06/04/2021

Research Reveals 178 Genes Are Associated With Depression

11:43 minutes

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If you have a family member that suffers from depression, chances are you may have more than one. Doctors often say “depression runs in families,” but scientists really had no good idea how—until a major analysis of the genomes of 200,000 military veterans uncovered the 178 genes that influence your risk of major depression. 

Science Friday producer Katie Feather talked to Dr. Daniel Levey, assistant professor of psychiatry at Yale University School of Medicine. He explains why there are so many associated genes, and more about the massive database that helped scientists find them.


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Segment Guests

Daniel Levey

Daniel Levey is an assistant professor in the Department of Psychiatry, Division of Genetics at Yale University School of Medicine in New Haven, Connecticut.

Segment Transcript

IRA FLATOW: This is Science Friday. I’m Ira Flatow. If you have a family member who suffers from depression, you may have more than one. Doctors often say depression runs in families. We’ve all heard that, but scientists really had no good idea of how until recently.

An analysis of the genomes of 200,000 military veterans uncovered the genes that put one at risk. Science writer producer Katie Feather is here to chat more about it. Hey, Katie.

KATIE FEATHER: Hi, Ira.

IRA FLATOW: So scientists have found the gene that influences your risk of depression?

KATIE FEATHER: Not gene, Ira, genes, 178 of them.

IRA FLATOW: Whoa, that’s a lot of genes. Why so many?

KATIE FEATHER: Yeah, that’s exactly what I wanted to know. People often think about this one gene causing this one disorder in someone, but that’s not what’s happening here. And Dr. Daniel Levey, who is an assistant professor of psychiatry at Yale University School of Medicine and co-author on the study, answered that by explaining that, well, depression is really complicated.

DANIEL LEVEY: Depression ends up being a pretty big basket. So we call it one thing. We say this is major depressive disorder, but probably people that have this diagnosis get it for a wide variety of reasons. And it can come from biologically– many different genes could be linked to the increased risk. Different environmental exposures and societal factors can also influence that. So it’s because it’s such a complex trait that so many genes have the potential to influence your risk for it.

KATIE FEATHER: And did you have an idea of which genes you wanted to look at ahead of time?

DANIEL LEVEY: No, that’s the beauty of this kind of study because at this point, we really are early on understanding this disorder, and through treatments– through some effective ones but we can really do a whole lot better– and so the point is to look at the entire genome. And we’re trying to discover new targets for further study.

KATIE FEATHER: When did we start to think that depression might be genetically linked?

DANIEL LEVEY: So the research in this goes back a lot of years. It wasn’t until very recently, the last couple of decades where the technology’s been to a place where you can really start investigating it, we know that genetics only makes a small proportion of your risk for developing depression, but we think it’s an important piece.

KATIE FEATHER: And how common is major depression among the population? Do we know that?

DANIEL LEVEY: Yeah, I think it’s approximately 20% of the population. And something we didn’t study in this paper but something that is something we want to look at in the future is there does seem to be a difference in prevalence between men and women with women being as much as twice as likely to be reported being diagnosed.

KATIE FEATHER: What does genetically linked depression actually mean? Does it mean you inherit it?

DANIEL LEVEY: So there is a portion of heritability that we explain with how we’re looking at genetics. But, again, that’s not any kind of fate. It just gives you an increased probability, an increased risk. It’s only going to give you a small window into your increased risk. So the individual variations we see have small effects individually, but we’re finding if we can combine those small effects into a large panel of many, many variants up to millions of variants, we can explain a lot more. And so that might give an indication of if you’re increased risk, then maybe there’s some preventative measures you can take, but we’re still I think a few years out on having a good grasp on that.

KATIE FEATHER: So tell me about this massive data set. You needed the genetic information of people, and then you needed information about their mental health. So how did you get those two pieces of data?

DANIEL LEVEY: So the big thing we added was from the Department of Veteran Affairs million veteran program, and that’s a project within the Veteran Affairs system where they’re trying to recruit more than a million people, veterans. And we have access to– unlike many other systems within the US, the VA has excellent medical health records. So we were able to look up people’s health codes– ICD codes just like an insurance record almost– of what they’ve had claims for disease-wise. And so we were gonna use that to identify people that had depression, and then in this huge cohort, we could look at what genetic variants associated with the diagnosis of depression. We also work with some other cohorts from the UK Biobank in England, FinnGen, which is a Finnish biobank, and also the personal genomics company that many people have heard of 23andMe provided a lot of people that we included in a big meta analysis for depression.

KATIE FEATHER: So what is the value there of having this huge data set?

DANIEL LEVEY: So as we were saying earlier, it’s part of the seeing so many genes, 178 genes. We think that as studies get larger, we’re going to see even more, twice that, three times that.

KATIE FEATHER: Really?

DANIEL LEVEY: Yeah, absolutely. And so it’s because the risk is so broadly distributed across your entire genome. And so the individual variations have a small effect size. So we need to look at all of them to get a combinational score for how these genes influence depression.

KATIE FEATHER: What does that tell you about the biology of depression versus the biology of something that’s really just influenced by one or two genes?

DANIEL LEVEY: Well, there’s very few things that are influenced by one or two genes, and it’s some specific kind of trait. So, yeah, it’s just– it just really speaks to how complicated brain disorders and psychiatric disorders are. It’s the most complicated organ, and the things that influence are going to be complicated as well.

KATIE FEATHER: Do you think maybe depression has been too broadly defined with so many genes influencing it?

