The Peter Attia Drive - #266 - AMA #50: Genetics: how they impact disease risk, what you can do about it, testing, and more

Starting point is 00:00:00 Hey everyone, welcome to a sneak peek, ask me anything, or AMA episode of the Drive Podcast. I'm your host, Peter Atia. At the end of this short episode, I'll explain how you can access the AMA episodes in full, along with a ton of other membership benefits we've created. Or you can learn more now by going to PeterittiaMD.com forward slash subscribe. So without further delay, here's today's sneak peek of the Ask Me Anything episode. Welcome to Ask Me Anything, episode number 50. In today's episode, we focus heavily on genetics. If you've listened to previous episodes, you've heard us touch on genetics

Starting point is 00:00:50 in terms of a few genetic risk factors for various diseases, most notably the APO E4 gene and Alzheimer's disease. However, we really haven't spent time discussing how exactly genetics relate to disease more broadly and why it's so valuable to know these risks. In today's AMA, we've gathered a lot of questions that you've poured in over the past couple of years, and we cover a variety of items.

Starting point is 00:01:12 We cover some fundamental background on genetics, reasons for getting genetic testing when it is useful, when it is not, and what types of tests are available, what the testing logistics are, and how to interpret the results. All of this will help give us a foundation for when we talk about commercial direct to consumer genetic tests, and considering when they're useful, as well as which ones stand out and what the best options are for anyone looking to learn about their health. I think that's really an important discussion around a topic that we see a lot of people talk about, we see a lot of questions about, but truthfully, there are some fundamental things that I think are not necessarily understood by the public,

Starting point is 00:01:48 and I tend to think that people overweight the importance of genetic testing. I've certainly been vocal about that, but I want to call out areas where I think genetic testing can be valuable, and I hope that this AMA really lays that foundation so that you can become a more valuable consumer of genetic tests. Finally, I think this will provide a great foundation for any upcoming discussions we have on the topics of genetics, and I know that we have at least one really interesting one in the pipeline. So if you're a subscriber and you want to watch the full video this podcast, you can find it on our show notes page.

Starting point is 00:02:20 If you're not a subscriber, you can watch this sneak peek of the video on our YouTube page. So without further delay, I hope you enjoy AMA number 50. It's going okay. Well, we'll get right into this one. I think it should be a good one, mainly because it's really on a subject that we get a lot of questions on, but we haven't talked about this heavily in detail. I was actually looking back and some of this was covered a very small section in AMA number eight. So way, way back in the day with you and Bob. But for people who have listened to podcasts, they'll have heard us touch on genetics, but often in terms of how genetic risk factors

Starting point is 00:03:12 for disease. So, the most notable example of what we've talked about is ApoE and the ApoE4 and Alzheimer's disease. But we've never really spent a lot of time discussing how exactly genetics relate to disease, haven't really talked about why it's so valuable to know these risks, and we get a ton of questions on these, mainly from people who are saying, hey, I can do this direct to consumer test, I can do this direct to consumer test. Are they valuable?

Starting point is 00:03:40 What do they tell me? What do they not tell me? And so, from pile to all those questions, and we're going to really focus today just to understanding at a basic level, genetics, reasons for genetic testing, types of tests available, how to interpret results, which will really frame the conversation on when thinking about commercial direct to consumer DNA tests, where are they useful, where are they not, how should someone think about them? So I think anyone who listens to the podcast is going to find value in this topic. It's a topic we really haven't covered in detail ever before. So I think it's going to be really

Starting point is 00:04:18 good and hopefully really interesting for a lot of people. So with all of that said, anything you want to say before we get started? No, I don't think so. Let's get into it. Alright, so I think it'll be helpful to just kind of talk about the term genetics. It's thrown around a lot when you hear people talk about inherent in certain traits or having risk factors. And people kind of ask, what are we really talking about when we refer to, quote unquote,

Starting point is 00:04:46 genetics and why is it even important? Yeah, so I mean, look, when you hear people talk about nature versus nurture, well, this is what we mean by the nature part of it. So when we're talking about genetics, we're talking about the part of a person that has been passed down from the parents. Of course, we differentiate this from the stuff that we talk about that's nurture-related. These are non-genetic traits that could be passed down, by the way, cultural, socioeconomic traits, et cetera.

