Gene editing solution not far away?

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NF52
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Re: Gene editing solution not far away?

Post by NF52 »

J11 wrote: 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.
...For those who want to make informed genetic choices, this will no longer need to be a haphazard random process. ...What is very very odd is how unaware most people appear to be about their family histories much beyond 2 or 3 generations... When I moved out to the level of 4-5 generations, the pattern became self-apparent.
Hi J11,
Your level of enthusiasm for the change of unknown-unknowns to known-and-used treatments is evident. I too hope that treatments and the ability to provide both a personalized risk assessment and, more importantly, a highly personalized treatment protocol, are just over the horizon.

However, I doubt that researchers, who have to get IRB (Institutional Board Review) approval for any studies that involve humans, would be able to obtain that for studies that would amount to informing people who have neither sought it, nor given their permission to be contacted, information that they are part of a group with a level of ApoE 4 risk, for example. I have more than 2 dozen relatives who I am fairly certain have at least the risk of an ApoE 4 allele. They may not know that, but they do know the cardiac and especially dementia risk in their mothers and grandmothers. And that's as far as the knowledge goes. There is no tracing back 4-5 generations. Those people either lived abroad and the knowledge of their hometowns is gone, much their their lives, or they lived here and died of stroke, cancer, accidents and childbirth years too early to experience dementia. I do not feel that I have the right to tell any relatives that they likely have a genetic risk, especially since I have seen the impact of that knowledge on people on this site.

Nor do I think that people will be choosing mates or children based solely on genetic risk--because epigenetics and lifestyle are so much more important, as are the vast array of traits we hope for in mates. My oldest son was born with life-threatening congenital (not genetic) anomalies. My husband and I would never have chosen not to have him, and he is healthy, happy and successful today. And my husband, who I asked today, said he would pick me over my two possibly 3/3 sisters.

People are just not that rational as you may hope--and I think that's okay.
4/4 and still an optimist!
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Re: Gene editing solution not far away?

Post by J11 »

Thank you for replying and giving me the opportunity to clarify that point.

Specifically I was referring to the recent research with the near causal variants that were found when 20,000 AD patients
were exomed scanned. Of those 20,000, they found 17 SORL1 variants, some of which appeared to be super rare and caused a large
increase in AD risk.

You are quite correct about being cautious in any communication with family who might not want to know of their AD risk. Within the context especially of epsilon 4 this would be the recommended approach. The actual risk from carrying epsilon 4
allele(s) can vary widely according to the entire AD polygenic score.

The problem with the 17 SORL1 variants found was it appeared that they were not able to find many confirming relatives. epsilon 4 has been verified to certainty for over 20 years now. With some of these ultra-rare variants, it is still somewhat unclear whether they are truly valid variants. Those on the forum have likely been familiar with SORL1 as a AD gene for a few years. It has taken all these years to finally confirm that SORL1 variants can actually be causal of dementia. Only a handful of genes are known to cause AD.

Given the importance of this research it would seem that a responsible plan could be formulated to leverage the resources of GEDmatch. What is especially interesting in this instance is that it is essentially a causal variant. The people that might be contacted would already likely be fully aware of the devastation that the variant caused as they would probably have deep histories of dementia-- with dominant Alzheimer's every generation would be expected to have affecteds. For such families, the information might be a particular blessing, though admittedly there is still a range of issues that emerge such as the guilt some feel that they were spared while others were not. Clearly there would be delicate issues to tackle. However, a well worded email something along the lines of

...." The university of so and so is doing genetic research and we are interested in contacting you. If you would like to further information about the nature of our research please visit our website."

Everything could be left vague enough initially so that no hint was given about the actual nature of the genetic research. The information could be gradually revealed so that people could opt-out at any point if it went beyond their comfort point. Only those interested would pursue it further. Such an incremental info flow might be seen as the proper way in the future to reveal such information. Sometimes a single sign off on informed consent is really not adequate.

I suppose that another great avenue for this would be snpedia. Moving beyond all the IRB restrictions, one could draw on the hidden wisdom of the crowd (especially those who are actively seeking out genetic knowledge) to narrow down on some of these answers.
If this is not done, then it could years and years of more expensive research to arrive at the answers that so many of us desperately need to be found today. I think it is highly reasonable to think that privacy and the right not to know etc, could all be respected, while at the same time giving people the opportunity to make a real contribution to the well-being of their extended family. I have contacted a large number of my extended family and it is now surprising to me to realize that I hardly remember any of them having
concerns about talking about dementia. For those who did not have a demented close family history, it seemed a great relief to them that they dodged it. For those who did not dodge it, it seemed a great relief for them to talk about how dementia had impacted their lives. I have had positive interactions with almost all of my extended family related to cold emailing them about possible dementia histories. It has occurred to me that any government, corporation, organization or otherwise that tried to extract the type of information that I have accessed from my relatives without very clear and pristine moral intentions would almost certainly be
censured in the harshest terms available.
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Re: Gene editing solution not far away?

