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

[J11]

I have made this massive discovery.
It is right up there with discovering life on planet earth: might be terribly obvious (somewhat hard to overlook), though
nonetheless overwhelmingly important.

Ancestry.com!!

They can almost automatically fill in your family tree on almost any line back to the 18th Century.
I had no idea where to start with our family tree.
Our family greatly believes in minding your own business and letting the rest of the extended family live their own lives.
With such a mentality, it was difficult to push the tree much before the 20th century.
Yet, with Ancestry.com you can keep going back and back.

This will be enormously helpful in trying to sort out our family dementia history.
Others on the forum who are also unsure about their dementia genetics might also want to investigate this.

The one thing I am unsure of right now is whether Ancestry.com allows people to upload their 23andme results.
This will be like rocket fuel if we can then add in DNA!

[J11]

I have been making some exciting progress on figuring out our family's genetics with the genealogy approach, though I will keep this quiet until things are more certain.

In the meanwhile, I have just been reading the top science stories for 2015 as chosen by one of the science magazines.
One of the stories they included was the recent report that Alzheimer has prion like ability to spread. This captured some media
attention not so long ago. This could be the go to story whenever a ratings bump is needed.

The referenced article cited another article which had used next generation sequencing to identify genetic variants that caused early onset dementia. {Validation of next-generation sequencing technologies in genetic diagnosis of
dementia Neurobiology of Aging: 35(1); p. 261-265).

This article noted 16 dementia disease genes (PRNP, PSEN1, PSEN2, APP, GRN, MAPT, TREM2, CHMP2B, CSF1R, FUS, ITM2B, NOTCH3, SERPINI1, TARDBP, TYROBP, and VCP) as possibly involved with early onset AD.

There were almost a whole page of NOTCH3 variants in the exome file, though the one that was the most scary is the one below.

chr19 15299051 rs11670799 G A 690.34 PASS BaseQRankSum=-1.276;DP=64;Dels=0.00;FS=2.094;HRun=0;HaplotypeScore=2.6603;MQ=52;MQ0=0;MQRankSum=0.685;QD=10.79;ReadPosRankSum=-0.161;SB=-469.36;AA=g;AF=0.01;EVS=0.0155|28.0|6501;GMAF=A|0.0055;phastCons;CSQT=NOTCH3|NM_000435.2|missense_variant GT:AD:DP:GQ:PL:MQ:GQX:VF 0/1:33,31:64:99:720,0,736:52:99:0.484

A rare missense variant in NOTCH3 that Mutation Taster called as disease causing.
It sure will be great when the genetics is all worked out and then at least people would know one way or the other.

I suppose this is a present of sorts.
Merry Christmas everyone!

[circular]

J11 you might be interested in FGC's announcement of its new full genome sequencing product at 30x coverage. Still way expensive at $1,650 but Promethease and other tools can work with the raw data. I'm not sure why they say:

As with other Full Genomes products, this is intended for ancestry/research-use only, and should not be relied upon for medical or diagnostic purposes.

https://www.fullgenomes.com/news/

We wait for prices to continue to fall … and in the meantime exome sequencing's an option.

[J11]

The family genealogy is ongoing though somewhat stealthily at this time.
I am hoping that some of the family will make contact us!

After looking at the exome scan, I had thought the mitochondria looked very clean.
There was hardly any mutations in the whole sequence.
I have now become aware that one can have mitochondrial deficits from nuclear DNA.

Our loved one has variants in the SOD2 (MnSod) gene on chromosome 6 that appear related to AD.
Seems like a back door into the mitochondria through the nuclear DNA. These are fairly common variants, though i wonder how they might combine with the HFE 280Y variant. 23andme confirmed the rs4880 AG genotype.

chr6 160103084 rs5746136 C T 1248.84 PASS BaseQRankSum=2.003;DP=103;Dels=0.00;FS=1.754;HRun=1;HaplotypeScore=1.6229;MQ=58;MQ0=0;MQRankSum=-0.507;QD=12.12;ReadPosRankSum=0.745;SB=-426.47;AA=C;AF=0.32;GMAF=T|0.3214;CSQT=SOD2|NM_001024465.1|intron_variant GT:AD:DP:GQ:PL:MQ:GQX:VF 0/1:56,47:103:99:1279,0,1400:58:99:0.456
chr6 160113872 rs4880 A G 143.78 SB BaseQRankSum=1.196;DP=20;Dels=0.00;FS=0.000;HRun=0;HaplotypeScore=2.6641;MQ=60;MQ0=0;MQRankSum=-0.536;QD=7.19;ReadPosRankSum=0.371;SB=-0.01;AA=G;AF=0.37;EVS=0|57.0|6502;GMAF=G|0.3709;clinvar=other:non-pathogenic;CSQR=ENSR00001232418|regulatory_region_variant;CSQT=SOD2|NM_001024465.1|missense_variant GT:AD:DP:GQ:PL:MQ:GQX:VF 0/1:14,6:20:99:174,0,388:60:99:0.300

[circular]

I'm glad you brought up SOD2. I am homozygous T,T for decreased function on SOD2 rs10370. My notes say SOD2 binds to manganese in the mitochondria and is the principal antioxidant enzyme in the mitochondria. Given my mysterious and obstinate inflammation maybe I should take this more seriously.

