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Researchers have estimated that about 80 percent of the risk for developing schizophrenia is hereditary and yet that doesn’t mean people with that genetic component in their family history will actually develop the disorder. Sometimes schizophrenia risk increases through a random mutation that is not passed from parent to child. In this episode, we’ll be looking at the role genetics plays in the development and onset of schizophrenia. Is it all about your genes? Or are there other potential risks that can trigger it? To help answer some of these questions we’ll be talking to two people — Dr. Robert Stowe, a behavioural neurologist in the UBC Neuropsychiatry Program and a member of the Genetic Testing Task Force of the International Society for Psychiatry Genetics; and Courtney Cook, who works as a genetics counsellor on UBC’s MAGERS project.

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Transcript

PERSON 1: When I was first diagnosed, I went and was trying to understand the contributing factors to having psychosis. And it listed genetics has been one of them, but maybe not one of the highest factors, but definitely one of them.

PERSON 2: My identical twin, who had passed away at the age of, uh, 26. So he has schizophrenia, but ironically, on the topic of genetics, he was able to take Ativan, and I was unable to take Ativan.

PERSON 3: I have mental illness in my family history. And sometimes it makes me nervous about having my own kids. I don’t know how I feel about passing on mental illness. But I also think, like who better of a parent to have than someone with mental illness, to help someone go through something like that.

PERSON 4: I have an uncle who has schizophrenia. I remember, I did think he was crazy and I feel so awful that I thought that. Then I was diagnosed with schizophrenia. And it’s like, oh, that was a little bit of a reality check.

FAYDRA: My name is Faydra Aldridge. Welcome to Look Again: Mental Illness Re-Examined, a podcast about mental illness brought to you by the BC Schizophrenia Society and our BC partner organization. Researchers have estimated that about 80% of the risk of developing schizophrenia is hereditary. And yet, that doesn’t mean people with that genetic component will actually develop the disorder.

So today, we want to get into the why is that the case? We’re going to be looking at the role genetics play in the development and onset of schizophrenia. Is it all about your genes? Or are there other potential risks that can trigger this illness? So to help us understand some of these questions and many more, we’re going to be talking to two people.

Dr. Robert Stowe is a behavioral neurologist in the University of British Columbia Neuropsychiatry Program. He’s also a member of an international genetic testing task force. He’s also a researcher involved in a clinical and genetic counseling research project, dealing with treatment resistant schizophrenia and schizoaffective disorder. It is called the MAGERS project at UBC in the Faculty of Medicine. We are going to be hearing more about that project in just a little while, but first let’s meet Courtney. Courtney Cook has her master’s in genetic counseling from UBC and works as a genetic counselor on the MAGERS project.

As part of her work with this project, she provides psychiatric genetic counseling, and does genome sequencing. Dr. Stowe and Courtney, welcome to the show.

  1. STOWE: Thank you very much Faydra, for that generous introduction.

FAYDRA: And we have a lot to unpack, so let’s get to it. Dr. Stowe, I really wanted to get into the work that you and Courtney have been doing around this MAGERS project. But first let’s back up and start talking about genetics and serious mental illness. Now we all know that psychiatric conditions are usually caused by a combination of environmental and biological factors. But how much of a role does genetics play when it comes to an illness like schizophrenia?

  1. STOWE: I think you’re quite correct in saying that on average, about 80% of the heritability of schizophrenia is attributable to genetic risk factors.

However, having said that, there is no known genetic condition that is a hundred percent predictive of the risk of schizophrenia. So there’s always some additional component.

FAYDRA: I find it fascinating Dr. Stowe. 80% is quite high. Why is it that some people get it, and some people don’t, with such a high percentage?

