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A Spotlight On: Genetics and Mental Health – Gerome Breen

Gerome Breen, Professor of Psychiatric Genetics, King’s College London.

Please note the transcript has been edited for brevity and clarity.

FLG: Hello, and welcome back to another “Spotlight On” interview. Today I’m joined by Gerome Breen, Professor of Psychiatric Genetics at King’s College London. Gerome is going to talk us through his work on the genetics of mental health. So without further ado, Gerome, can you introduce yourself and give a little background about your work, please?

Gerome Breen: Hi, thanks for having me on. I’m a Professor of Psychiatric Genetics at the Institute of Psychiatry, Psychology and Neuroscience at King’s College London. That’s a bit of a mouthful, but basically, I’m not a clinician. I’m a geneticist, and I study the genetics of psychiatric disorders. Primarily I study depression, but also anxiety, and I also do a lot of work on eating disorders as well. But here today, I’m going to talk to you about a study that we ran called the Genetic Links to Anxiety and Depression (GLAD) study.

FLG: So how did you get into this line of work?

Gerome Breen: Well, I started off my university career wanting to be a chemical engineer. I didn’t find that entirely satisfactory, and I ultimately found that in engineering people cared that things work but they didn’t necessarily care why they worked. The reason things work and what causes things are what interest me more. Genetics is really the ultimate example of that, and that’s what drew me into wanting to study genetics. So, after my degree, I went to do a medical molecular genetics MSc at the University of Aberdeen in Scotland and, during that, I started to do a project on psychiatric genetics, and I ended up doing a PhD on schizophrenia genetics. After that, I came down to King’s College London for the usual succession of academic posts, and I’ve studied mood disorders consistently throughout my career.

FLG: That’s great. Could you talk us through the Genetic Links to Anxiety and Depression study and explain what the main goals of the study are?

Gerome Breen: GLAD or the Genetic Links to Anxiety and Depression Study is a research project where we aim to recruit 40,000 or more people who have experienced anxiety or depression during their lifetime. The goal is to recruit these individuals into an NIHR BioResource supported framework that will allow us to gather questionnaire information about their mental health, link to their medical records, and to collect DNA samples for genome-wide association studies and potentially whole genome sequencing of the dataset. In addition to genetics, we also focus on social and environmental risk factors. Our goal is to recruit a very large sample not just for the discovery of specific risk factors, but also to make the study participants available for follow-up studies based on their genetics, polygenic risk scores, clinical features, and response to treatments. By creating the study, we aim to make translational research in depression and anxiety more affordable and provide the largest contactable resource for depression and anxiety research in the world.

FLG: Have you overcome any major challenges in this study or in studying psychiatric disorders in general? What are the major challenges?

Gerome Breen: Setting up the study itself wasn’t hugely challenging but we were careful in our approach, engaging a wide variety of stakeholders. We worked with people with lived experience of anxiety and depression, as well as major charities such as Mind and Anxiety UK. My co-PI, Thalia Eley, was instrumental in this. During that engagement, we sought feedback on what we were proposing to do. We asked for suggestions on how to alter our objectives or how we should describe the project. Then, we ensured we put their feedback into practice.

FLG: Were attitudes towards the GLAD study generally positive when you first set out?

Gerome Breen: Yes, I think so. We set out from the start not to take a fundamentalist viewpoint, all too often we see this “nature vs nurture” debate. People generally understand that there is a contribution from both genes and environment, as well as social risk factors. We set out to measure all of these factors and to reflect the complete picture of what causes depression and anxiety.

FLG: How do you measure the nurture aspect of anxiety and depression in the GLAD study?

Gerome Breen: Measuring the environment is not as straightforward as measuring genetic variation. We ask people about their demographics, education, socio-economic status, and experiences of interpersonal trauma and other life events. We then integrate this information into our studies of genetics or do joint genetic and social-environmental risk factor studies.

FLG: Is the GLAD study helping to understand the comorbidity of psychiatric disorders better?