FWIW NutraHacker says encourage manganese and Vitamin E in tocotrienol form. He also says avoid alcohol (I do), and noise, because it's associated with a greater chance of hearing loss. I instead actually have hyperacusis and 30+ years of bilateral tinnitus, but maybe it's related to this? I don't rely on NH's recommendations so need to find something firmer. I'm not sure why encouraging manganese would help if there's reduced SOD2 to bind to it?

SOD isn't supposed to be absorbed too well. Some believe that tied to wheat gliadin it gets absorbed, but gliadin's no good. Others take wheat grass but probably don't get much out of it. I found a Kal version on Amazon that's enteric coated so may give that a try

[circular]

Glad I checked this at SNPedia. It's appears a bit more complicated and not necessarily as bad as I'd thought:

There appears to be some conflict in the literature over the effect of this SNP. Having a valine at codon 16 is said to reduce enzyme activity [PMID 15864132], and thus lead to increased oxidative stress, yet in at least one study of the actual enzyme levels measured in people, SOD2 activity was 33% higher in (C;T) or (T;T) individuals compared to (C;C) individuals [PMID 16538174]. Regardless of how this resolves, several phenotypic associations have been reported for this SNP, including: … The C allele of rs4880 appears to be associated with Alzheimer's disease. [PMID 17376152] rs2758346 rs4880 and rs2855116 association with Alzheimer's disease.

Most of the other studies concerned the C allele as well and/or were in limited populations I don't fall within.

rs4880 is TT in about 37% of the population. Most of my other SOD2 SNPs are heterozygous and the frequencies are more mid-range.

SOD2 rs2855116(T;T) … C is associated with LOAD.

SOD2 rs5746136(G;G) … G is associated with LOAD.

SOD2 rs2758346(C;C) … T appears' to be more related to LOAD.

There are other SNPs on SOD2 that don't have much if anything on them.

http://www.snpedia.com/index.php/Rs4880

[J11]

11 family members affected by AD exome sequenced: another AD gene found TTC3.

More of this should be done!
After spending millions of dollars and genotyping 100,000 people 20 AD genes were found.

Exome sequencing AD families with dominant disease patterns is very economically sensible.
Low cost, high reward.
More of this should be done.

AD Dominant Exome Project?

http://www.ncbi.nlm.nih.gov/pubmed/27066578

[J11]

Admittedly it has been quite frustrating trying to work through our family's non-APOE4 AD genetics.
The online tools that would make this automatic are not on the major gene chipper sites such as 23andme and GEDmatch.

And Alzheimer's has certain clinical features that adds complexity to determining its genetic basis.
For example, onset often occurring at ages where survival effects become involved, environmental factors ...

Would be great if there were an easier illness target that I could use to illustrate what I had in mind for the genetic genealogy appproach.

How about hereditary colorectal cancer (polyp) syndrome?
Our loved one before developing dementia had recurring rounds of colorectal cancer.

I have just checked the COSMIC cancer genetics website for genes involved with recurrent CR cancer.
There were only a few listed.

I checked through the mutations in our exome file and a rare variant in the mutYH gene came back as a hit
dbsnp cautiously confirmed it. (The problem with some of these rare variants is that dbsnp does not have enough
evidence to offer clear verification.)

Went to Mutation Taster.
The Taster came back with a clear Disease causing status for this mutant.
It cited an HGMD ID and considers it to be a known disease mutation.

This was so easy!
I have been trying to find the Alzheimer's variant for years!
I have found lots and lots of very interesting variants, though it is not clear which of these if any I should be concentrating on.

With the colorectal syndrome the answer popped out almost immediately.
It was automatic, didn't even have to work up a sweat.

This will be a fairly big step forward for out family.
This is 21st Century medicine!

It was perhaps 10 years ago since our loved one was last rushed to emergency and another round of
CRC surgery and treatment was required. The doctors had absolutely no idea what was causing it. The first time it happened our loved one
waited until there was substantial pain. A very large growth had to be removed.

Knowing that this mutation has been present will make things very easy for us.
We will know decades ahead of time that this will (or will not) be a problem and we can have everything prepared.

We will also be able to haggle about prices.
The days of medicine as a near perfect example of a market with perfectly inelastic demand could soon be coming to an end.
We already have a list of likely disease causing variants from our exome file (including those for Alzheimer's)
which could simply be managed preventatively throughout life without there ever being a need to
rush to ER. Being aware of disease risks throughout life will have substantial implications for managing the
expenses related to medical care.

When you have a very large GI tumor that is causing substantial pain, it really comes down to finally getting into
the car and rushing to the nearest ER and giving them your credit card.
Money no longer matters. It is simply a question of fix the problem--fast.

With genetic knowledge, it would not be like this at all.
You could gene chip it and know whether the variant were present.
If it were present, you could monitor it with the pill cam.
You could treat the problem decades before there were any significant problem.
By treating at such an early stage, an entirely minimally invasive approach might be all that is needed,
possibly even less than day surgery.