DANIEL LEVEY: Absolutely 100% agree with that. I think that as we move forward in psychiatry– and that’s not just the biological or genetic perspective. That’s also nosology, looking at the study of the disease itself. I think that we will over time identify many different subtypes, people with similar symptoms but different causes, and that might influence how we end up treating it.

KATIE FEATHER: This brings me to an ethical question. I know these veterans signed up to have their data used in research studies, but is there any concern about someone getting identified from their data and then having that get used against them in some way?

DANIEL LEVEY: That’s a great question. So I think that there’s something that’s been in the news a bit lately is through some of these genetic tests that try to identify risk for I think it’s for different psychiatric traits for babies that are in development. And I think the point is that we’re just nowhere near close enough that the things we’re studying are not going to single you out as, yes, you’re definitely going to have depression or anxiety disorders or any of these other psychiatric disorders.

But I don’t think that will get to the point where you could tell just from somebody’s genetics that you have depression. It’s more about identifying risk factors, and when we see what genes– and it’s gonna be widely distributed number of genes– are impacted by depression, we’ll have new ideas for how we can treat it. I don’t think we’re going to get to the point where we can say, yes, you definitely will have this disorder purely based on the genetics.

KATIE FEATHER: But even someone with a high risk of depression who may never get it because their environmental factors don’t lead to that could still be profiled because they have that high risk either by insurance companies or medical providers or employers and things like that.

DANIEL LEVEY: It’s a possibility, but I think it’s one of those things where intervention could be highly beneficial. And so if it’s looked instead as a way to intervene and provide benefit for people, that could help employers. Essentially, you’re going to want to keep– well, I don’t know. That’s actually a great question.

I think really at this point, the concern is maybe a little overhyped just because I don’t think we’re going to be able to explain that much data. And then my hope is if we did get to that point that this is something that could be used in a more beneficial way for the people that have this trait and that people wouldn’t be screaming out just based on elevated risk. They’d be hopefully be looking for ways that they can help. But, of course, we know that the world doesn’t always work that way.

KATIE FEATHER: But let’s talk for a second about the benefits to people experiencing depression. Could the results of this study be used to help them in any way?

DANIEL LEVEY: So I feel like the main benefit from this kind of work will end up coming down the road where we’ve identified new novel ideas for future investigation for new therapeutics. One thing that could be more influential sooner would be repurposing of drugs. So we were able to identify certain pathways that are involved with other treatments.

I believe one of those drugs was riluzole, which has previously been used for ALS. I think there have been some trials investigating that drug in treatment for depression. So we might be able to identify some things that are already approved for other indications that might be beneficial for depression.

KATIE FEATHER: You’ve talked about what we’re going to know further on as we keep studying this. What would we need in order to learn more about the genetics of depression and other mental illnesses? Would we need more of these types of data sets, more computing power interest, or funding?

DANIEL LEVEY: I think funding. We need to increase our recruitment. One thing that I often forget to mention but I think is very important is that a lot of the recruitment for these kinds of studies happened in America and in England and in Europe. And you’re going to end up studying the population’s most prevalent. That ends up being people of European ancestry. So we need to do a better job of recruiting underrepresented ancestries to make sure that what benefits we expect to come down the line is available to everyone.

So the MVP, one of the great advantages of that is it’s one of the largest collections of non-European ancestry, and so the MVP specifically is doing a good job of starting to address that. But that is an area that is lagging behind looking at understudied ancestries.

KATIE FEATHER: Were you able to see any differences based on race or ethnicity?

DANIEL LEVEY: So when we looked at an African ancestry sample, we didn’t identify anything that was significant like individual variants. We were able to look at some overlap across the samples, and there did seem to be some positive correlations that [INAUDIBLE] would see in one population indicated it might be there in the other population. [INAUDIBLE] concern that– if we might be missing something of value.

KATIE FEATHER: And this work was primarily funded by the Department of Veterans Affairs. What does the VA have to do with all this?

DANIEL LEVEY: So they’re trying to enhance treatment [INAUDIBLE] for veterans and so they’re able to access this large data set and to really drive this kind of discovery that wouldn’t be available other through other areas, very specifically again looking at a non-European ancestries because America is much more diverse than many other places that are collecting samples currently.

KATIE FEATHER: Did you see anything in the data that would confer some type of resistance to major depression? So we had that susceptibility to it, but are there any trends that show you, oh, this person with this type of genetic profile would actually be the least likely to have depression?

DANIEL LEVEY: Yeah. One way you can look at it it’s just the first of the increased risk you’ll also see on the flip side of the distribution and people will be at reduced risk. And individual variance sometimes, they confer increased risk, and sometimes they do confer protection for your depression. So nothing specific. But, yes, the polygenic risk score at one end of the spectrum is going to people that are at increased risk for depression, but also there might be some indication at the other side of the scale of people that are more resilient.

KATIE FEATHER: When people think about genetics, they might think about inheritability and maybe natural selection. So why haven’t we seen cases of depression decrease over time?

DANIEL LEVEY: Psychiatry is a field that’s still somewhat new. I think that there are elements within many of the psychiatric disorders that track maybe with empathy, with things that we consider to be very positive traits. And also when we consider how broadly distributed the genetic variations are, there’s not going to be a lot of selective pressure against many of them. So that’s why I think that it’s persisted.

KATIE FEATHER: Dr. Dan Levey is an assistant professor in the Department of Psychiatry at the Yale University School of Medicine. Thanks so much for joining us.

DANIEL LEVEY: Well, thank you very much for having me.

KATIE FEATHER: For Science Friday, I’m Katie Feather.

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