  1. STOWE: Heritability in some cases includes some environmental risk factors. So for example, if you look at identical twins, they will share the vast majority of their genome, over 99%. But if they’re exposed to a risk factor in utero, then that can account for some of the risks and it would be inherited by both of them. But it’s truly, the environmental piece is not then part of their genetics. There is a mechanism by which genes exert their influence in our bodies and our brains. And that’s called epigenetics. That is a type of genetic risk factor, but it’s not one that’s transmitted by our genes. It’s the way that our genes are expressed in the body, in the brain, that can be modified by environmental risks.

FAYDRA: Courtney is going to fill us in. So Courtney let’s hear it. Let’s talk about the environmental factors that could potentially lead to an illness like schizophrenia.

COURTNEY: Absolutely. I think how I want to do that actually, is bringing it all in together with an analogy that we use with patients in the clinics.

It’s a way that psychiatric genetic counseling is really done. And it’s facilitated by the use of something called the mental illness jar analogy. So it’s really helpful for just conceptualizing all of this together. How do genes, environment, all of this fit into a picture that actually makes sense to the average person. So thinking of this analogy, you think of an empty glass jar.

This is our mental illness jar. And everyone has a mental illness jar, which means that everyone has the possibility of developing a mental illness. So when it’s full all the way to the top, that’s when someone’s having an active episode of mental illness. And so thinking about the genetic factors first, or the role that genes play.

So thinking of that empty jar, you can have small balls in that jar. And each of those little balls is a genetic risk factor. Only having a small effect individually, fill up this charge with certain capacity. And each individual is going to have some of this genetic vulnerability to develop mental illness.

Some individuals are born with more balls in their jar. Other individuals are born with a lot less. The vast majority of the population is going to be somewhere in the middle. And that’s not the whole story. We also have this role of environment. You can think of the environmental, or the sort of life experience, as these triangles that get added into that jar.

Like head trauma in childhood, the time of the year that someone’s born at, different stressful life experiences. So environmental sort of emotional stressors that someone might experience throughout their life. That those then get added into the jar. And some of those things where these protective factors. It’s the things that we know are good for us, but are always harder to do, like diet, exercise, good sleep, nutrition.

You can think of them as these rings that are getting stacked on to that jar. So making the jar larger, making it less likely to fill to the top. And these can be helpful for individuals with schizophrenia. But if they’re able to employ those protective factors that work for them, they may not be experiencing an active episode of mental illness.

So someone could be born with a high degree of genetic vulnerability, but if they don’t have those environmental factors throughout their life, they’re not going to go on to develop a mental illness. Conversely, someone could have a lot lower genetic vulnerability, but because they have all of these sort of known environmental risk factors, life stressors, throughout their life. That they might develop mental illness themselves.

  1. STOWE: So you can imagine that the environmental, the triangles, you can actually remove some of them. And so the triangles are mobile. They can go in or out of the jar. And temporarily, when you’re under a lot of stress, you’ve got more triangles in the jar and it goes over the top. And then with medications, with psychotherapy, and stress reduction, with various other approaches, you can take some of those triangles out of the jar.

FAYDRA: Courtney, can you back up and just tell us what it is and what exactly do you do?

COURTNEY: Genetic counseling. Helping individuals with genetic conditions adapt to the social, the familial implications of that condition. In the context of psychiatric, you know, counseling is a lot what we’re doing. Going through that jar model with people, helping them to understand the different factors that may have contributed to their illness, and really with the goal of helping individuals adapt to that.

So helping with feelings of guilt, or shame, or blame that a lot of individuals with mental illness experience, but it wasn’t your fault that you developed a mental illness.

FAYDRA: You’re listening to Look Again: Mental Illness Re-Examined. A podcast brought to you by the BC Schizophrenia Society and BC partner organizations.

I’m your host Faydra Aldridge. This podcast would not be possible without the support of the entire community. From the bottom of our hearts, we want to thank you for caring about mental illness. Together we truly can make a difference.

