Periodic Reporting for period 1 - GENDOSIS (GENOTYPE - ENDOPHENOTYPE ASSOCIATIONS IN PSYCHOSIS)
Reporting period: 2017-07-15 to 2019-07-14
Psychotic disorders, including schizophrenia and bipolar disorder, are imposing an increasing burden on the health of the European population, with an estimated five million affected individuals. As available drugs remain ineffective for 30% of the patients and come with many secondary effects, there is urgent need to develop more effective and safer therapeutic agents. Due to the high level of heritability of these disorders, discovering which genetic alterations are responsible for their appearance and through which mechanisms they promote disease is a promising venue for the discovery of better drugs. There are two main types of genetic alterations that have been shown to be implicated in the risk of developing psychotic disorders. On one hand, the single nucleotide polymorphisms (SNPs), which are changes in an only position in the genome and, on the other hand, copy number variants (CNVs), which are deletions or duplications of large chunks of DNA. One of the methods that can be used to shed light on the mechanisms through which those genetic alterations lead to disease is the study of endophenotypes, that is, biological characteristics that are altered in the disease and affected by some of the genetic alterations implicated in the disease. Among the endophenotypes that have been shown to be altered in psychotic disorders we can find cognitive abilities, volumes of brain regions and patterns of brain activity as measured by electroencephalography (EEG).
Thus, we aimed at exploring how CNVs and SNPs might influence different endophenotypes of psychosis in order to shed light on the mechanisms through which they contribute to the development of the disease.
To that aim, we performed several studies exploring the effects of genetic alterations on cognitive, brain volume and brain activity features. The results of those studies have revealed that copy number variants have an important role in producing some of the alterations observed in patients with psychosis, like learning and memory impairments and changes in the volume of brain regions, and that they need to be taken into account to fully understand the genetic changes responsible for the disease. It has also shown that some of the biological alterations we observe to be present in the adult patients, like the MMN response, are determined by molecular changes happening much earlier, even in the fetal brain. This reinforces the idea of searching for biological markers of the disease before the appearance of symptoms and emphasizes the need to improve our technology that, currently, is not capable of identifying those early molecular changes.
Thus, we aimed at exploring how CNVs and SNPs might influence different endophenotypes of psychosis in order to shed light on the mechanisms through which they contribute to the development of the disease.
To that aim, we performed several studies exploring the effects of genetic alterations on cognitive, brain volume and brain activity features. The results of those studies have revealed that copy number variants have an important role in producing some of the alterations observed in patients with psychosis, like learning and memory impairments and changes in the volume of brain regions, and that they need to be taken into account to fully understand the genetic changes responsible for the disease. It has also shown that some of the biological alterations we observe to be present in the adult patients, like the MMN response, are determined by molecular changes happening much earlier, even in the fetal brain. This reinforces the idea of searching for biological markers of the disease before the appearance of symptoms and emphasizes the need to improve our technology that, currently, is not capable of identifying those early molecular changes.
We first performed a study to explore the effect of CNVs on cognitive performance. On one hand, we reviewed the results of several previous studies exploring the effect of CNVs on general intelligence and analysed their results collectively. And, on the other hand, we explored the effects of CNVs on different aspects of cognition using data collected by ourselves. The study revealed that carrying one of the CNVs that in previous studies have been shown to increase the risk to suffer from schizophrenia impairs learning and short-term memory. The results also suggest that having more genes affected by deletions is related to the same impairments. However, no effect was observed on general intelligence as measured by IQ.
We then performed an study to explore the effect of not only CNVs, but also SNPs, on the volume of the lateral ventricles, that is, the two largest of the cavities inside the brain. The lateral ventricles have been shown to be enlarged not only in patients with schizophrenia, but also in their close relatives that do not suffer from the disease, indicating that there must be one or more genetic alterations that affect both the volume of the lateral ventricles and the risk to suffer disease, but that is/are not enough to cause it. The results of the study revealed that, while the number of psychosis-associated SNPs a person has does not affect the size of their lateral ventricles, having more genes affected by deletions is linked to larger volumes. However, these results were not robust from a statistical point of view, so, in order to confirm their validity, they need to be replicated in an independent sample of individuals.
