GENE Amsterdam Interview Session 6: Dorret Boomsma

Interviewed by: Jana Hirzinger and Anaïs Thijssen

Looking back, what inspired you to focus on twin genetics? Was it something you set out to do from the beginning?

No, not right from the beginning. As a student, I applied for a bursary that allowed you to do whatever you wanted for one year. I had taken a course from a twin researcher at the VU and thought it was a fascinating topic that I would like to study in the US for a year. He advised me to apply in Minneapolis and Boulder. Minneapolis turned me down, but Boulder accepted my application. Robert Plomin was there at the time, and I had a great introduction to quantitative genetics by John DeFries. It was the methodological work that made this field of huge interest to me. When I came back to Amsterdam, it was at least as difficult as it is nowadays to get a position in academia. So I actually started my career as a statistician at the Department of Dentistry, and then I moved on to a PhD position on cardiovascular risk factors in twin families. Many years later, I was the president of the Behaviour Genetics Association and had to give the speech at the annual meeting in Minneapolis. And I still had my rejection letter, so it was a fantastic moment to show that I had returned as president of the Behaviour Genetics Association to the university that turned me down. The funniest thing was that afterwards, many people from the university wrote me emails saying it wasn’t them who rejected my application.

What are some of the most memorable or surprising discoveries you’ve made about twins or twin genetics over your career? 

Already early on in our work, within the first 10 years of results based on the Netherlands Twin Register, we saw that at very early ages (before 7 years), the influence of the genome on behavioural problems and psychopathology in children is very large. I believe we would have predicted that the influence of genetics on early life traits is quite small and that when children develop genes become much more influential, which is what we see for IQ, for example, but which is not at all what we see for other traits. Traits like attention problems or aggression in very young children are highly heritable. In the early days, this was one of the more surprising outcomes.

How do you look back on your career?

It has been and still is a very happy journey. When I started working in human genetics, we almost exclusively did statistical modelling using twin and family data. Then came the development of multivariate models, as initiated by Lindon Eaves and Nick Martin, which was a huge progress in statistical software. And then, at the point in time where one might start to wonder, well, am I going to spend my life estimating heritability for yet another trait? Along comes the possibility of doing linkage studies for quantitative traits. In hindsight, we recognize that those studies were hugely underpowered because we did not have a good feeling about the large degree of polygenicity that is responsible for the heritability in most traits. After that, we moved on to the somewhat miserable period of candidate gene studies, and then finally, there were technological breakthroughs that meant we could do large-scale SNP typing and GWAS for about every trait. It has been fun to see the field develop this much. What the next breakthrough will be is difficult to predict. We should be careful not to think that with the discovery of SNPs, we now know everything. 

Where do you see the future of twin studies going?

I think the enormous value of (monozygotic) twins will remain. Take a trait like schizophrenia, for example, which is a highly heritable disorder with estimates of up to 80% of the variation on the liability scale. However, if you look at the concordance of schizophrenia in monozygotic twins, the upper limit seems to be somewhere between 40-50%. So why are two people who share the same genetic variants not more alike in their phenotype? This is a very important finding to keep in mind for personalized medicine. If you cannot predict from the characteristics of your monozygotic twin whether you will also become a schizophrenia patient, then you can also not predict this longitudinally in the life of a single individual. There is still a lot going on that we cannot and probably will never be able to predict, so the hype around genomic prediction is not really warranted.

And then there is the exciting new development of what the aetiology of twinning itself might mean. The Netherlands Twin Register was established with two large grants that aimed to resolve the aetiology of twinning. For thirty years, this was a spectacularly unsuccessful enterprise. Only when GWAS became available, we found the first sets of genes for having dizygotic twins as a trait in mothers of twins. Interestingly, a polygenic score that predicts dizygotic twinning is also predictive for female infertility, greatly expanding the value of discovering those genes. Finally, we found evidence for the hypothesis that there is a continuum that goes from multiple ovulation on the one extreme to no ovulation on the other extreme, with everything in between almost varying on a quantitative scale.

Have you studied any twin phenomena that are not well known to the public, but that you think deserve more attention or research?

