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An Estonian geneticist found that while people predisposed to schizophrenia have a slightly lower body mass index than average, the medications they are prescribed may lead to weight gain. This study based on data from the Estonian Biobank was preceded by three years of post-doctoral studies at the University of Geneva, which broadened the researcher’s horizons but required a great capacity for independent work.
Compared to the general population, patients diagnosed with schizophrenia are almost one third more likely to have metabolic syndrome. This means that they are more likely to experience symptoms of cardiovascular disease, such as hypertension and obesity. “At the same time, schizophrenia is characterised by episodic hallucinations and delusions, as well as a lack of interest and energy, a decline in mental capacity and an inability to perform everyday activities,” adds Maris Alver, a researcher of functional genomics at the University of Tartu.
“The vision for the future is to get to a point where the genetic component is taken into account at the clinic: the doctor has access to it and can easily incorporate it into the model.”
While Alver’s doctoral thesis focused on cardiovascular disease genetics, she completed her post-doctoral studies at the University of Geneva from 2019 to 2022, where she completed two papers that clarified the role of the genome in the development of schizophrenia. Back in Estonia, she focused on the link between the two diseases.
Alver is now using data from the Estonian Biobank to study how to develop a risk assessment model for schizophrenia patients. In the future, a model that takes metabolic syndrome into account should become part of the doctor’s toolkit. She adds, “The vision for the future is to get to a point where the genetic component is taken into account at the clinic: the doctor has access to it and can easily incorporate it into the model.”
Can a high fever prevent schizophrenia?
Maris Alver and colleagues studied 677 people diagnosed with schizophrenia in a new study that is still awaiting peer review. To establish a point of comparison, for each patient with schizophrenia, they also studied four patients without schizophrenia of the same age and sex. “We found that genetic predisposition to schizophrenia was significantly greater in the patients than in the control group,” said Alver. “This showed that we are studying the right population, and that genetic predisposition has a significant role in the development of the disease.
“A number of studies have shown that if you naturally have a heightened inflammatory response, you also have a lower risk of developing schizophrenia.”
Patients were also found to have fewer genetic variants associated with a rise in body mass index than the control group. Patients also had a significantly lower genetic predisposition for a heightened inflammatory response – their immune system does not respond to pathogens as extensively and effectively as it should. “The inflammatory response and body mass index are genetically linked,” Alver explained. “A number of studies have shown that if you naturally have a heightened inflammatory response, you also have a lower risk of developing schizophrenia.”
Alongside the genetic data, the research team also looked at the participants’ purchase history for medication. By doing this, it was possible to distinguish between healthy individuals and patients who did or did not follow their prescribed treatment regimen. “We monitored these people for ten years on average,” said Alver. “We started following each person from the moment they were diagnosed with schizophrenia. We found that over time, antipsychotics increase body weight.
We can see that in the control group, and in patients who never take medication, the body mass index increases by approximately one and a half points in ten years, which is to be expected. However, once a patient starts taking medication every year, we can see that their body mass index rises by four and a half points in ten years.” At the same time, without treatment, people predisposed to schizophrenia always had a slightly lower body mass index than the control group.
However, if the genetic predisposition for a higher body mass index is high in a patient receiving treatment, weight gain will be significantly more pronounced. “This shows that individual genetic traits need to be taken into account,” Alver points out.
“Broadly speaking, the literature suggests that patients who receive treatment are more likely to be aware of what they need to do.”
In other words, going above the normal weight range is almost inevitable, but Alver says that in no case do the research results suggest not taking the medication. “We saw that patients generally get diagnosed with metabolic syndrome earlier than controls, but if the patient has a good treatment outcome, then this may actually prevent these complications in the long run,” Alver explains.
According to her, previous research demonstrates the positive impact of physical activity and a healthy lifestyle in preventing complications. “Broadly speaking, the literature suggests that patients who receive treatment are more likely to be aware of what they need to do. They also take other necessary medications and keep an eye on their health behaviours.”
According to the researcher, further research in this area is needed: for example, she plans to evaluate the impact of different antipsychotics separately. “Here, we only studied body mass index and all medications combined, but patients are assessed on a number of different parameters,” she discusses. “We could examine the trajectories of metabolic syndrome for a number of different parameters and take medication-specific effects into account, too.”
Through hardship towards comprehensiveness
As mentioned, Maris Alver spent three years as a post-doctoral researcher in Switzerland. “It is a process following doctoral studies where the researcher can get out of their home base and go somewhere else,” Alver explains. “There, they will conduct research in a new environment, with different people and supervisors, and sometimes on a slightly different research topic.” In addition, post-doctoral experience is a prerequisite for applying to several research grants.
“Post-doctoral research is a process following doctoral studies where the researcher can get out of their home base and go somewhere else.”
Alver herself has varied emotions about her experience at the University of Geneva. On the one hand, she found herself in a very strong research team. Its lead professor had been studying the role of the regulatory genome in gene expression and disease development for a long time. “He always asked very simple questions with a transparent analysis,” remembers Alver. “On the other hand, he was tough as a professor and reinforced the idea that you have to be fully responsible for your own work.”
According to Alver, many researchers at the Estonian Genome Centre, University of Tartu are working with the Estonian Biobank data source on a wide variety of questions. If you ask a colleague for help, they will help you. “In Geneva, I had to download all the data from the database and clean and analyse it from start to finish,” she describes. She also had to know every detail of her research and be able to anticipate what the supervisor would ask next. “This sort of research standard made a strong impression on me,” she says.
While Alver spent the first year getting settled in and the second year delving deeper, at the end of the second year, her supervisor announced that he is leaving the university to work for a private company. On top of this, the COVID pandemic began during the second half of the first year of her post-doctoral studies. “We were kind of on our own in the final year,” she remembers. “During this time, I felt like I lost the support system at the university. I had to fight alone to pull everything together.”
By the end of the demanding third year, Alver become exhausted. “When I came back, I did not feel like doing anything at all. I was feeling burnt out. At the same time, as I returned, I really felt like I was coming home.” She wanted to apply for the returning researcher grant but was not eligible because she had by then already been in Estonia for some time. She also failed to publish the required number of scientific papers at the required speed. “Publishing scientific papers is a long process, and it can often take another year after the project ends to finish writing,” she explains.
“On the one hand, I believe that the current system needs some adjustments. On the other hand, post-doctoral studies were irreplaceable for me.”
The next step was to apply for a starting grant. “I knew that my project wasn’t perfect and was going to be very large in scale, but I still pursued it – while still feeling burnt out,” she explains.
Despite of the hardships, Alver does not regret her three years in Geneva. According to her, the three years abroad were also good for her daughter, who was a shy five-year-old when they went to Geneva. When she left at the age of eight, she was fluent in French and could easily socialise with her friends. “On the one hand, I believe that the current system needs some adjustments,” says Alver. “On the other hand, post-doctoral studies were irreplaceable for me. Going forward in my research career, it gave me the courage to think, to speak and to approach issues with increased self-awareness and broadened horizons.”
On her return, she is grateful to her colleagues at the Estonian Genome Centre as well as to her new research associate, psychiatrist Liina Haring. “Working with her motivated me to get back into action and got me out of that hole. Thanks to her, I not only feel like my work will have some kind of impact in the future, but I can also already see an impact today, as she works with these people on a daily basis. The impact of our work is tangible in real life.”
This article was originally published on the Estonian Public Broadcasting online news portal. Author: Airika Harrik
