In this podcast, we are joined by Dr. Alex Neumann, of the VIB Centre for Molecular Neurology at the University of Antwerp, and Professor Henning Tiemeier, Professor of Social and Behavioural Science at the Harvard T.H Chan School of Public Health in Boston and professor of psychiatric epidemiology at Erasmus University Medical Centre, Rotterdam.
Alex and Henning begin by providing us with a quick insight into how they became interested in the field of child and adolescent mental health, before providing us with an insight into what their JCPP paper looks at and why they choose to explore this area.
Alex and Henning then provide insight into the methodology used in the research and share some of the findings, including how polygenic risk scores associated with school age psychopathology tended to either be associated with general psychopathology only or general and specific, but not except in the case of anxiety specific psychopathology only. Alex and Henning explain the importance of this finding and what it means for assessment and diagnosis.
Furthermore, Alex and Henning describe what the implications of their findings are for professionals working with young people and their families, what message they have to researchers in this field, and what they concluded in the paper.
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Henning Tiemeier, MA, MD, PhD, is Professor of Social and Behavioral Science and the Sumner and Esther Feldberg Chair of Maternal and Child Health at the Harvard T.H. Chan School of Public Health. Dr. Tiemeier received both his medical and sociological degree from the University of Bonn, Germany, and his PhD from the Erasmus University in Rotterdam, Netherlands. Since 2018, he leads the Maternal and Child Center of Excellence at Harvard Chan. As one of just 13 HRSA-funded Centers of Excellence in Maternal and Child Health in the United States, the center trains future leaders in the field. Dr. Tiemeier have worked broadly in pediatric epidemiology for more than 20 years with an emphasis on child developmental research. At Harvard his research focusses on high-risk children, such as preterm children and homeless families.
Dr. Tiemeier has published extensively on the etiology of child developmental problems with a particular focus on prenatal exposures. His other research interests include social and family environmental determinants of brain development, parental feeding and child eating behavior, and psychometric studies of child development, among others. He is a principal investigator of the Generation R Study, a large pre-birth cohort in Rotterdam, that enrolled nearly 10,000 mothers and their children. Ongoing research projects and interests focus on genetic and early life exposures; as his previous work showed that this shapes the vulnerability to neurodevelopmental problems. His ongoing studies include investigate how parenting and other environmental risk factors relate to brain development as assessed by braining imaging. (Bio and image from Harvard T.H. Chan School of Public Health)
Dr. Neumann currently studies the genetics of Alzheimer’s disease biomarkers, by examining rare genetic variants obtained from whole exome sequencing (WES). The work focuses on pleiotropic effects on multiple biomarkers, as well as mediation analyses to test whether genes influencing Alzheimer’s risk do so by affecting biomarker levels. Dr. Neumann obtained a PhD in psychiatric epidemiology from Erasmus University Rotterdam. The PhD thesis focuses on the genetics and epigenetics of child psychopathology, as well as the co-occurrence of child psychiatric problems. Dr. Neumann has experience leading genome-wide (GWAS) and epigenome-wide association studies (EWAS) in international consortia, such as the The EArly Genetics and Lifecourse Epidemiology (EAGLE) and Pregnancy And Childhood Epigenetics (PACE) consortia. He also worked on white matter integrity in relation to general psychopathology in childhood, as well as on the genetics of cortisol. (Bio from University of Antwerp, image from VIB Centre for Molecular Neurology at the University of Antwerp)
[00:00:27.490] – Jo Carlowe: Welcome to a different type of In-conversation podcast from the Association for Child and Adolescent Mental Health, ACAMH, where we will look at the paper ‘Combined polygenic risk scores of different psychiatric traits predict general and specific psychopathology in childhood’. Published in the Journal of Child Psychology and Psychiatry, the JCPP. I’m Jo Carlowe, a freelance journalist with a specialism in psychology, and I have with me Dr. Alex Neumann of the VIB Centre for Molecular Neurology at the University of Antwerp, and Henning Tiemeier, Professor of Social and Behavioural Science at the Harvard T.H Chan School of Public Health in Boston and professor of psychiatric epidemiology at Erasmus University Medical Centre, Rotterdam.
