Welcome back. This is last module in the third unit, in which, we have talked about quantitative genetics really in the, in the concept of heritability, but really what I am going to talk about today is, something that doesn't easily get incorporated into the heritability analysis. So is the concept of gene-environment interaction. And this is an extremely important concept not only in behavioral genetics but actually human genetics today. And it's so important that we're actually going to have two modules on gene environment interaction. Kind of an introductory one now, because it fits in with our discussion on heritability, but later when we talk about how behavioral genetic research has helped us understand. Aspects of environmental influence, as well as genetic influence and it's much later in the course. But I want to begin our discussion, before I even define gene and environment interaction. I want to begin by a study, a study I really like. And it's a study by a man, a doctor, a child psychiatrist named Remy Cadoret. Was at the University of Iowa sadly he passed away a few years ago. But what Remi Cadoret was doing, he was actually do an adoption study. And what he was interested in, and he spent his career studying was the origin of aggression or anti social behavior. So that, and he, he used adoption studies to try to understand. Why it is some of us end up being aggressive or antisocial and others of us don't. And in this particular study, what he did is he took we don't need to get into all of the details of the study, but what he did is he has a sample of adopted children. And he did classify the sample as to whether or not they had a birth parent, who had a history of antisocial behavior, and he was able to get information on that. And he also had a sample of adopted children whose birth parents had no history of antisocial or aggressive behavior. And the outcome he's looking at here, is he actually looks at multiple outcomes, but I'm just going to focus on one. The, the pattern of results is very consistent across the multiple outcomes. But the, the outcome here, is how aggressive, these children were. He not only knows about their birth background, but he knows about the environment, the adoptive home that they are reared in. Some of the adoptive homes were, quote unquote, high risk homes. They may have been characterized by aggressive parents, who argued a lot, maybe even physically fought with one another, maybe the home was chaotic. Versus adoptive homes down here that were much more nurturing and protective. So what's plotted here is for the adopted children who had a family history of anti-social behavior versus adopted children who did not. How aggressive they were as a function of the type of home they were reared in. Now the adopted children that have a family history of anti-social behavior. We would consider if antisocial behavior is inherited, and to a certain degree it is, we would consider these children to have some sort of inherited liability to developing antisocial aggressive behavior. These would not necessarily have that, right. They don't have a history, of anti-social behavior. And so the question here for you, before I move to the next slide. I'd like you just look at this slide and look at the results of the, of Cadoret's study and answer to the question for yourself, do genetic factors, which are here indicated by the birth parent background. Due to genetic factors, influenced the level of aggression in these children. So take a second and look at that slide, and come up with an answer to that question. Do genetic factors, is biological background important in predicting aggression? Well, the answer to the question is whether or not genetic factors are important here depends. Depends on the rearing environment of the children. If they are reared in the nurturing, protective home, it didn't matter. If they are reared in the chaotic, dysfunctional, aggressive home, it did matter. So, go back to the slide. Down here, their background didn't matter at all. They had very similar levels of aggression. Up here, it did matter, these are, they chaotic dysfunctional homes. Here are the nuturent homes. So whether or not there's a genetic effect depends upon the environment these children are being reared in. That is a gene environment interaction. The magnitude of the genetic effect, depends upon the environment the children are being reared in. That's an interaction. It literally. It's a statistical interaction. In this case, genetic effect here indexed by the birth parent background, is interacting with the rearing environment, to predict whether or not the level of aggression in the child. Cadoret's evidence for gene environment interaction is indirect. That is, he didn't directly measure the genotypes of these children. He actually, back when he did the study in the early 1990s, we wouldn't have been able to even know how to measure their genotypes for aggression. What he did is he assessed their family history of antisociality, and used that as an index of their genotype. Presumably if you could directly measure their genotype, it would have even a much more sensitive and powerful test for this genotype environment interaction effect. It turns out, that with the development of the Human Genome Project, we can now begin, to at, to actually estimate these gene environment interaction effects by measuring genotypes directly, rather than indirectly as Cadoret had to do back 20 years or so ago. And the real breakthrough in this approach came in 2003 in a paper published in Science. I'll give you the citation in a couple slides here. And I'm going to go through the study because it illustrates how the field now is transitioning from the type of study Cadoret did, where the genetic effect is measured indirectly to one where it is measured directly by genotype in the participants. In this case, the researchers were looking for a gene environment interaction for depression. So a little background about depression. First of all, twin studies again, not surprising hopefully to you at this point. Twin studies show that monozygotic twins are more similar than dizygotic twins for level of depression. It's heritable. As it turns out though, among forms of psychopathology, depression is probably the least heritable forms of mental illness. Things like bipolar and