It would be a new era of consumer empowered medicine.
The days of health or bankruptcy would be passed.
The room for negotiation over price in medicine until this point has been fairly narrow.
However, for a medical problem that might be decades away, such negotiations could be prolonged.
One could take time looking for the provider who would offer the lowest possible price, done at a very early stage.

This is amazing! Life can be BETTER!

The only snag that I have hit so far is that I looked up the segment that housed the variant on the mutYH gene on 23andme
and I found a DNA relative that shared the segment. This match was only in the 5 cM range so it is a bit on the low side and it is
not clear whether this match actually has the strand with the variant (it would be 50-50).

The big snag was that this was from 23andme's now no longer supported Countries of Ancestry tool and this relative is listed as anonymous. This poses something of an ethical dilemma. This relative (from France) has a fairly significant chance of having this variant that can cause an hereditary colorectal cancer syndrome. It might not be entirely obvious to this person that they actually have this mutant as this variant is not 100% penetrant. (Our loved one had no pre-warning before being rushed to ER that this was present in the family.)

What does one do in such a circumstance? 23andme has provided no means of communicating with this relative who we know might develop serious cancer though they might be completely unaware of this. In fact, 23andme has recently changed the rules which makes it impossible to contact anonymous relatives. This certainly raises a host of difficult ethical and legal questions.

We will soon be genechipped on other DNA sites, so we might be able to find many others who also have this mutant and hopefully help them avoid an emergency visit to ER. It is possible that we could have many confirmed instances in which this mutant caused CRC. Might even have more than that are listed on dbsnp. It would be great if there were some site that such information could be uploaded so that these rare variants would have more substantial confirmatory evidence. (Sort of a dbsnp+ site)

It will also be great when we connect up with more of our mutant mutYH + relatives because then we could determine which strand the mutant is on. All we know now is our loved one has this mutant in the exome file, the VCF file was not phased. When we find other affected relatives, we could simply determine which strand is shared on 23andme. This should mean that we would not even have to bother doing more exome scans. A $100 gene chip would give us the same information as a $1000 exome scan. (Would want to double and triple check this idea, because it would obviously be worth $1000 to be 100% sure.)

[J11]

I do not agree with how snpedia handles mutYH variants.

snpedia has only assigned a non-zero magnitude to 2 of these SNPs.

rs34612342 which is one of the most common of these variants at 0.0016.
Surprisingly this (known?) cancer causing variant has been given a magnitude of 2.
The study listed on their site cited an article in which this variant increased the risk of Head and Neck cancer.

rs36053993 has been assigned a magnitude of 2.5-3.1. The homozygote carriers have a higher risk of colorectal cancer.
T=0.0028 considered pathogenic by dbsnp.

Surprisingly, dbsnp is calling quite a few of the SNPs listed in snpedia's table for mutYH as pathogenic.
For example, rs121908380 A=0.0013, rs121908381 A=0.00010, rs138775799 A=0.00002 etc.
All of these are given a magnitude of 0.
http://www.snpedia.com/index.php/MUTYH

There would be the question of whether polyps form instead of cancer, though it was a medical emergency when
it was finally understood that our family member had a problem.

It is also not entirely clear whether these variants are recessive or dominant.
Our loved one's mutYH variant is heterozygous and there has still been a problem with CRC.
This variant might be the cause of one of the only illnesses our loved has ever had and we would give it
a magnitude of 10 on snpedia, if we could. Perhaps when more people are exome scanned then there will
be more of a push to have these rare variants included on SNPedia.

As it is it might take decades for these rare mutations to be extensively researched.
SNPedia wants replicated results involving 500 or more patients.
With MAFs of 1 in a million that might never happen.
Yet, when you add together all these rare variants the risk starts to accumulate.
There are over 40 mutYH variants!


dbsnp is listing over 40 rare variants that are claimed to be pathogenic. All of these are rare .
Some measure in the range of 1 in a million.

Yet, these are the variants that quite probably are correct.
How many times would it take for someone with one of these variants to show up before you just gave up
and accepted that it was very likely true?

The way most of the GWAS have been done so far is that they have chosen common SNPs that seemed to be real hits.
On further examination, none of them were.
If you throw enough 50-50 coins, you will create an overwhelming number of false results.
The same does not happen so much when you throw 1 in a million heads coins.

Funnily enough the mutYH variant in our family is not even listed on the known pathogenic page.
It is on the possibly pathogenic page.

http://www.ncbi.nlm.nih.gov/variation/v ... 0001405.25

[SNPedia]

Feel free to contact us directly to suggest updates; we're always looking for community feedback.

In the case of MUTYH, as you said, the variants are so rare that it's somewhat hard to know what to conclude about them. A quick scan of related literature came up with the following relatively recent article having information on risk in relation to both monoallelic (i.e. those with one MUTYH mutation) and biallelic carriers, and even it surveyed only 12 mutations over the 2,300+ individuals sequenced:

http://www.ncbi.nlm.nih.gov/pubmed/24444654

Take a look at it and then hopefully you can message or email us directly with your suggestions.