Journal
EBIOMEDICINE
Volume 42, Issue -, Pages 188-202Publisher
ELSEVIER
DOI: 10.1016/j.ebiom.2019.03.051
Keywords
Polygenic score; Insulin; Dopamine; Gene networks; Impulsivity; Addiction; Alzheimer's disease
Funding
- Toxic Stress Research network of the JPB Foundation
- Sackler Foundation
- Canadian Institutes for Health Research
- Ludmer Family Foundation
- Norlien Foundation (Calgary, Canada)
- WOCO Foundation (London, Canada)
- Blema & Arnold Steinberg Family Foundation
- Faculty of Medicine of McGill University
- Jacobs Foundation (Switzerland)
- Brain Canada
- Kids Brain Health Network Developmental Neurosciences Research Training Award
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Background: Activation of brain insulin receptors modulates reward sensitivity, inhibitory control and memory. Variations in the functioning of this mechanismlikely associate with individual differences in the risk for related mental disorders (attention deficit hyperactivity disorder or ADHD, addiction, dementia), in agreement with the high co-morbidity between insulin resistance and psychopathology. These neurobiological mechanisms can be explored using genetic studies. We propose a novel, biologically informed genetic score reflecting the mesocorticolimbic and hippocampal insulin receptor-related gene networks, and investigate if it predicts endophenotypes (impulsivity, cognitive ability) in community samples of children, and psychopathology (addiction, dementia) in adults. Methods: Lists of genes co-expressed with the insulin receptor in themesocorticolimbic system or hippocampus were created. SNPs from these genes (post-clumping) were compiled in a polygenic score using the association betas described in a conventional GWAS (ADHD in themesocorticolimbic score and Alzheimer in the hippocampal score). Across multiple samples (n = 4502), the biologically informed, mesocorticolimbic or hippocampal specific insulin receptor polygenic scores were calculated, and their ability to predict impulsivity, risk for addiction, cognitive performance and presence of Alzheimer's disease was investigated. Findings: The biologically-informed ePRS-IR score showed better prediction of child impulsivity and cognitive performance, as well as risk for addiction and Alzheimer's disease in comparison to conventional polygenic scores for ADHD, addiction and dementia. Interpretation: This novel, biologically-informed approach enables the use of genomic datasets to probe relevant biological processes involved in neural function and disorders.
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