And, finally, we performed a third study to explore which genes across the genome may affect mismatch negativity (MMN), a brain activity pattern in response to regular and salient stimuli observed in EEG measurements. Patients with schizophrenia and their unaffected relatives have been shown to present impaired MMN responses, meaning that their brain responds more similarly to regular and salient sounds than the brain of healthy people unrelated to psychosis patients do. We thus performed a transcriptome-wide association study, or TWAS, to explore which genes might be implicated in determining MMN responses. The TWAS approach estimates the tendency of each gene of being highly or lowly active in each person looking at the SNPs (single position changes) across the whole genome and tries to establish a connection between that tendency of higher/lower activity for each gene and any biological characteristic like, for example, the MMN response. The TWAS study on MMN revealed that the genes that have an effect on the MMN response tend to be very active in the brain during fetal development, that is, before birth, and silenced in the adult brain. This suggests that the characteristics of the brain that determine how strong its MMN response is going to be in adulthood are mainly shaped before birth.
We then performed an study to explore the effect of not only CNVs, but also SNPs, on the volume of the lateral ventricles, that is, the two largest of the cavities inside the brain. The lateral ventricles have been shown to be enlarged not only in patients with schizophrenia, but also in their close relatives that do not suffer from the disease, indicating that there must be one or more genetic alterations that affect both the volume of the lateral ventricles and the risk to suffer disease, but that is/are not enough to cause it. The results of the study revealed that, while the number of psychosis-associated SNPs a person has does not affect the size of their lateral ventricles, having more genes affected by deletions is linked to larger volumes. However, these results were not robust from a statistical point of view, so, in order to confirm their validity, they need to be replicated in an independent sample of individuals.
And, finally, we performed a third study to explore which genes across the genome may affect mismatch negativity (MMN), a brain activity pattern in response to regular and salient stimuli observed in EEG measurements. Patients with schizophrenia and their unaffected relatives have been shown to present impaired MMN responses, meaning that their brain responds more similarly to regular and salient sounds than the brain of healthy people unrelated to psychosis patients do. We thus performed a transcriptome-wide association study, or TWAS, to explore which genes might be implicated in determining MMN responses. The TWAS approach estimates the tendency of each gene of being highly or lowly active in each person looking at the SNPs (single position changes) across the whole genome and tries to establish a connection between that tendency of higher/lower activity for each gene and any biological characteristic like, for example, the MMN response. The TWAS study on MMN revealed that the genes that have an effect on the MMN response tend to be very active in the brain during fetal development, that is, before birth, and silenced in the adult brain. This suggests that the characteristics of the brain that determine how strong its MMN response is going to be in adulthood are mainly shaped before birth.
The studies performed in the context of this action have taken our knowledge of the neurobiology of schizophrenia and psychosis one step further. It has become clear that copy number variants influence cognitive performance but, rather than affecting global intelligence, their effect is revealed in specific cognitive abilities like learning and memory. We now also know that they can affect the volume of the lateral ventricles in the brain, which have been observed to be enlarged in patients with psychosis. And, finally, the fact that, according to our TWAS, the genes that influence the tendency of assigning salience to the stimuli in our environment exert their effect mainly in pre-natal development strengthens the hypothesis of schizophrenia being, mainly, a disease that results from altered neurodevelopment and opens up the possibility of identifying molecular changes that predict the development of the disease much earlier than the appearance of the symptoms.
This deepening of our understanding of both the genetics and the neurobiology of schizophrenia will most likely contribute to the development of more effective and safer pharmacological agents and of better informed non-pharmacological therapeutic strategies that will help alleviate the increasing burden of the psychotic disorders in the European population. The identification of early molecular alterations that will help us identify who is at high risk of developing schizophrenia, would allow us to perform early interventions aimed at, on one hand, reducing the likelihood of the person actually developing the disease and, on the other hand, reducing the negative impact of the disease if/when is clinically revealed.
This deepening of our understanding of both the genetics and the neurobiology of schizophrenia will most likely contribute to the development of more effective and safer pharmacological agents and of better informed non-pharmacological therapeutic strategies that will help alleviate the increasing burden of the psychotic disorders in the European population. The identification of early molecular alterations that will help us identify who is at high risk of developing schizophrenia, would allow us to perform early interventions aimed at, on one hand, reducing the likelihood of the person actually developing the disease and, on the other hand, reducing the negative impact of the disease if/when is clinically revealed.