[00:01:15.260] Both are co-authors of the paper that we’ll look at in today’s podcast. If you’re a fan of our In-conversation series, please subscribe on your preferred streaming platform. Let us know how we did with a rating or review and do share with friends and colleagues. Henning and Alex, welcome. Thank you so much for joining me. Can you each start with an introduction about who you are and what you do?
[00:01:36.900] – Dr. Alexander Neumann: Thank you for inviting us. I’m an epidemiologist. I study the genetics of psychiatric and neurological disorders. I currently focus on Alzheimer’s disease, but my background is actually more in child psychiatry. I did my PhD on the biology, also general psychopathology factor in childhood together as Henning as my PhD supervisor.
[00:01:58.350] – Professor Henning Tiemeier: Yes, so thank you for having me here in Boston. I’m a Professor of maternal and child health. I’m the chair of Maternal and Child Health, and for many years I’ve been doing aetiological research into child developmental and child psychiatric disorders, and I’ve been leading in the Generation R Study for many years the behavioural and neurodevelopmental research line. So it’s really to understand why children develop disorders and that could be biological factors, but also very often interactions, environmental factors.
[00:02:31.580] – Jo Carlowe: Can you also each say a little about how you became interested in the field of child and adolescent mental health.
[00:02:38.370] – Dr. Alexander Neumann: So for me it was when I was doing my Bachelor in Isenberg, a German town and my Bachelor in cognitive science and was more interested in brain function in general, not necessarily clinical aspects of it, but then I kind of realised doing a Bachelor how common mental health problems are. Something which I wasn’t really aware beforehand and this in combination with the fact that we don’t know that much about it, that led me then to become more interested in mental health and especially in the biological aspects of psychiatry. So I then further specialised doing my Master in psychopathology, then was looking for a PhD which would combine genetic research and psychiatric research and this is how I then found Henning at Erasmus Medical Centre in Rotterdam, the Netherlands.
[00:03:29.650] – Jo Carlowe: Great. Thank you. Henning what was your journey into child and adolescent mental health?
[00:03:34.630] – Professor Henning Tiemeier: There’s two things to mention. One, I had to go to research because I moved to private reasons to the Netherlands from Germany and I didn’t speak any Dutch. So working as a psychiatrist was no option. So I went into research just for practical reasons to learn the language and I stayed and loved it. I went into research of psychiatric problems in the elderly, and I liked it. Then after a while they asked me to help run a study in children and that was more because I was perhaps trained well as an epidemiologist and I was very good at managing data collection, and my mentor then said, oh, I’ll train you in child development, and he really did. I stayed for 20 years now.
[00:04:11.320] – Jo Carlowe: Let’s turn to your paper ‘Combined polygenic risk scores of different psychiatric traits predict general and specific psychopathology in childhood’, published in the JCPP. Can you set the scene? What did you look at and why?
[00:04:25.920] – Dr. Alexander Neumann: So if you think about a typical genetic study in the psychiatric field, how it’s often done is you have participants with a particular diagnosis and then a control group without a psychiatric diagnosis. Let’s say, for example, you have participants which are diagnosed with ADHD. Then you have a control group who do not have any psychiatric diagnosis, and then you can test millions of variants of genetic variants and compare for each of those variants. Do they occur more frequently than children with ADHD, or do they occur less frequently compared to the control group?
[00:05:02.120] Or perhaps are they approximately the same? So if you perform such a genetic association study, then you get estimates for each of those genetic variants, and the effects of single variants are typically very small. However, you can aggregate the effects of many different genes depending on how you do it could. It could be an aggregate of hundreds of thousands of variants. So if we stick with the example of ADHD, so your expectation would be then if you perform such a study comparing children with ADHD to those without, and then you create a genetic risk score based on the information of your genetic study, then trying to aim to predict whether somebody develops ADHD given their genetic risk, the expectation would be then you can take this information from your study and then predict reliably ADHD in children.
[00:05:52.490] However, researchers have noticed is that while genetic risk scores based on these human association studies, do, for example, predict ADHD symptoms. They also predict lots of other different symptoms, which you wouldn’t normally think immediately about in regards to ADHD. So, for example, a group from [inaudible] saw that genetic risk score for ADHD predicts ADHD symptoms but also symptoms such as depression or anxiety and many different other psychiatric problems. So it seems to be that a genetic risk score for ADHD is actually a quite general risk score.
