8 ms·

Exome sequencing and analysis of 450k UK Biobank participants

76 points by ahurmazda 5y ago

jasonhansel 5y ago
A reminder that these sorts of genome-wide studies are not particularly reliable due to the problem of multiple comparisons: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3270946/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3270946/
- aabaker99 5y ago
  https://en.m.wikipedia.org/wiki/Bonferroni_correction https://en.m.wikipedia.org/wiki/Bonferroni_correction
- gwern 5y ago
  A reminder that these sorts of genome-wide studies haven't used 0.05 but genome-wide significance (10e-8 usually, and 10e-11 in OP) for a decade now for precisely that reason, and have since replicated just fine, thank you very much.
omarhaneef 5y ago
I think I missed the novel technique they applied. Surely others try to match particular genes to diseases. Surely that’s one of the pillars of the entire field.
- flobosg 5y ago
  The novelty lies in the size of the data set. ~450,000 exomes is a lot.
dekhn 5y ago
awful lot of resources were spent to find very little of deep value. Genomics is just marginal gains for each huge new amount of capital invested.
- car 5y ago
  Why the pessimism? Lots of really interesting leads are coming out of this study.
  - dekhn 5y ago
    well, I worked in the field for several decades and got really tired of the constant overhyping of the results. These results really aren't useful (they're not predictive, or useful for genetic screening) and the cost is really extraordinary (hundreds of millions of dollars). There are other areas of biology that provide much more value per dollar spent.
- twofornone 5y ago
  We're talking about the source code of the human being. There's a ton of value in learning to translate it.
flobosg 5y ago
Twitter thread from one of the corresponding authors: https://twitter.com/gabecasis/status/1450289834543697925 https://twitter.com/gabecasis/status/1450289834543697925
- car 5y ago
  Great explainer of the significance of this study by Goncalo Abecasis. Basically human gene knock-outs, courtesy of mother nature. This study yields tons of gene function leads. Just awesome. Edit: quote The data is so rich that we had no more than a single paragraph to summarize association signals relevant to cancer and brain function. Ouch. A tweet won’t do them justice, but @uk_biobank will be sharing all the data with researchers for follow-up.
hybrid_cluster 5y ago
Not too related, but I got my genome sequenced for fun the other day (< $500 for 30x whole genome), and after a few scrolls through the results (200+ interpretations of my genome in the context of studies like the one linked here), I'm already losing interest. Ok, so I have a high genetic predisposition for thinness, walking fast [0], and bipolar disorder? So now what? I never noticed except for the thinness. They even scared me with 'you're genetically in the 99th percentile for critical covid disease progression,' but reading the results of the paper in question, it turned out the heritability of the effect under study was only 6%. Thanks for letting me know. These studies are interesting from a general genomics perspective, but not so much yet from a personal one (with the exception of a few traits that are determined by one or a few well-understood genetic variants. Hopefully this space will expand over the next few decades). [0] https://www.nature.com/articles/s42003-020-01357-7 https://www.nature.com/articles/s42003-020-01357-7
- epistasis 5y ago
  This is precisely right, and for most people it's unlikely that their genome will be particularly useful any time soon. For an individual, the questions are usually much more focused: for example if I have a baby with my partner, what are the chances that our child will have a recessive genetic disorder? This is answered right now with a carrier screen, where the only genes tested as the genes with variants that are known to cause disease. Much cheaper, much more highly curated, and put together and run entirely by experts in the field, rather than general technologists that are just running samples through a big machine. Interpretation of the genome will take millions upon millions more individual genomes sequenced, but those individuals will only rarely, if ever, see personal benefit.
- deleted 5y ago
  [deleted]
- pfisherman 5y ago
  In most cases, your sequence info will be useless to you, but in some situations it can have a huge impact, such as predicting how you might respond to epidural anesthesia if you are a woman in labor. Also, things like personalized immunity therapies for cancers and such are not far off. Unless they completely fail - which is always a possibility in therapeutic development.
DoreenMichele 5y ago
For people with health problems, identifying the genetic stuff contributing to their health issues can be game changing.
sjg007 5y ago
This is neat and will lead to a lot of interesting discoveries. Golden age for genomics is ahead.
- wombatmobile 5y ago
  The golden age for genomics has been “ahead” since 1990. It’s still ahead. We just don’t know which decade will yield the eureka. Voyages of discovery are like that.
pfisherman 5y ago
Wow, what a time to be alive! For those who are not into bio, this type of information is invaluable for untangling the molecular mechanisms of disease and can provide important clues about where we should intervene with a small molecule or antibody drug to disrupt disease processes. To give a coding analogy, you can think of this as trying to debug a program written in a language we can’t read. We have no idea what lines are doing what, but there are many different versions / forks of this program floating around. By looking at all the diffs and comparing the outputs, we can start to figure out what some of the code is doing, and which lines we might want to comment out to correct certain types of bugs.
