Estudo sobre a interação entre determinantes sociais e vulnerabilidade genética para psicose e sua associação com fenótipos clínicos em crianças e adolescentes
Data
2022-12-09
Autores
Fonseca, Laís Moreira 
Orientadores
Araripe Neto, Ary Gadelha de Alencar
Tipo
Tese de doutorado
Título da Revista
ISSN da Revista
Título de Volume
Resumo
Introdução: Os transtornos psicóticos representam o produto de uma complexa interação entre vulnerabilidade genética e exposição a estressores ambientais ao longo do desenvolvimento, de modo fase-específico. Ampliar a diversidade em pesquisas sobre fatores genéticos e ambientais, incluindo populações pouco representadas nos estudos, é uma necessidade ainda não atendida. Nos últimos anos, o escore de risco poligênico (PRS – Polygenic Risk Score) tem sido amplamente explorado para patologias psiquiátricas, entre elas a esquizofrenia (SZ). Contrário ao esperado, pesquisadores não encontraram correlações claras entre PRS-SZ e manifestações sublimiares do espectro psicótico, como experiências psicóticas (PE), durante a infância e adolescência. Resultados mais expressivos foram obtidos em estudos que investigaram associações entre o PRS-SZ e alterações comportamentais inespecíficas ou dificuldades cognitivas.
Objetivo geral: Discutir a importância de ampliar a representatividade de populações não caucasianas nos estudos genéticos sobre psicose e explorar associações que evidenciem os efeitos precoces da vulnerabilidade genética para esquizofrenia, individualmente e junto a exposições ambientais, ao longo do neurodesenvolvimento
Objetivos específicos: Estudo 1: Discutir como a investigação genética de transtornos psicóticos em países da América Latina pode ajudar na compreensão da psicose. Estudo 2: Testar a capacidade de dois escores poligênicos (PRS-SZ e PRS-PE) e de um escore agregando os riscos ambientais (PERS) em prever experiências psicóticas em uma amostra comunitária de crianças e adolescentes no Brasil. Estudo 3: Investigar a associação entre PRS- SZ e função executiva (EF), e o possível papel mediador de EF nas relações entre PRS-SZ e desfechos comportamentais e funcionais em uma amostra comunitária de crianças e adolescentes no Brasil.
Métodos: Estudo 1: Revisão de escopo sobre os estudos já realizados e os desafios e oportunidades ligados à investigação genética de psicose em países latino-americanos. Estudos 2: Uso de modelos de mediação e moderação para testar a associação entre PRS-SZ / PRS-PE e experiências psicóticas, através do PERS (usado como mediador e moderador). Foram analisados dados
xvi
longitudinais (primeiro follow-up – 3 anos) do Projeto Conexão – INPD, uma coorte que inclui a avaliação inicial de 2.511 jovens de 6 a 12 anos. Estudo 3: Uso de modelos lineares para testar a associação direta entre PRS-SZ e EF; uso de modelos de mediação para testar a associação entre PRS-SZ e desfechos mais distais – psicopatologia geral, sintomas ansiosos, experiências psicóticas e desempenho escolar –, através de EF (mediador). Foram analisados os dados da mesma corte citada no Estudo 2.
Resultados: Estudo 1: Menos de 2% dos estudos sobre genes candidatos (19 de 1,188 publicações) e apenas 1 estudo de associação genética em larga escala (GWAS – Genome-wide association study) foram conduzidos na América Latina. A falta de diversidade étnica nas amostras limita a replicabilidade dos achados e avanços na compressão da esquizofrenia como um todo. Estudo 2: Os escores poligênicos não foram capazes de predizer o desfecho, nem combinados (PERS+PRS-PE e PERS+PRS-SZ) nem separadamente. Os resultados demonstram que não há associação entre PE e PRS ou PERS nos jovens na amostra estudada. Estudo 3: Escores mais altos de PRS-SZ se associaram com medidas de EF mais baixas. Associações diretas entre PRS-SZ e psicopatologia geral, sintomas de ansiedade, PE ou desempenho escolar não foram significativas. Entretanto, EF atuou como mediador em três modelos de mediação, produzindo efeitos indiretos de PRS-SZ em psicopatologia geral, sintomas de ansiedade e desempenho escolar. Nenhuma associação foi significativa em relação à PE.