[00:06:31.460] So then the question came up, is it something special about the genetics of ADHD or the genetic risk score for ADHD. Does it seem to have such general predictive ability, or is this something which can be applied to also other risk scores? Maybe that’s just how psychiatric genetics works. Maybe if you create a genetic risk score for one particular disorder, maybe what you get is a prediction for many different disorders.
[00:07:01.430] – Jo Carlowe: I want to ask you a bit about the methodology that you use in the research.
[00:07:05.560] – Dr. Alexander Neumann: We try to test a broad collection of different polygenic risk scores or PRS essentially systematically get an overview how general or specific different PRS scores are. In total computed 16 different PRS scores for different psychiatric traits or disorders such as schizophrenia, depression, as mentioned ADHD, but also related traits such as cognitive ability or neuroticism. Then we tested for each of those 16 polygenic risk scores, whether they predict psychiatric symptoms in general, or whether they have predictions for specific psychiatric problems in childhood, and to get into more detail specifically we looked here at the associations with general psychopathology factor and specific psychopathology factors, and maybe Henning can say a bit more about those factors.
[00:08:01.930] – Professor Henning Tiemeier: First, the terms general psychopathology factor and specific psychopathology factor are not so easy, and they were coined a few years back by Ben Lahey, who did the following. He said it was a sort of factor, analytical technique he pulled out from different disorders what is in common? So he had the idea that all people who are vulnerable to one of the different psychiatric disorders share something in common. Have the same traits and characteristics, if you wish. So there is a liability to have any disorder, and when you do that you also with this technique obtain what’s not part of that general disorder, but what is more specific for emotional problems or more specific for behavioural problems as aggression, so that you get these general and specific psychopathology factors.
[00:08:56.830] – Jo Carlowe: What can you share of the findings?
[00:08:59.420] – Dr. Alexander Neumann: We associate these 16 PRS scores with general specific psychopathology and we found that all of the 16 we tested seven PRS scores associate consistently across three different cohorts with general psychopathology. So we have seven project risk scores which associate with psychiatric vulnerability to different psychiatric disorders in general, and there was no particular pattern to it. There were very different PRS scores. We had a PRS score for ADHD, genetic risk for depression, genetic risk for schizophrenia, but also genetic risk for cognitive ability and neuroticism. So very different PRS scores. They all were associated with genetic psychopathology in children. The predictive ability of the score was at most 1%.
[00:09:49.350] So each score individually blamed at most 1% variance in general psychopathology in childhood. This was our first main findings that we have the observation. I initially elaborate on ADHD that ADHD seems to have a very broad association, a very broad predictive ability towards different disorders. That doesn’t seem to be the case just for genetic risk for ADHD, but seems to be a more common phenomenon that genetic risk towards other disorders also shows us broad predictive ability. So then our next question was, okay, if all these seven PRS associate with general psychopathology, can we maybe perhaps combine them and then have better prediction of general psychopathology in childhood?
[00:10:41.190] So, in other words, if you are genetically vulnerable to both ADHD and, for example, to depression, do you then have a higher propensity of psychiatric problems in general, and saying this out loud it seems kind of obvious the answer, yeah, probably right. But actually it’s not quite that obvious because let me give you an example. So let’s say we have a genetic risk score which is based on two genes. Let’s say for ADHD, and we have two genes. One gene is called general gene and a second gene called ADHD gene.
[00:11:12.560] Then we might have a genetic risk score for depression, which also has a general gene and includes also a depression gene. So in this case we have two times the same general gene. So it wouldn’t make any sense to combine these two generic risk scores because you’re essentially just counting twice the same genes which have general effects. However, this is not what we saw in our results. We could combine the seven genetic risk scores and saw that they have almost all of them had independent effects, which then has a consequence that we could actually improve our predictive ability. We could double it from 1% to 2% if you look jointly at different polygenic risk scores at the same time.
[00:11:58.930] – Professor Henning Tiemeier: It’s complicated as you know. So let’s try it a bit differently. So the first thing we noted is that if you try to predict child psychiatric disorders, you can do it, but you don’t do it very well. What you explain is very little. That is the first observation. The second observation is that if you predict in this case general psychopathology, you can predict it with very different polygenic risk scores from very different disorders and the next observation is that you can predict it independently. So each of these disorders, of these polygenic risk scores adds more information, so you can predict it a bit better and a bit better and a bit better by ever adding the information from different risk scores.