Starting point is 00:05:14 Genetics obviously play a very important role in understanding physical, psychological, social factors. But what we really want to talk today are about these genetic pieces. Genetics can't be chained, shy of genetic engineering, which maybe we can talk about gene therapy and things like that. But for the most part, what we're thinking about is understanding how genes shape and predispose us to various conditions, how perhaps having certain genetic conditions might make us choose certain lifestyle modifications as a result of that to modify risk. And for example, there are some genes

Starting point is 00:05:46 that are completely deterministic. We'll talk about what that means. So there are certain genes where if you have the gene, it's going to produce a trait regardless. And there are many more genes for which if you have a certain gene, you might not necessarily get the trait. So anyway, we hope to make a sense of all of those topics today because I do think this is not a particularly well understood field once you get beyond the surface level.

Starting point is 00:06:07 I agree, and I think the next question we received, which I think makes a lot of sense, at least from a non-science background of myself, a lot of times when you think of genes, I don't know why, maybe it's just me, you think of DNA as well. And so maybe just give us a quick rundown on what DNA is, how it works, really in the sense of how it can impact our biology and traits. DNA is just a code of instructions that tell a cell how to function. So there are lots of analogies here, but I really think that the best one is kind of thinking of it as a cookbook. So a cookbook will have, you know, discreet sets of instructions in the form of individual

Starting point is 00:06:49 recipes. And DNA also has a discreet set of instructions in the form of individual genes. You know, a recipe is just a recipe, right? For it to become a meal, someone needs to do something about it. Someone needs to read it and then follow it and actually do the cooking. And genes are sort of the same way. So they only work by being expressed. So when you hear gene expression, that's what we're really talking about. So expression means making a copy of that DNA into something called RNA, that process is called transcription, and then turning that RNA into a protein, and that process is called translation.

Starting point is 00:07:29 And again, if you think about it, like proteins are more than just muscles, right? Proteins are enzymes and other cofactors and things of that nature. So, basically, everything that needs to get carried out in a cell is being done via this process. I think one of the biggest surprises of the genetic revolution was the relative small number of genes that humans have. And maybe for folks who aren't even familiar with this subject matter, I think this is kind of a startling stat, which is that humans only have about 20,000 protein coding genes in total.

Starting point is 00:08:04 Maybe that sounds like a lot, but if you consider the fact that lab mice on average have about 23, 25,000 genes, krill, these tiny sea plants, whatever, we're talking about like 29,000 genes, rice, mushrooms, maybe 50,000 genes. So when you think about things that are far simpler than we are, and they have far more protein-coding genes,

Starting point is 00:08:33 you realize that that's just part of the story. And again, I think one of the things that this now illustrates is that it had been long assumed that one gene led to one function. And we now know that this isn't the case. So a single gene can often be read in many different ways, giving rise to many different strands of RNA and by extension proteins, which can then be modified post-translation to create even greater functional heterogeneity. Another question we got, which fits really well right here, is how are genetics

Starting point is 00:09:06 passed down from a parent to child? You know, when we talked in the past about the ApoE4, you get two copies and for someone to have a for, you know, one of their parents must have a for as well, but maybe we should walk through how genetics are just passed down in general. There's actually a really nice figure here that we'll use to make this a little easier to understand. So Nick, if you don't mind pulling this up for those watching this, I think this is an easier way to see it. If you're not watching this and you're only listening, I'll do my best to also explain this. The figure will also be in the show notes, of course. Okay, so let's start from the simplest and go to the more complex. So we're going to go

Starting point is 00:09:45 all the way from a base pair to a chromosome. So there are four base pairs in DNA. They're called nucleotides. They're abbreviated by their letters, GC, A, and T, but just so we can say them once, it's wanting, cytosine, adenine and thymine. The Gs and the Cs can only be paired together, the A's and the T's paired together. So in other words, if you know what one strand is, you automatically know the other because each nucleotide can only be paired with one other nucleotide. And that has to do with the way that they fit and the type of hydrogen bonds across them. So the string of nucleotides is the genetic sequence,

Starting point is 00:10:26 and a certain number of them create a gene. So a certain number of nucleotides strung out, and it's usually thousands of them to be clear, make up a gene. So as you see looking at this figure, you have like a long string of nucleotides, and remember the whole thing with DNA is that it creates that helix.

Starting point is 00:10:45 It's a double helix. And that lengthy string of DNA are divided into segments known as genes. Now these long strands of DNA as genes wrap around other proteins called histones. And those histones further organize and wrap up around really, really large things that you can actually see under a microscope called chromosomes. Now humans have 23 pairs of chromosomes. So for each pair, what that means is we get one chromosome from the mother, one chromosome from the father. And the only thing that is a bit wonky here, of course, is that there are two of those that are sex-specific. So we have 22 pairs that would look identical

Starting point is 00:11:38 from a mother or father, and then you have your sex chromosomes, which if you are, in most cases, phenotympically female, you would have an X and an X. If you are phenotypically male, you would have an X and a Y. There are very rare exceptions to this rule. So if you have an X, X, Y, you're sort of phenotypically male, but you have these other characteristics, so that's called client-felture syndrome, if you're X and no Y, I think that's Turner's syndrome, which is sort of phenotypically female, but has different characteristics. So again, just for the most part, it's going to be 22 pairs plus an XX or an XY. What that means, by the way, is you're getting basically two sets of every gene.

