the fraternal
twin who would not develop AD and would match the fraternal twin who would develop AD to the spouse who
would develop motor neuron disease.

This struck me as simply too terrible. Coping with both motor neuron disease and then severe AD possibly also with
affected children would be catastrophic! As it is now we have been able to manage OK. How will people who are
dealt a double whammy possibly cope?

In the future, some families could be divided by those who got their get out of jail cards and those who did not.
As it is now, families affected by illness are mostly united by trying to help their family members. If all the debts were
to placed only in a part of the family and all the credits in another part, the level of crisis in coping with genetic illness
could rapidly escalate.

As much as I feel honored to be a caregiver for a family member with a severe illness, if I could simply select against it: I probably would.
When I find this causative AD variant I will know the future and I will be able to create the future that is in my rational
self-interest.

One snag that has emerged is that both of the affected uncles that my relative alerted me to have passed away. Neither of them had any children. There is a affected cousin that is related by DNA to our loved one. Yet, apparently this relative is in the denial stage of dementia. I will have to keep an eye on this. The denial stage does not usually persist that long with Alzheimer's. If we could finesse a saliva sample from this relative it could be pivotal. I am not exactly sure how to play this one cool. We have had other relatives who also have flat out refused to give a sample and it has been extremely frustrating. Even with all the dementia that they witnessed first hand, they simply did not believe that AD was a genetic illness. Strangely, they do not appear to be affected by dementia themselves.

We have now established contact with the second branch of the family that has experienced dementia. Considering how large the families were a generation or two back, there could be a simply massive number of family members out there who also have the variant that we are looking for.

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Re: Genetic genealogy raw data and Alzheimer's research ...

Postby J11 » Thu Jun 09, 2016 5:40 pm

Things are really picking up!

I have found a 4 generation transmission of dementia through the contact on Ancestry!

While I have not as yet found many genotypable carriers, I now have a clear line of sight of where the carriers should appear in the tree.
It would be even better if I could push the tree back another generation. The problem that is cropping up is that when you try and go back past the start of the 19th century government vital statistics start to become sparse. Having that extra generation or two would have been helpful. A generation or two more could greatly increase the number of descendant carriers.

One of the things that I found very sad when going through some of the family documents was that up till very recent past dementing illness became untreatable once the swallowing reflex was no longer effective. There was nothing that could be done. With one of our relatives with dementia it was clear that starvation was the actual cause of death. Without an enteral feeding pump there would be almost no way for dementia patients to be fed. This makes it easy when looking back on the family tree to find the ancestors that likely had dementia. Nearly all of our relatives with known dementia passed away at the same age, the age at which they could no longer swallow. Our loved one is now the second generation that has been able to use modern feeding technology and live beyond this limitation.

The other lesson that I have picked up on is to contact the Ancestry users who build trees with ancestors of interest. If I can find another relative who can point me to those in the family with AD then the variant will be easily found.

circular
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Re: Genetic genealogy raw data and Alzheimer's research ...

Postby circular » Thu Jun 09, 2016 5:58 pm

Thanks for reporting from the front lines! Very cool to observe and hoping this works well. Also, your comments are very perceptive and interesting: 1) about what it will be like when we all know what's in our deterministic cards and what it means, especially since in these cases there really isn't anything we can do (hopefully less of that over time too!), and 2) how technology is improving AD patient care.
ApoE 3/4 > Thanks in advance for any responses made to my posts.


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