Patrícia Maidana Miguel1, Lenir Orlandi Pereira1, Barbara Barth2, Euclides José de Mendonça Filho3, Irina Pokhvisneva4, Thao T T Nguyen4, Elika Garg4, Bruna Regis Razzolini2, Dawn Xin Ping Koh5, Heather Gallant6, Roberto Britto Sassi7, Geoffrey B C Hall6, Kieran John O'Donnell8, Michael J Meaney9, Patrícia Pelufo Silveira10. 1. Programa de Pós-Graduação em Neurociências, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil; Departamento de Ciências Morfológicas, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil. 2. Ludmer Centre for Neuroinformatics and Mental Health, Douglas Mental Health University Institute, Montréal, Quebec, Canada; Integrated Program in Neuroscience, Faculty of Medicine, McGill University, Montréal, Quebec, Canada. 3. Programa de Pós-Graduação em Psicologia, Instituto de Psicologia, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil; Ludmer Centre for Neuroinformatics and Mental Health, Douglas Mental Health University Institute, Montréal, Quebec, Canada. 4. Ludmer Centre for Neuroinformatics and Mental Health, Douglas Mental Health University Institute, Montréal, Quebec, Canada. 5. Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research, Singapore, Singapore. 6. Department of Psychology, Neuroscience and Behaviour, McMaster University, Hamilton, Ontario, Canada. 7. Mood Disorders Program, Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Ontario, Canada. 8. Ludmer Centre for Neuroinformatics and Mental Health, Douglas Mental Health University Institute, Montréal, Quebec, Canada; Department of Psychiatry, Faculty of Medicine, McGill University, Montréal, Quebec, Canada. 9. Ludmer Centre for Neuroinformatics and Mental Health, Douglas Mental Health University Institute, Montréal, Quebec, Canada; Integrated Program in Neuroscience, Faculty of Medicine, McGill University, Montréal, Quebec, Canada; Department of Psychiatry, Faculty of Medicine, McGill University, Montréal, Quebec, Canada; Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research, Singapore, Singapore. 10. Programa de Pós-Graduação em Neurociências, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil; Ludmer Centre for Neuroinformatics and Mental Health, Douglas Mental Health University Institute, Montréal, Quebec, Canada; Integrated Program in Neuroscience, Faculty of Medicine, McGill University, Montréal, Quebec, Canada; Department of Psychiatry, Faculty of Medicine, McGill University, Montréal, Quebec, Canada. Electronic address: patricia.silveira@mcgill.ca.
Abstract
BACKGROUND: Genetic polymorphisms of the dopamine transporter gene (DAT1) and perinatal complications associated with poor oxygenation are risk factors for attentional problems in childhood and may show interactive effects. METHODS: We created a novel expression-based polygenic risk score (ePRS) reflecting variations in the function of the DAT1 gene network (ePRS-DAT1) in the prefrontal cortex and explored the effects of its interaction with perinatal hypoxic-ischemic-associated conditions on cognitive flexibility and brain gray matter density in healthy children from two birth cohorts-MAVAN from Canada (n = 139 boys and girls) and GUSTO from Singapore (n = 312 boys and girls). RESULTS: A history of exposure to several perinatal hypoxic-ischemic-associated conditions was associated with impaired cognitive flexibility only in the high-ePRS group, suggesting that variation in the prefrontal cortex expression of genes involved in dopamine reuptake is associated with differences in this behavior. Interestingly, this result was observed in both ethnically distinct birth cohorts. Additionally, parallel independent component analysis (MAVAN cohort, n = 40 children) demonstrated relationships between single nucleotide polymorphism-based ePRS and gray matter density in areas involved in executive (cortical regions) and integrative (bilateral thalamus and putamen) functions, and these relationships differ in children from high and low exposure to hypoxic-ischemic-associated conditions. CONCLUSIONS: These findings reveal that the impact of conditions associated with hypoxia-ischemia on brain development and executive functions is moderated by genotypes associated with dopamine signaling in the prefrontal cortex. We discuss the potential impact of innovative genomic and environmental measures for the identification of children at high risk for impaired executive functions.
BACKGROUND: Genetic polymorphisms of the dopamine transporter gene (DAT1) and perinatal complications associated with poor oxygenation are risk factors for attentional problems in childhood and may show interactive effects. METHODS: We created a novel expression-based polygenic risk score (ePRS) reflecting variations in the function of the DAT1 gene network (ePRS-DAT1) in the prefrontal cortex and explored the effects of its interaction with perinatal hypoxic-ischemic-associated conditions on cognitive flexibility and brain gray matter density in healthy children from two birth cohorts-MAVAN from Canada (n = 139 boys and girls) and GUSTO from Singapore (n = 312 boys and girls). RESULTS: A history of exposure to several perinatal hypoxic-ischemic-associated conditions was associated with impaired cognitive flexibility only in the high-ePRS group, suggesting that variation in the prefrontal cortex expression of genes involved in dopamine reuptake is associated with differences in this behavior. Interestingly, this result was observed in both ethnically distinct birth cohorts. Additionally, parallel independent component analysis (MAVAN cohort, n = 40 children) demonstrated relationships between single nucleotide polymorphism-based ePRS and gray matter density in areas involved in executive (cortical regions) and integrative (bilateral thalamus and putamen) functions, and these relationships differ in children from high and low exposure to hypoxic-ischemic-associated conditions. CONCLUSIONS: These findings reveal that the impact of conditions associated with hypoxia-ischemia on brain development and executive functions is moderated by genotypes associated with dopamine signaling in the prefrontal cortex. We discuss the potential impact of innovative genomic and environmental measures for the identification of children at high risk for impaired executive functions.
Authors: Geraldo Busatto Filho; Pedro G Rosa; Mauricio H Serpa; Paula Squarzoni; Fabio L Duran Journal: Braz J Psychiatry Date: 2020-06-08 Impact factor: 2.697