Schizophrenia is a severe psychiatric disorder which affects about 1 % of the population worldwide. Although current treatments are at least partially effective in most individuals, there are no biological tools to identify an individual’s risk to develop schizophrenia or the probability of a patient responding adequately to treatment. The lack of biological tools is hampered by our limited understanding of the biological causes of schizophrenia.
Studying gene regulation
Schizophrenia is caused by an interplay of genetic and environmental factors, such as obstetric complications, traumatic experiences, and infections (1). Many studies have found genetic variants, positions in the DNA that vary in the population, that are associated with the development of schizophrenia (2). However, genetic variants are established at fertilization and stay constant over an individual’s lifetime. By contrast, the regulation of genes varies dynamically throughout the life and is also involved in the causes of schizophrenia (3). Gene regulation is the process of controlling the timing, location, and amount of gene expression in the cells. Age, disease pathology and exposure to environmental factors are examples of factors that change gene regulation.
DNA methylation regulates genes
One method to explore gene regulation is to study DNA methylation, a mechanism which is the addition of a chemical group to a part of the DNA molecule. This addition does not change the actual DNA sequence but can affect the gene activity. Therefore, DNA methylation is a gene regulation mechanism that controls which genes are active throughout all stages of development from fetus to adult and further through the aging process. DNA methylation also changes as a response to environmental factors such as the food we eat, smoking, trauma and physical exercise.
However, there is a challenge in studying DNA methylation: it is cell-specific. This means that the DNA methylation in a blood cell is not the same as in a brain cell. As schizophrenia is a disorder that affects the brain, we need to study the DNA methylation in brain cells to understand the disorder’s causes. Yet, direct access to the living brain to collect samples is not feasible.
Predicting DNA methylation in the brain by using blood cells
Historically, peripheral tissues such as hair, skin and blood have been used to study the biology of schizophrenia. Peripheral tissues are useful because they can be easily collected from the individual without causing any harm, and they can give to researchers a very relevant biological information: the genetic variants.
In my project, we apply a statistical method that predicts the level of DNA methylation in the brain by using genetic variants obtained from blood. This method is called “imputation of DNA methylation” (see figure below) and can be done because the DNA code is the same in all cells of the human body. Although the DNA methylation differs among cells, part of DNA methylation is determined by the DNA code. Therefore, by having the genetic variants from an individual, we can predict the levels the DNA methylation that is driven by the genetic variants in their brain.
Predicting the levels of DNA methylation in the brain of patients with schizophrenia allows us to better understand the biology of schizophrenia. The understanding of its biology is necessary to create medical tools that will allow physicians to identify individuals at high risk of developing schizophrenia before they have the first symptoms or to give more effective treatment for their patients with less size effects.
References
- Schizophrenia. Nat Reviews Disease Primers 1, 15069 (2015).
- Trubetskoy, V., Pardiñas, A.F., Qi, T. et al. Mapping genomic loci implicates genes and synaptic biology in schizophrenia. Nature 604, 502–508 (2022).
- Hannon, E., Spiers, H., Viana, J. et al. Methylation QTLs in the developing brain and their enrichment in schizophrenia risk loci. Nat Neurosci 19, 48–54 (2016).
Contact