RHR: The Pitfalls of Genetic Testing, with Dr. Tommy Wood

RHR: The Pitfalls of Genetic Testing, with Dr. Tommy Wood

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As the popularity of consumer genetic testing services continues to climb, more and more consumers are making decisions about what to eat or what supplements to take based on their testing results. In this episode of Revolution Health Radio, Dr. Tommy Wood and I discuss the problems with consumer genetic testing and explain why the results are not as helpful or actionable as we’ve been led to believe.

Revolution Health Radio podcast, Chris Kresser

In this episode, we discuss:

  • An introduction to genetics
  • The value of consumer genetic testing
  • What your SNPs [single nucleotide polymorphisms] can tell you about your individual disease risk
  • The potential harm to consumer genetic testing
  • MTHFR mutations
  • FTO mutations
  • ApoE4 and Alzheimer’s disease risk
  • Why we should focus on behavior change, not genetic testing results

Show notes:

Hey, everybody, Chris Kresser here. Welcome to another episode of Revolution Health Radio. This week, I’m really excited to welcome Dr. Tommy Wood as my guest. Dr. Wood is a research assistant professor in the Department of Pediatrics at the University of Washington, specializing in neonatal and pediatric brain injury as well as long-term brain health. He has an undergraduate degree in biochemistry from the University of Cambridge, a medical degree from the University of Oxford, and a PhD in physiology and neuroscience from the University of Oslo.

Dr. Wood previously spent three years as the Chief Scientific Officer of Nourish Balance Thrive, using advanced biochemical testing to optimize health and performance in athletes, as well as developing software tools to help understand and interpret blood tests. Along with his main academic research, he continues to work with elite athletes, as well as develop cost-effective and easily accessible tools to help people improve their health and reverse chronic disease.

I’m really excited to talk with Dr. Wood about consumer genetic testing. I’m sure many of you are familiar with these tests like 23andMe. And there’s a lot of awareness now in our field about polymorphism, single nucleotide polymorphisms like MTHFR or COMT, or FTO, and many people are making decisions about how they eat and what supplements they take based on polymorphisms in these genes. Dr. Wood has done some very interesting research in this area. And I think the results may surprise many of you. So, without further ado, let’s dive in.

Chris Kresser:  Tommy, welcome to the show. I’m so glad to have you. I’ve been looking forward to this.

Tommy Wood:  Yeah, me too. Thanks so much for having me.

An Introduction to Genetics

Chris Kresser:  So we’re really going to dive into this topic of consumer genetic testing and what useful, actionable information that we can get out of it both as consumers, for lack of a better term, just people who are interested in improving their health, and as practitioners who are working with patients or clients using this data or these data.

So maybe we can start just from the 30,000-foot view for the listeners that are not as familiar with some of the basic terms that we might use in this interview. What is a genotype? What is a phenotype? You talk a little bit about the big picture differences between genetics and epigenetics to set the stage.

Tommy Wood:  Sure. So, genotype, depending on who you’re talking to, might be used to mean a few different things. So, in general, in its loosest [sense], it basically means your whole genetic sequence in a given person. So, people who are familiar with some of the biochemistry will know this is about 3 billion base pairs. These are nucleotide bases. They may have heard of As and Cs and Gs and Ts. This is basically the code within your DNA that is then used to make up certain genes of which we have 20-something thousand.

Each one is made up of hundreds to potentially millions of these bases. And they code for a protein, which does something in a cell. When we’re then talking about genotype and disease risk, we’re most frequently talking about potential polymorphisms. So, they’re changes within the code of a single person relative to other people. So, you’ll hear something like single nucleotide polymorphisms, or SNPs. And this is basically where a single base, a single one of those As or Cs, Ts [or] Gs is changed.

So, say from a C to a T, and this might then alter the amino acid that is made in the protein. It might somehow alter the function of the gene or the protein. And for each of these SNPs, you can usually have, you can be one of three things. You can either have zero, one, or two copies of that SNP. So you can be homozygous. That means that you have two copies of the same. Or you could be heterozygous, which means you have one copy of each. So, in that setting, when we’re talking about genotype, it’s usually your genotype for a given SNP, or maybe a collection of SNPs that all affect a certain phenotype.

A phenotype is a measurable characteristic, which we usually think of as being the interaction between your genetics and the environment. So, this could be anything that you might measure, as a practitioner, or as a person, as you said, and this could be heart rate, blood glucose, your height, your weight, your homocysteine level, if you’re worried about methylation. We’ll talk about that later. So, anything you can measure, that’s usually part of the phenotype. When we talk about genetics, this is generally just the study of the heritability of genes. So, like, how much is a certain phenotype heritable or associated with a given genotype? Or how much is a disease risk associated with a certain genotype? When we talk about epigenetics, these are the factors that are associated with changes in the expression of genes rather than changing the genome itself.

And this happens at multiple different levels in the cell. But people may have heard about things like methylation. You can methylate the DNA itself out of the methyl group to the DNA. Or acetylation, you can acetylate the histones, which are the proteins that DNA is, kind of, wrapped around. And this changes the way a gene might be accessed in terms of its ability to be turned into mRNA to then code for the protein, all various ways that you might change the function of that gene. And the epigenetics determines how we express our genes, but it also determines the actual cell itself, right? Every cell has the same DNA, but different genes will be switched on to make a muscle cell versus a brain cell, for instance.

And epigenetics is very hot at the moment. You’ll often hear people talk about, “Oh, you know, it’s not the genetics; it’s the epigenetics.” That is certainly true. And we can definitely talk about the broad strokes of epigenetics. That’s not really what we’re going to talk about today. But we know that there are certain methylation patterns you can see as, like, a person or a cell ages. There are certain factors that we know are directly associated with a certain methylation pattern. So, you can see certain patterns of people who smoke, and if they stopped smoking, some of that pattern will come away. But the study of epigenetics is kind of like the next frontier is incredibly hard.