And we’re back with Dr. Stowe and Courtney Cook. This episode, we’re getting into the genetics of schizophrenia. And there’s a lot to unpack when it comes to why someone develops a serious mental illness. There are so many factors to consider. Both environmental and biological. And it’s those biological factors, our DNA, which can affect brain function that Dr. Stowe and his team at UBC are looking at through the MAGERS project. I’d like to hear more about the genetic component of schizophrenia. Is there a single gene that causes this illness or are there a number of genes that can cause schizophrenia?

  1. STOWE: So in the vast majority of cases, there doesn’t appear to be a single gene that contributes a major risk of illness.

We believe that individuals who have treatment resistant schizophrenia, and severe schizophrenia, are more likely to have rare mutations in a single gene. That contributes a very substantial part of their risk of schizophrenia. But for most individuals with schizophrenia, the genetic component is actually what we call polygenic risk. Which is basically the sum of many variations that are fairly common in the population. Each of which contributes a tiny amount of risk. But when you add them all up, they can put you over the threshold for susceptibility to schizophrenia.

FAYDRA: That’s really fascinating. Here with our families and the people we work with, a lot of frustration around why have we not been able to come up with a treatment that can cure schizophrenia? But hearing you talk about the mutations within the gene makes sense to me, as to why it would be so difficult for people like yourselves to come up with basis and understanding which will hopefully lead to effective treatment.

  1. STOWE: We know that there are over a thousand genes, that actually where a common variation in these genes, actually contributes a little bit of risk to schizophrenia. And there are many different pathways that are targeted by these genes, or that the proteins that these genes encode function in. And so our project is basically what we call a precision medicine focused project.

It’s based on the assumption that everybody is different. We all are individuals. And individuals with schizophrenia have in many cases, different reasons why they ended up with their illness, both genetic and environmental. And so we think that actually studying individuals who have severe psychosis and are treatment resistant, will help us identify those rare and potent mutations in genes, that will help pinpoint the pathways that are operative to predispose them to illness.

And then, if we understand the pathway and we understand the mechanism, we may be able to come up with a treatment that’s individualized. Furthermore, identification of the pathway, even if it may not have benefit for an individual, will advance the field. Because then we can look for other genes that are involved in the same pathway, and see if they’re also targeted by some of these rare mutations or by common variation.

FAYDRA: Tell us, when did it start? Who’s involved? Let’s talk about the MAGERS project.

  1. STOWE: We recruited our first participant in 2016, and it’s really involved a very large group over 40 co-investigators. And they run the gamut from clinicians like myself and Courtney, to individuals at BC Genome Sciences Centre. There are individuals at the Royal Columbian Hospital Cytogenetics Lab. We have a group at BC Children’s Hospital. We have investigators at the Biomedical Research Centre at BC Children’s, and we’ve got a bioinformatics group at the Michael Smith Labs. So it’s really a very eclectic group.

FAYDRA: What are you hoping to achieve with this project? What would you like to see as the final outcome?

  1. STOWE: As I indicated earlier, individuals who harbor rare variants, can point to very important mechanisms, that may predispose to psychotic symptoms. We’re hoping to find some of those. And we have found some of those already. But we believe that individuals who are unfortunately afflicted with severe illness, or treatment resistant illness, are a very important population to focus in on. Because they’re more likely to harbor these rare variants, and the pharmaceutical industry has spent billions of dollars trying to mind the common variant, and they have largely been unsuccessful. So now I think it’s really important that we focus on the rare variants, and I think our patients, our participants, are very valuable in this, in this process. And they’re valued collaborators in the process. They’ve been very generous with their time and their support for the project.

COURTNEY: Something that’s unique to the MAGERS project is this design, and the genetic counseling within the protocol of the study. So, well our participants at entry into the study received psychiatric genetic counseling, and that all the return of the different genetic testing results that we’ve done is under this sort of umbrella of genetic counseling.

Unfortunately, psychiatric genetic counseling isn’t widely available to individuals. There is a clinic in Vancouver here. But across Canada it’s not something widely available to the general population. And so they’re building in some of these outcome measures within this study. We want to be able to show that genetic counseling is effective and it’s helpful for this population.