I would love to talk about a phenomenon called chimerism. It means that, in addition to your DNA, you’re also carrying the DNA of another person. This was initially discovered in dizygotic twins and thought to be extremely rare. In the 1990s, we showed that chimerism is actually much more common. For some time, this paper was a Sleeping Beauty. No one picked it up. Then, one Friday afternoon, the New York Times called me because the paper had been supplied as evidence in a court case involving a cyclist accused of blood doping. He claimed the blood was from his twin brother, arguing he was chimeric because of a vanishing twin. Of course, that was disproven easily, and he was found guilty in the end. Chimerism also became much more of a focus because it turned out that people are not only chimeric with their twin brothers or sisters, but all women who have been pregnant are chimeric with their offspring, and vice versa. 

Follow-up question: Are there any specific questions regarding chimerism that you would like to have answered?

I would love to extend the research into chimerism because it is related to many health outcomes, both favourably and unfavourably. Autoimmune disorders, especially those that have a higher prevalence in women and that become apparent in their 30s when women often have their first child, seem to be linked to chimerism. But chimerism also seems to protect against developing cancer. I would like to assess the degree of chimerism in a much larger group with more advanced methods, for example, developing technology to determine chimerism in males. The next step would be to find out who the donor of the chimeric material is.

What do you think the future holds for you?
In the Netherlands, the rule of retirement at 67 is strictly enforced. But if there is a department that invites you to stay on, you can work and supervise your PhD students for another five years. I feel extremely happy in this department of Complex Trait Genetics, where I have gotten the opportunity to continue to work. I have no idea what will happen after five years. Maybe five years is enough.

Picture by B. Bronshoff

GENE Amsterdam Annual Day 2024: a re-cap

Two weeks ago, the third edition of the annual Genetics Network Amsterdam meeting took place at the Doelenzaal in Amsterdam. We look back at a great day of department talks, flash talks, networking and keynote session by prof. dr. Dorret Boomsma.

We were welcomed by organizer Nikki Hubers, who gave us an overview of the activities of the network of the past year, and additionally presented the schedule for the day. In the past year, we had 6 research meetings and one symposium on epigenetics. If you are or know someone who would like to present during one of the research meetings in 2025, do not hesitate to reach out to Wonu Akingbuwa or Elleke Tissink!

After the warm welcome, we listened to four department talks by: Emma Pruin (AUMC, psychiatry VUmc), Joëlle Pasman (AUMC psychiatry, AMC), Sean Jurgens (AUMC, Cardiology), and Douglas Wightman (VU, complex trait genetics). In these presentations, we heard about a new GWAS for cannabis use (Joëlle), different GWASs for cardiomyopathy and the (overlap in) genetic mechanisms for these (Sean), rare disease genes associated with brain volume (Doug), but also about using family history, instead of measured genetic markers) to predict depression (Emma).

After a short coffee break, we continued with a set of short, 5-minute flash talks by junior career researchers from different research groups. In this first set of flash talks, we hear from:

  • Nathaniel Bell on Exploring the impact of non-additive SNP effects on genetic risk prediction
  • Renata Androvicova on Genetic architecture of sexual violence
  • Susanne Bruins on Genetic and environmental influences on aggression across the lifespan: a longitudinal twin study
  • Marijn Schipper on Identifying addiction genes using FLAMES
  • Daniel Alvarez Sirvent on The effect of HLA alleles on becoming a Centenarian

Next, following a lunch break, we continued our afternoon session with a keynote lecture by prof. dr. Dorret Boomsma on The legacy and future of Dutch Twin Research: From Heritability to Personalized Omics. Prof. Boomsma is one of the most outstanding behavior geneticists in the field and founder of the ever-influential Netherlands Twin Register. During her lecture, we heard about the establishment of the twin register, different research lines that she has explored and even some twin studies that were not so successful due to having a response rate of 0%!

This inspiring lecture was a great way of starting our afternoon, and set a nice stage for our second set of department talks by Kahish Kohabir (AUMC, department of Human Genetics), Lianne de Vries (VU, Biological Psychology), and Matthijs de Waal (AUMC, department of Human Genetics). Again, the session was very varied, starting with a talk on CRISPR-Cas12a detection (Kavish), followed by a genetically informative Ecological Momentary Assessment study for wellbeing (Lianne), and ending with a talk on specific SORL1 variants on Alzheimer’s disease.