tweedledee 5y ago
This is absolutely world changing. I've known that this was coming and was only a matter of time, it did get here sooner than I expected. I have hypermobile Ehelers Danlos Syndrome (hEDS) from a TNXB mutation. I was incorrectly told by doctors for decades that I was perfectly healthy and my issues were psychosomatic. It wasn't until I did a careful large scale behavioral analysis that I was able to identify similar people and from there the root cause. A $500 (30x) DNA test confirmed it. hEDS is massively under diagnosed, the vast majority never get a diagnosis. I strongly suspect that most mental problems are physical in nature and most physical problems are DNA related. And even when they're not DNA related, treatment ideas could be gleaned from 'natures large scale experiment'. The number of issues that can be identified from a $100 (1x) test and then subsequently treated is mind boggling. For me, that cost is less than a single doctors visit. This side steps the medical establishment which is slow and in many ways archaic. This will lead to a massive leap forward in medicine. In other news; I'm also of the opinion that IQ is largely determined by DNA, nature as opposed to nurture, and once that is properly figured out I'm sure designer babies are next. I don't think that is a door that can be kept closed. There is already a black market for it. I'll be watching from the sidelines, I think this is going to get interesting.
- tudorw 5y ago
  I think most anyone should have a CYP2D6 test if they are considering taking, or taking, medication, it affects so many drugs out there, yet here in the UK, the GP's I have encountered are not familiar with gene<>drug interactions and I had to request it after working it out myself. It's a complex area, but if you happen to be a poor or ultra metaboliser it's a good thing to know. https://www.ncbi.nlm.nih.gov/books/NBK99699/ https://www.ncbi.nlm.nih.gov/books/NBK99699/
  - tweedledee 5y ago
    100% it’s cheap enough that everyone should do it. The TNXB mutation has a ton of weird drug interactions. Anesthesia resistant being just one.
    - 5y ago
cblconfederate 5y ago
I think DNA data should be considered public data. 99% of our DNA is shared, and the DNA degrees of separation between you and me is ~3. Practically we are all already identifiable from the small sample that exists in genealogy companies and it s been repeatedly done by law enforcement. I think it's bonkers that , after 10 years, companies like 23andme are not allowed to give us health reports because ... what reasons really? Especially in Europe it makes no sense to have such draconian laws about something that's important to everyone's health. Full sequencing costs like $200 today and i m sure millions would be willing to give their data to a public database that would take the field meaningfully forward. Instead what we get is we allow these companies to sell data which should be public domain. The US has its problems with their broken social security - here's a suggestion: fix it. Europe could use its public healthcare advantage to get ahead in genomic research while simultaneously improving the quality of its health systems. Instead we are stuck with outdated privacy laws (yet somehow making tax information public is OK). China could be using their own advantage and databases to get ahead in genomics while we 're still playing hide and seek.
- dekhn 5y ago
  My DNA is public data: https://my.pgp-hms.org/profile/hu80855C https://my.pgp-hms.org/profile/hu80855C
ahurmazda 5y ago
From abstract: “… We discover several risk-increasing associations with traits related to liver disease, eye disease and cancer, among others, as well as novel risk-lowering associations for hypertension (SLC9A3R2), diabetes (MAP3K15, FAM234A) and asthma (SLC27A3)…“
msandford 5y ago
Does anyone remember the days when some geneticists were saying that 98% of DNA is "junk" DNA? When I heard it I knew it couldn't be true but it's probably going to take another 50 years to figure out how much really does get used. I can't help but suspect that a lot of the genome is a part of the boot sequence that helps you go from one cell up to all the differentiated organs and tissues and systems.
- hyperbovine 5y ago
  That hypothesis is a little dated, but it should be noted that the exome (the thing being discussed in this article) is 1% of the overall human genome.
- xyzelement 5y ago
  Had the exact thought when I read the headline. What arrogance. "I don't understand what these genes do. Must be junk"
  - da39a3ee 5y ago
    Actually no, that's not the intellectual level at which any science is performed, let alone population genetics and molecular genetics. Do you perhaps see the irony in making such a grotesquely arrogant suggestion yourself? People working on population genetics and molecular genetics, who came to the conclusion that much DNA has no phenotypic relevance, were doing so based on several decades of literature and 10-20+ years of their own education and scientific training. Would you care to give your own qualifications in this field?
    - xyzelement 5y ago
      > Would you care to give your own qualifications in this field? I am a programmer, and I trust my ability to call out junk code. Except if I am reading code from someone like Carmack or Linus. In those cases, I am gonna assume whatever I don't understand is my fault. What hubris would it be for me to call Linus' code junk, even if I really can't make sense of it despite my best effort? Same here. It's fine to say "we did our best to understand this and as far as we can tell, these genes are not utilized" to go like "yeah it's junk" is quite different. You're a mere mortal, and DNA has been the foundation of all life for millennia. You don't get to judge so easily.