Like, people who are talking about epigenetics may not realize that it’s incredibly expensive, [and] it’s incredibly complex to do. And we still don’t really know how a given environmental input changes the epigenome of a given cell. And just as an example, this is a nice paper that came out recently and, I mean, you’re a scientist, I spent most of my time looking at the brain in the lab. A recent paper came out that said that in a mouse, there are 565 transcriptionally distinct cells in the mouse brain. And what that means is, if you look at the mouse brain, there are 565 different epigenomes or cells with different types of epigenome in the mouse brain. I mean, so we’re ready to go hundreds of cells, just in a mouse brain, which is much less complicated than the human brain.

Chris Kresser:  We’re going to need AI [artificial intelligence].

Tommy Wood:  Yeah, and then to think about how each individual environmental component is going to change the individual epigenome in every cell. Like, we’re talking about millions, billions, trillions of data points. And looking at how they interact is, we’re just way, we’re a long way away from figuring out how that’s going to work.

Chris Kresser:  Yeah, not even close. Boggles the mind. It’s one thing for AI to beat someone in Go. It’s another thing for them to decode the epigenome.

Tommy Wood:  Absolutely.

Chris Kresser:  That’s a whole other level of intelligence.

Tommy Wood:  Yeah.

Chris Kresser:  So, one of the things you mentioned, genetic changes are heritable, but one of the biggest discoveries in epigenetics was that those changes can also be passed onto future generations.

Tommy Wood:  Absolutely.

The Value of Consumer Genetic Testing

Chris Kresser:  Which is important, I think, to remind the listeners. Because that was a previous misconception that only our genes could be passed down. But we now know that even epigenetic changes can be passed down, or at least one successive generation, but a lot of studies are showing it can be even two or three successive generations. Which means, of course, that the choices that we make don’t just impact us, they actually impact our future generations if we’re going to have children and grandchildren.

So that’s a great intro and a good starting place. And let’s begin with what the positive aspects of this kind of testing are. What the potential value of knowing our genes is. What kind of outcomes can we imagine in the future once we get our heads around this stuff or AI does that for us? There was obviously a reason that we started going down this path. So, what do you see as the potential for this once we’re able to really realize that?

Tommy Wood:  Yeah, so, the original hope of the Human Genome Project and since then we’re doing what we call genome-wide association studies where we look at individual polymorphisms, and a phenotype or a disease risk it might be associated with. The hope is that we can identify people who are at high risk of a given disease. We can discover or target specific pathways and give personalized therapies based on a person’s genetics. And at the moment, this is kind of something that is suggested in the direct-to-consumer market, but it’s really not something that we’re able to do.

So, there are an increasing number of academic works in the published literature, where they take what we call now polygenic risk score. So, this might be dozens, or hundreds even, of SNPs, and then look at, stratify people based on their then subsequent risk of something like Alzheimer’s disease or cardiovascular disease. And then, within those subgroups, you may want to give a different type of intervention. So, when I, one study has looked at people’s responses to statins and those who are at risk of cardiovascular disease, and then those [who] are the highest genetic risk, they seem to respond best to statin therapy.

So, you might be able to identify one particular subgroup that’s really at risk, and they might respond better to a therapy; whether statins are the approach that we wish to take is a whole different conversation that I don’t think we’re going to have here. But one thing that I still, if you want to step back a little bit from that, one thing that is kind of a common theme in almost everything that I’ve seen in the world of genetics is that I’m still not really sure that when you identify somebody at genetic risk, you’re going to change what you’re actually going to do with them.

So again, if we stick with cardiovascular disease, there was a paper in the New England Journal [of Medicine] in 2016 called “Genetic Risk, Adherence to a Healthy Lifestyle, and Coronary Disease.” And they took 55,000 people and they looked at 50 risk SNPs for coronary disease, and they found that those who had at least three or four healthy lifestyle factors were [at a] significantly greater, or significantly lower, risk of coronary artery disease. And the effect in terms of improvement was biggest in those of the biggest genetic risk.

But when you look at the things that they consider the healthy lifestyle factors, it was three to four. It was not smoking, not being obese, physical activity at least once a week, and then a healthy diet pattern, which they’ve sort of, they talk about red meat and those kinds of things. But it’s basically a whole, a whole foods type, real food diet.

Chris Kresser:  Yeah, we’re not talking about, like, intermittent fasting and meditating for an hour a day. Or to [use], like, the cyclical ketogenic diet or sauna or pulsed electromagnetic field therapy. We’re talking about just the absolute basics. Like, not being the furthest down the track of the standard American diet and lifestyle, right?

Tommy Wood:  Yeah, exactly. And the other thing to note is that the effects, or these factors, were beneficial, regardless of your actual genetic risk. So, if you’re somebody who’s worried about your risk of heart disease, don’t smoke, try to avoid being obese, exercise at least once a week, and eat real food. I mean, but you would have told that to everybody, regardless of whether they had genetic risk or not.

Chris Kresser:  Exactly.

Tommy Wood:  So, even though we can start to stratify, based on risk and potential interventions, I think for most of the people who are listening to this podcast, the genetics really aren’t going to come into play because you’re still going to recommend the same things.

Chris Kresser:  Yeah. And I give a presentation on this topic. It’s called, “Why Genes Aren’t Your Destiny.” And I have a slide in there about a study, you probably saw it. It was, I think, 2018, and it was a large study, and they found that adopting just five health habits extended lifespan by an average of 12 years in men and 14 years in women. So, it’s 13 years on average. And those habits were:

  • Healthy BMI [body mass index]
  • At least 30 minutes of moderate activity a day
  • Not smoking
  • Not drinking excessively
  • Following a (I’m doing air quotes here) “healthy diet”

Same thing there, right?