[00:12:43.520] And what does that tell you? It tells you that indeed genetically this general psychopathology is indeed found from very different disorders, but it’s found across all the different disorders. So they indeed all have this aspect of a general vulnerability, or that you could say all different disorders are driven by, in part driven by similar things.
[00:13:04.790] – Jo Carlowe: It is complicated. I want to go more into the implications. So Alex and Henning in your paper you describe how polygenic risk scores associated with school age psychopathology tended to either be associated with general psychopathology only or general and specific, but not except in the case of anxiety specific psychopathology only. Can you explain to the layperson the importance of that finding and what it means for assessment and diagnosis?
[00:13:37.220] – Dr. Alexander Neumann: So indeed, we had two polygenic risk scores which predicted specific externalising psychopathology and five which predicted specific internalising psychopathology. However, as you noted, there was almost complete overlap with those genetic risk scores which predict general psychopathology, and yeah, it’s difficult now to translate it into what does this mean practically, since the construct of general psychopathology are a bit abstract, but the way I think about it is right now, as mentioned, the predictive ability of our current PRS scores are not very reliable, and they’re not used clinically yet, but for the sake of this question, let’s pretend we are a bit more further ahead in the future, maybe where we get more reliable PRS scores.
[00:14:28.450] I think the implication, then, is that let’s say you have three children and one child scores high for genetic risk for ADHD, a second child scores high for genetic risk for depression, and the third child does not have high scores for any psychiatric disorder. So given that, you know the genetic risk for each of these two children you would expect intuitively that the child with the high ADHD score would most likely develop ADHD symptoms. The child with high depression scores would develop depression, and the child with low scores is not at risk and probably not develop psychiatric disorder.
[00:15:11.810] This is compatible with our findings. However, what you have to realise is because of the strong associations with genetic psychopathology the difference between the child with a high score for ADHD and high genetic score for depression is actually very similar. In other words, the child with the high genetic risk score for ADHD is also very likely to develop depression. Vice-versa, the child with high genetic score for depression is also very likely to develop ADHD symptoms. So yes, it’s not all just general psychopathology. We do have some specific predictions, but what we need to realise and what the implications of these findings are, is that there’s lots of overlap, and that genetic risk scores for a specific disorder also very likely predict risk for many different other symptoms as well.
[00:16:09.880] – Professor Henning Tiemeier: Can I add something? So for me, the lesson we learnt from these studies is that I think we should in psychiatry think more of this general vulnerability for psychiatric disorders. This is not at all represented in our DSM. That means the typical classification system we use to diagnose mental disorder. Whereas in cognition think of a general intelligence we lack something similar like that in psychiatry. On the other side of the coin, I think it means for our diagnostic system and our diagnostic thinking is that we probably if we come to genetics, think too small.
[00:16:51.170] That means we split up the diagnostic groups in ever smaller categories, ever specific categories, subtypes of depression, subtypes, many subtypes of anxiety, and at least at the moment it seems that genetically if you just look at the genetics, that’s not justified, and I must say if you look at environmental factors it’s equally not justified.
[00:17:15.010] – Jo Carlowe: But I’m wondering, given what you said about the general vulnerability and the limited way that it’s looked at at the moment, what are the implications of your findings for professionals working with young people and their families?
[00:17:28.580] – Professor Henning Tiemeier: Well, this is indeed related. I think one of the things we must realise that in child psychiatry the idea that we can use genetics for prediction is not close by, but on the far horizon, if it will ever come but it’s not there. It’s different in adult psychiatry, but it’s far away to use genetics for prediction of disorders. Secondly, I think personally that we must point out that this study was conducted in different cohorts from the UK, from the Netherlands and Canada, but they all share, like all these psychiatric disorders, largely the characteristics that it is maternal report on which the classifications and the ratings are based upon, which makes it very hard to find a large genetic signal.
[00:18:14.620] And thirdly, I think if you really ask, what does it mean for professionals, I think they must realise that a child they see as one disorder, let’s say, ADHD or autism might have a different disorder later. A child with anxiety or psychotic experiences may have borderline depression, anxiety later down the road. These disorders, they know are not stable clinically, but they know that the genes do not define stable course either. That’s I think what they must realise.
