All right, welcome back to the podcast. I am joined today with Liam Browning and Nicholas Fabiano. They have both been on the podcast before. See, before we talked about Cretein and Liam was on for Microdowsing, whole series on adverse childhood experiences and many more. So yeah, welcome back to the podcast. Today we are doing an episode on the Heritability and Environmental influencers of schizophrenia and we have an amazing handout. As always, go to to PsychiatryPodcast.com to get the full handout. It is vastly more detailed, maybe than we're going to hit. But I think the important part of this is to kind of bring the mental health sphere up to date with where the data is. I think the data's changed. We have to bring it all together for you guys so you guys can understand how genetic, how environmental schizophrenia is, what are the genes, what are the mechanisms for us, gets frontier sort of relayed? And so yeah, Liam, where do you want to start out? Yeah, thanks for having me back on as always. I think it'd be useful to start with the history of the schizophrenia diagnosis just because I think schizophrenia is somewhat of a poster child in psychiatry for like severe mental illness and the biological psychiatry model. So I just want to touch on where that initial conceptualization comes from. So it really goes back to the early 20th century with a meal Creplin when he did a dementia precox from manic depressive insanity as many people are familiar with. But at the time, Creplen and the field of psychiatry was really focused on symptoms at the time. Like, they had terms for symptoms like mania melancholy insanity, but there is not a clear diagnostic classification system that they had. So Creplplin, through his observations of thousands of patients,

wanted to like add to this field by having some classifications of symptom clusters. And so, what he found was through his observations, he saw that there are some patients within sanity who had a chronic deteriorating course that started in early adolescence or adulthood. and they went on to develop personality disillusionment, cognitive decline, and then inevitably would end up with dementia or various various illness. And he noticed that there are other psychotic patients who had more of a shorter term course, a more fluctuating course, and a preservation in their cognition and personality. So with this line of thinking, he believed that there were neuroanatomical reasons for why people were presenting with these different symptoms. At the time, there wasn't really a clear explanation, but he believed that there would be explanations behind the neurobiology of these different disorders. I think some of the early or one of the early people found syphilis in the brain. And so they kind of had, oh, look, there's something physically in the brain causing the psychosis, right? Right. Even before Cripplin came onto the scene, there was they had the syndrome recognized, but they didn't know exactly that there there is a bacteria causing the syndrome. So that was one of the first syndromes that people had tied to a brain pathology, or they thought this presents with these certain sets of symptoms. Yeah, so Creplin mostly came up with the categorization, and I think it's a helpful, in general, splitting between, okay, this person has episodic, manic episodes, some depressive. And this person is chronically, you know, psychotic, paranoia, delusions, hallucinations, right? Someone with bipolar can have those things, but they can be episodic in nature. They can have like one patient who's bipolar. They could be normal for a year and then have a severe episode, start ramping up over weeks, get manic. Okay. So keep going with this history lesson here. So after Creplin, the next sort of major thinker in this topic was Eugene Boiler. He renamed the condition of dementia precox to schizophrenia in 1911. And he believed that it was more so a group of schizophrenia. He noticed that there was heterogeneity in terms of how people presented. So after Boiler, there was sort of a dying off of this type of this line of thinking with a rise of psychoanalysis in the mid-20th century. And then after this wave of psychoanalysis in the 60s and 70s, there was this growing movement to want to legitimize psychiatry within the medical field. And so people were turning towards biological mechanisms to try to understand the symptoms and the diagnoses that we're seeing. So that ultimately led to the DSM-3, as again, we were trying to legitimize psychiatry. And And ever since then, we've had a biological, oriented field where we're trying to look at diseases through the understanding the mechanisms. Yeah, and there's, um, I think you were going to talk about how the Nazis utilized some of the early stuff. Were you going to talk about that? Yeah. Is that the? Yeah, so, yeah, the first genetic evidence actually comes from one of Krupplin's successors. His name is Ernst Ruden, and he conducted like the first large-scale family study in psychiatry. Prior to him, there was an understanding that insanity ran in families like sometimes that the parent would have peculiarly their behaviors and so would the children, but it wasn't always guaranteed. Not all the children would develop that. Some would have resilience. But Rudin identified that after Creplen recognized Dimitra Precox, Rudin was trying to look into whether there was a medalian pattern of inheritance behind Skitsferna. So he conducted the first large scale study of 2700 siblings of 800 people with Skitsferna and essentially was looking at the rate of Skitsferna in the siblings and he found that there is about a 5.4 to 7.7% increased risk of schizophrenia and the siblings of people with schizophrenia. And this is actually remarkably close to some of the modern day estimates of schizophrenia that are produced by looking at these family studies. It's a little bit on the high end of what modern people, what the modern estimates would be, but I still think it's