schizophrenia or autism are actually much more heritable. The heritability of depression is actually not that high. It appears to be on the order of about 30 to 40%. But it's definitely heritable. We also know there's a lot of research on depression. That indicates that particular environmental factors seem to trigger depressive episodes. Right, people who suffer depression aren't always depressed. They cycle in and out of depression. What often seems to trigger a depressive episode, for an individual like this, are life stressors that precede maybe by a few months, maybe by a few weeks, their life begins to get stressful, and that seems to trigger or bring on a depressive episode. So we knew a little bit about the genetics. We know a little bit about the environment. We also now know how depression is treated. Do, one common, it's not the only pharmacological intervention for depression, is to used what are called selective serotonin reuptake inhibitors. The symbol for serotonin is 5-HT. And what selective serotonin reuptake inhibitors, many of you have probably heard of these before, are called SSRIs. And essentially, what selective serotonin reuptake inhibitors allow, is allow, it, it provides greater access to serotonin. And that's thought to be therapeutic for a depressive episode. The, the, the mechanism by which selective serotonin reuptake inhibitors are thought to be therapeutic is they block something called the serotonin transporter. So 5-HT is serotonin. 5-HTT is the serotonin transporter. Depression is heritable. We know something about the specific environmental factors that can trigger a depressive episode. It's treated by a drug that blocks the serotonin transporter and therefore makes serotonin more available in the neuratic, in the, in the central nervous system. There happens to be a gene that codes for the serotonin transporter, and there's different generic variants of this gene. In this study, in this 2003 study, the phenotype they looked at was the diagnosis of major depression, whether or not somebody suffered from major depression. The environment was the number of life stressors the person had experienced up to five years previous, to when the assesed for major depression. The genotype is now being measured directly. What they did is they genotype the serotonin transporter gene. And the reason they looked at this gene is because of the relationship to the therapeutic effect here. The SSRIs. And it turns out that there's a risk allele for the gene here, and the risk allele is called the S allele. There's two alleles, an S allele and an L allele. S actually in this case stands for short, and L stands for long. We don't have to worry too much about why one is called short and long. Those are the two alleles. The S allele. Is the risk allele or thought to be the risk allele before they did this study. Here's the major finding from the study. Again, they looked at actually multiple indicators of depression. The results are very consistent across the multiple indicators. What's displayed here is the number of stressful life events the individual had experienced in the five years previous to their being assessed for depression. Here is the probability that they met diagnostic criteria for having a depressive episode. And there are three different lines here. One for each of the three genotypes. Two alleles, one locus, three genotypes. The s/s homozygotes, the l/l homozygotes, and the heterozygotes here. The question here, to ask is, I said that s is thought to be a risk allele, is it a risk allele for depression. Again, think about that for a second. Is the s allele really a risk allele for depression? Well the answer is, just like the Cadoret study, it depends. If they didn't experience a lot of stress, the genetic effect didn't matter. Right? All these genotypes had similar risk for depression. So, the genetic effect was irrelevant at low levels of stress. At high levels of stress, it does matter. An interaction. The genetic effect here depends upon the level of the environment, a gene by environment interaction. Whether or not the s allele is a vulnerability allele here depends upon whether or not you're exposed to high levels of stress. If you're at low levels of stress, it does, the genotype here is not mattering. Much like the Cadoret study. Family background of anti-sociality, only mattered if the children were reared in a chaotic family. If they're in a nurtured family, the genetics didn't matter. There was an interaction. This form of gene environment interaction is actually fundamental to the way psychologists and psychiatrists think about psychopathology generally, not only depression, but schizophrenia, or autism, or any type of psychopathology. There's a model, heuristic model of psychopathology called the Diathesis-stress model of psychopathology. And what it really is, is a form of gene-environment interaction, and the notion of diathesis stress is individuals inherit a level of Diathesis that is the genetic background. Whether or not that diathesis manifests as psychopathology depends upon the environment you're reared in. That's the stressor. So that if you inherit the diathesis, that doesn't mean necessarily you get the disorder. What you're really inheriting is a genetic vulnerability. Whether or not that vulnerability manifests. As the disease depends upon whether or not you're reared in whatever the, the appropriate provocative environment is. So those children back in the Cadoret study might have inherited a vulnerability to be aggressive but they may or may not have been aggressive at the end. Depending upon the environment, they were reared in, what they've inherited is a vulnerability. They don't inherit the disorder. There's a gene environment interaction. Similarly for depression. The diathesis-stress, and we'll talk about this again when we get into, to schizophrenia. The diathesis-stress notion. As applied, let's say, to schizophrenia's. Some of us in, have inherited a vulnerability, a genetic vulnerability, a diathesis for schizophrenia. We may or may not become schizophrenic depending upon our environment. If we don't inherit that diathesis, we're not going to develop schizophrenia. We, no matter what our environment is, we might develop something else, but we didn't inherit the vulnerability, we're not going to get schizophrenia. That's