Welcome back. I want to refresh your memory about something that I, I actually introduced you, in the first week of this course. And that is, I see the behavioral, the field of behavioral genetics, as interested in using genetic methodologies to understand etiology of physiological psychiatric phenotypes, regardless of whether those ideologies are genetic or environmental. I think these genetic methodologies provide psychologists like myself with powerful tools. Last time, I talked about twin adoption studies and what we've learned about the genetics of schizophrenia from those studies. This time I'm hoping to illustrate that these studies also inform us about environmental influences. Later in the course, I'll come back to this feature of behavioral genetics, because I think it's a very fundamental aspect of the behavioral genetics that is often misunderstood. We'll talk about the same thing when we talk about intelligence and also other phenotypes, later in the course. And I also want to refresh your memory about the way behavioral geneticists think about the environment. We distinguish between two major source of environmental influence. Shared environmental influences correspond to the influences of factors an individual shares with the relatives he or she is reared with. And because he or she shares those factors, they are a potential source for their behavioral or phenotypic similarity. Factors such as social class of the home, the neighborhood you live in, the way your parents rear you, those are called shared environmental factors. The second major class, from behavioural genetic perspective, are called non-shared environmental factors. These are environmental factors that you don't share with the relatives you grew up with. And because you don't share them, they're a potential source of your behavioral differences, or dissimilarity, non-shared environmental factors. So in trying to think about what behavioural genetics or twin and adoption studies have told us about schizophrenia, what we really need to do is, what have they told us about shared or versus non-shared environmental influences? So let's first talk about shared environmental influences. For schizophrenia, I think the twin and adoption research is pretty consistent. The shared environmental influences don't appear to be very important. There might be some shared environmental influence, but it doesn't seem to be the major class of environmental influence. And there are several lines of evidence to support that. I'm going to just highlight three here in this module. The first is really a consequence of something I gave you in the last module. The last time I told you that the risk to a first degree relative of somebody with schizophrenia is 1 out of 10, 10%. That means in most families that have an individual that suffer schizophrenia, there's one individual with schizophrenia. If the shared environment is an important factor in influencing schizophrenia, then how do we explain that in the typical sibship only one person, if anybody has schizophrenia, only one of them will have schizophrenia. It's hard to explain if the shared environment is the critical factor, that particular observation. The second, and I won't go into the specifics of the study, but remarkably there have been adoption studies, these actually come out of Denmark, where we've looked at, or the researchers looked at, what happens when you take an an individual who's adopted and place that individual in a home where one of the parents suffers from schizophrenia. Now you might wonder, how that happened. And, I tell you, I, I can't explain how that happened, but it did happen. It happened and researchers have followed up those children. And, what we see is clearly, if somebody is suffering from debilitating schizophrenia, if a parent is suffering that, that's a liability to the children in that family. But it doesn't appear to be a liability to developing schizophrenia in those children. Having a parent with schizophrenia doesn't appear to increase your risk of schizophrenia for other than genetic reasons, based on the adoption research. And there's a last line of evidence that's kind of novel. And it takes a couple slides to kind of explain this, but it's, it's kind of a clever tool that behavioral geneticists have used here to explore this. And it's by looking at the offspring of discordant twins. And the reason I want to go through a couple slides here and give you the results of a particular study here is because I think it begins to illustrate, is how those genetic tools can really give us unique leverage into trying to understand the environment. Here's the, an illustration of the study design. This was actually done in Denmark, by Erving Gottesmann and Axl Bertelsen. Gottesman is an American. Bertelson is a Dane. And what they did is they, they found monozygotic twins, where one twin. Here the shaded, these are men, shaded box here. Suffered from schizophrenia, but his co-twin did not. And then they looked at their offspring. And although they had to, to look for a, through a lot of pairs of twins to find this particular type of pedigree, because even though 50% of monozygotic twins with schizophrenia are discordant for the disorder, so there are a lot of twins that look like this, right, there is a reduction in fertility, so they don't always have children. But they could search to the whole country and they found enough pedigrees to do this study. Now think about this study. So we have a pair of monozygotic twins there. And they, they have their spouses. They could be either males or females. But it, here I made them males. And then they have children. If the twins are monozygotic, what is the genetic risk here? Well, the genetic risk here, right, is they have a first degree relative with schizophrenia right. They are the children of somebody with schizophrenia. That's easy to understand. Their genetic risk is having a first degree relative with schizophrenia. Now here's the clever part. What is the genetic risk for these individuals? Think about that for a second. So maybe many of you get this. The genetic risk here is they also have a first degree relative with schizophrenia. This individual has the same genotype as that individual. So genetically, they're not, their father doesn't have schizophrenia, but somebody genetically identical with them does. They, also, have a genetic parent with schizophrenia. So genetically, these two groups, this sibship and this sibship, are at identical risks for developing schizophrenia. They both have a genetic parent with schizophrenia. See that? It's clever. But environmentally these individuals are growing up with a schizophrenic parent. These individuals are not. So environmentally, these individuals have a rearing parent who's schizophrenic, these individuals have an uncle who's schizophrenic. If the familial transmission of schizophrenia is due to genetics then we would expect the risk here to be the same as the risk there, right, because genetically they first both have a parent who's schizophrenic, who has schizophrenia. If there's an environmental component to the transmission of schizophrenia, right, these individuals should be at greater risk than these individuals. This is whats happens if we have monozygotic twins. Of course, they also had dizygotic twins. And so if they're dizogotic twins, right, these individuals have a first degree relative, genetically, with schizophrenia. These individuals have a second degree relative. They have an uncle. Environmentally, they're being reared by a, with a schizophrenic