  1. STOWE: And I just want to amplify a point that Courtney made about availability. And so just as psychiatric genetic counseling is not readily available, genome sequencing is not readily available either. It’s not covered by MSP under ordinary circumstances. And in fact, the agencies that do approve it under special circumstances, have been very resistant to ordering and to paying for it in individuals with psychiatric illness.

Even when we know that these individuals are likely to harbor these rare variants, and that it might have some impact on treatment. So another goal of the project is to really demonstrate that, at least in individuals with more severe illness, that we should be considering genome sequencing and making it available.

Which will not only, we think moves the field forward, but hopefully lead to some targeted treatments for some of the individuals. And I should point out the treatment doesn’t necessarily have to be a prescription medication. It could be a nutraceutical like a vitamin and mineral, depending on what the actual mechanism is. And we’re hoping to find treatments that are better tolerated and more effective, than some of the treatments we have.

FAYDRA: Genetic testing is controversial. I’d like to get into that. Why is it so controversial in our country right now?

  1. STOWE: I think there are a number of possible reasons for that. The first is maybe a historical reason, and that there’s been a resistance to the idea that major psychiatric illnesses like schizophrenia are genetically driven.

And the concern is that we might blame everything on the genetics and forget about the importance of environment, and then downplay the importance of psychotherapy and mindfulness, then all these other strategies that can help promote wellness. Another is that it’s the wild west out there in terms of direct to consumer genetic testing.

So there are companies out there that will do your whole exome and sorting out the wheat from the chaff. Trying to figure out which ones are really important is technically difficult. And so there are risks of over interpretation. And one of the reasons we have genetic counselors like Courtney on the project, is because they’re very well-trained in trying to separate the wheat from the chaff. My colleagues on the International Society of Psychiatric Genetics taskforce on genetic testing, we don’t think that sequencing is advisable in most individuals with schizophrenia. Because the yield is going to be very low. But in individuals who have treatment resistant illness, or severe illness, that’s a different story. And there we think there is a role for this sort of testing. I think it is important to recognize that genes are not the whole story, and there’s a balance, but I think the controversy in the field will eventually resolve itself as we discover more of the genetic risk factor.

COURTNEY: Um, and just to really, I think really summarize what Bob was saying there, is that genetic testing isn’t necessarily going to be helpful, beneficial in every individual with schizophrenia. Um, that there’s really, there’s certain unique things that we’re looking for in the family history, in that medical history, that might raise our suspicion. That there might be one of these more significant genetic risk factors. One of these rare variants.

FAYDRA: What do you think is the connection between genetic testing and the stigma associated with schizophrenia?

COURTNEY: I think that’s not unique to psychiatric genetics either. There’s often this idea of if something’s inherited, or it’s genetic, or you’re born with it, that there’s more stigma. There’s more blame within a family.

I think one thing that we really try to emphasize with families, no one has control over their genetic information. That’s the way it is. You don’t control it. You pass on to your children, you don’t have control over what you’re born with. And yeah, like really enforcing that fact. Cause that’s often, it’s just it’s common people just have that.

They internalize that at some point. And it’s really important for us to emphasize again, it’s nothing that we have control over.

  1. STOWE: I would just add to that. In our study, you know we’re doing pre-test genetic counseling as well. And that’s important, because it’s an opportunity to explore how an individual might react to a genetic finding.

And in some cases, we think in most cases, parents are relieved to hear that if a child has inherited a strong genetic risk factor, that it wasn’t bad parenting that contributed to the illness. On the other hand, there might be some parents who say “Oh, I had a brother with schizophrenia, or I had a grandfather, or an uncle with schizophrenia and I should have known better. I shouldn’t have had children. This is my fault.”

So it’s important I think, that individuals think about what the implications of genetic testing might mean for them, and whether it would be helpful or harmful. And we think in the vast majority of cases, there are ways to deliver that information that actually relieves guilt, and stigma, and blame and those sorts of things.