Starting point is 00:12:27 Those two copies could be identical, or they could be different, and the different versions are referred to as alleles. So some traits result from a combination of the effect of both copies. So hair texture is an example of that. But other traits tend to follow a dominance pattern. So one allele, meaning one of the parents allele tends to be dominant. So hair color, for example. So brown is dominant over blonde red.

Starting point is 00:12:53 All things considered equal. If somebody with black hair, somebody with blonde hair, have a kid, there's a more likely chance that that child is going to have darker hair. For most genes, like roughly 90% of the time, having one functional copy is typically enough to produce a normal phenotype. That image is really helpful to kind of paint the picture a little bit more of how this works. And so, the next question we received is, how much do genes vary across individuals? This is where it starts to get a little complicated, right? So, everyone has the same set of genes, but different individuals have small variations in the

Starting point is 00:13:29 sequence of those genes, or in the surrounding DNA. These are called SNPs or single nucleotide polymorphisms, and these influence the genes level of expression, or even the level of function of the genes protein product. So just to put this in perspective, think about how distinct you and I are genetically, right? Like, you probably descend from Vikings in Northern Europe, I clearly descend from people in the middle of Africa. We are still 99.5% or greater genetically identical.

Starting point is 00:14:01 In fact, all humans are at least 99.5% genetically identical to each other. Again, pretty remarkable that SNPs are only present in less than 0.5% of all base pairs for the entire human genome. And yet, that small, small variation accounts for all the genetically attributable differences in variability across humans. In height, hair, skin color, susceptibility to diseases, everything like you name it, all the things about us that are genetically different are contained within less than 0.5% of our genome. Just to put this in perspective,

Starting point is 00:14:37 we share 99% of our DNA with chimpanzees. We share about 90% of it with cats, you know, like a pet cat. Perhaps my favorite statistic of all, when getting, you know, prepared to talk about this, that I didn't know, was we're about 50 to 60% genetically identical to bananas. And basically any other plant for that matter. Is that bananas with nubbins or without nubbins?

Starting point is 00:15:03 It depends. I have a unique snip that makes me much closer homology to those without nubbins. I'm only like 4% related to bananas with nubbins. Which makes sense on why they're so dangerous to you. Absolutely. Yeah. So genetic variation is not necessarily a bad thing, of course. When you do have genetic variation for humans, it can exist on a spectrum. So there are certain changes that can be completely benign, likely benign. Many of them are unknown

Starting point is 00:15:31 significance. So people who are used to going through their own genetic material using third-party applications like Prometheus, what you'll notice is they have a lot of things that exist in the unknown significance, right? So we think of it as benign, likely benign, unknown, possibly pathogenic and pathogenic. And the reason for this is that a number of changes don't really affect the way DNA is read and transcribed into RNA and protein. So remember, DNA, purpose of this is to create the template that gets transcribed into RNA, RNA gets translated into protein. So our head of research, Katherine Bergman back came out with, I think, just a fantastic

Starting point is 00:16:13 analogy here using the cookbook metaphor. So imagine you have a recipe and it calls for two eggs. So it's two space, e-g-g-s. And there's a typo. Somewhere in the process of re-translating that book, it gets turned from two space e-g-g-s into two space e-g-s-s. Okay.

Starting point is 00:16:36 Is the person who looks at that cookbook gonna know what to do? Yeah, they will. So there is a mutation there. There's a polymorphism, but it doesn't change the overall food product, it doesn't change the translation. But what if the typo instead was changed from 2e GGS to 5e GGS? So it went from 2x to 5x, that's a material change, and that's likely going to result

Starting point is 00:17:01 in pathology. So I loved that example that she came up with because it really illustrates why there are a lot of different ways you can re-translate to space e, g, g, s. You could get rid of the space. You could get rid of one of the g's. There's a lot of ways you could do that and you'd still get the right answer.