parent. Their, have an uncle, a second degree relative. So what do the results look like? Well, let's first look at those offspring of monozygotic twins. The risk right, the risk would be greater. I'm sorry, greater here than here, if there's environmental liability associated with having a parent with schizophrenia. The standard errors that are reported here are pretty large because, it's hard to get large size here, but it's clear that the risk here is not greater than the risk there. And in fact, even though the differences here are, don't appear to be trivial, statistically, they are not significantly different. The risk here looks like the risk for first degree relatives for both these sibling groups. What happens when we look at the dizygotic twins? The risk here is like the risk here, or there, they're not actually, don't significantly differ, they're all statistically indistinguishable from about 10%. But look at what happens to this group here. It drops down to the typical risk that you get for a second degree relative. We don't think shared environmental influences are important for schizophrenia because one, you don't get families with multiple people suffering from schizophrenia. Two, adoption studies that looked at the offspring of adopted parents with schizophrenia, don't show elevated risk of schizophrenia in those offspring. And three, because of studies of discordant twins, the risk appears to be distributed or inherited genetically and not environmentally. That isn't to say that there aren't environmental influences here. There are environmental influences. There are non-shared environmental influences. We know they're clearly important. Why? Because by definition, failure of concordance in monozygotic twins has to be due to the non-shared environment. Monozygotic twins have the same genomes. Therefore, if they're phenotypically different, it has to be because they have different environments. By the way behavioral geneticists are defining the term, it has to be their non-shared environment. So we know the non-shared environment has to be really important. Right? 50% of the time they're discordant. What about the non-shared environment is important? What is it about the environments of monozygotic twins that would lead one to develop schizophrenia and the other not? That seems very important to understand. And we know, this is a very active area of research, and we know a little bit about this. We know a little bit about what causes, or what seems to cause, discordance in monozygotic twins for schizophrenia. A first very important observation comes from brain scans. Actually, I think these are CAT scans. They might be MRI scans. There's an old literature, that reports that individuals who develop schizophrenia tend to have somewhat larger ventricles in their brains. And the ventricles are cavities in your brain. We all have them. By themselves they are not a marker of pathology. They are cavities in your brain that are attached to the spinal cord. And on average individuals who develop schizophrenia have somewhat larger ventricles than individuals who don't. So it, it suggests that there's some brain pathology that's going on and again, that's not all that surprising. What's really interesting though, is that if you look at monozygotic twins where one develops schizophrenia like this individual here, and the other did not, they're discordant. They have the same genomes, but something about their environment led to this discordance. Almost every time, the one that develops schizophrenia has the largest ventricles. 90% of the time, the individual in these pairs with the larger ventricles will develop schizophrenia. This is one pair here. Here's another pair here. You can see, the ventricle sizes are, are quite a bit different than here. But again, the individual who went on to develop schizophrenia had larger ventricles than the one who didn't develop schizophrenia. The size of the ventricles themselves are probably not the basis for the pathophysiology of schizophrenia. It's probably a marker of something that occurred early, early in neural development. But it's a marker for something going on environmentally. What might be that, those environmental events? [NOISE]. Well, other studies of monozygotic twins discordant for schizophrenia, as well as other individuals, point to a class of factors that might be an important source for these non-shared environmental events. We know for example that low birth weight is associated with developing schizophrenia. It's not a real powerful predictor but there's certainly a statistical association between having low birth weight and subsequent risk for developing schizophrenia. Within monozygotic twin pairs discordant for schizophrenia, almost always the twin, the twin who was smaller at birth is the twin who would develop schizophrenia when he or she is in late adolescence or early adulthood. We know that obstetrical complications, kind of non-specific general obstetrical complications. These might be prenatal or perinatal deprivation of oxygen, Rh incompatibility, other factors, are associated with schizophrenia. These factors are also associated with increased ventricle size. Finally, related to these as well, is maternal conditions. Severe malnutrition study coming out of not only the People's Republic of China but Holland where there was a a famine an induced famine at the end of World War II. Show that severe maternal malnutrition or maternal exposure to influenza increases the risk for schizophrenia in their offspring. So what we have are a class of factors, increased ventricle size, low birth weight, obstetrical complications, exposure when the mother is pregnant, that all increase risk for schizophrenia. These are not gigantic effects but they're all there. They increase risk. They might double it. It might increase it 2.5 fold. It appears that a major source of the non-shared environment occurs very early in development and leads to some sort of lesion in the brain where one of the twins has that lesion and the other doesn't. And the way the lesion can be observed is this increased ventricle size, even though the ventricle by itself isn't the, the key factor. It must be some sort of marker of this. So the non-shared environment is clearly important. Where epidemiologists are looking for the source of that non-shared environment are factors that occur very early in development and somehow upset the normal course of neurodevelopment. Next time, we're going to begin talking about identifying the genetic variants that underly the heritable, the heritability of schizophrenia. the, I'm going to ask you to, we're going to talk about, I'm going to introduce a strategy of doing this called the positional cloning strategy. But, I'm actually going to spend the next module going in depth about a particular study that was published a few years ago. Because the study, I think, is a beautiful illustration of two things. It's an illustration of this strategy. And secondly, it's an illustration that this strategy did not work and that's actually going to be very important to us understanding how to identify those genetic variants for schizophrenia. It's a challenging study, but I'm going to ask you to, at least, kind of read it over. Try to understand what the study is. I'm going to go into it in pretty good depth next time and after next time if you've kind of looked over paper ahead of time, I'm pretty sure you're going to understand what this study is about and why I think it's a terribly important study to our understanding the genetics of schizophrenia. Thank you.