Conclusão: Estudo 1: É essencial incentivar a investigação em populações latino-americanas. Colaborações internacionais na América Latina representam uma possível solução para esses problemas. Estudo 2: A ausência de associações entre PRS, PERS e PE pode ser resultado da falta de generalização de PRS e PERS na população brasileira. Adicionalmente, questiona-se a especificidade de experiências psicóticas. Estudo 3: Nossos resultados, positivos e negativos, sugerem que EF representa um meio para entender como o PRS-SZ pode impactar fenótipos comportamentais e funcionais durante o neurodesenvolvimento, indicando também a sobreposição da vulnerabilidade genética entre esquizofrenia e outros transtornos mentais.
Introduction: According to the most accepted pathophysiological theories, psychosis represents the product of a complex interaction between genetic vulnerability and exposure to environmental exposures throughout development, in a phase-specific way. However, most of the genetic studies available have explored Caucasian populations, which limits the replicability and generalization of their findings. Expanding diversity on research of genetic and environmental factors, especially including populations that are poorly represented in the studies, is an unmet need. In addition, detecting how both genetic and environmental liabilities are expressed during neurodevelopment can facilitate the pathophysiological understanding of psychosis, and also inform on new treatment interventions or even preventive ones. In recent years, the polygenic risk score (PRS - Polygenic Risk Score) has been widely explored for psychiatric pathologies, including schizophrenia (SZ). But contrary to expectations, researchers found no clear correlations between PRS-SZ and subliminal manifestations along the psychotic spectrum, namely psychotic experiences (PE) during childhood and adolescence. More robust results were obtained in studies that investigated associations between the PRS-SZ and unspecific behavioral changes or cognitive impairments. Models that explore these phenotypes interact and the proximal effects of genetic risk for schizophrenia, acting in conjunction with environmental exposures, constitute another gap in the literature. Main objective: To discuss the importance of expanding the representation of non-Caucasian populations in genetic studies on psychosis and to explore associations that show the early effects of genetic vulnerability to schizophrenia, individually and combined with environmental exposures, throughout neurodevelopment. Specific objectives: Study 1: To review previous studies carried out in Latin American populations and discuss how the genetic investigation of psychotic disorders in Latin America, with its admixed population and socioeconomic contexts, can improve the understanding of psychosis. Study 2: To investigate the ability to predict PE using two polygenic risk scores (PRS-SZ and PRS-PE) and polyenvironmental risk score (PERS), in adolescents from a xxBrazilian sample. Study 3: To explore early associations of PRS-SZ and test if executive function (EF) mediates the effect of PRS-SZ on psychopathology and functional phenotypes in a community-based sample of children and adolescents. Methods: Study 1: Comprehensive review on previous studies conducted in Latin America and discussion of challenges and opportunities of genetic investigations on psychosis in Latin American countries. Studies 2: Mediation and moderation models were used to test the association between PRS-SZ / PRS PE and psychotic experiences, through PERS (used as mediator and moderator). Longitudinal data was analyzed (first follow-up – 3 years) from Projeto Conexão, from the Instituto Nacional do Desenvolvimento, a cohort that includes the initial evaluation of 2,511 youths aged 6 to 12 years. Study 3: Linear models were used to test the direct association between PRS-SZ and EF; mediation models were used to test the association between PRS-SZ and more distal outcomes – general psychopathology, anxiety symptoms, psychotic experiences and school performance – through EF (mediator). Data from the same court mentioned in Study 2 was analyzed. Results: Study 1: Less than 2% of candidate gene studies (19 of 1,188 publications) and only 1 Genome-wide Association Study (GWAS) have been conducted in Latin America. Such lack of representativeness hinders the applicability of the findings and a better comprehension of issues of ethnic diversity and allele frequency in psychotic disorders. Thus, it is essential to encourage research in Latin American populations. International collaborations in Latin America represent a possible solution to these problems. Study 2: The polygenic scores did not predict outcome, neither combined (PERS+PRS-PE and PERS+PRS-SZ) nor separately. The results demonstrate that there is no association between PE and PRS or PERS in adolescents in our sample. Study 3: Higher PRS-SZ scores were associated with lower EF measures. Direct associations between PRS-SZ and general psychopathology, anxiety symptoms, PE or school performance were not significant. However, EF acted as a mediator in three mediation models, producing indirect effects of PRS-SZ on general psychopathology, anxiety symptoms and school performance. No association was significant in relation to PE. Conclusion: Study 1: It is essential to encourage further research in Latin American populations. International collaborations in Latin America represent a xxipossible solution to these problems. Study 2: The absence of associations between PRS, PERS and PE may be a result of the lack of generalization of PRS and PERS in the Brazilian population. Additionally, the specificity of psychotic experiences is questioned. Study 3: Our results, both positive and negative, suggest that EF represents a hub to understand how PRS-SZ may impact behavioral and functional phenotypes during neurodevelopment, also indicating overlapping genetic vulnerability between schizophrenia and other mental disorders.