76 points by ahurmazda 5y ago

A reminder that these sorts of genome-wide studies are not particularly reliable due to the problem of multiple comparisons: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3270946/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3270946/

aabaker99 5y ago
https://en.m.wikipedia.org/wiki/Bonferroni_correction https://en.m.wikipedia.org/wiki/Bonferroni_correction
gwern 5y ago
A reminder that these sorts of genome-wide studies haven't used 0.05 but genome-wide significance (10e-8 usually, and 10e-11 in OP) for a decade now for precisely that reason, and have since replicated just fine, thank you very much.

omarhaneef 5y ago

I think I missed the novel technique they applied. Surely others try to match particular genes to diseases. Surely that’s one of the pillars of the entire field.

flobosg 5y ago
The novelty lies in the size of the data set. ~450,000 exomes is a lot.

dekhn 5y ago

awful lot of resources were spent to find very little of deep value. Genomics is just marginal gains for each huge new amount of capital invested.

car 5y ago
Why the pessimism? Lots of really interesting leads are coming out of this study.
- dekhn 5y ago
  well, I worked in the field for several decades and got really tired of the constant overhyping of the results. These results really aren't useful (they're not predictive, or useful for genetic screening) and the cost is really extraordinary (hundreds of millions of dollars). There are other areas of biology that provide much more value per dollar spent.
twofornone 5y ago
We're talking about the source code of the human being. There's a ton of value in learning to translate it.

flobosg 5y ago

Twitter thread from one of the corresponding authors: https://twitter.com/gabecasis/status/1450289834543697925 https://twitter.com/gabecasis/status/1450289834543697925

car 5y ago
Great explainer of the significance of this study by Goncalo Abecasis. Basically human gene knock-outs, courtesy of mother nature. This study yields tons of gene function leads. Just awesome. Edit: quote The data is so rich that we had no more than a single paragraph to summarize association signals relevant to cancer and brain function. Ouch. A tweet won’t do them justice, but @uk_biobank will be sharing all the data with researchers for follow-up.