Post by LG1 »

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, :shock:
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.
Thanks for the reply to my post, a lot to unpack, lol!
ε4/ε4
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Re: Gene editing solution not far away?

Post by J11 »

This is without question a global emergency.

For some reason the imminent IQ uplift of humanity has not been thought worthy of public discussion.
Yet, a profoundly severe social crisis continues to smolder.

This needs to be openly discussed by the global leadership before human society completely disintegrates.
The problem is that it is now that severe, the thought leaders are fully aware of the approaching disruption, though for whatever
reason the conversation has not even started.

An uplift of 15 IQ points which now seems possible for all parents to be, would profoundly change human existence.
Human technological progress would increase by an order of magnitude.
Life would be profoundly different.
Such a change might already underway in some nations.

The trigger event for the unveiling of the uplift could occur when fertility suddenly disappears.
This would be the logical response to wide recognition that technology would allow for IQ enhancement.
Having children that were 1 standard deviation or more below the enhanced would mean that the unenhanced
would simply have no future. They would essentially be unemployable. In fact, it is currently within legal norms
of government hiring to discriminate against those with IQs 1 SD below 100 mean. When IQ uplift occurs, this
discrimination might then apply to those who today would be regarded as having average intelligence.

However, it is entirely possible that the current strategy is simply let time roll forward and life continue as always and
then when the IQ technology has finally fully developed break the headline that the technology is now ready. The main
question mark is whether people could be so unaware of what is happening to drift into such a future without realizing it.
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SusanJ
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Re: Gene editing solution not far away?

Post by SusanJ »

A new study that suggests CRISPR is still a ways from being ready for prime time.

https://www.statnews.com/2018/07/16/cri ... estimated/

Here is the paper.
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Re: Gene editing solution not far away?

Post by circular »

J11 wrote: Given the importance of this research it would seem that a responsible plan could be formulated to leverage the resources of GEDmatch...

Clearly there would be delicate issues to tackle. However, a well worded email something along the lines of

...." The university of so and so is doing genetic research and we are interested in contacting you. If you would like to further information about the nature of our research please visit our website."

Everything could be left vague enough initially so that no hint was given about the actual nature of the genetic research. The information could be gradually revealed so that people could opt-out at any point if it went beyond their comfort point. Only those interested would pursue it further. Such an incremental info flow might be seen as the proper way in the future to reveal such information. Sometimes a single sign off on informed consent is really not adequate.

I suppose that another great avenue for this would be snpedia. Moving beyond all the IRB restrictions, one could draw on the hidden wisdom of the crowd (especially those who are actively seeking out genetic knowledge) to narrow down on some of these answers.
If this is not done, then it could years and years of more expensive research to arrive at the answers that so many of us desperately need to be found today. I think it is highly reasonable to think that privacy and the right not to know etc, could all be respected, while at the same time giving people the opportunity to make a real contribution to the well-being of their extended family.
Hi J11! Although it will take years and a ton of money, I think the 'All of Us' research project underway in the US is going to be the way forward. It's heavily funded through NIH (although over time they'll need more funds for all the genetic sequencing they hope to do, roughly 1,000,000 genomes). A similar project is underway in the UK. All the appropriate opt-in mechanisms will be in place after heavy vetting by the committees that administer and get these approved for use by thousands of researchers. When you apply for and get acquainted with the All of Us project, you begin to realize the enormity of the task, planning, legalities and mechanisms in order to produce viable research outcomes, from both science and privacy perspectives. These initiatives are going to build a much more scientifically robust database for what you want than GEDmatch can. Then, the individual researchers that make use of these databases will have IRBs, peer review etc. I know it's slow as molasses, but the outcomes may actually be something insurance companies will put some faith in, due to the integrity of the genetic databases used from a medical/scientific perspective.

For example, GEDmatch is comparing files from different companies that test overlapping, but not completely the same, SNPs, and only 23andMe actually focuses on medically useful SNPs (at least those we currently know). This works for genealogical research, but may not be ideal for genome fishing for medically meaningful SNPs. If there's a so far unknown SNP raising risk of AD that's tested by some of the companies but not others, then in the GEDmatch database the associations may look weaker than they actually are. Granted, most of the SNPs will overlap, but I think the scientific, legal, and privacy logistics with this type of inquiry are beyond what GEDmatch is suited for.
ApoE 3/4 > Thanks in advance for any responses made to my posts.
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Re: Gene editing solution not far away?

Post by J11 »

If this doesn't send chills up your spine, then .. oh never mind.

https://www.nature.com/articles/s41588-018-0147-3
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