pretty interesting to note that he found a very similar number to what we see now. But again, you can't really talk about rooting without mentioning his role in the forced sterilization movement and the genetics movement that ultimately led to the Holocaust. And yeah, I just thought it was interesting how psychiatry and behavioral genetics is rooted in this dark history of root. And there's always going to be some people who are echoing some of these thoughts. So I think it's important to have that historical background of where things have gone. And I think even the name of the schizophrenia is interesting that we've retained it because as you mentioned, it eludes to split psyche or split mind. And we know that's not the case yet. We still use the term. So there's even been recent literature and experts in the field saying maybe we should rename it to positive and negative symptom disorder. But with all this historical contact, you still retain the name, it gets a front end, which has stigma behind it. It has even the nomenclature isn't entirely correct. So I think from the genetic background and even the nomenclature perspective, it's interesting that how accurate some of these measurements were, but also how the nomenclature has persisted. Yeah. that the names are sometimes archaic, but necessary for us to continue to talk about the same thing, right? But I think there's other worse words, but I think, okay, it's obviously awful that Rudens work became sort of weaponized to create this master race by eliminating people with mental illness. And I think one of the interesting statistics is like, most people with schizophrenia do not have family relatives. Can you talk about that? Yeah, most people with schizophrenia don't have a relative with it. Up to 60 to 90% of people with schizophrenia don't have the relative. And most people will use that as an argument to say, well, actually, all of schizophrenia is sporadic. It's not inherited then if it doesn't run in families. But in reality, that's not what a heredability in epidemiology would indicate. So you can still have a disorder that's heritable and influenced by genetics without having it run in families. So that leads us to the discussion of what actually is heritability. A lot of people will hear that a kid's friend is 80% heritable and that means that 80% of cases of schizophrenia are due to genetics or if my dad had schizophrenia, I have an 80% chance of getting it because it's 80% heritable. When in reality, 80% heritability and the context of heritability means that 80% of the variance in liability for schizophrenia in a population is associated with genetic variation. So again, Ngen, heritability is a measure that describes the population, the phenotype that differs across the population due to differences in genetics within that population. So it doesn't apply to individuals, it doesn't say anything about an individual's risk or what percent chance that they had developed is schizophrenia. That's confusing to a lot of people, I think. It seems 80 percent seems very high and it seems to say that this is almost genetically determined 80 percent of the time. And that is not what you're saying. No, no, it's the how much the phenotype can thought to be attributed to genetic differences across the population. It's not an intuitive concept because it's two different ratios of change. And I think to put it into context, it makes it a little bit easier to understand that hairadibility also depends on the environment. So when environmental conditions are the same within a population, then hairadibility actually plays a larger role. That means because the genetics are being able to exert more difference if the environment is exactly the same for the entire population. And the inverse is true too, where if there's environmental disparities, so for example, looking at how countries different malnutrition, if one country is highly malnourished, then they're going to be small. They're going to be shorter on average, even though height is a highly heritable condition in most circumstances. So for example, with China, they lifted 1 billion people out of poverty from the 1980s to today, and they actually increased their height by 3.1 inches, the average male. So that tells us that their height didn't change due to genetics, it changed due to the environment. So in this example, when China was malnourished, they had more of their phenotype of height influenced by the environment than the genetic. So the heritability in that population was actually less than 80%. Nicholas, do you have another way to put this to make? Yeah, I think Liam did a good way of explaining it. I think it's looking at it almost like two different variables where you have, if you're controlling one and Liam explain maybe heightened example, if you're controlling say a population level of food intake and resources and sunlight exposure, if all of that's the same for a population and you're looking at a variable like height, for instance, and nutrition and all that different things. Then the genetic influence becomes so much more important because that other variable is not really moving.

Everyone else is receiving the same thing, So that genetic part is really the only significant difference, which is why we see heribality differences when we hold one thing constant. You can kind of look at it through the lens of how we conduct RCTs even. When you're holding that one variable constant, if you're changing something else, that being the genetics, that becomes so much more important when everything else is the same.