Before ending with an award ceremony, we listened to a second set of flash talks by junior career researchers:

  • Tessa Zonneveld:  DNA Cinema
  • Sahar Moukadem: Heritability of fertility traits
  • Natalia Azcona Granada: Multi-omics of wellbeing
  • Alexandra Starr: Investigating causal effects of children’s home learning environment
  • Mark Grannetia: Targeting tumor-specific genomic sequences using CRISPR-Kill

After some deliberation by the jurors, we had a festive end of the day with an award ceremony for best department talk by a junior researcher and best flash talk by a junior researcher and drinks. On the department talk side, Sean Jurgens was awarded best talk. For the flash talks, Marijn Schipper took home the prize!

We thank our organizers, Nikki Hubers, Tanya Phung, Gilad Gren, Adrià Túnez Aquilué and Tessa Zonneveld for this great day. Interested in organizing next years event? Let us know!

1) Nikki welcoming us 2) the organization committee, 3) department talk by Sean Jurgens that was awarded best department talk, 4) flash talk by Marijn Schipper that was awarded best flash talk, 5&6) snapshots from the keynote lecture by prof. Boomsma, and 7) the participating members this year

GENE Amsterdam Interview Session 5: Dirk Smit

This month’s interview by Anaïs Thijssen and Jana Hirzinger with Dr. Dirk Smit, Assistant Professor Electrophysiology and Genetics at the department of Psychiatry at Amsterdam UMC.

What drew you to work at the intersection of psychiatry, genetics, and the neurosciences?

That’s a good question because this is not what I was trained for. I was trained as a cognitive psychologist doing vision research, and my first EEG experience came from a thesis project combining EEG with cognitive tests. After that, I moved into psychophysics, which was very experimental. Later, I was a computer programmer, but I decided to go back to academia and do a PhD. It was a bit of a risk trying to get a PhD position at 35. I ended up finding a PhD opening in genetics, an area I had no formal training in, but it sounded fascinating. Combining EEG with genetics felt like a unique approach. It’s a happy marriage, looking at things from a different perspective, combining cognitive neuroscience, EEG and genetics. Nowadays, with large fMRI databases, more people are starting to see the benefits of combining these kinds of databases with genetics.

You mentioned that you’re interested in the noisy nature of human behaviour, and you’re exploring it through equally noisy brain measures. At first glance, that seems counterintuitive – trying to explain one type of noisy data with another. How do you approach that challenge, and where do you see the benefits?

In a way, we try to simplify everything by having this clear separation between noise and signal. Noise is what we don’t want, and we try to get rid of it. But geneticists and developmental psychologists are more interested in noise than we think. In the simplest form, we are interested in variation: individual differences, but also changes within a person at the root level. So when I talk about this kind of noise, I’m thinking more about variation. The brain is different. The dynamics of the brain are actually very noisy. EEG researchers usually try to cancel out noise by averaging across trials, but we look at noise to see how stable or unstable the brain is as a marker of having stable or unstable behaviour. This approach fits within the study of individual differences while also accepting that the brain and behaviour are quite dynamic. 

Follow-up question: How do you distinguish between true variability and variability inherent to the measurement?

I think the short answer is genetics. Part of the dynamics in the brain can be explained by genetics, and the good thing about genetics is that if you find these associations, they are very stable. At first glance, combining genetics and EEG might seem like a strange idea – genetics is mostly stable over the lifetime, while EEG signal changes every millisecond. But it turns out that certain aspects of the EEG signal are very highly genetic. So the trick to linking EEG and genetics is to find EEG parameters that are genetic and stable, although they reflect the highly dynamic organization of the brain.

What type of phenotypes can you extract from EEG to use in genetics?

One of the most important EEG features is oscillations, or the rhythms of the brain. These oscillations reflect the excitability and sensitivity of groups of neurons and enable communication between different brain regions. For example, beta activity, a specific frequency at about 20 Hertz, plays a crucial role in communication between the cortex and subcortical brain areas. In Parkinson’s disease, beta activity is elevated, which is directly linked to the rigidity symptoms. In our GWAS of brain oscillations, we found that healthy people with a higher genetic risk for epilepsy had increased brain oscillations—essentially, they had a more excitable brain. This aligns with neural models of excitation and inhibition, where heightened excitability leads to more pronounced oscillatory activity. This imbalance in excitation and inhibition could represent a shared mechanism underlying various brain disorders. EEG phenotypes like these allow us to investigate such mechanisms through genetics, opening research avenues to better understand a range of behavioural and neurological phenotypes.

