Okay welcome back. This is Module E in Unit 7. And in this module we're going to come back again to gene-environment interaction, something that we talked about in Unit 3. And the rea, there are several reasons to come back or that I wan, would like to come back and talk about gene-environment interaction. One is, you saw a version of this slide before when we talked about gene-environment interaction in, in unit three. This is just a plot of the number of publications, involving gene-environment interaction, as a function of chronological year, in both the behavioral, and non-behavioral sciences. And what you can see is in, sometime beginning in the early 2000s, there was really an exponential increase in interest in gene-environment interaction. Gene-environment interaction is a very important phenomena that behavioral geneticists and human geneticists more generally study today. And so, one, I'd, I'd like to come and look at some of the topics, or some of the issues surrounding gene-environment interaction in a little bit greater depth. The other reason that I'd like to come back to it now that we're in the seventh week of the course, we have a greater foundation, is to really look at some differing perspectives on GxE interaction. First of all there are actually differing perspectives on, and will talk about this first, what exactly gene-environment interaction means. And secondly, and I'll, I'll discuss this second in this lecture, the significance of a landmark study of gene-environment interaction, which was published in 2003 and I've already mentioned before in this course. But let's first talk about this first issue, what exactly is gene-environment interaction. I recommend this book to you highly. I had the good fortune of, of meeting the author of this book Jim Tabery a couple months ago. He's a philosopher at the University of Utah. And he's devoted quite a bit of his career to try to understand behavioral genetics and the implications of behavioral genetics. And he's written this book about actually dealing with gene-environment interaction. And a good part of the book discusses how different scientists have different perspectives on gene-environment interaction. And in particular, there are two major traditions in thinking about what gene-environment interaction is in the field. That first perspective has been variously called interactionism, or developmental gene by environment interaction. And I'm sure you're, you're almost all familiar with the, the perspective that is reflected by this approach. In this case, people that adopt this version of gene-environment interaction maintain that in thinking about our characteristics, our phenotypes, the genes and the environment are so inextricably linked, that it's meaningless to talk about their separate influence. Or another way of putting it the whole nature-nurture debate, is it nature or is it nurture doesn't make any sense. And here I have a, a quote from a, so from a book, actually re, of, not that old book. That kind of reflects this, that it doesn't really, according to it, I'm not going to read the quote, but according to the quote, it doesn't really make sense to talk about the separate inf, influences of nature, nurture because nature, nurture work together, not in opposition. Well, how does this perspective play out? Let's take an example, it's not a behavioral example. But hopefully it's this example with help you understand the differences between the two perspectives that we're talking about here. Here's a woman with blue eyes. From a developmental gene-environment interaction, or interactionism perspective, it doesn't make sense to ask whether or not she has blue eyes because of her genes, or because of her environment. Her gene does, her genes do not have blue pigment in them, so the genes alone can't determine that she has blue eyes. Her blue eyes have to reflect some sort of com, combination of some genetic information as well as her environment. And it, it doesn't make sense to say, well she has blue eyes, because she, of her genes, or blue eyes because of her environment. Clearly both are important in producing her blue eye color. And for a developmental G by E researcher, what he or she wants to understand is how it is those two factors, the genes and the environment, somehow come together to lead to this woman having blue eyes. [SOUND] The second perspective is called a statistical or biometrical perspective. And it has, it takes a much different view of gene by environment interaction, and it actually dates back, as Tabery shows in his book to R. A. Fisher, the great statistician R. A. Fisher. In this case, what statistical, or biometr, metricians are interested in, is in, individual differences. And what they're trying to determine is if you need to account for individual differences, and recall from unit two that individual differences are typically measured in statistics by a variance, if you want to understand the variance in a phenotype, then you can ask to what extent that variance is due to genetics and environment. And as well as some non-linear interaction between genes and environment. So if we go back to to unit two, we had this equation that individual differences or variance in a phenotype could be written as a function of genetic effects plus environment effects. So from this perspective, genetic and environmental effects are being separated. In this case, what R. A. Fisher and his disciples have said is that sometimes maybe they're not fully separable and we need some interactive function between the two to account for individual differences. So try to understand this perspective. Let's go back to the blue eye example. The interactionists would argue that you can't separate genes and environment in understanding why this woman got blue eyes. But it's a much different question and this is the question the statisticians are asking, is why does she have blue eyes and he have bla, brown eyes? Even though it's definitely the case that our eyes have color, is somehow some joint