[00:18:46.230] – Jo Carlowe: That’s really helpful, and what about the message to researchers in this field?
[00:18:50.980] – Dr. Alexander Neumann: I think there are two aspects I would like to mention. One is that if you’re trying to create genetic prediction scores for psychiatric disorder, I think you should consider using multiple GMI association studies as a basis for your genetic risk scores. As we saw here, the combination of different [inaudible] seems to improve prediction of psychiatric outcomes, and I think also you could also even consider genetic studies which are not on strictly speaking, psychiatric outcomes. One thing which surprised me here is that genetic risk of cognitive ability was one of the best performing PRSs in terms of prediction of general psychopathology and cognitive ability by itself is not a psychiatric outcome, though I think this shows that it’s worthwhile to combine different genomic association studies if you want to do prediction of a specific disorder.
[00:19:47.260] And I think the second message, I think we have to be careful when interpreting results from pro-genic risk scores or pro-genic risk cost studies. Some of your listeners might be familiar with randomisation studies, and I don’t want to go too much into detail here, but essentially you can use genetic risk scores to quantify genetic risk to what particular traits, and then you can link it to another outcome. Let’s say you want to link genetic risk for depression to obesity, for example, and in this case you would have to then be careful if you don’t make conclusions, for example, that genetic vulnerability to depression is linked to obesity. That it might be actually more genetic vulnerability to psychiatric problems that’s linked to obesity. So you have to be careful how specific your conclusions can be.
[00:20:38.390] – Professor Henning Tiemeier: I would like to make for researchers on a sort of more abstract level two big points, I think to take away. One is we need to understand better and do more research into pleiotropy. That is the concept that one genetic variant has different effects in the body, and that can be for many, many reasons. That could be because one disorder down the road causes another. So you might be more vulnerable to depression because you have anxiety, but of course also be that one gene causes anxiety and depression by very different pathways.
[00:21:15.290] So this phenomenon of pleiotropy which seems to be more common than we thought, more complex, is bigger studies more prominent. It’s poorly understood, and I would argue poorly researched in its quality, certainly in psychiatry. The other closely related point is comorbidity. That is, the co-occurrence of different disorders in our studies which are increasingly longitudinal. We still don’t take care of why two disorders co-occur? Why they co-occur in time and how to deal with it. Sometimes we ignore them. For example, in imaging research we don’t know what to do with the signal that we see for one disorder could actually be because there is another disorder commonly co-occurring. So the signal we see for ADHD might be because there’s also anxiety or autistic traits.
[00:22:05.200] – Jo Carlowe: Just returning to the paper itself. Is there anything else in the paper that you’d like to highlight?
[00:22:10.070] – Dr. Alexander Neumann: You mentioned most interesting things. One thing which I personally find interesting is how often neuroticism comes up in research of general psychopathology. So we talked about cognitive ability as a non-psychiatric trait, but I think neuroticism is also another important correlate of psychopathology. So we have non-genetic studies which often find high correlation between measures of neuroticism or stress activity and genetic pathology, and also here we see that genetic risk scores for neuroticism also predictive of general psychopathology. So that’s one thing which also, I think, is quite interesting and maybe also has some broader implications.
[00:22:56.470] – Professor Henning Tiemeier: I think that’s a wonderful point, Alex. Let me just emphasise it. I think it’s been realised for many years that psychiatric disorders are genetically related to non-psychiatric disorders like smoking. When you have the first child your cognitive abilities, your body mass index, and what we see here again that even in children psychiatric problems are related to the genetic risk for all these others, but it’s there even in the common child psychiatric orders. I think that point of Alex is really important.
[00:23:29.610] – Jo Carlowe: What about the conclusions? What did you conclude in the paper?
[00:23:33.940] – Professor Henning Tiemeier: Our conclusions were that we see now not for the first time, but here very strongly biological genetic evidence for this construct of general psychopathology. This general psychopathology factor that I described earlier that we see there is a genetic [inaudible], if you wish for this vulnerability that each of us may have to some degree of psychopathology. So that means we can think of us as having, like, an intelligence trait. We can also think of us like a trait of psychiatric vulnerability which is genetically determined and likely also environmentally determined.
