J11 wrote:LG1 welcome back to the forum!
Thank you J11! I still have a lot of other things going on but miss being involved here.
I am so excited about what is happening now in IQ genetics!!!
I get the excitement as well as why people might be inclined to freak out over this,
I have no idea how we will be able to navigate through the next 5 years.
For many of us the extreme social disruption that is now clearly imminent will happen well before dementia sets in.
The latest and soon to be published GWAS research has found 37 SD of Educational Attainment.
37 SD of IQ would be over 500 IQ points. It is not accurate to compare Educational Attainment and IQ in this way,
though at the same time it would be equally inaccurate to suggest that the current findings have not revealed a great deal of
the genetic architecture of IQ.
It seems highly likely that once this research is more widely appreciated that there will be a range of disease communities that will champion this technology so as to create the cures and the treatments for their loved ones that we have been unable to create even after many decades of intense effort.
The research is filling in more and more of the AD genetics.
However, I continue to be surprised at how much of the genetics of Alzheimer's still remains undiscovered and how little initiative appears to be devoted to find the remaining pieces. For example, some rare Sorl1 variants have recently been found to be causative for AD. Yet, the larger scale exome/genome studies that would find all the large and intermediate risk variants for dementia still have not been done. The recently identified rare Sorl1 variants represent 2% of AD. Why is it not recognized that such discoveries have large social relevance? The payback for this discovery will be enormous. Why is it not more of a priority to identify yet more of them?
No idea but I'll have a look around at the Sorl1 variant studies and the researchers that published them and see what if anything I can fine. Thanks for the nudge.
I also find it quite odd that the below url notes that it is difficult to fill in AD genetics because some family members do not want to participate etc. I certainly understand this problem. However, I am not sure why they did then not go to GEDmatch. They could find relatives on the known DNA stretch and then contact them. It would be somewhat awkward in terms of privacy, some people would not want to know, though I would think that there could be a reasonable why to accommodate such viewpoints.
Yes, people are very particular about privacy. Some more so than others. I'm on Gedmatch and contacted a 3rd cousin that declined to respond but another cousin emailed me so... you never know. I'll bet there would be enough to agree to a study.
Having the intermediate and high risk AD genes would be a great help to me. Even with the below url, I was able to consult our exome file and find variants of interest for 2 of the 4 genes noted in the research. When you have 60,000 variants to choose from almost any gene could produce a plausible variant. For the latest 4 genes, SORL1 gave a rarish variant within 150 bp of one of those mentioned, GRID2IP gave 2 rare variants none of which had rs numbers, though they were both of low quality while Mutation Taster called them both as disease causing. With this information I could go onto GEDmatch and find relatives who shared these stretches. It is a very easy process. If I could be told the 20-50 or so genes that substantially increase AD risk, I would probably be able to rapidly figure out the cause of our dementia.
https://www.alzforum.org/news/research- ... mers-genes
It is also disappointing that the HEX database only has 500 people sequenced. This is very difficult for me to understand. It would not be only the lobbying voice of the dementia community; Every single genetic diseases community would benefit from an online database of healthy people variants. A database of perhaps 200-300,000 people would give everyone valuable information about their genetic risks by eliminating the very large number of variants that have no obvious role in illness. Typical exomes VCF files have between 50-100,000 variants. This makes actually finding even a causative AD variant through individual efforts almost impossible. I would guess that nearly all of the variants (perhaps 98%) that are in a typical exome/genome could be easily identified as non-causal if a large scale Healthy exomes database were available. It is possible that this resource does already exist, though I am not aware of it.
https://www.alzforum.org/exomes/hex
Notwithstanding my above comments, there is a concern that we are moving to the time in which genetics will be highly predictive.
Up till this point the simple-minded conception of genetic technology being able to predict many of the common illnesses (including Alzheimer's) has largely been unrealized. Most illnesses (including AD) are highly polygenic and even a single epsilon 4 only adds risk; it is not causative. In fact, epsilon 4 is one of the intermediate risk variants that is common. Yet, in my family a single epsilon 4 did not seem to contribute to AD risk.
What happens when AD risk can be accurately predicted with a polygenic score? How will our society respond to such knowledge?
I would want the information immediately but the most concerning thing to me is that so would my insurance company! Even changing names is not enough if you have several family members on the various genetic health/ancestry sights. Scary.
It should be obvious to all of us that these are no longer hypothetical questions. Human genome sequencing now costs about $700. At a price point of $100, genome sequencing will be wide spread. It is not entirely unreasonable to expect that the $100 genome is not that far off in the distance.
LG1, I am not sure whether you are aware, though Right to Try is now the law of the land.
Yes, I think this is awesome.This could be of considerable help for the AD community because typically CRISPR and almost any other new technology that might be of help to those at risk for dementia probably would be on a time line of decades
I choose to believe otherwise. I am going to do my best to get the information from one of the research team members. I put a lot of emotional bank in this technology.(possibly a few). All of us have watched the years recede and potential treatments appear to remain stationary. The years become decades and still there is often little or no progress; at most there might need to be yet more clinical studies. Right to Try does offer some hope, though with CRISPR one might perhaps like to be more cautious than is allowed by the law ( especially if one had a time cushion).
Aside from CRISPR there is also the anti-oligos that are moving ahead.
https://www.alzforum.org/news/research- ... -av-spigot
This is interesting LG1, how you found e4 dementia in your father's line. The expression of e4 dementia through generations is probably different from what my family has experienced. I am not completely sure, though I would guess that typical e4 dementia families would not have a clearly observable dominant style transmission pattern. In most instances within families, most would only have a single e4 and for males this might not result in a great deal of dementia risk. Of course, as happened in my family, there does seem to be AD assortative mating. For those who want to make informed genetic choices, this will no longer need to be a haphazard random process.
Lazy on my part to say it was e4. No idea, just assumed it was a contributing factor. I wish I had my father's dna file but nope. I asked my first cousin, his nephew, to contribute a sample so I could have a look at it.
What is very very odd is how unaware most people appear to be about their family histories much beyond 2 or 3 generations. Most of the relatives who I contacted that did not have direct experience with demented family members had no awareness that in a broader context such dementia was clearly present.
Yes and people just don't talk about their dead relatives much. Doesn't seem to come up in normal conversations at Thanksgiving and such. I think I will inquire a little more on both sides.When I moved out to the level of 4-5 generations, the pattern became self-apparent.