Introduction: According to the most accepted pathophysiological theories, psychosis represents the product of a complex interaction between genetic vulnerability and exposure to environmental exposures throughout development, in a phase-specific way. However, most of the genetic studies available have explored Caucasian populations, which limits the replicability and generalization of their findings. Expanding diversity on research of genetic and environmental factors, especially including populations that are poorly represented in the studies, is an unmet need. In addition, detecting how both genetic and environmental liabilities are expressed during neurodevelopment can facilitate the pathophysiological understanding of psychosis, and also inform on new treatment interventions or even preventive ones. In recent years, the polygenic risk score (PRS - Polygenic Risk Score) has been widely explored for psychiatric pathologies, including schizophrenia (SZ). But contrary to expectations, researchers found no clear correlations between PRS-SZ and subliminal manifestations along the psychotic spectrum, namely psychotic experiences (PE) during childhood and adolescence. More robust results were obtained in studies that investigated associations between the PRS-SZ and unspecific behavioral changes or cognitive impairments. Models that explore these phenotypes interact and the proximal effects of genetic risk for schizophrenia, acting in conjunction with environmental exposures, constitute another gap in the literature. Main objective: To discuss the importance of expanding the representation of non-Caucasian populations in genetic studies on psychosis and to explore associations that show the early effects of genetic vulnerability to schizophrenia, individually and combined with environmental exposures, throughout neurodevelopment. Specific objectives: Study 1: To review previous studies carried out in Latin American populations and discuss how the genetic investigation of psychotic disorders in Latin America, with its admixed population and socioeconomic contexts, can improve the understanding of psychosis. Study 2: To investigate the ability to predict PE using two polygenic risk scores (PRS-SZ and PRS-PE) and polyenvironmental risk score (PERS), in adolescents from a xxBrazilian sample. Study 3: To explore early associations of PRS-SZ and test if executive function (EF) mediates the effect of PRS-SZ on psychopathology and functional phenotypes in a community-based sample of children and adolescents. Methods: Study 1: Comprehensive review on previous studies conducted in Latin America and discussion of challenges and opportunities of genetic investigations on psychosis in Latin American countries. Studies 2: Mediation and moderation models were used to test the association between PRS-SZ / PRS PE and psychotic experiences, through PERS (used as mediator and moderator). Longitudinal data was analyzed (first follow-up – 3 years) from Projeto Conexão, from the Instituto Nacional do Desenvolvimento, a cohort that includes the initial evaluation of 2,511 youths aged 6 to 12 years. Study 3: Linear models were used to test the direct association between PRS-SZ and EF; mediation models were used to test the association between PRS-SZ and more distal outcomes – general psychopathology, anxiety symptoms, psychotic experiences and school performance – through EF (mediator). Data from the same court mentioned in Study 2 was analyzed. Results: Study 1: Less than 2% of candidate gene studies (19 of 1,188 publications) and only 1 Genome-wide Association Study (GWAS) have been conducted in Latin America. Such lack of representativeness hinders the applicability of the findings and a better comprehension of issues of ethnic diversity and allele frequency in psychotic disorders. Thus, it is essential to encourage research in Latin American populations. International collaborations in Latin America represent a possible solution to these problems. Study 2: The polygenic scores did not predict outcome, neither combined (PERS+PRS-PE and PERS+PRS-SZ) nor separately. The results demonstrate that there is no association between PE and PRS or PERS in adolescents in our sample. Study 3: Higher PRS-SZ scores were associated with lower EF measures. Direct associations between PRS-SZ and general psychopathology, anxiety symptoms, PE or school performance were not significant. However, EF acted as a mediator in three mediation models, producing indirect effects of PRS-SZ on general psychopathology, anxiety symptoms and school performance. No association was significant in relation to PE. Conclusion: Study 1: It is essential to encourage further research in Latin American populations. International collaborations in Latin America represent a xxipossible solution to these problems. Study 2: The absence of associations between PRS, PERS and PE may be a result of the lack of generalization of PRS and PERS in the Brazilian population. Additionally, the specificity of psychotic experiences is questioned. Study 3: Our results, both positive and negative, suggest that EF represents a hub to understand how PRS-SZ may impact behavioral and functional phenotypes during neurodevelopment, also indicating overlapping genetic vulnerability between schizophrenia and other mental disorders.