So again, not, like, super advanced stuff here. Just following your basic healthy lifestyle factors and that increased lifespan by 13 years. I mean, that’s an enormous difference. And I’m often reminding people, as I know you are, Tommy, like, a lot of the studies that you hear about in the media are not about you. You, meaning if someone’s listening to this podcast, and they’re doing even those basic things, you can’t make the assumption that these data in the studies have really anything to do with them.

Tommy Wood:  Absolutely, yeah.

Chris Kresser:  So, we have this promise and it was, we’re old enough to remember all the exciting predictions from the ‘90s about how decoding our genome was going to completely revolutionize healthcare and change our destiny. And another slide I have from that presentation is from Craig Venter, who, ironically, was one of the first people, he was one of the first to sequence the genome, but he was also one of the first to recognize its limitations. He said, “We simply don’t have enough genes for this idea of biological determinism to work.”

Tommy Wood:  Yeah.

Consumer genetic testing services (like those offered by 23andMe) continue to boom. But what can these results really tell us about our health? Check out this episode of RHR to find out. #functionalmedicine #chriskresser

Can Your SNPs Tell You About Your Individual Disease Risk?

Chris Kresser:  Which is kind of related to what you’re saying. Like, it’s really more directed to the environment. So, let’s talk more about that. So, we had decoding of the human genome, this exciting promise that if we understand our genes, we’re going to be able to revolutionize healthcare. There is some significant potential value somewhere down the road, once we have AI that’s sophisticated enough to really work through this. But even then, as you pointed out, is that knowledge really going to alter the recommendations that we would make on a public health level, and also, if you’re a practitioner working directly with patients?

So those are the big questions. Let’s dive in now a little bit to the more specifics here. I know you gave a great talk at AHS [Ancestral Health Symposium]. I, unfortunately, wasn’t able to be there, but you generously sent it to me, and I watched it and really enjoyed it. And you talk a little bit about some of the currently available consumer genetic tests and also the algorithms that you can put your test results through like 23andMe or MTHFR support and not to single any algorithms out here, because I think most of these are from people that I know we both respect and are doing good work and are out there trying to help people. But the question is, when you really dive deeply into this, how much value do we get out of the information that comes from this?

And I guess the corollary question would be, is there a risk in putting too much attention and energy into this kind of information? I definitely have some thoughts about that from my experience as a practitioner, as I imagine you do. So, let’s talk a little bit about these tests and what they can tell us and not tell us.

Tommy Wood:  Yeah. So, we talk briefly about the state of the academic literature and I think that there is potential promise there. But none of that really has been translated to the consumer market yet. And when you read the academic genetic literature, [it’s] very clear about the fact that individual common SNPs that you’ll get on a 23andMe, or if you run it through some third-party tool, that they tell you almost nothing about your individual disease risk.

Yet, when you’re presented with your data from whoever it is you’ve maybe paid a few dollars to, to analyze your 23 or Ancestry DNA report to give you some idea of risk, they’re saying that this SNP is associated with X percent increase in the risk of diabetes. And, in reality, the population data is so variable that it’s almost impossible to determine for an individual, how much their risk might be increased or decreased. And this is the problem with translating these large studies. Now, they’re doing genome-wide association studies, with hundreds of thousands of people looking at hundreds, if not more, SNPs, and you can definitely stratify that whole population based on their risk.

But for an individual, the absolute variability in their potential outcome is so large that it’s almost impossible to tell about their risk. And the problem is, one of the biggest problems that I see is that, when you read a paper, what they give you [are] what we call summary statistics. So, they’ll tell you, like, the average effect of a genotype and then they’ll give you an arrow. Something like a 95 percent confidence interval or the standard error of the mean. And it gives you these nice, tight variables on a graph, which makes them look really good. And you think, “Okay, wow, this, if I have this SNP, I’m definitely ….”

Chris Kresser:  This is a real strong signal here.

Tommy Wood:  This is a real strong signal. Absolutely. But what I did in the talk, and what I’ve tried to do since, is, if you have that information, you have the average, and you have some kind of confidence interval, you can recreate a whole bell curve of potential effect. And you can really start to see how variable some of this data is. And then you can start to calculate the actual effect of having a certain amount of, a certain SNP. But when you’re looking at what we have currently in the consumer market, they’re very much still focusing on these individual SNPs, which the academic genetic literature left a decade ago because they appreciated that it was almost useless.

And sometimes, they’ll maybe collect together, like, a handful of SNPs that are associated with a given phenotype, say, being obese. But they haven’t, like, waited and accounted for the error and how these things combine, like you would have to do if you were doing a proper study that you were going to publish. So again, like, every time this is presented to you, as a consumer, the effect of a given SNP is hugely overestimated. And then when you think about how people are, how people are applying this.

Now I see adverts all the time for, “Do this genetic test and we’ll tell you how you can eat or should eat. Do this genetic test and we’ll tell you about your response to exercise.” I work with a lot of athletes. So, I’ve had to, you know, debunk some of these genes associated with athletic ability in a similar way as some of the health-related ones and it’s exactly the same. The response to a given training program is hugely variable. And your genotype is just a tiny, tiny portion of that.

So, I mean, they’re basically promising things they can do with your genetic results that are basically impossible. And that doesn’t even include the fact that these tests can be quite inaccurate. And they’ve, I know you’ve written previously about the fact that there was a study where they compared different genetic or tests from different companies. And they didn’t all agree on SNPs and specific genes. And it even gets more serious than that. Occasionally, a mutual friend of ours, Chris, I know, she had her 23andMe tested, and then they highlighted that she had a twin in Germany or something like that. And she wrote back and was, like, “This is physically impossible. I know I don’t have a twin in Germany.” And they’d sent her the wrong results. Like, all of her SNPs are wrong. And she only realized that because of this, because of this twin association.