Gerome Breen: Yes because GLAD is broadly addressing common mental health disorders. We designed the GLAD questionnaire to assess different types of depression and anxiety disorders. Depression and anxiety are often comorbid, but more research has been done on depression. In GLAD, we administer a detailed questionnaire that asks about symptoms of both depression and each different anxiety disorder. This has allowed us to build a unique dataset on anxiety and depression comorbidity, which is valuable and interesting to clinicians. We also asked about physical health and found that a high BMI is linked to depression in our dataset. In other studies, such as in East Asia, lower BMI is associated with higher depression risk. Although this (higher or lower BMI) could be thought of as a comorbidity, it may reflect the social environment that predisposes people to depression in different parts of the world.

FLG: Yeah, I suppose different socio-economic backgrounds and access to resources will affect both of those things.

Gerome Breen: Yes, and what is stigmatized within society.

FLG: The GLAD study is currently only in the UK. Do you think it’s important to carry out studies like these on a global scale? That would be a big undertaking.

Gerome Breen: Yes, we think it’s very important to carry out studies on a global scale. The environment affects our genetic results, and this is often overlooked. For example, we find that 15-20% of the genetic variants associated with depression in European samples are related to BMI. However, studies in East Asia have revealed that these genetic associations are probably mediated by the environment.

To take that further, if we gather large samples from different populations around the globe, we can develop a good understanding of the core biology of depression. Social and environmental risk factors vary across different countries, and to understand the core biology of depression, we need samples from different ethnicities, populations, and countries at a very large scale. This is even before considering global equity in research and addressing the fact that almost no studies have been done on depression genetics in African populations.

Along with investigators in Edinburgh and Cardiff, we have initiated a project called Depression Genetics in Africa (Dec. Gen. Africa) in collaboration with investigators in Ethiopia, Malawi, Nigeria and South Africa with funding from the Wellcome Trust. Our goal is to recruit 10,000 people from these countries with severe depression to carry out the first large-scale depression genetics study in Africa. The project will also train African investigators in psychiatric genetics and set up the local infrastructure to allow larger studies to take place.

FLG: Do you think these kinds of studies will help us determine whether certain people are more prone to psychiatric disorders or depression, for example?

Gerome Breen: Yes, they will help us understand why certain people are more prone to developing depression or why, given the same environmental stressor, some people develop depression or anxiety while others are unaffected. More interesting to me, as someone focused on biology, is what this could mean in terms of drug discovery and understanding the biological pathways of depression and anxiety to develop new medications for these disorders.

FLG: There is, of course, a huge need for better therapeutics in this area. Do you think personalized medicine could exist given the genetic background of psychiatric disorders?

Gerome Breen: I do. There are only one or two mechanisms of action for current medications for depression, for example. This means that if a person fails to respond to one antidepressant, they have a reduced probability of responding to a second one. Thanksfully, many people do respond to different antidepressants, but it would be better if someone who failed to respond to a common type of antidepressant like a serotonin reuptake inhibitor (SSRI) could be tried on a drug with a totally different mechanism of action. This is similar to what people do with pain medication, where they switch the mechanism targeted to address the pain. I think genetics could give us a diversity of mechanisms to target; it could be great to have 10-12 different mechanisms that can be targeted by medications as if a patient doesn’t respond to SSRIs, they could potentially respond to another mechanism.

By broadening the spectrum of therapeutics, more patients will have access to a therapeutic that works for them.

FLG: How can genomics improve the clinical trial approaches that are currently used in mental health?

Gerome Breen:  I think one of the key areas that interests us is the ability to recruit participants based on their genetic makeup. For example, we could recruit people with high or low polygenic risk scores and use different trial designs that focus on genetic selection (of participants) rather than phenotypic clinical variables. Another example would be if a drug company is developing a therapeutic, and they know that a specific genetic variant is important for the drug’s target or response, they could recruit participants based on that genetic variation.

FLG: So perhaps by better understanding the genetic links, and also having more different types of therapy, it could be possible to tell which patients will respond better to which therapeutics?