Starting point is 00:17:18 But there's a lot of ways you can screw that up. And so I think the last question, this kind of foundational section came from someone who said, you know, which traits are determined by genetics versus experience or environmental factors? The degree to which a given trait or a health characteristic is determined by genetics is known as the heredability of a trait. Heredability describes the amount of phenotypic variation in a given trait in a population that can be attributed to the genetic variation in that trait. Heritability describes the amount of phenotypic variation in a given trait in a population that can be attributed to the genetic variation in that trait. So most traits are influenced

Starting point is 00:17:51 by a combination of genetics, environment, experience, and through a number of influence effectors. So let's just kind of go through some of these. So some traits are entirely determined by genetics, your blood type, your eye color, these are a hundred percent heritable. Others are basically completely determined by your environment and your experiences. So your native language, your religion, so that would be the other end of the spectrum. Those are zero percent heritable. But most things that we talk about fall somewhere in the middle. And therefore, genes and the environment and experience interact to determine many outward characteristics of appearance and personality and susceptibility to disease, but not all. So let's

Starting point is 00:18:30 talk about the things that people tend to care about. So height. Height is about 80% heritable. So that means it's mostly determined by genetics, but a lot of factors, i.e. 20% of that can be determined by things such as childhood and gestational nutrition, hazardous exposures like if the mom was smoking during pregnancy, those can contribute to the other 20%. This is kind of best studied, you know, looking at basically mono and dizagotic twins. So Peter, maybe just for people who aren't sure the difference, do you want to just define those two terms real quick too? Yeah, sorry for the jargon. So monozygotic twins are identical twins and what that means is that one egg and sperm

Starting point is 00:19:16 were fertilized and then split into two identical, meaning two identical genetic differences. So monosigotic twins are identical twins and that arises when an egg and a sperm are fertilized and after fertilization, they split. So then you get two new cell growths that ultimately each become a fetus, but they're genetically identical. The dizygotic twins are when two eggs,

Starting point is 00:19:43 two different eggs are either inserted via IVF or ovulated through natural conception, and then obviously they're fertilized with two different sperms. So dizygotic twins are effectively siblings, just normal siblings that happen to be born or carried at the same time. So the difference between those genetically, again, at the macro level is pretty small, because remember, we talked about how, you know, we're all pretty similar. And of course, here you have non-identical versus identical siblings.

Starting point is 00:20:12 So the study of dizygotic versus monosigotic twins is a really interesting way to study certain diseases. For example, consider schizophrenia or autism. When you look at the occurrence of schizophrenia or autism in monosigotic twins versus dizygotic twins, what are you controlling for? So in the monosigotic, you're able to look at what happens in the same genes in the same in utero experience. In dizygotic, you have different genes, same in utero experience, and then you also have other experiments where you have monosigotic twins raised apart. So same genes, same in utero experience, different environmental triggers. These types of studies

Starting point is 00:20:55 are what allow us to understand how heritable certain traits are. And it's doing studies like this that we see that there is, you know, reasonable concordance for schizophrenia and even more concordance for autism. So, for example, looking in the particular case of schizophrenia, I believe that the studies have shown about a 7% concordance between dizygotic twins while a 33% concordance in monosigotic twins, which suggests about a 79, 80% heritability for the condition. So this is kind of more real world stuff where it's not black and white and it's not entirely heritable and it's not completely environmental. I feel we've talked a lot about in podcast or you have with guests, you often bring up, you know, have you studied this in twins? It seems like it's a very popular thing

Starting point is 00:21:46 across nutrition, exercise, whatever it may be. Do researchers just always try and seek out twins? If you're a twin, do you just have the ability to be in many more research studies? How does it actually work? Yeah, I mean, certain studies, especially studies that are trying to really understand mechanism of action, to be able to have twins is a very powerful tool. I mean, to put it in perspective, Nick, think about how much animal research is done in effectively twins.

Starting point is 00:22:15 I mean, most animal studies are done in the equivalent of identical twin mice because they're just genetically read to be identical. You know, they're monosigotic at all low side throughout their entire genome. You might be doing an experiment on 300 mice, but they're all exactly the same. So there is great advantage to that. Of course, there's a disadvantage to that as you move further down the study from efficacy to effectiveness. At some point, you want to know what works for everybody, but everything has

Starting point is 00:22:44 its time and its place. And clearly, there are certain things where studying identical twins is valuable. Yeah, super interesting. I think that kind of wraps the foundational section. So we'll move to this next section, which is just looking at genetic tests, the different types, uses, limitations, and more details. So I think the first question that makes sense to start here is just, what are some of the reasons for someone to even get genetic testing done? Thank you for listening to today's sneak peak AMA episode of The Drive. If you're interested in hearing the complete version of this AMA, you'll want to become a premium member. It's extremely important to me to provide all of this content without relying on paid ads. To do this, our work is made entirely possible by our members, and in return, we offer exclusive

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The Peter Attia Drive - #266 - AMA #50: Genetics: how they impact disease risk, what you can do about it, testing, and more

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