So, when you’re trying to make these decisions on something, that even if you know the data, it’s not really associated with the outcome in a meaningful way or it’s so highly flawed or there are errors in the process. Like with any medical test, you really just don’t know what you’re doing.

Chris Kresser:  Yeah, that’s pretty scary. I want to touch briefly on something that you covered in your talk, which is relevant to what you just said. It’s a Robert Sapolsky quote from Behave where he says, “Having the warrior gene,” which maybe we’ll talk about later, “probably has less of an effect on your behavior than does believing that you have it.”

Tommy Wood:  Absolutely.

Chris Kresser:  And then there was a study a while back, and I imagine you saw it, maybe you can refresh my memory on the particulars, but essentially, they took a group of people. They separated, randomized them into two groups and said, and told one group that they had SNPs that affected their exercise performance in a negative way. And then they didn’t tell the other group that. And then the group that they told that they had those SNPs, they actually did perform worse than the other group, even though there were actually no differences in their genotype.

Tommy Wood:  Yeah.

Chris Kresser:  That’s the nocebo effect, right? Which we know is very real.

Tommy Wood:  Yeah, absolutely. So, this is a, this is Turnwald et al in Nature Human Behaviour this year. Yeah, absolutely. And they, they randomized people to being told they have a certain genotype regardless of what their actual genotype was. And those who were told they had the good endurance genotype, I’m using air quotes here, they had them, when they redid a treadmill test, they sort of performed about the same. But those who were told that they had the bad endurance gene ended up doing worse. And they also did something similar with FTO genotype, which is the SNP most associated.

Chris Kresser:  Yeah, we’re going to talk about that.

Tommy Wood:  Which we’ll talk about. And they first gave people a test meal and then looked at, measured hormone levels, things like GLP-1 [glucagon-like peptide 1], and then looked at, and asked about their satiety. This is the same thing, and they told, the people who they told had actually the protective version of FTO. This is one of the few examples where you actually might get a placebo effect from genotype. When they told them they had the protective version of FTO that was associated [with] less risk of obesity, when they repeated the test meal, they had higher levels of GLP-1 and higher levels of satiety again, regardless of their actual genotype. So being told about your genotype or thinking of a certain genotype actually changes physiology; it changes the hormones you can measure in your blood. Like, it’s just incredible the effect that you can have by telling people about their genotype. And what worries me, particularly, is the way that we talk about genetics.

So like MTHFR again, we’ll talk about it, incredibly, the mutations are incredibly common and it’s incredibly common to talk about MTHFR SNPs in the Functional Medicine world. And it always comes with language, like if your MTHFR isn’t working properly, right? It’s always negative language. It’s always saying, “Oh, yes, you have a deficiency. Oh, your MTHFR is bad or is defective.” And, in reality, I mean, you’re probably having a much larger effect on that person by telling them that then the actual gene itself.

The Potential Harm to Consumer Genetic Testing

Chris Kresser:  Right. And that’s why I asked the question, which admittedly, was a little bit leading, is there potential harm here. I absolutely think that there is because of what we’re talking about now, both placebo and nocebo. I mean, there can be potential benefit, I suppose, if you’re trying to leverage placebo, like in the case of FTO. But much more potential for harm, because, usually, the way these are being used is to tell people how much higher their increased risk of disease is.

Not to tell them that things are going, you’re in a great spot, because you’ve got these phenomenal genes. It’s usually telling people how much higher, why they’re going to die sooner, or what kind of disease they’re going to get. And I’ve had patients come into my practice and tell me they have the MTHFR disease.

Tommy Wood:  Oh, wow.

Chris Kresser:  So that’s a big, that’s a big belief system to take on.

Tommy Wood:  Absolutely.

Chris Kresser:  I’ve got the MTHFR disease, which means that I’m always going to have this issue and be struggling.

Tommy Wood:  Yeah. And, I mean, usually if I talk about MTHFR, I like to point out that only 15 percent of people have the, quote unquote, “best version” of MTHFR. So, all of us, I mean, the vast majority have some kind of MTHFR mutation.

Chris Kresser:  Right. It’s highly prevalent, but has low penetrants, right?

Tommy Wood:  Exactly, yeah.

Chris Kresser:  To use the genetic speak. And if a gene or if a SNP is, 35 percent of the population has it, we have to really wonder what the clinical impact of that is going to be.

Tommy Wood:  Exactly.

Chris Kresser:  Right? Well, let’s talk about some specifics now. Because we’ve thrown, we’ve mentioned a few that we were planning to discuss, FTO and MTHFR, maybe COMT if we have time for it. So, you did some really interesting data analysis in your presentation. And I’d love for you to just go through some of these common SNPs that people talk about and get concerned about and tell us what you found in terms of the actual modification of risk, that they pose or don’t pose.

Understanding MTHFR Mutations

Tommy Wood:  Yeah, so we can start with MTHFR, seeing as we’re talking about that most recently. And it’s actually a really nice case study looking at how different SNPs affect the function of a protein, which then affects phenotype. Because there are two common SNPs that we talk about in the MTHFR gene. They are A1298C. So, [an] A being replaced with a C, and then C677T. And those who are 129880, and 677CC, those are the people who have quote unquote “100 percent” MTHFR function.

And the way that they measure that, just in case people are interested, is they take people’s blood cells or a tissue sample, and then they extract out the protein, this is an enzyme, and then they test it in a test tube to look at, like, how well that protein works. And later on, particularly with COMT, is quite a nice example of how just, like, looking at that in isolation, maybe it doesn’t really tell you much about what’s happening in the system as a whole. Anyway, if you combine these different SNPs, in different combinations, you get a range of activity of MTHFR. So, those who are 677TT, they’ve lost or have about, they have lost about 70 percent, 75 percent of function compared to the best version.

Chris Kresser:  Yep, that’s me.