hybrid_cluster 5y ago

Not too related, but I got my genome sequenced for fun the other day (< $500 for 30x whole genome), and after a few scrolls through the results (200+ interpretations of my genome in the context of studies like the one linked here), I'm already losing interest. Ok, so I have a high genetic predisposition for thinness, walking fast [0], and bipolar disorder? So now what? I never noticed except for the thinness. They even scared me with 'you're genetically in the 99th percentile for critical covid disease progression,' but reading the results of the paper in question, it turned out the heritability of the effect under study was only 6%. Thanks for letting me know. These studies are interesting from a general genomics perspective, but not so much yet from a personal one (with the exception of a few traits that are determined by one or a few well-understood genetic variants. Hopefully this space will expand over the next few decades). [0] https://www.nature.com/articles/s42003-020-01357-7 https://www.nature.com/articles/s42003-020-01357-7

epistasis 5y ago
This is precisely right, and for most people it's unlikely that their genome will be particularly useful any time soon. For an individual, the questions are usually much more focused: for example if I have a baby with my partner, what are the chances that our child will have a recessive genetic disorder? This is answered right now with a carrier screen, where the only genes tested as the genes with variants that are known to cause disease. Much cheaper, much more highly curated, and put together and run entirely by experts in the field, rather than general technologists that are just running samples through a big machine. Interpretation of the genome will take millions upon millions more individual genomes sequenced, but those individuals will only rarely, if ever, see personal benefit.
deleted 5y ago
[deleted]
pfisherman 5y ago
In most cases, your sequence info will be useless to you, but in some situations it can have a huge impact, such as predicting how you might respond to epidural anesthesia if you are a woman in labor. Also, things like personalized immunity therapies for cancers and such are not far off. Unless they completely fail - which is always a possibility in therapeutic development.

DoreenMichele 5y ago

For people with health problems, identifying the genetic stuff contributing to their health issues can be game changing.

sjg007 5y ago

This is neat and will lead to a lot of interesting discoveries. Golden age for genomics is ahead.

wombatmobile 5y ago
The golden age for genomics has been “ahead” since 1990. It’s still ahead. We just don’t know which decade will yield the eureka. Voyages of discovery are like that.

pfisherman 5y ago

Wow, what a time to be alive! For those who are not into bio, this type of information is invaluable for untangling the molecular mechanisms of disease and can provide important clues about where we should intervene with a small molecule or antibody drug to disrupt disease processes. To give a coding analogy, you can think of this as trying to debug a program written in a language we can’t read. We have no idea what lines are doing what, but there are many different versions / forks of this program floating around. By looking at all the diffs and comparing the outputs, we can start to figure out what some of the code is doing, and which lines we might want to comment out to correct certain types of bugs.

tweedledee 5y ago

This is absolutely world changing. I've known that this was coming and was only a matter of time, it did get here sooner than I expected. I have hypermobile Ehelers Danlos Syndrome (hEDS) from a TNXB mutation. I was incorrectly told by doctors for decades that I was perfectly healthy and my issues were psychosomatic. It wasn't until I did a careful large scale behavioral analysis that I was able to identify similar people and from there the root cause. A $500 (30x) DNA test confirmed it. hEDS is massively under diagnosed, the vast majority never get a diagnosis. I strongly suspect that most mental problems are physical in nature and most physical problems are DNA related. And even when they're not DNA related, treatment ideas could be gleaned from 'natures large scale experiment'. The number of issues that can be identified from a $100 (1x) test and then subsequently treated is mind boggling. For me, that cost is less than a single doctors visit. This side steps the medical establishment which is slow and in many ways archaic. This will lead to a massive leap forward in medicine. In other news; I'm also of the opinion that IQ is largely determined by DNA, nature as opposed to nurture, and once that is properly figured out I'm sure designer babies are next. I don't think that is a door that can be kept closed. There is already a black market for it. I'll be watching from the sidelines, I think this is going to get interesting.

