A biologically-informed polygenic score identifies endophenotypes and clinical conditions associated with the insulin receptor function on specific brain regionsResearch in context
Shantala A. Hari Dass,
Kathryn McCracken,
Irina Pokhvisneva,
Lawrence M. Chen,
Elika Garg,
Thao T.T. Nguyen,
Zihan Wang,
Barbara Barth,
Moein Yaqubi,
Lisa M. McEwen,
Julie L. MacIsaac,
Josie Diorio,
Michael S. Kobor,
Kieran J. O'Donnell,
Michael J. Meaney,
Patricia P. Silveira
Affiliations
Shantala A. Hari Dass
Sackler Institute for Epigenetics & Psychobiology, McGill University, 6875 Boulevard LaSalle, Verdun, QC H4H 1R3, Canada
Centre for Molecular Medicine and Therapeutics, BC Children's Hospital Research Institute, Department of Medical Genetics, The University of British Columbia, 938 West 28th Avenue, Vancouver, BC V5Z 4H4, Canada
Julie L. MacIsaac
Centre for Molecular Medicine and Therapeutics, BC Children's Hospital Research Institute, Department of Medical Genetics, The University of British Columbia, 938 West 28th Avenue, Vancouver, BC V5Z 4H4, Canada
Josie Diorio
Sackler Institute for Epigenetics & Psychobiology, McGill University, 6875 Boulevard LaSalle, Verdun, QC H4H 1R3, Canada
Michael S. Kobor
Centre for Molecular Medicine and Therapeutics, BC Children's Hospital Research Institute, Department of Medical Genetics, The University of British Columbia, 938 West 28th Avenue, Vancouver, BC V5Z 4H4, Canada
Kieran J. O'Donnell
Department of Psychiatry, Faculty of Medicine, McGill University, 6875 Boulevard LaSalle, Verdun, QC H4H 1R3, Canada; Ludmer Centre for Neuroinformatics and Mental Health, Douglas Mental Health University Institute, McGill University, 6875 Boulevard LaSalle, Verdun, QC H4H 1R3, Canada; Sackler Institute for Epigenetics & Psychobiology, McGill University, 6875 Boulevard LaSalle, Verdun, QC H4H 1R3, Canada
Michael J. Meaney
Department of Psychiatry, Faculty of Medicine, McGill University, 6875 Boulevard LaSalle, Verdun, QC H4H 1R3, Canada; Ludmer Centre for Neuroinformatics and Mental Health, Douglas Mental Health University Institute, McGill University, 6875 Boulevard LaSalle, Verdun, QC H4H 1R3, Canada; Sackler Institute for Epigenetics & Psychobiology, McGill University, 6875 Boulevard LaSalle, Verdun, QC H4H 1R3, Canada; Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research (A*STAR), Brenner Centre for Molecular Medicine, 30 Medical Drive, 117609, Singapore
Patricia P. Silveira
Department of Psychiatry, Faculty of Medicine, McGill University, 6875 Boulevard LaSalle, Verdun, QC H4H 1R3, Canada; Ludmer Centre for Neuroinformatics and Mental Health, Douglas Mental Health University Institute, McGill University, 6875 Boulevard LaSalle, Verdun, QC H4H 1R3, Canada; Sackler Institute for Epigenetics & Psychobiology, McGill University, 6875 Boulevard LaSalle, Verdun, QC H4H 1R3, Canada; Corresponding author at: Department of Psychiatry, Faculty of Medicine, McGill University, Douglas Hospital Research Centre, 6875 Boulevard LaSalle, Montreal, QC H4H 1R3, Canada.
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. Keywords: Polygenic score, Insulin, Dopamine, Gene networks, Impulsivity, Addiction, Alzheimer's disease