function of our genes and our environment, I might have blue eyes, and you have brown eyes, because we have di, inherited different genes. Or because we have had different sets of environments. So, it's much, it's fundamentally different to ask about how it is a trait developed in a single individual, versus what are the sources of differences among us. The statisticians are trying to identify the sources of differences among us. That's the biometrical concept of G by E. So from their perspective, from R. A. Fisher's perspective, and I've already given you this definition before, what is a statistical, or biometrical gene by environment interaction? Literally it means, and there's different ways we could say the same thing statistically, it means that the influence of the environment depends upon your genotype. Or equivalently, that the, the, the influence of your genotype depends upon the environment you're reared in. In the very first week of this course I gave you an example of phenylketonuria, PKU. PKU is an example of a gene-environment interaction. We hadn't, I actually hadn't defined gene-environment interaction at that point, but it is an example of a gene-environment interaction. It's actually a term I've used before in this course, a, an example of what's called the diathesis-stress form of gene-environment interaction. How is it a form? And it's a statistical gene-environment interaction. We're trying to talk about individual differences, in this case individual differences in whether or not you have an intellectual disability. The diathesis here is the genotype you inherit. The stressor is how much phenylalanine an individual has in their diet. The phenotype is intellectual disability. If you don't inherit the phenylketonuria genotype you're really not sensitive to how much phen, phenylalanine you in your diet, so long as it's within typical, normal limits. You're, you're not going to increase your risk or decrease your risk for suffering an intellectual disability, depending upon how much phenylalanine. However, if you've inherited the phenylketonuric genotype you are sensitive to how much phenylalanine you have in your diet. If you have a high phenylalanine diet you have a very high chance you will suffer from an intellectual disability. If you're able to control phenylalanine in your diet, you drastically, or in fact almost eliminate the chance that you have an intellectual disability. A statistical gene by environment interaction. The effect of the environment depends upon the genotype. In this case, this genotype is sensitive to the environment. This genotype is not. So the environment, this particular environment has no effect on this genotype. It does on this one. Conversely, and equivalently, statistically, the, the environmental effect is de, dependent, I, I'm sorry, the genetic effect is dependent upon the environment. At a high phenylalanine environment, there's an effect of the PKU genotype. At a very low level, the PKU genotype no longer has an effect on your suffering from an intellectual disability. So, there's equivalent ways of defining and characterizing statistical G by E environment interaction. Why is it important? Why are there so many publications now, 400 or 500 publications on gene environment interaction every year? PKU also illustrates I think this, nicely. By determining that the environmental influence is dependent upon genotype in the case of phenylketonuria, what it's led clinicians to do is actually adapt the environments of people who inherit the at risk genotype. So the, the observation that there's a statistical interaction here, leads them to say that for those of you who have the at-risk genotype, you need to reduce your diet, dietary intake of phenylalanine. For those of you who don't have the at risk genotype you don't need to worry about phenylalanine in your diet. So the observation of a statistical gene environment interaction actually ultimately leads to a clinical you application that leads to an effective intervention for phenylketonuria. That's something that's the basis of something that we'll talk about next week, when we, in the last week of the course, personalized, individualized genomic precision medicine. Those are synonymously used today. The second thing I said I wanted to talk about, I want to come back to a landmark study of G by E, that I actually introduced to you, in the second week of this course. And this is a study that involves the serotonin transporter system. The serotonin transporter, actually what it does is it takes serotonin in the synaptic cleft and pumps it back into the pre-synaptic neuron. So it eliminates serotonin, in a sense, from the synaptic cleft. And it turns out, and I, I think I've mentioned this before, that one of the most common treatments for depression actually interacts with the serotonin transporter. It actually blocks the serotonin transporter from reuptaking the serotonin. So it allows serotonin to remain active in the synaptic cleft for a longer period of time. The serotonin transporter's a protein, there's a gene that codes for that protein. It happens to be on chromosome 17. And there is two there is a genetic variant in that gene. In particular, in the promoter region of the gene. The genetic variant is an example of something that we've talked about before, an insertion versus a deletion. So some people have more DNA in that region. Others have, have less. The in, the deletion form of the variant is called the short allele. The insertion is called the long allele. So we all have, either a short or a long allele, some combination of those in our chromosome 17s. It turns out that if you've inherited the short allele, you produce less of the serotonin. It's in the promoter region of the gene, and it actually results in less of the serotonin transporter gene transporter being produced. If you have the long allele, you produce more of the serotonin transporter molecules. Because of this biological functionality of this polymorphism, this polymorphism is probably one of the