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Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/118023
Genetic risk factors in Schizophrenia and Neurodevelopmental disorders: Association and epistatic analyses of Neuritin-1 gene and white matter related genes = Factores genéticos en esquizofrenia y enfermedades del neurodesarrollo: análisis de asociación y epistáticos en el gen Neuritina-1 y en genes relacionados con la materia blanca
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[eng] Nowadays, it is estimated that about 450 million people suffer from a mental or behavioural disorder in the world. According to World health organization (WHO), 33% of the years lived with disability (YLD) are due to psychiatric disorders. In this regard, psychotic disorders including schizophrenia (SZ), remain one of the most mysterious and costliest mental disorders in terms of human suffering and social expenditure.
In recent years, the field of molecular genetics has been uncovering evidence of the complex polygenetic architecture of SZ and related disorders. In addition, GWAS studies have identified several genes associated with SZ, which have been shown to converge in complex and identifiable molecular pathways related to synaptic plasticity, neurotransmission and connectivity processes. Also, these studies have reported an important genetic overlap across several psychiatric disorders such as Schizophrenia (SZ), Bipolar disorder (BPD), Major Depressive Disorder (MDD) or Autism Spectrum Disorders (ASD), which adds to the consideration of common pathophysiological mechanisms among these disorders. In this sense, a growing body of evidence has established that connectivity and synaptic plasticity, modulated by neuronal activity, is an inherent feature of brain function during both development and adulthood.
The present dissertation hypothesizes that genetic variability of genes involved in either synaptic plasticity (NRN1, BDNF and DTNBP1) and/or white matter related pathways (and their interactions) will be associated with SSD. In addition, due to the clinical, cognitive, neuroimaging and genetic overlap observed across different psychiatric disorders, we also hypothesize that the studied genetic variability will be also associated with other neurodevelopmental psychiatric disorders, such as ASD and BPD. In this sense, four studies have been carried out. The first three studies, analyse genetic variability at Neuritin-1 gene (NRN1) and its relationship with the risk for developing SSD and BPD, and also with some clinical and cognitive phenotypes both in patients and in healthy subjects from the general population. Moreover, in these studies we also analyzed whether NRN1 action is modulated by other genes such as BDNF and DTNBP1. The fourth study analyses the integrative effects of a set of white matter related genes (Oligodendrocyte/myelination related genes - OMR) and its contribution to both SSD and ASD. Our results focused on the genetic variability at NRN1 gene, suggest that genetic variability of NRN1 gene has an impact on the risk for developing SSD/BPD and also on the presence of depressive symptoms in the general population. Its pleiotropic effect is also evidenced by its effect on different phenotypes: such as cognitive performance and age at onset. Moreover, our genexgene interaction results suggest that NRN1 action is modulated by the BDNF and DTNBP1 genes. On the other hand, the results of the fourth study suggest that some of the OMR genetic risk variants seem to be shared across SZ-ASD continuum. The fact that some OMR genes are marginally associated with both disorders and also, due to their involvement in the detected epistatic effects, seem to support the notion that dysregulation in myelination processes may underlie susceptibility to develop ASD or SSD. To conclude, further genetic studies are needed to elucidate the biological background underlying mental disorders, which can ultimately lead to better treatment in order to improve the quality life of the patients.
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PRATS BALADO, Claudia. Genetic risk factors in Schizophrenia and Neurodevelopmental disorders: Association and epistatic analyses of Neuritin-1 gene and white matter related genes = Factores genéticos en esquizofrenia y enfermedades del neurodesarrollo: análisis de asociación y epistáticos en el gen Neuritina-1 y en genes relacionados con la materia blanca. [consulta: 5 de desembre de 2025]. [Disponible a: https://hdl.handle.net/2445/118023]