Is the genetic architecture of EEG phenotypes different from behavioural traits?

It’s not as oligogenic as you would think, but the effect sizes of EEG phenotypes are bigger than those we normally see in complex behavioural traits. We find significant hits with sample sizes of 15,000, so there is loads and loads of signal. There are also fewer genes that explain more SNP heritability, which is now up to 30%. Some of the effects are quite explainable. We, for instance, find genes that are related to postsynaptic potential maintenance, which is exactly the signal that EEG picks up. At the moment, we can relate this genetic signal to neuronal traits like epilepsy, but the potential link with behavioural traits like ADHD or other psychiatric disorders is still hard to establish.

What is the biggest strength of EEG in uncovering the genetic basis of behaviours?

Well, there seems to be some truth to the endophenotype concept. When GWAS became common practice, we went straight from genes to complex behaviour, skipping everything that happens in between, even though we knew that there had to be something happening in the brain. Right now, we can find the link from genes to EEG and the link from EEG to neurological traits. But for psychiatric phenotypes, finding this link is a lot harder, probably because of the complexity of the phenotypes. All kinds of different pathways could lead to a complex behaviour like ADHD, meaning that it is very hard to find the aetiology of such a trait. Genetics can be a promising step in uncovering the basis of such complex traits. With complex modelling like genomic SEM, we could find genetically homogenous phenotypes and then potentially find more systematic differences in the brain. I truly believe there is promise in this approach.

You are involved in many different research consortia. What do you find the most rewarding, and what are the biggest challenges of being part of a consortium?

With ENIGMA EEG, the main hardship was a lack of funding. Now, with funding in place, the focus is on studying genetics and EEG, which is exciting. Another challenge is, of course, to get all the cohorts to do their work. The other consortium I’m a part of is the PGC, where we work on OCD genetics. That was actually a lot of fun because the OCD PGC group is not that big, and the cooperative nature of consortium work is really rewarding. This level of cooperation is probably the biggest strength of genetics research overall, and the same is true for ENIGMA.

Interview with PhD Candidate Tessa Zonneveld

Most of us spend our time writing manuscripts for scientific journals, but GENE Amsterdam PhD candidate Tessa Zonneveld additionally writes scientific poetry ✍, Curious? Read (in Dutch) an interview with her:https://www.folia.nl/wetenschap/163292.

Or (in English) read her poem on her research into the association between cardiovascular disease and serious mental illness: https://www.tessazonneveld.nl/science-communication/poetry/when-darkness-takes-hold/.

DNA Cinema: NWA Science Communication Funding for GENE Amsterdam Outreach

Members of the GENE Amsterdam Outreach committee, Dr. Dennis van ‘t Ent (VU, biological psychology), Dr. Margot van de Weijer (AUMC psychiatry), Tessa Zonneveld (AUMC psychiatry) & Melanie de Wit (VU, Clinical Developmental Psychology) will receive NWA (nationale wetenschapsagenda) funding to set up an outreach program “DNA Cinema” in collaboration with Scholieren Filmfestival, VU audiovisueel centrum and Rialto:

Summary: Genetic research is currently developing at a rapid pace, and more and more is possible, such as determining predispositions for diseases and behavior, embryonic selection, and DNA modification. The current generation of adolescents will be the most confronted with these developments. It is therefore essential that this group is well-informed about the interpretation and implications of genetic research, and about aspects of ethics and privacy. Conversely, it is important that scientists in genetic research are aware of the thoughts and possible misconceptions among young people and learn about the most optimal ways to communicate research findings. To this end, we want to approach high schools for the ‘DNA cinema’ project, in which students prepare and execute a film festival. During this project, the students make videos on topics around the theme of genetic research and society. The videos are shown during the festival along with an existing feature film on this theme and activities where the topics from the films are discussed with scientists. Throughout the project, the students reflect together on the theme and there is dialogue with scientists. In this way, we ensure that the students become more knowledgeable in an accessible manner, and that young people and scientists learn from each other’s perspectives on this theme.

We are extremely excited about this novel GENE amsterdam collaboration/activity, and for the opportunity to invest in our outreach and contribute to the education of high school students. If you have questions about this project, or are interested in implementing this in your local high school, do not hesitate to reach out to the network, or the individual researchers.