GENE Amsterdam Interview Session 3: Philip Jansen

Can you tell us about your background and how you became both a clinical geneticist and researcher in complex trait genetics?

I went to Erasmus Medical Center where I completed my medical degree in 2014. Interestingly, my medical training included very little education in genetics, which is surprising given its growing importance in healthcare. After graduating, I pursued my Ph.D. in the Department of Complex Trait Genetics led by Danielle Posthuma, where my focus was on polygenic risk scores for psychiatric disorders and brain imaging. After obtaining my Ph.D. I started my clinical training, which I will finish next year, and will start working as a clinical geneticist at the Amsterdam UMC (location AMC). Currently, my clinical work is mainly focused on monogenic diseases, such as heritable forms of Alzheimer’s disease and dementia, movement disorders, and developmental problems in children. My research is mainly focused on complex trait genetics in the broadest sense.

Is there any significant overlap between your clinical and academic work?

The overlap is currently minimal, unfortunately. That’s because, in monogenic disease genetics, there is hardly any involvement of common or complex genetics in genetic diagnostics. However, this is slowly changing with the development of polygenic risk scores. Recent papers (e.g. Khera et al. (2018)) have shown that for some conditions, being in a high percentile of polygenic risk can be compared to a relative risk of a monogenic mutation that we test for in the clinic. People are now thinking about ways to bring polygenic scores to the clinics. To provide a potential example I encountered in my own work: We have an expertise center for genetic obesity, where individuals are tested for monogenic forms of obesity. A subset of patients have a very high polygenic score and do not have monogenic mutations for obesity. Whereas in the lower polygenic score segment, we find many more rare monogenic mutations. I think that’s a way we can use polygenic risk scores in the future, by informing us in which individuals a monogenic cause might be found and aiming our genetic sequencing mostly on that group. 

Do you see a role for a clinical geneticist in the field of psychiatric disorders as well?

Yes, I do. We often see patients who have multiple family members with, for example, schizophrenia who want to know their children’s risk of that disorder, which is very difficult to estimate based on the literature. 

It would be great to improve our estimates using genetic testing. There are recently discovered rare mutations that increase the relative risk of schizophrenia by 50 times. It would be useful to incorporate this kind of information into the clinic, and maybe combine it with polygenic risk scores to further improve our risk estimates. 

What does your research focus on?

I am currently working on the relationship between sleep problems and dementia, which have an epidemiological correlation with each other, but we’re still not sure whether one causes the one or the other way around, or whether there are genes that could explain this correlation. To tackle this, I am looking into the genetics of brain aging. With machine learning, we can estimate someone’s age from their MRI brain scans with an average error of about three years. We did a GWAS on the gap between someone’s actual age and their predicted age based on their brain scans. The associated genetic variants were not strongly related to insomnia, but we found many significant genetic correlations with psychiatric disorders, mainly anxiety-related disorders. You can imagine that if you are more anxious, you may have higher cortisol levels or a less optimal healthy lifestyle which could explain this finding.

How do you balance your time between your clinical and academic work?

When working in the clinic, it is sometimes difficult to switch gears to focus on research. Alternating weekly between both helps but clinical work always goes on, so you cannot separate it that easily. If a patient needs to be called about new test results, this always comes first. While it can be tricky, it also has benefits. Clinical work can be quite overwhelming, but it does provide you with a lot of diversity that research doesn’t, because you’re working with new people every day, and every patient contact is different. Clinical work brings you a lot, but there is a commitment and offer that you need to be able to make. It also makes it easier to come up with clinically relevant research questions and fill a need.

What does a typical day in the clinic look like?

This morning we started with patient rounds, which are multidisciplinary discussions with other specialists. Then I saw three new patients who were referred to our clinic. We have plenty of time for each new patient, which is relatively rare in a hospital. This time is necessary since an important part of the intake is to look at the family history and draw a family tree with the patient to get a first idea about the inheritance pattern of the disease. Afterward, I had a research discussion about a polygenic risk score project. But the bulk of my days (like many other clinical specialties) are taken up by the administration.

If you could have dinner with any scientist (living or dead), who would it be and why?

There is an influential Dutch geneticist who you hardly hear about. His name is Hugo de Vries, a contemporary of Mendel’s who coined the term mutation. Similar to Mendel, he’s done a lot of plant experiments and was an important discoverer of his work. Can you imagine telling him about GWAS, that would probably blow his mind. I think it is time to start thinking about developing a Hugo de Vries prize for outstanding scientists in the field!

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