A biologically-informed polygenic score identifies endophenotypes and clinical conditions associated with the insulin receptor function on specific brain regions
| Autor: | Josie Diorio, Thao T. T. Nguyen, Shantala A. Hari Dass, Kathryn McCracken, Zihan Wang, Irina Pokhvisneva, Barbara Barth, J.L. MacIsaac, Michael J. Meaney, Patrícia Pelufo Silveira, Elika Garg, Moein Yaqubi, Michael S. Kobor, Kieran J. O’Donnell, Lisa M. McEwen, Lawrence M. Chen |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Male Research paper Endophenotypes media_common.quotation_subject Impulsivity Hippocampus Polymorphism Single Nucleotide General Biochemistry Genetics and Molecular Biology 03 medical and health sciences 0302 clinical medicine Insulin resistance mental disorders medicine Attention deficit hyperactivity disorder Dementia Humans Gene Regulatory Networks Genetic Predisposition to Disease Genetic Association Studies media_common business.industry Addiction Gene Expression Profiling Brain Reproducibility of Results Cognition General Medicine medicine.disease Receptor Insulin 3. Good health 030104 developmental biology Phenotype Gene Expression Regulation 030220 oncology & carcinogenesis Endophenotype Female medicine.symptom business Neuroscience Psychopathology Genome-Wide Association Study |
| Popis: | Background Activation of brain insulin receptors modulates reward sensitivity, inhibitory control and memory. Variations in the functioning of this mechanism likely 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 the mesocorticolimbic 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 the mesocorticolimbic 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. Fund Toxic Stress Research network of the JPB Foundation, Jacobs Foundation (Switzerland), Sackler Foundation. |
| Databáze: | OpenAIRE |
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