Tommy Wood:  Yeah, and I am the next worst, which is I am heterozygous for both. So, I’ve lost about 52 percent of my function.

Chris Kresser:  Yeah. That’s a compound heterozygous.

Tommy Wood:  Compound heterozygous, exactly. And so, what you can do, is you can take all these different activities, sort of average activities, of the different SNPs, and then you can look at something that we might care about, like homocysteine level. Which 5-MTHF, which is produced by MTHFR, is used to recycle homocysteine as is choline, which is one of the reasons why people might recommend more choline for people with MTHFR SNPs. But if you look at the whole range of potential function, your MTHFR SNPs only explain about 1 percent of your homocysteine level. It’s just, it’s so little that it’s a rounding error on a lab test.

Chris Kresser:  Less than a lab error, yeah.

Tommy Wood:  Exactly.

Chris Kresser:  I mean, that’s inside of the standard variation you get from testing homocysteine every day in the blood.

Tommy Wood:  Absolutely. Yeah. And then, if you sort of create these full bell curves that I talked about, you compare me with my 52 percent loss of function to the best possible person, the likelihood that I have a homocysteine that is elevated greater than a person with the best MTHFR function is just 8 percent, right? So then, more than 90 percent of people who have my specific genotype will have no change or no difference in their homocysteine relative to the people who have the quote unquote “best” MTHFR function. So, you can see overall, the effect is so small that it’s barely even worth worrying about.

Chris Kresser:  That’s so interesting, just that specific number. Because there was a big study that was, I can’t remember if alphabet had something to do with it, but they analyzed genes, and they found that over 90 percent of what determines lifespan was environmental, not genetic. And then there is another. A lot of the studies that have been done on chronic disease risk show that about 85 to 90 percent of the risk of chronic disease is environmental and not genetic.

And as I was going through your presentation, it seemed like most of the genes that you were talking about fall into that 10 percent or less influence number, which is consistent with these larger studies that aren’t looking at specific SNPs, but they’re just looking at overall patterns.

Tommy Wood:  Yeah, absolutely. If you look at any particular SNP, either, like, compare best to worst, however you want to call it, like, the actual likelihood that you’ll see a meaningful effect is always less than 10 percent. And even when you start to compound these in large genetic risk scores, that still only increases the risk incrementally. And that’s when you’re comparing, like, the bottom 1 percent to the top 1 percent.

So, you may have, like, a 20 percent increase of risk, but, like, the middle 98 percent, like, your genetics really aren’t going to tell you anything, and almost all of it is an expression of the environment itself. So, when we’re thinking about MTHFR SNPs, we know that there’s some requirement for nutrients that are going to make the whole, going to make the whole cycle run, and we can test those. We can test homocysteine itself. And you would, you can intervene as a practitioner. You may want to supplement with certain nutrients or make sure someone’s getting more of a certain nutrient in the diet. For this whole thing, we might think about [vitamin] B12, riboflavin, [and] folate.

Chris Kresser:  Just eat liver.

Tommy Wood:  Just eat liver, exactly. This is the thing.

Chris Kresser:  Which is what we’ve been saying for years.

Tommy Wood:  If people just ate liver and eggs, if they’re not sensitive to eggs, like, this whole problem goes away. You don’t even need to bother measuring any of it.

Chris Kresser:  Just save yourself the trouble [of] going through all this stuff. Yeah. No, I know, Alex Leaf has dug up some interesting info on homocysteine variability. It really kind of disappears when you consider riboflavin or a factor in riboflavin status. So, in other words, riboflavin deficiency is really what explains most of the difference in homocysteine levels in people with MTHFR.

Tommy Wood:  Yeah.

Chris Kresser:  And we’re not talking about huge amounts, right?

Tommy Wood:  Well, it’s 2 milligrams. Or I think they tested 1.6 milligrams in that study. And this is particularly in people like you who have the 677TT. By the way, if you just took 2 milligrams of riboflavin, if you’re not getting it from your diet for whatever reason, again, the whole problem goes away.

Chris Kresser:  Problem solved, yeah. Or at least [the] problem that you think is being driven by MTHFR. So, it might not solve all your problems. But problem solved from the perspective of the influence that your MTHFR polymorphism is having on your health.

Tommy Wood:  Absolutely, yeah.

Chris Kresser:  Yeah. So, I know this is going to be a head spinner for a lot of people listening because MTHFR has been really, I mean, I find I’m constantly having to kind of talk people off the ledge when it comes to MTHFR. Because in my intake paperwork, like I said, I’ve had patients say they have the MTHFR disease. I have people kind of, [on] the forms I use, I have people list their top five concerns, and it’s not uncommon for people to list MTHFR in one of their top five concerns on the intake paperwork. So, we’re always living and learning in healthcare, and I certainly was not blameless in my early enthusiasm for MTHFR. And as practitioners, we’re always looking for ways that we can help our patients.

Tommy Wood:  Absolutely.

Chris Kresser:  And there certainly was early data that suggested this might be a lever that we could push that would lead to positive results. So, all I can say is, I’m sorry that I contributed to that.

Tommy Wood:  I did it, too. I did it, too. Yeah, absolutely.

Chris Kresser:  And the best we can do is continue to learn and be willing to change our mind in the face of new data, right?

Tommy Wood:  Yeah, absolutely.

What Are FTO Mutations?

Chris Kresser:  I mean, that’s why they call it a practice. I’m constantly reminding myself of that, and my patients, as well. So, what about FTO? So, this is a gene that’s gotten a lot of attention. You briefly mentioned earlier talking about obesity risk. And, of course, now we have seven out of 10 Americans who are overweight and four out of 10 are obese. So, this is obviously a big concern.

