A biologically-informed polygenic score identifies endophenotypes and clinical conditions associated with the insulin receptor function on specific brain regions

作者：Shantala A. Hari Dass, Kathryn McCracken, Irina Pokhvisneva, Lawrence M. Chen, Elika Garg, Thao T. T. Nguyen, Zihan Wang, Bárbara Barth, Moein Yaqubi, Lisa M. McEwen, Julie L. MacIsaac, Josie Diorio, Michael S. Kobor, Kieran J. O’Donnell, Michael J. Meaney, Patrícia Pelufo Silveira · 发表于：EBioMedicine · 年份：2019 · DOI：10.1016/j.ebiom.2019.03.051 · 被引用次数：77 · 研究领域：Attention Deficit Hyperactivity Disorder、Genetic Associations and Epidemiology、Neurotransmitter Receptor Influence on Behavior

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 chi...