Massive AD GWAS! YEAH!!!

Insights and discussion from the cutting edge with reference to journal articles and other research papers.
J11
Contributor
Contributor
Posts: 1834
Joined: Sat May 17, 2014 4:04 pm

Massive AD GWAS! YEAH!!!

Postby J11 » Wed Feb 24, 2021 9:03 pm

https://www.alzforum.org/news/research- ... mers-genes

There is so much potential to totally unlock the AD genome.
With full genome scans approaching ~$100 perhaps full genome sequencing could become common in AD clinical trials
and these sequences (with patient approval) could be analyzed in GWAS. Fully unlocking the full AD GWAS would tell us so much. It really should be done sooner than later.

We know that at a scale of ~1 -2 million everything would be revealed. This isn't an eternal money pit searching a bottomless void.
Basically, $100 million. If we make it a project for the people, might reduce down to scrounging some CPU from morally conscious tech titans and possibly some takeout.

J11
Contributor
Contributor
Posts: 1834
Joined: Sat May 17, 2014 4:04 pm

Re: Massive AD GWAS! YEAH!!!

Postby J11 » Wed Feb 24, 2021 9:16 pm

"We also generated a novel polygenic risk score strongly associated with the risk of future dementia or progression from mild cognitive impairment to dementia."

https://www.medrxiv.org/content/10.1101 ... 2.full.pdf

Whoa!
I believe them.

This could start to move the ball forward for clinical trials.
We could see precise genetic selection of those who would be most likely to benefit in a clinical trial.
AD clinical trials used to have ~40% of AD patients who did not have AD.
Then they introduced amyloid positive inclusion requirements; yet even then a significant percentage of patients
would not progress during a 78 week trial. Finding the right patients could make a very large difference.

J11
Contributor
Contributor
Posts: 1834
Joined: Sat May 17, 2014 4:04 pm

Re: Massive AD GWAS! YEAH!!!

Postby J11 » Wed Feb 24, 2021 9:19 pm

This is so great!

I have my full genome sequence being processed and I have R code that can extract genotypes and effortlessly compute polygenic scores! Yeah this is great! This AD polygenic score from the massive AD GWAS will probably be at the top of the list. Yet, the funny thing is that this GWAS does not appear to include the gene that drives the dementia in my family. I have quite a few genetic relatives that I can contact about this to confirm. I'll share the code when I have my sequence on file. Perhaps we can all explore this wondrous world of the genome together and make it easy to unlock its mysteries.

circular
Senior Contributor
Senior Contributor
Posts: 5197
Joined: Sun Nov 03, 2013 10:43 am

Re: Massive AD GWAS! YEAH!!!

Postby circular » Mon Mar 01, 2021 2:45 pm

WOW! Wish I had time to delve but need to get back to the day's to-do list.
Carlos Cruchaga at Washington University in St. Louis called the work a tour de force.
ApoE 3/4 > Thanks in advance for any responses made to my posts.

J11
Contributor
Contributor
Posts: 1834
Joined: Sat May 17, 2014 4:04 pm

Re: Massive AD GWAS! YEAH!!!

Postby J11 » Thu Mar 11, 2021 5:08 pm

circ, I am surprised that more effort has not been put into completing the genetics of AD. My impression is that many there are many people out there who do not have a good understanding of the genetic origins of their family's dementia. The cost savings related to genetically selecting against AD embryos could be extremely large. Why governments have not perceived that AD GWAS is strongly in their self-interests is not immediately obvious to me. One could imagine the top 30 nations committing to collecting 10,000 AD genotypes over 5 years that would pretty much unlock the AD genome. The actual cost to do this would be minimal. The political payback of at least appearing to do something would be immediate. Sometimes life is not easy to understand. Probably the best way to explain this is that the default in life is to do nothing- if you do nothing then at least no one can say that you actively made a mistake. It needs a sharper cookie to recognize that doing nothing can also be a mistake.