So it's a very confusing way when we describe it

in 80% hairadibility because I think like we alluded to

in the beginning, you think that means

I have an 80% chance of developing schizophrenia,

but it's so much more complicated than that.

And yeah, it just shows how much,

and we'll get into it more, how much your genes

and environment interact to produce the phenotype of schizophrenia or whatever that may be. So if you're confused at this point, consider yourself to be ready for the rest of this episode. We have to start with some degree of confusion, right? What does this 80% mean? I think height is such an interesting one because height is so genetic, but yeah, you're right. If you have a culture with a lot of poverty, with a lot of amount of nutrition, with a lot of stress, in general, the whole population is gonna not be as tall. Interesting, I was looking at all the variables for height because I want my kids to be tall because they play basketball and sleep is one of those variables. So because when you sleep while you produce human growth hormone, so we're like, eight, 20, let's go to bed. Let's get those hours in. One thing that's interesting to, with the conversation, it's good to from a heritability perspective and even evolutionary, I think, is the concept of selecting and non-selecting for different genes. And you would imagine something like schizophrenia, which, societally, sometimes for these people, it's hard for them to live, hard to get a job, all these different things would select for not passing on those genes. Yeah, what we see in the population is either stability or even increases in some areas. It's very interesting to see and it shows how much more complex it is than the eye can see because you can imagine other traits in the past that were negatively selected for that natural selection stuff goes away. But with schizophrenia, even though it's detrimental to our societal functioning for that person with schizophrenia, it stays. Which is, I think it's a very interesting phenomena that we're seeing where it doesn't intuitively make sense. And then it just adds more layers to this question of heritability and why stuff is selected for and why things are expressed. So not to add more confusion, but I always thought that was an interesting point to think about from an evolutionary psychiatric perspective as well. Right. Right. Yeah. A lot of skits and front-end patients that I treat have a more difficult time being in a relationship. Right. They have a more difficult time. Like a lot of them are very isolated, very, you know, in their own sort of room, locked to, you know, not really getting out much, not doing a lot.

The common sort of pathway of, in my mind,

towards schizophrenia and severe mental illness,

is isolation.

So yeah, it's interesting to think like,

okay, why is the population,

it's about 1% of the population, right?

Like why is that the case?

Okay, let's get into the twin studies. Liam, what do the twin studies say? Right, so the twin studies, we're kind of talking about holding one variable constant, like keeping the environment constant and that allows for genetic effects to be observed for the most. And twins are the best example of that where you hold the genetics constant and you can pretty much assume that the environment is constant too because they're growing up in the same household, same parenting dynamics, same nutrition, same schooling system, same peer system, pretty much. So you can look at the differences in phenotypes from identical twins and fraternal twins, and essentially the difference between the two phenotypes, you can almost entirely attribute two genetics if you assume that they are under the same environmental influences. So that's where that 80% figure comes from, is looking at the rate of schizophrenia between the identical twins and the fraternal twins, and seeing that difference. Yeah, so if a monozygotic twin, which shares 100% of the genes, has schizophrenia, what percentage of the time does the other monosegotic twin have schizophrenia? Earlier estimates were suggesting around 50 to 60%, but some of the modern day estimates are actually around 15 to 30 to 35% around that range. So it's not an 80% type of deal just because hairadibility is 80% doesn't mean like the genetics are automatically going to determine that they're going to have, if they have the same genetics, they have an 80% chance of developing. It's actually far less than that. And to me that's really interesting too because beyond genetics genetics of monocycotic twins, you can imagine being reared together, all these different factors as well too. Their environment is very similar as well too. So it's very interesting to see that these figures aren't closer to even 100%. When you have exactly the same genetics, and a lot of the exposures are likely the same as well too. So it's very interesting to see these estimates. And when we hear like, okay, so let's say it is 50%. We could say, oh, it's 50% because of the exact copy of the genes that they both share. But we also have to consider they were in the womb at the same time. And they were subjected to very similar, like if the mother got ill, the mother had an infection, they both were experienced that, right? So there are these kind of environmental factors which models got twins experience, but you could say like, okay, but don't die as I got a twins, experience the same sort of things, right? So that what is the, if one die as I got a twin has schizophrenia, what percentage risk does the other one have? Schizophrenia. It's about 10%. Right? We don't want to overlay you with too many statistics, seven to 17%, but about 10%. So we're looking at about 50% for monozygotic, 10% for dizygotic. But I think you have the important point, Liam, that monozygotic might experience life differently than dizygotic twins. How do you say that's true? And that's like the crux of what's called the equal environments assumption that because the way you calculate the heritability is assuming that the environment's exactly the same between the two. So you kind of simplify things. Some of the modern studies will try to account for these effects, but I think it's easier said than done because there's just so much complexity that goes into someone's life course. But monozygotic twins, you can imagine they're treated very similarly by their peers, by their parents, because they look the same, they act more similar. For almost every trait that we've looked at in genetics, monozygotic twins are more similar on them than anything else than any other siblings. Even if they're reared apart, they tend to develop the same preferences for jobs, partners, like eating habits, like fitness, all these different variables in someone's life. They're far more likely to end up on that same path. So the assumption that the environment is the same between them is kind of violated by the fact that they are going to act similarly and interact with the environment the same way where you wouldn't expect dizygotic twins to have that same interaction with their environment. The dizygotic twins are going to do their own thing and that environment is going to exert itself differently on the dizygotic twins compared to the monosagotic twins because they they're gonna put themselves in more different situations.

