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

Hey everyone. Welcome to a Sneak Peek, Ask Me Anything or AMA episode of the Drive podcast. I'm your host, Peter Attia. 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 Peteratti md.com 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 in terms of a few genetic risk factors for various diseases, most notably the APOE4 gene in 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. 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, and I tend to think that people 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 of this podcast, you'll you can find it on our Show Notes page. If you're not a subscriber, you can watch a sneak peek of the video on our YouTube page. So without further delay, I hope you enjoy AMA number 50.

Peter, welcome to another ama. How you doing?

Doing well, how about you?

I'm doing good. How's the day so far?

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 the podcast, they'll have heard us touch on genetics, but often in terms of how, how genetic risk factors for disease. So the most notable example of what we've talked about is APOE and the APOE 4 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? What do they tell me? What do they not tell me? And so compiled 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 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.

All right, 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 inheriting certain traits or having risk factors and people kind of ask, what are we really talking about when we refer to, quote, unquote, genetics? And why is it even important?

Yeah, so, I mean, look, when, you know, 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. And 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, geoeconomic traits, et cetera. 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 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 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.

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, discrete sets of instructions in the form of individual recipes. And DNA also has a discrete 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 sor 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. And again, if you think about it like proteins are more than just muscles, right? Proteins or 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. 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 wheat, we are, and they have far more protein coding genes, 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 passed down from a parent to child? You know, when we talked in the past about the Apoe 4, you get two copies, and for someone to have a 4, you know, one of their parents must have a 4 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 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, G, C, A and T. But just so we can say them once, it's guanine, cytosine, adenine and thymine. The G's and the C's 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, 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. 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 from mother or father. And then you have your sex chromosomes, which if you are in most cases phenotypically 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 xxy, you're sort of phenotypically male, but you have these other characteristics. So that's called Klinefelter syndrome. If you're X and no Y, I think that's Turner 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. 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, so meaning one of the parents alleles, tends to be dominant. So hair color, for example, so brown is dominant over blonde, red. You know, 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 sequence of those genes or in the surrounding DNA. These are called SNPs or single nucleotide polymorphisms. And these influence the gene's level of expression or even the level of function of the gene's 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. 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, 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 identified, identical to bananas and basically any other plant for that matter.

Is that bananas with nubbins or without nubbins?

It depends. So 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 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 proteins. 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 Birkenbach came out with, I think, just a fantastic analogy here using the cookbook metaphor. So imagine you have a recipe and it calls for two eggs. So it's two space E GGs, and there's a typo somewhere in the process of retranslating that book, it gets turned from two E GGs into two E G S S. Okay, 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, doesn't change the translation. But what if the typo instead was changed from 2e ggs to 5e ggs? So it went from 2 eggs to 5 eggs. That's a material change, and that's likely gonna result 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 gg 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, but there's a lot of ways you can screw that up.

And so I think the last question in 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 heritability of a 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 by a combination of genetics, environment, experience, and through a number of influencer factors. So let's just kind of go through some of these, right? 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 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 that is 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 dizygotic 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 were fertilized and then split into two identical, meaning two identical genetic differences. So monozygotic 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, 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. So the study of dizygotic versus monozygotic 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 monozygotic twins versus dizygotic twins, what are you controlling for? So in the monozygotic, you are 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 monozygotic twins raised apart. So same genes, same in utero experience, different environmental triggers. These types of studies 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. Or while a 33% concordance in monozygotic 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 podcasts or you have with guests you'll often bring up, you know, have you studied this in twins? It seems like it's a very popular thing 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 that 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. I mean, most animal studies are done in the equivalent of identical twin mice because they're just genetically bred to be identical. You know, they're monozygotic at all loci 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 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 detail. 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?

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