Jgreg80
Contributor
Contributor
Posts: 4
Joined: Wed Feb 13, 2019 12:37 pm

Re: Massive AD GWAS! YEAH!!!

Postby Jgreg80 » Sat Mar 13, 2021 5:33 am

Anyone have access to the SNPs?

J11
Contributor
Contributor
Posts: 1834
Joined: Sat May 17, 2014 4:04 pm

Re: Massive AD GWAS! YEAH!!!

Postby J11 » Sat Mar 13, 2021 8:35 am

Here's the pdf.


MEGA Table 1b.GIF
MEGA Table 1a.GIF
MEGA GWAS.GIF
You do not have the required permissions to view the files attached to this post.

J11
Contributor
Contributor
Posts: 1834
Joined: Sat May 17, 2014 4:04 pm

Re: Massive AD GWAS! YEAH!!!

Postby J11 » Sat Mar 13, 2021 8:38 am

Here's the Manhattan plot so you don't have to get a sore neck.
Notice the genes shown in red: Those are the newly discovered genes!
The sample size is still smallish ~100K and they are on an exponential growth path.
There must be a great deal of variants still to find.

I am anxiously waiting for another AD by proxy GWAS.
Simply ask those in a large GWAS if they have a family history of AD.
This was done in UKBB and there were many with an Alzheimer family history.
The Million Veteran study is nearing enrollment; this would be another
large GWAS that could use the proxy GWAS method.


MEGA GWAS rotate.gif
You do not have the required permissions to view the files attached to this post.
Last edited by J11 on Sat Mar 13, 2021 8:50 am, edited 1 time in total.

User avatar
SusanJ
Senior Contributor
Senior Contributor
Posts: 2890
Joined: Wed Oct 30, 2013 7:33 am
Location: Western Colorado

Re: Massive AD GWAS! YEAH!!!

Postby SusanJ » Sat Mar 13, 2021 8:39 am

J11 wrote:I have my full genome sequence being processed and I have R code that can extract genotypes and effortlessly compute polygenic scores!


Have you heard of any companies thinking that they will offer this type of scoring?

J11
Contributor
Contributor
Posts: 1834
Joined: Sat May 17, 2014 4:04 pm

Re: Massive AD GWAS! YEAH!!!

Postby J11 » Sat Mar 13, 2021 9:23 am

Variant? Chr? Position Gene* Known locus Minormolor MAF* App.OR' 95% CP Pp Locus Variant? Chr? Position! Gene* Minowmtalor MAF* App.OR' 95% CP pe