So imagine like for monosagotic twins, if they have an increased risk for substance use, then they interact with an environment that has a lot of substances around it, then they're far more likely to develop substance use versus does agotatuins, maybe one doesn't have as much of a genetic proclivity for it, or they're not in that same environment, because they act differently than the monosic addict twins.

So the equal environments assumption that goes into producing these heritability estimates, I think it makes it so that the heritability estimates from twin studies are a little bit inflated. We're like the placenta. I think what, tell me about often monozygotic first-dizygotic twins share placenta? Yeah, monozygotic twins almost always share the same placenta. And there's also other factors that go into that too. Like sometimes there can be twin, twin transfusion syndromes. One twin will get more nutrients than the other. but for the most part, sharing the same placenta exposes you to more similar like blood flow environments and like toxins, exposures compared to having two different placenta. So at least presumably. Yeah, you know, it depends on when the zygote splits. Do they share the placenta or not? But dizygotic twins never share a placenta. See, maybe that has an impact as well in the difference. So there's these small differences that we kind of maybe don't think of when we think of that 10 versus 50%. Okay, let's talk about the molecular genetics and human genome project and how it gave rise to candidate, this candidate gene era. Right, so at this time in the 1990s and early 2000s, we had the dopamine hypothesis as the forefront to explain what's going wrong with schizophrenia. And around the same time, we also have the development of human genome sequencing and the first, the sequencing of the first human genome. So there's a lot of excitement in the field to find genes that are responsible for schizophrenia. As we saw with Huntington disease, it's the single gene that's disrupted. There is cystic fibrosis, sycocel anemia. All of these single gene disorders with the complex phenotype. So we're hopeful that maybe mental health disorders can also have be traced back to faulted genetics. So in the 90s and early 2000s, we looked into certain subsets of genes because it wasn't as cheap to sequence the entire genome. So we just looked at a handful of genes, maybe a couple hundred genes that might be important. So again, we looked at some of the dopamine regulating genes, we looked at genes important for neurodevelopment. And we essentially found that there are dozens of genes that were associated with an increased risk of schizophrenia and we found genes that had gene environment interactions, such as cannabis, early adversity, being exposed to, you name it, there's hundreds of Canada gene studies, but the problem is that none of them are really replicated and they're pretty much all chalked up to false positives because the way that you account for multiple comparisons in a study. So if you're testing hundreds of genes and only reporting on the one that's statistically significant at a p-value threshold of 0.05, you have a 5% chance that that was just a fluke if you tested 100 genes. So when these kind of gene studies were coming out, there wasn't any correction for multiple different genes that they were looking at. A lot of times they were just reporting this one gene and when they looked at a shotgun approach of hundreds of genes. So that led to a lot of false positives and low replica capability. Nicholas, how hard is it going to be to get your paper published if you show only negative findings? It's going to be pretty hard. I think that's the problem with treatments or genomic findings. When there's anything negative, it'll probably end up in pre-print land forever and journals aren't very interested. There's always this narrative of, you know, publisher negative findings. It's great and I agree with that, but the reality of it is, you know, journals oftentimes, You end up in the cycle of submit reject, submit reject because how it works is people like the philosophy results, they like the things that go into news headline. This is what gets you another grant, this is what gets the journal citation. So a lot of these findings that Liam's describing that were negative, there's probably a whole larger literature source out there that hasn't even been published. And the problem with that is then we re-explore these things over and over and over.

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