the Diathesis-stress model. Earlier I said phenylketonuria, we talked about in the very first week, phenylketonuria is kind of the favourite disorder for human geneticists to talk about. It's an example of a diathesis stress model. If you inherit the Pena [UNKNOWN], the PKU genotype then you are vulnerable. In this case the phenotype is whether or not you suffer from an intellectual disability. The environment is how much phenylalanine is in your diet. People with the PKU genotype are vulnerable to developing intellectual disability, but whether or not that vulnerability manifest as an intellectual disability, depends upon how much phenylalanine they have in their diet. If we can control their diet, they are not going to suffer intellectual disability even though they inherit the vulnerability. Fo those of us who don't inherit that genotype, we're not vulnerable. It doesn't really matter if we have a low or a high phenylalanine diet. We're not. That's not going to affect our level of intellectual disability, because we haven't inherited the underlying diathesis, the vulnerability. Diathesis-stress is actually very fundamental to the way psychopathologists think about major mental disorders. The last thing I want to say before wrapping this up, third week up, is that a common mistake is to think of, of, of something like this as a gene environment interaction. It's not. In this case, just to illustrate this, I've taken as our phenotype IQ, and suppose we could actually, we can't really do this today, and we'll get into why we can't do it a little bit later, but suppose we could really identify people with the high IQ genotype, and a low IQ genotype, and we could classify whether or not they were reared in this stimulating, versus a low stimulating intellectually stimulating environment. In this case, having the genotype has an effect and having the environment has an effect, right? The, the IQs are higher in this environment than they are in this environment. And these IQs are higher than those IQs, but there's not an interaction. The genetic effect is the same in every level of the environment. Saying that there's a gene environment interaction isn't the same as saying both genes and environment are important. It's saying that the particular way the gene's environment are important is that they interact, that there's some synergy between the two. So this, genes and environment are important here. But there's not a gene environment interaction because the effect is the same in all levels of the environment, the genetic effect. Gene environment interaction research has absolutely taken off. This is the just a count of the number of times I, I did a, a bibliographic search for it. The number of references and abstracts to gene environment interaction, went back I guess to 1988, where nobody said anything about gene environment interaction, to 2011. And you can see there is an exponential increase in our interest in gene environment interaction. Two reasons for that. One is our ability to actually genotype people for these risk alleles. And again, we're going to talk more about that as we go through the course, and, and secondly, is that we really think, geneticists really believe that gene environment interaction is a very fundamental mechanism, that we need to understand. Why do the, it's think, thought to be very important. Well. Think about the intervention implications of the examples I've just gone through here today. Because there's a genotype environment interaction, we know that we should differentially treat people that have the PKU vulnerability than people who don't. We should regulate their Phenylalanine in their diet. If we want to intervene for people who have inherited the vulnerability to, to display, or develop aggressive, or anti-social behavior because of the gene environment interaction, we should target their families. And make sure that they grow up in nurturing, and cohesive families, rather than dysfunctional, and broken up families. If we look at the depression example, we can think of that s allele and L allele, might there be a way to actually pharmacologically intervene. We can't do that now, believe me, but could we, but people speculate that in the future we will be able to do this, because of that interaction. Maybe those people who've inherited the s allele that's the vulnerability maybe there might be a pharmcological intervention for them that is different from other people. It might be particularly intuned to their genotype. So we've came to the end of this introduction to the qunotive genetics, kind of a challenging topic. But we're beginning to build, I hope, a foundation from where we can rigorously look at the behavioral genetic literature for things like schizophrenia and intelligence a little bit later in the course. We begin to build a vocabulary of terminology. We're going to continue that next week. We introduce the concept of biometrical contributions to phenotypic variance. Phenotypic variance is very fundamental. It's a measure of individual differences. This is a course about why people differ. So variance is the statistic that we're going to really be interested in. We discuss what heritability is, how it's estimated, what its limitations are. And hopefully you get a sense despite the limitations, that there are some things that heritability are very useful for. Finally, I introduce this very important notion of gene-environment interaction, that, really, when we think about how the mechanism by which genes and environment might affect our behavior. One reasonable way of thinking about them is, at least, when we talk about mental illness, what we're probably inheriting is a vulnerability to develop a mental disorder. Whether or not we develop that mental disorder is going to depend on our environment. Some of us are lucky. We don't inherit that vulnerability. So regardless of the environment we're reared in, we may never develop a disorder like schizophrenia, or bipolar disorder because we didn't that vulnerability. Unfortunately, some of us had inherited that vulnerability. And will develop the disorder or not depending upon the environment that they are reared in. So, next week we actually begin talking about molecular genetics. A little primer on molecular genetics. Thank you for your time, and hope to see you next week. [BLANK_AUDIO]