rs679515 1 207577223 cR1 cR1 TIC 0.188 1.13 1.11-1.15 7.2x10%°
1 rs141749679 1 109345810 SORTL cit 0.004 1.38 1.24-1.54 7.5x10° 5
6733839 2 127135234 BIN1 BINL TIC 0.389 1A7 1.16-1.19 641x107"
2 872777026 2 9558882 ADAM17 G/A 0.144 1.06 1.04-1.08 2.7x10° 13
10933431 2 233117202 ~—sINPPSD INPPSD GIC 0234 «4093 092-095 36x10"
3 1517020490 2 37304796 PRKD3 ct 0145 1.06 = 104-108 = 3.310? 1s
6846529 4 11023507 ‘CLNK ‘CLNK/HS3ST1 ct 0.283 1.07 1.05-1.08 2.2x10°" 4
rs143080277 2 105749599 NCK2 ct 0.005 147 1.33-1.63 2.1x10"
rs6605556 6 32615322 HLA-DQA1 HLA GIA 0161 091 090-093 71x10 5
rs139643391 2 202878716 WDR12 We 0.131 «0.94 = 0.920.961.1108
rs10947943 6 41036354 UNCSCL TREM2 AIG 0.142 094 0.93-0.96 1.1x10° 6 1
rs16824536 3 155069722 MME AIG 0.054 0.92 0.89-0.95 3.6x10° 5
143332484 6 41161469 TREM2 TREM2 Tie 0.013 «141 132-150 28x10
6 18 61762319 3 155084189 MME GIA 0.026 «1.16 9112-221 = 2.2x10"" 13
75932628 6 41161514 TREM2 TREM2 Te 0.003 239 209-2.73 25x10"
7 13822030 4 993555 IDUA ct 0429 «0.95 0.940.986 8.3x107
rs60755019 6 41181270 TREML2 TREM2 G/A 0.004 1.55, 1.33-1.80 2.1x107 8
rs2245466 4 40197226 RHOH cic 0.343 1.05 1.03-1.06 1.2x107 15
7767350 6 47517390 CDZAP CD2AP TW 0271 «1.08 «106-109 —_7.9x107 9
rs112403360 5 14724304 ANKH AT 0073 1.09 :1.06-1.12 —-2.3x10° 15
6966331 7 ~~ 37844191 EPDR1 NMES Te 0349 «4096 0940.97 46x10"
10 1562374257 5 86927378 cox7c ct 023° «1.07 = -1.05-1.09 14x10"
rs7384878 7 100334426 SPDYE3 ZCWPWIL/NYAPL c/T 0.31 0.92 0.91-0.94 41.1x107° "1
rs871269 5 151052827 TNIPL Tic 0.326 0.96 0.95-0.97 8.7x10%
rs11771145 7 143413669 EPHAL EPHA1 AIG 0348 «4095 093096 33x10"
12 -rs113706587 = § = 180201150 RASGEF1C AIG 0.14 409 107-112 2.2x10" 1s
73223431 8 27362470 PTK2B PTK2B TIC 0.369 1.07 1.06-1.08 4.0x1077 13
rs785129 6 114291731 HS3STS. Tic 0.35 1.04 1.03-1.06. 2.4x10° 1
11787077 8 27607795 clu clu TW 0392 091 090-092 1,7x10“ 14 7
6943429 7 7817263 UMADI TH 042 1.05 = -1.03-1.06 —1.0x10""
rs7912495 10 «11676714 USP6NL ECHDC3 GIA 0462 1.06 105-108 97x10"
15 1510952097 7 8204382 IcA1 Tie 0114 «1.07 -1.05-1.10 6 8x10"
rs10437655 1 47370397 SPI1l CELF1/SPI1 AIG 0.399 1.06 1.04-1.07 5.3x10"*
16 513237518 Fr 12229967 TMEM1068 AIC 0411 0.96 0.94.0.97 49x10" 15
1562763 41 60254475 = MS4A4A MS4A NG 0371 «091 090-092 37x10"
17 11160871 7 —- 28129126 JAZFL G/GTCTT 0222 0.95 0.93097 9.8x10" 5
3851179 1186157598 EED PICALM Te 0358 #4009 089-092 30x10" 18 1

76928645 7 ‘4873635 SEC61G TK 0.103 0.93 091-095 1.6x10"°
rs74685827 WwW 121482368 SORL1 SORL1 G/T 0.019 1.419 1.13-1.25 2.8x10""

19 rs1065712 8 11844613 CTSB CG 0.053 1.09 1.06-1.12 1.9x10" 13
11218343 11 121564878 = SORLI. SORLI cr 0.039 «0.84 081-087 —1.4x107"