Tommy Wood:  Yeah, absolutely. And FTO is, or fat mass and obesity associated protein is the protein or gene that’s most strongly associated with the risk of obesity or being overweight. And we’re not really sure what it does. But, or in some tissues, at least in the brain, it seems to be associated with regulating food intake, which kind of makes sense. And if you look at the various meta-analyses, it seems like for each copy of the particular, there are multiple different SNPs in FTO.

But there’s one particular one that’s talked about the most. And for each copy you have, your BMI on average goes up by 0.3; it’s maybe about two pounds per copy. And so, you think about that and you’re like, “Okay, there’s potentially something meaningful there if I have this.” And again, like for most of the things I talk about, I’m either heterozygous or I have the worst version. It sounds like you’re potentially the same, Chris.

Chris Kresser:  Yeah, I’m screwed.

Tommy Wood:  And so, when you look at, so I do a similar analysis, right? I sort of recreate a full bell curve and try and look at the full possible range of results for a given person, rather than saying, “Okay, well, I have this SNP, so I’m definitely going to be two pounds heavier.” And it turns out that your FTO genotype predicts about 0.2 percent of your BMI. I think in the talk, I was like, that’s basically whether you have a glass of water before you weighed yourself or not. And so, even though it’s the SNP most strongly associated with obesity, on its own, it’s essentially meaningless.

So, over the years, there’s been an increasing number of these polygenic risk goals I talked about earlier. And obesity is a really nice example. So, one I talked about in the talk, I spent a long time analyzing. They looked at eight SNPs, the eight SNPs most associated with obesity, and both in the paper and then when I tried to recreate the data set and analyze it myself separately, they agreed quite nicely. It was about 4, 4 to 5 percent of your BMI is explained by these eight SNPs that are most associated with obesity. And like I was talking about earlier, now in this particular paper, if you compare the bottom 1 percent of risk to the top 1 percent of genetic risk, there’s just a 20 percent, there’s a 20 percent chance that those in the top risk profile will have a BMI that’s greater than [those in] the bottom risk.

Or the bottom risk group, what bottom percent, 1 percent, top 1 percent versus bottom 1 percent. And that’s, 20 percent potentially sounds like a lot. But when you think about these, just like right at the extremes of people, I think, yeah, and then in the middle, there’s basically no effect of your genetics on your BMI, or the predictability is very, very low. And then, so that was any eight SNPs. And more recently, I was looking at another paper that came out in Cell this year, and they looked at 141 SNPs associated with BMI.

So, we’re trying to sort of add this up and increase our predictability. And one thing that really bothered me about this paper is that they only give you the average BMI in each genetic risk group. So, I’ve no idea about the variability. And this is incredibly dishonest to do this, like, from a statistical viewpoint, because you have no idea of knowing, like, what the actual overall pattern of risk is for each genetic group. And I’m actually really surprised that Cell published it like that. But even then, with 141 SNPs predicting, associated with BMI, that only predicted 13 percent of the variability in BMI.

And in those people in the lowest genetic risk group, when they applied this to another population to test it, and it was the same in that previous eight SNP score that was talking about, the lowest risk people had a BMI above 25. So, at baseline, the people they’re studying these genetic risk causes in are overweight or worse.

Chris Kresser:  Right.

Tommy Wood:  So, when you’re trying to apply this to yourself, again, as somebody listening to this, I mean, and of course, you may be struggling with weight loss, but if you’re looking at your genetic risk, almost all of it is in an environment, which is already driving people to be overweight and obese, and the best genetic risk or the people with the lowest risk are still already overweight.

And this is definitely an expression of the environment because when you look at even polygenic risk scores and you look at what might modify the risk. So polygenic risk scores for obesity, if you’re doing just the recommended amount of exercise, which will be, like, 45 minutes to an hour, not of intense work in the gym, but just walking, standing.

Chris Kresser:  It could even just be walking, standing at your, if you’re working retail, standing up or walking around if you’re, yeah.

Tommy Wood:  Exactly, that’s enough.

Chris Kresser:  Not a Tabata.

Tommy Wood:  Yeah, yeah, yeah, anything. It doesn’t need to be strenuous at all, but just moving for an hour a day.

Chris Kresser:  Not metcon, five metcons a week.

Tommy Wood:  And that’s enough to eliminate almost all your genetic risk of obesity, which is incredible. But it also tells you that it’s not going to have to be really hard work. And similarly, when they looked at the FTO genotype, there’s a nice paper that came out in PNAS a couple of years ago. They basically showed the FTO wasn’t associated with obesity at all until after the Second World War.

Chris Kresser:  Right. Change of lifestyle.

Tommy Wood:  So, these risk genotypes, yeah. They’re completely a reflection of the change that, in the Western lifestyle. So, if you’re, again, somebody listening to this and you’re moving frequently, eating real food, getting some sleep, maybe doing something to increase your distress tolerance, all of that regardless of your genetics, and you would recommend that for everybody, then the risk disappears.

What would be even more revealing, is if there was a side-by-side comparison in these studies of, like, “Okay, well, modifying your, even if we had the technology, let’s say through CRISPR [clustered regularly interspaced short palindromic repeats] or something eventually, to modify our genes, here’s what the potential benefit could be in terms of risk reduction, you know, less than 10 percent. And that’s the best-case scenario, right?

Tommy Wood:  Yeah, absolutely.

Chris Kresser:  But here’s the risk reduction that could come from eating a nutrient-dense whole foods diet, exercising, increasing your non-exercise physical activity and [engaging in] exercise, which are two different, but related, benefits. Distinct. Sleeping for eight hours a night versus six hours a night, which is what 35 percent of Americans are doing now.

Managing your stress a little bit. Actually, we could just stop there. I mean, I have no idea what the actual percentage of risk reduction would be there, but I’m absolutely certain that it would be in the 10s of percent and way higher than what you could get by modifying the genes.