[00:24:13.180] I think that this paper is one of very many, but it’s sort of the increasing papers that will make us think about do we have to reshape our diagnostic categories and diagnostic categorisation methods to be more broad and encompass broader categories of disorders? That’s another take away.
[00:24:36.130] – Dr. Alexander Neumann: Maybe one just thing to add, which I find most important. So we’ve been talking a lot of genetic risk today, but of course genetic risk is always a probability. Sometimes people think that genetic factors are these fixed deterministic things which cannot be changed, and you can’t do anything about it, but when we talk about genetic risk, especially here, we’re talking about descriptive probabilities, and it might be difficult in practice, but at least conceptually there’s always the potential that there are things you can prevent or treat problems from occurring.
[00:25:12.810] – Jo Carlowe: Are you planning some follow up research that you can reveal to us?
[00:25:18.190] – Dr. Alexander Neumann: Currently we are looking into incorporating the environment and our risk predictions, because even with highly heritable disorders such as ADHD or schizophrenia we still have a substantial environmental component which we at some point have to integrate somehow into our risk prediction systems. So the same team which was working on this paper we are now also looking into specifically the pregnancy environment. So things like stress, maternal stress during pregnancy or maternal depression during pregnancy, how this might interact and interplay this genetic risk for disorders. Whether it has some additive predictive value, but also whether there might be also some interaction effects going on so that you might be especially at risk if you have both genetic risk and perhaps an environmental risk during pregnancy, which then combined could especially reside in high risk to develop a disorder, or maybe the other way around. Maybe especially a good environment might protect you from genetic risk factors. So those are the things we are currently looking at.
[00:26:31.170] – Professor Henning Tiemeier: Can add two current ongoing projects of mine. One is looking at what I mentioned before this pleiotropy which I defined as genetic risk factors or genetic loci having effects on different outcomes or in this case, different psychiatric disorders. Together with a team from Rotterdam we are trying to develop new statistical methods to look at this phenomenon because we think we’re getting it a bit wrong. So we might try to change the way we look at it statistically and redefine it a bit because I think what we do is we’re just pulling everything together and then the biggest signal takes over, which is not really what we should do.
[00:27:09.570] So that is quite statistical, and the other is perhaps more interesting for the listener is that there is good reason to assume that our understanding of environmental risk factors and genetic risk factors is ever increasing, but what I think we can now do better and a colleague of ours in King’s College has shown that with a wonderful new method. JB Ping Guo has shown that we can use the heritability together with these polygenic risk scores to look at how much genetic factors underlie things we always thought were environmental. That we’re redefining what is environmental? What is parenting? What is screen time? Is that really partly driven by your own genetics and the other way around too because there’s colleagues in Sweden at the Karolinska who showed that all we do is this polygenic risk scores. In part in some of them may be essentially, there may be a bit of error and there may be a bit of non-genetic effects in them. So then we have to rethink what we think is genetic and think is environmental and that’s two fascinating roads of research.
[00:28:15.530] – Jo Carlowe: And finally, Alex and Henning, what are your takeaway messages for those listening to our conversation today?
[00:28:22.220] – Dr. Alexander Neumann: Yeah, I think we have to really be mindful of co-occurrence of psychiatric disorders. Whether they occur because of common genetic factors, whether it’s common environmental factors. Either way I think it’s sometimes easy to just focus on one particular problem or one very salient symptom, but I think it’s both from a research and probably also more prevention or treatment perspective. We have to look at the whole complexity of psychopathology. I hope that this will also help us to better prevent and treat psychiatric disorders in the future.
[00:29:00.170] – Jo Carlowe: Thank you, and Henning?
[00:29:01.350] – Professor Henning Tiemeier: I’ll give you my takeaway. I have no doubt that there is a general psychopathology factor. I have no doubt it’s partly genetically determined, but I have no doubt that at the moment we cannot predict it well at all. That is my takeaway.
[00:29:18.590] – Jo Carlowe: Thank you both so much. For more details on Dr. Alex Neumann and Professor Henning Tiemeier, please visit the ACAMH website, www.acamh.org and Twitter @acamh. ACAMH is spelt A-C-A-M-H and don’t forget to follow us on iTunes or your preferred streaming platform. Let us know if you enjoyed the podcast with a rating or review and do share with friends and colleagues.