Gerome Breen: Yes, that’s right. And we might also be able to predict which patients are more likely to have side effects.

FLG: Do you think by studying the genetics of mental health, one day we can have the predictive power to assess certain people that might be more susceptible to psychiatric disorders?

Gerome Breen: No, I don’t think that we can do that accurately. Mental health disorders like depression and anxiety are simply too complex for that kind of prediction. However, what we might be able to do better is assess a person’s genetic risk for certain disorders when they present at a clinic. For example, if someone presents with severe depression, we might be able to determine their risk for developing bipolar disorder (manic depression). We might also be able to develop a profile for that person that indicates potential side effects, likely comorbidities, and their likelihood of responding to certain medications. But I think this would be more useful once someone has already presented with symptoms and is being referred to a clinic. Otherwise, the risk of false positive predictions at a population level would be too high.

FLG: You also do some work with eating disorders? Are there certain disorders that have a stronger genetic link?

Gerome Breen: Yes, when we look at psychiatric disorders as a whole, they can be grouped into three categories based on the strength of their genetic effects. Disorders like schizophrenia, bipolar disorder, autism, and ADHD have heritability rates of between 65% and 90%. Eating disorders have heritability rates of between 45% and 70%. And disorders like anxiety and depression have heritability rates of 30% to 40%. Heritability refers to the proportion of the risk of developing a disorder that can be attributed to genetic factors. So, while there is a substantial genetic component to depression and anxiety, it is a minority while the majority of the risk for eating disorders can be attributed to genetics.

FLG: Oh, that’s interesting. I had no idea that eating disorders were more genetically linked than anxiety and depression, for example.

Gerome Breen: Yes, that’s not very well known. In fact, they’re much easier to study from a genetic standpoint than depression and anxiety.

FLG: So how have you been studying them? Have you been working on a program similar to GLAD?

Gerome Breen: Yes, we have a sister project to GLAD called EDGI-UK, which stands for the Eating Disorders Genetics Initiative in the UK. We’re trying to recruit 10,000 people with experience of any eating disorder. We launched the project one week before the pandemic started, and despite various problems related to that, we’re now at around 4400 cases and hope to keep recruiting to meet our target.

FLG: That’s amazing. And you’re collecting similar information from patients, I assume.

Gerome Breen: Yes, it’s very similar. We’re part of a global set of projects that are recruiting using the same methods, and we hope to be able to combine our data together

FLG: And are there similar goals as well of improving therapeutics and finding new drug targets?

Gerome Breen: Yes, there are. What we’ve found in our genetic studies so far, which have focused on anorexia nervosa, is that about half of the genetic effects are probably related to body composition and metabolism, as opposed to just being purely psychiatric and brain-related. The sample sizes we have for eating disorders are smaller than those for depression globally, and various studies are at an earlier stage. But they’re already transforming the way clinicians think about these disorders. It’s becoming much better acknowledged that there’s a metabolic component to them, and we’re beginning to do various experiments to find the exact metabolic abnormalities that might underlie some of the risk for developing these disorders.

FLG: That’s really exciting. I’m sure the future holds a lot for this subject area. And just one last thing to wrap things up, you’ll obviously be joining us at the Festival of Genomics and Biodata in January, which I’m very much looking forward to. Could you just tell us why you’re looking forward to the Festival?

Gerome Breen: I think what’s really interesting about genetics is that every two years represents at least one decade of scientific advancement in other fields. What’s really interesting to me about genomics is seeing all the new things people are doing across various disorders, and all the new resources and technologies that are coming out. And I think also, you know, we’ve all been missing meeting colleagues during the pandemic, so it will be really interesting to see everyone together and to meet people from different fields. Because when we work in different fields, we’re often slightly siloed in the methods and approaches we use. It’s useful to see what other people are working on in a broad way because it improves everyone’s science.

FLG: Yeah, it’s definitely a fast-paced topic, so it’ll be good to get updates from everyone. Thanks so much for your time today and for talking us through your work. We look forward to hearing more about your work at the festival.

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