Tommy Wood:  There’s another example that I gave looking at risk of type 2 diabetes, which is on the rise in the United States. And so, my, so again, I have a SNP in my melatonin receptor 1B that increases my risk of type 2 diabetes by 67 percent. But if you go and look at hunter–gatherer populations, their risk of type 2 diabetes is basically 0 percent. So, even if they had the worst possible genetics, any percent increase above 0 percent is still 0 percent. So, almost all of this is an expression of the environment that we’re exposing ourselves to.

Chris Kresser:  And we also have the migration studies that show what happened to hunter–gatherer populations or even people who were not hunter–gatherers but were just living on a more traditional diet and lifestyle, like the Okinawans. And then they moved to LA. They acquire diseases at the same rate or even a greater rate than people, like Western Europeans. And that really interesting research of Weston Price, when he showed side-by-side pictures in his book of what happens to the dental, the structure of the jaw and the teeth and the palate, in just one generation moving from a traditional diet to a Western diet.

ApoE4 and Alzheimer’s Disease Risk

Chris Kresser:  So yeah, it’s really revealing. I’m curious. I know you did, you talked about COMT in the presentation. I’m curious if you’ve looked into ApoE and relationship with cardiovascular disease and particularly Alzheimer’s disease. Because that is a gene that gets a lot of attention. And particularly with Alzheimer’s. People who have, who are homozygous for ApoE4 are basically told, “Look, just start making your plans for having Alzheimer’s because you’re going to get it.” I mean, that’s, that’s what patients are told.

Tommy Wood:  Yeah.

Chris Kresser:  So, have you looked into that?

Tommy Wood:  Yeah, briefly, and ApoE is an interesting one, because it’s probably the gene, which has one of the highest in individual heritability scores. It explains about 5 percent of the heritability of Alzheimer’s disease, which is much more than any of the other genes that we’ve talked about.

Chris Kresser:  Right.

Tommy Wood:  And you’re right, that’s kind of how we talk about ApoE4. But it’s very interesting because there was enough data to suggest that it’s also very dependent on the environment that we expose ourselves to. So, in the setting of continuous neurological insults, ApoE4 being either heterozygous or homozygous, that changes the way we respond to injuries to the brain. And that injury could be either being punched in the face if you’re a boxer or being in a car accident, or it could be massive glucose spikes because you’re eating loads of refined carbohydrates. Those are also neurological stresses that ApoE4 may exacerbate the response to.

So, in that setting, ApoE4 certainly does seem to increase risk. But in a more sort of hunter–gatherer setting, they looked at this in the Bolivian Tsimané and they showed that those who had a high parasite burden, and that was elevated eosinophils and/or some kind of evidence of a parasite infection, actually had protection of cognitive function.

Chris Kresser:  They were protected.

Tommy Wood:  Yeah.

Chris Kresser:  Yeah.

Tommy Wood:  So, yeah, in a Western, in the Western world, if you are an ApoE4 carrier doing Western world-type things, yes, I do think that ApoE4 is something that’s going to contribute to your long-term Alzheimer’s disease risk. But if you’re doing all the things that we might recommend, again, to decrease the risk of Alzheimer’s and that, diet, sleep, stress, we’ve talked about all of those already, we actually have very little evidence to suggest that ApoE4 is going to be that much worse than any of the other ApoE genotypes. And again, this is, kind of, just conjecture at [this] point. But all the other data would suggest that you’re probably doing most of the things that are going to, at least dramatically reduce your risk. And that is modifiable with if you are an ApoE4 carrier.

Chris Kresser:  Right. And when I looked into this several years ago, I came to basically the same conclusion that it’s, it affects our response to oxidative stress and inflammation in the brain. And so, if you want to take steps to reduce your risk of Alzheimer’s, reduce oxidative stress and inflammation. Which is, as you pointed out, the same thing you should be doing even if you don’t have that genetic risk for Alzheimer’s.

Tommy Wood:  Absolutely.

Chris Kresser:  That’s still the name of the game, basically. But this is the one that I get most concerned with in terms of the nocebo effect. Because Alzheimer’s is a really scary disease. I mean, I’ll take a heart attack any day of the week over going out with Alzheimer’s. It’s a very, very nasty disease, both for the person who’s suffering from it, and even more so, arguably, for the people around them. And most people would choose just about any type of death like shark, great white shark attack. It’s scary, but it’s over pretty quickly, right?

Tommy Wood:  Yeah.

Chris Kresser:  And so, when people are told that they, it’s, like, almost inevitable that they’re going to get Alzheimer’s, that creates some real fear and that living in that fear state with your amygdala activated and the downstream consequences of that in terms of, like, being in a constant fight or flight response, of course, can become a self-fulfilling prophecy. Because being in that fight or flight response will exacerbate inflammation and oxidative stress if it’s a chronic thing.

Tommy Wood:  Absolutely.

Chris Kresser:  So, I know, for a while it was like, early on, that kind of information was only being delivered by a genetic counselor who could explain some of these things. But now, since consumers have access to it, my concern is just, I’m glad that we’re starting to see some studies like the one in 2019 about the effects of genotype on exercise. But I hope we see more studies even about, like, the effects of people knowing about some of their other SNPs and how that impacts their behavior and even their disease risk prospectively over time.

Tommy Wood:  Yeah, and I think a lot of people are doing this with good intentions or they want people to know about their risk.

Chris Kresser:  Sure.

Tommy Wood:  But I mean, the problem is that to date, there’s very little evidence to suggest that telling somebody about their risk is going to change their behavior. So, if you were trying to tell ApoE4s that they’re carriers because then they’re more likely to focus on their sleep, and meditate and exercise, and eat a high-quality diet, that would be great. But there’s only a very small percentage of the population who are going to respond in that way. And the rest of them [are] then just going to spend a lifetime worrying about how they’re going to get Alzheimer’s.

Chris Kresser:  Exactly. This is why I’ve become such a powerful believer in health coaching because information is not enough to change behavior.