tudorw 5y ago
I think most anyone should have a CYP2D6 test if they are considering taking, or taking, medication, it affects so many drugs out there, yet here in the UK, the GP's I have encountered are not familiar with gene<>drug interactions and I had to request it after working it out myself. It's a complex area, but if you happen to be a poor or ultra metaboliser it's a good thing to know. https://www.ncbi.nlm.nih.gov/books/NBK99699/ https://www.ncbi.nlm.nih.gov/books/NBK99699/
- tweedledee 5y ago
  100% it’s cheap enough that everyone should do it. The TNXB mutation has a ton of weird drug interactions. Anesthesia resistant being just one.
  - 5y ago

cblconfederate 5y ago

I think DNA data should be considered public data. 99% of our DNA is shared, and the DNA degrees of separation between you and me is ~3. Practically we are all already identifiable from the small sample that exists in genealogy companies and it s been repeatedly done by law enforcement. I think it's bonkers that , after 10 years, companies like 23andme are not allowed to give us health reports because ... what reasons really? Especially in Europe it makes no sense to have such draconian laws about something that's important to everyone's health. Full sequencing costs like $200 today and i m sure millions would be willing to give their data to a public database that would take the field meaningfully forward. Instead what we get is we allow these companies to sell data which should be public domain. The US has its problems with their broken social security - here's a suggestion: fix it. Europe could use its public healthcare advantage to get ahead in genomic research while simultaneously improving the quality of its health systems. Instead we are stuck with outdated privacy laws (yet somehow making tax information public is OK). China could be using their own advantage and databases to get ahead in genomics while we 're still playing hide and seek.

dekhn 5y ago
My DNA is public data: https://my.pgp-hms.org/profile/hu80855C https://my.pgp-hms.org/profile/hu80855C

ahurmazda 5y ago

From abstract: “… We discover several risk-increasing associations with traits related to liver disease, eye disease and cancer, among others, as well as novel risk-lowering associations for hypertension (SLC9A3R2), diabetes (MAP3K15, FAM234A) and asthma (SLC27A3)…“

msandford 5y ago

Does anyone remember the days when some geneticists were saying that 98% of DNA is "junk" DNA? When I heard it I knew it couldn't be true but it's probably going to take another 50 years to figure out how much really does get used. I can't help but suspect that a lot of the genome is a part of the boot sequence that helps you go from one cell up to all the differentiated organs and tissues and systems.

hyperbovine 5y ago
That hypothesis is a little dated, but it should be noted that the exome (the thing being discussed in this article) is 1% of the overall human genome.
xyzelement 5y ago
Had the exact thought when I read the headline. What arrogance. "I don't understand what these genes do. Must be junk"
- da39a3ee 5y ago
  Actually no, that's not the intellectual level at which any science is performed, let alone population genetics and molecular genetics. Do you perhaps see the irony in making such a grotesquely arrogant suggestion yourself? People working on population genetics and molecular genetics, who came to the conclusion that much DNA has no phenotypic relevance, were doing so based on several decades of literature and 10-20+ years of their own education and scientific training. Would you care to give your own qualifications in this field?
  - xyzelement 5y ago
    > Would you care to give your own qualifications in this field? I am a programmer, and I trust my ability to call out junk code. Except if I am reading code from someone like Carmack or Linus. In those cases, I am gonna assume whatever I don't understand is my fault. What hubris would it be for me to call Linus' code junk, even if I really can't make sense of it despite my best effort? Same here. It's fine to say "we did our best to understand this and as far as we can tell, these genes are not utilized" to go like "yeah it's junk" is quite different. You're a mere mortal, and DNA has been the foundation of all life for millennia. You don't get to judge so easily.