Aspectos genéticos e fisiológicos envolvendo estresse crônico relacionados a deficiência intelectual e habilidades cognitivas de crianças e adolescentes da Coorte de nascimentos de Pelotas de 2004

Abstract

Cognitive ability in childhood is an important predictor of health, educational performance, and income in adulthood. Approximately 1% to 3% of children worldwide have some form of intellectual disability, which is a major public health problem. Neurological problems such as intellectual disability (ID) are known to be caused by environmental and/or genetic factors. In addition, children with neurological impairment have endocrine alterations, such as in the hypothalamic-pituitary-adrenal (HPA) neuroendocrine axis, the main effect of which is the production of cortisol. The aim of this thesis was to contribute to the elucidation of genetic and physiological factors associated with ID and general intelligence through a systematic literature review and meta-analysis, as well as original analyses in individuals participating in the 2004 Pelotas Birth Cohort (N=4,231). ID in childhood is characterized by a deficiency in general mental ability, associated with an intelligence quotient (IQ) less than 2 standard deviations from the population mean, and adaptive limitations in various domains. ID is a condition of heterogeneous etiology and clinical presentation. Currently, for the etiologic diagnosis of ID, it is proposed to evaluate the presence of genetic variants causing the disorder by whole exome sequencing (WES). The aim of this thesis was to contribute to the elucidation of genetic and physiological factors associated with ID and general intelligence through a systematic literature review and meta-analysis, as well as original analyses in individuals participating in the 2004 Pelotas Birth Cohort (N=4,231). ID in childhood is characterized by a deficiency in general mental ability, associated with an intelligence quotient (IQ) less than 2 standard deviations from the population mean, and adaptive limitations in various domains. ID is a condition of heterogeneous etiology and clinical presentation. Currently, for the etiologic diagnosis of ID, it is proposed to evaluate the presence of genetic variants causing the disorder by whole exome sequencing (WES). However, most cases of non-specific ID remain undiagnosed. In this thesis, we investigated the rate of molecular diagnosis of ID by WES using a meta-analysis of articles published up to 2022. The results show that the WES test is responsible for an overall diagnostic rate of 42% of ID cases, and that this rate is even higher when samples from both parents are included in the analysis. In addition, we identified sets of genes that could be considered as proposed etiologic pathways of ID to be explored. With a greater focus on cognitive abilities, in an original article in the thesis, we aimed to identify factors associated with intelligence (IQ) in the period of child development in the 2004 Pelotas birth cohort. It is known that intelligence is a multifactorial trait that results from a complex relationship between genetic and environmental factors throughout the life cycle. Therefore, we sought to test the association of a polygenic score for IQ and early child stimulation (ECS), as well as the interaction between them, to modify IQ at 6 years of age. Both factors were independently associated with IQ and no effect modification was observed. Finally, in the last original article of the thesis, we tested the association between ID and hair cortisol concentration, obtained at the age of 15, in the same cohort. Our results suggest that individuals with DI have higher concentrations of capillary cortisol, mainly cases characterized as idiopathic, have a higher concentration of capillary cortisol compared to neurotypical children. Thus, it is possible that individuals with ID may have problems with the HPA axis or the stress response in adolescence. This work contributes to the elucidation of genetic factors involved in ID, as well as general intelligence, and opens up new ways of exploring etiological factors in ID.