Tommy Wood:  Absolutely.

Why We Should Focus on Behavior Change, not Genetic Testing Results

Chris Kresser:  We know this beyond a shadow of a doubt. There’s the CDC [Centers for Disease Control and Prevention], that famous CDC study that found that only 6 percent of Americans consistently engage in what they define as the top five health behaviors. So again, we’re not talking about intermittent fasting and keto and CrossFit and all of this, we’re just talking about:

  • Maintaining a healthy weight
  • Getting enough exercise
  • Not smoking
  • Not drinking excessively
  • Getting enough sleep

They didn’t even include diet anywhere in those five health behaviors. And yet only 6 percent of Americans engage in them. And I guarantee you, if you take 100 people off the street and you say, “Is it healthy to drink a lot and smoke and not exercise and be overweight?” They’re going to say, “No.” So they know it, they have the information, [but] they just don’t, [or] are not able to, change their behavior.

So for me, it’s like, what if we took some of this huge amount of financial resources that are being invested in research on SNPs and all this stuff and put it toward, like, really actually, a huge public health effort that involved scaling health coaching and learning more about how to actually assist people in changing their behavior and support them [in] doing that over a lifetime. Like, can you imagine the impact that would have versus this?

Tommy Wood:  Yeah. Which has been shown already to basically not make any difference. If you’re trying to tell people about their risk, it doesn’t change their behavior.

Chris Kresser:  Right. Right. So, yeah, it’s fascinating. I love that you have done this deep dive and are out there sharing this information. Because, I mean, you know as well as I do, that there’s a lot of misunderstanding. And practitioners, like me, have contributed to that misunderstanding. So, I consider this my public, act of public service to rectify that, and help get the word out so that we stay current with what the research actually really is showing us. I mean, this isn’t the first time that we have misunderstood something in medicine.

If you look back, I always like to say the history of medicine and science in general is most people being wrong about most things most of the time. So, the best we can do is correct those misunderstandings as we go, and I appreciate your efforts in doing that with the genetics and single nucleotide polymorphisms.

Tommy Wood:  Thanks. Seeing as my day job is being an academic, I am very familiar with the concept of being wrong most of the time and that’s just part of the job. So maybe that sort of helps.

Chris Kresser:  Yeah, that’s what you signed up for as a scientist, right?

Tommy Wood:  Exactly, yeah.

Chris Kresser:  So, yeah. Tommy, where can people find out more about your work? I know you’re involved in a lot of interesting stuff.

Tommy Wood:  So, the easiest thing at the moment is probably go to DrRagnar.com. D-r-r-a-g-n-a-r.com. Ragnar is my middle name. That’s my website and it has links.

Chris Kresser:  It’s a way cooler web URL than DrWood.com.

Tommy Wood:  Yeah, exactly. DrWood.com may have been taken, as well, when I started. But yeah, so I have my podcast on there. And there are some old blog posts. I haven’t blogged in a while, but you go there and you also have my CV and the papers I’ve published and stuff. And then Instagram @DrTommyWood. I usually post stuff on there, like, when I publish a paper again or go on a podcast. And yeah, there’s a couple of companies that I’m in the process of trying to work with to do exactly the things that you mentioned. Try and scale some of these health behaviors [to] help people support their behavior. And when those become successful, then those mediums will show that. So those are the best places to go.

Chris Kresser:  Great. Yeah. Yeah, that’s, it’s interesting that a number of our colleagues have all kind of reached the same conclusions after being in this field for many years. Which for some people will be good news and [for] others will be bad news. Because when I reflect on what is behind the desire for, or maybe the, what turns out to be the fantasy that genes are going to solve everything, is certainly it would be easier, right? If we could develop a kind of gene modification technology or even therapeutic drugs that would target certain genotypes, I wouldn’t have to do anything. I could just keep living my same lifestyle and eating the same diet and not have to pay the price.

Tommy Wood:  Yeah.

Chris Kresser:  And so, when it always keeps coming back to the simple things that we talk about, like cleaning up your diet, moving more, managing your stress, I think it’s a double-edged sword or it’s good news, bad news for people because change is hard. Let’s face it. If change wasn’t hard, we wouldn’t have only 6 percent of people following those top five health behaviors. And I don’t care who you are. Change is hard. Some people are just more successful at it. But even for them, it’s difficult.

And so, I’m really interested with our launch of the health coach training program that’s now just enrolled its third cohort. That’s what I’m investing in for the future, because I really believe that behavior change is the only way we’re going to reverse the epidemic of chronic disease. I don’t think fancy designer genetic drugs are going to do it. I don’t think any drugs are going to do it. And I don’t think just hammering people with information is going to do it either. So, we’ve tried that. It doesn’t work.

Tommy Wood:  Yeah, I completely agree. And I think you’re right, this is a double-edged sword because we’re fairly certain that most of the things that we’re doing in academia medicine aren’t really going to help that much despite the huge amount of money that we’re going to spend. But we probably do know what the answer is. It’s just, it’s just difficult.

Chris Kresser:  It’s not that sexy.

Tommy Wood:  Yeah, exactly. It’s not sexy. It’s simple, but it’s not easy.

Chris Kresser:  And you can’t patent it and make a billion dollars off it either. So, there’s that problem.

Tommy Wood:  Yeah, we both realize that, I think.

Chris Kresser:  Hard to raise venture capital in that on getting people to stop eating pizza and donuts.

Tommy Wood:  Yeah, definitely.

Chris Kresser:  All right, Tommy, thanks again for joining us. Appreciate your work and would love to have you back in the future after your next deep dive.

Tommy Wood:  Likewise, Chris. Thank you so much for your time.

Chris Kresser:  All right, take care.

Tommy Wood:  Yes, bye.

Chris Kresser:  Bye-bye.