But everyone’s different. And we have to look at each individual differently from that perspective.

COURTNEY: Absolutely. No, that’s a huge part of genetic counseling is taking that individual’s values, their reactions, and applying it to the situation. Helping them to process those results, or how they would feel about this testing, before it’s done. So it is going to be beneficial for that person.

FAYDRA: So if there is a family member that has one uncle, or a brother, or sister that has schizophrenia, what would you say if they were thinking about getting genetic testing to see if they have the gene for schizophrenia?

  1. STOWE: First of all I would emphasize again, that there is no one gene from schizophrenia. And I think what I would advise, is psychiatric genetic counseling. And that’s available outside our project through the Adapt Clinic. And psychiatric genetic counseling can be helpful in family members understanding risk to children, for example, or if you have a sibling with schizophrenia, what’s your risk of developing the illness.

And what they’ll do is actually look at the family history through three generations, and they can use that information to advise the individuals on what their risk might be in that situation. I don’t think anyone should go into genetic testing, or even whole genome sequencing, and assume that they’re going to get genetic, um, diagnosis.

Many individuals and families overestimate their genetic vulnerability. And so it’s often an individual may decide not to have children. Because they’re worried about they had an uncle, a grandfather, or somebody with schizophrenia and they’ve grossly overestimated the risk that their child would have schizophrenia.

So what would I advise in terms of genetic testing? If someone has treatment resistant illness, I think pharmacogenomic profiling can be helpful. And that is available on a sort of private pay basis. There are a variety of companies that do that even here in the Lower Mainland. And if the individual has had learning, or also has been diagnosed with as being on the autism spectrum, or if they have any unusual facial characteristics, or heart murmurs, or congenital heart disease. Or there are a variety of things that increase the risk that there is a single gene mutation or a chromosomal variant, then they could ask their psychiatrist or family physician to order a chromosomal microarray screening. Because that is actually available both at BC Children’s Hospital and for individuals who live in the Fraser Health region. And that’s covered, there’s no charge to patients for that testing.

That would be the first step. And then if that’s negative, but there are strong reasons to suspect that there’s a potent single gene mutation, that might in fact be transmitted through multiple effected individuals in the family, then the whole genome or whole exome sequencing might be worth looking at. But that would really require a consultation by a medical geneticist, typically.

Um, those are, unfortunately, they’ve got about a one-year waiting list at this point.

FAYDRA: Dr. Stowe, Courtney, it was such a pleasure speaking with both of you. Thank you so much for joining me today.

  1. STOWE: Thank you again for having us. It was a real pleasure and an honor.

COURTNEY: So appreciative of yourselves here at giving us this opportunity to talk about our project, and talk about the work we do.

FAYDRA: And a huge thank you to you, our audience for joining us for this episode.

Together, we can better understand and change the narrative around mental illnesses like schizophrenia. I hope you learned as much as I did today. And if you have any questions or any comments at all, tweet us at BC Schizophrenia. And to get our latest podcast episodes, be sure to hit follow on Apple Podcasts, Spotify, or anywhere where you listen to podcasts.

We hope you join us next episode. Talk to you soon.

MALE VOICE: This podcast is brought to you by the BC Schizophrenia Society and the BC partners for mental health and substance use information. We’re a group of non-profit agencies providing good quality information to help individuals and families maintain or improve their mental wellbeing. The BC partners members are Anxiety Canada, BC Schizophrenia Society, Canadian Institute for Substance Use Research, Canadian Mental Health Association BC Division, Family Smart, Jesse’s Legacy and North Shore Family Services Program and Mood Disorders Association of BC. A branch of Lookout Housing and Health Society.

The BC partners are funded and stewarded by BC Mental Health and Substance use Services an agency of the Provincial Health Services Authority. For more information, visit heretohelp.bc.ca.


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