20 15 34173062 8 144103704 SHARPIN AIG 0.081 91.13 1.09-1.16 = 4.7x10"* 15
17125924 14 -§2924962 «= FERMT2 FERMT2 GIA ooss 14 1.07-112 8.3x10"¢ 21
rs1800978 9 104903697 ABCA1 Gc 013 ©«- 1.06 = .04-1.08 = 1.610
rs7401792 14 92464917 SLC24A4 SLC24A4/RIN3 G/A 0.371 1.04 1.02-1.05. 4.8x10° 22
rs7068231 10 60025170 ANK3 TG 0.403 0.95 0.94-0.96 3.3x10?
rs12590654 14 92472511 SLC24A4 SLC24A4/RIN3 AIG 0328 «60.93 0.92095 4.2x107" 23
rs6586028 10 © 80494228 TSPANI4 cr 0.93 © 0.91-0.94 —2.0x10""
rs8025980 15 50701814 SPPL2A SPPL2A GIA 0.345 0.96 0.94-0.97 1.3x10* 24
rs6584063 10 96266650 BLNK GIA 0.89 0.86-0.92 67x10"
rs602602 15 58764824 MINDY2 ADAM10O AT 0.28 094 0.93-0.96 2.1x10"*
25 rs7908662 10 122413396 PLEKHAL GIA 0.96 0.95-0.97 2.6x10"
fs117618017 «1563277703 APH1B APH1B Te 0144 141 109-113 22x10
26 16489896 12 113281983 TPCNL ct 1.08 = 1.05-1.10 4.810"
rs889555 16 31111250 BCKDK KAT8 TIC 0.281 095 0.94-0.97 2.0x10""
27 rs7157106 14 105761758 IGH gene cluster AIG 1.05 1.03-1.07 2.0x10° 1
4985556 16 70660097 134 134 AIC 0115 1.07 = 1.05-1.09 60x10"
27 rs10131280 14 106665591 —IGH gene cluster AIG 0.94 092-096 43x10" 1
12446759 16 81739398 PLCG2 PLCG2 GIA 0403 «085 = 094.096 —1.2x10? 28 15

3848143 15 64131307 SNX1 G/A 105 9104-107 8.4x10""
rs72824905 16 61908423 PLCG2 PLCG2 Gic 0.008 0.74 0.68-0.61 8.5x10"7
29 s12592698 15 78936857 ‘CTSH AIG 0.94 0.92-0.96 4.2%10% 15
7225151 17 8233752 ScIMP SCIMP/RABEP1 AIG 0124 1.08 = 105-110 © 44x10"
30 rs1140239 16 30010081 poc2a Tc 0.94 0.93-0.96 —_2.6x10""
rs199515 17 46779275 WNT3 MAPT Gic 0.219 0.94 0.93-0.96 9.3x10"* 3
rs450674 16 79574511 MAF cit 0.96 0.95-0.98 3.2x10* 15
616338 1749219935 ABI3 ABI3 We 0012 132 123-142 28x10"

32 1516941239 16—=-86420604 FOXFL AT 143° (1.08-1.17 43x10" 15
2526377 17 58332680 TSPOAP1 TSPOAP1 GIA 0445 095 094097 16x10
33 1356407236 16 90103687 PRDM7 AIG 141 (1.08-1.14 65x10"
s4277405. 17 63471557 ACE ACE 0.384 094 0.93-0.95 8.8x10"
34 rs35048651 17 1728046 WDR81 TITGAG 1.06 1.04-1.08 7.7x10"" 1
12151021 19 1050875 ABCA7 ABCAT AIG 03360044 1.09-112 16x10"
35 rs2242595 17 18156140 MYO15A AIG 094 092-096 —1.1x10" 5
6014724 20 ©» 56423488 CASS4 CASS4 GIA 009 089 087-091 4.1x10"
36 rs5848 1744352876 GRN Te 107 1.06-109 2.4x10° 15
2830489 21 (26775872 ADAMTS1 ADAMTS1 TIC 0.281 0.95 0.94-0.97 1.7x10"°
37 rs149080927 19 1854254 KLF16, G/IGC 1.05 1.04-1.07 5.1x10°°
38 139304690 19 49950060 SIGLEC11 TIC 1.05 1.03-107 47x10"
39 rs587709 19 54267597 ULRB2 ct 1.05 1.04-1.07 3.6x107"
40 11358782 20 413334 RBCKL AIG 0.95 © 0.94-0.97 1.6x10°
41 rs6742 20 «63743088 SLC2A4RG Te 095 093-097 26x10"
42 rs2154481 21 26101558 APP ciT 0.95 0.94-0.97 1.0x10°?


Return to “Science and Research”

Who is online

Users browsing this forum: No registered users and 6 guests