most widely studied genetic polymorphisms in psychiatry. It interacts with a system that's thought to be very important in depression. It impacts the serotonin transporter which is the target of the pharmacological interventions that are used for depression. It's also been, this genetic variant has been a subject of a lot of gene by environment interaction research. And the motivation for doing that dates to this study that was published in 2003. I've mentioned before, in this study, which was based out of a, a, a landmark longitudinal study from Dunedin, New Zealand by researchers Caspi and Moffitt. They followed these individuals over time and they genotyped them on the serotonin transporter promoter region polymorphism. These individuals inherited two short alleles, so they'll produce the least amount of the serotonin transporter protein headers, these are the header zygotes in between and then two long alleles, so they produce the greatest quantity of the serotonin transport. They classified the individuals in this case in terms of whether or not as a child these, these are adults. They, they've actually followed them since birth. They classified them as to whether or not they experienced maltreatment in childhood. And then the outcome is depression. So what did they find? They found a genotype environment interaction. The effect of the environment depends on the genotype, so that the, if you inherit the two short alleles, whether or not you're maltreated has a greater effect than if you've inherited two long alleles. That's an interaction or conversely, if you're not maltreated, the genotype doesn't matter. But if you do experience ser, severe childhood maltreatment, the genotype matters a lot in terms of you risk for depression. So that's a gene environment interaction. And in fact, over the last however many years, ten, 12 years, this paper has been pub, been cited over 6,000 times in literature. That's a phenomenal number of citations. The typical, po, paper published in, in, even the best journals in psychiatry might get cited 10, 15, 20 times. The paper has been cited 6000 times. There is a lot of interest in this, because of the biological functionality of the polymorphisms, because of the significance, the potential clinic, clinical significance of depression, as well as maltreatment. And it, I think, hopefully, a natural question for you to ask at this point in the course is, well how has this interaction fared overtime? Has it held up? The remarkable thing is, it's not clear how well it's held up overtime. Even though the study has been cited 6,000 times, they're differing perspectives, just like they're differing perspectives on what gene environment interaction are. There are actually differing perspectives on whether or not this study from New Zealand actually showed a, a, a replicable gene environment interaction. Why is that? Well, first of all, there are multiple Meta-analyses of all these studies that have come afterwards. If you distinguish those Meta-analyses, the first Meta-analysis, Meta-analysis that I've highlighted here is by, a geneticist named Neil Risch from Stanford University. And what it is an example of is, Meta-analysis of direct attempts at replication. That is, by direct means, they did exactly the same thing as the original investigators. They measured the same phenotype, they had the same environmental exposure, and they handled the genotypes in exactly the same way. When he meta-analyzed studies that were direct attempts, he found no evidence for replication after the initial report. In a subsequent Meta-analysis published two years after Risch's, Karg et al took not only direct attempts but indirect attempts at replication. Well, what's an indirect attempt? An indirect attempt at replication is using a study design that doesn't actually parallel exactly what was done in the initial study. Maybe the genotypes aren't clustered in the same way. Maybe rather than comparing three genotypes, you're comparing two genotypes. Carriers of the S allele versus the LL homozygote. Or, maybe rather than maltreatment, you're looking at some other psychological stressor. If you look at indirect attempts at replication, Karg et al report that there is evidence for gene by environment interaction. So, what do you, what do scientists make of that? It's a little bit hard to know what to make of it. Some are concerned that if you allow for indirect replications, what's happening. And, if we go back to last week when we talked, if you listened to the supplemental lecture on the replication crisis, there's a concern that maybe what happens with indirect, replications where they don't exactly follow the recipe in the original investigation is people change the conditions in order to produce the result they want. Now, it's not clear whether or not that happened, but it leads people to wonder why it is direct replications don't find a result, but indirect replications do. Another reason that people have questioned whether or not this is a true interaction is that there is definitely evidence of publication bias. In the attempts to replicate, the larger the study, the less likely it is to be a positive replication. Typically, you would expect a larger study, you would more likely to get a result, if there really is a result to be had. Suggesting that in this case if you get, the larger the study, the less likely the result, there's a concern that people that are with small studies that aren't getting the result, are probably not publishing them. If you're interested in this debate, I've given you a nice citation there to a paper by Duncan & Keller that goes over the debate. Hopefully, at this, point in the course, the 7th week, we're ending the 7th week, a little uncertainty in the literature doesn't trouble you, because really, you get to uncertainty when you're on the, the, the really the frontiers of people doing research. This is what people are debating now in Behavioral Genetics. So, that ends this module, next time I'll talk about Genetics and Aging.
