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

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

doi:10.1016/j.ebiom.2019.03.051

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

EBioMedicine. 2019 Apr:42:188-202. doi: 10.1016/j.ebiom.2019.03.051. Epub 2019 Mar 26.

Authors

Shantala A Hari Dass¹, Kathryn McCracken², Irina Pokhvisneva¹, Lawrence M Chen¹, Elika Garg¹, Thao T T Nguyen¹, Zihan Wang¹, Barbara Barth³, Moein Yaqubi³, Lisa M McEwen⁴, Julie L MacIsaac⁴, Josie Diorio¹, Michael S Kobor⁴, Kieran J O'Donnell⁵, Michael J Meaney⁶, Patricia P Silveira⁷

Affiliations

¹ Sackler Institute for Epigenetics & Psychobiology, McGill University, 6875 Boulevard LaSalle, Verdun, QC H4H 1R3, Canada.
² John Abbott College, Sainte-Anne-de-Bellevue, 6875 Boulevard LaSalle, Verdun, QC H4H 1R3, Canada; McGill University, 6875 Boulevard LaSalle, Verdun, QC H4H 1R3, Canada.
³ McGill University, 6875 Boulevard LaSalle, Verdun, QC H4H 1R3, Canada.
⁴ 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.
⁵ 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.
⁶ 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.
⁷ 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. Electronic address: patricia.silveira@mcgill.ca.

Abstract

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: Addiction; Alzheimer's disease; Dopamine; Gene networks; Impulsivity; Insulin; Polygenic score.

MeSH terms

Brain / metabolism*
Brain / physiopathology
Endophenotypes*
Female
Gene Expression Profiling
Gene Expression Regulation
Gene Regulatory Networks
Genetic Association Studies*
Genetic Predisposition to Disease*
Genome-Wide Association Study
Hippocampus / metabolism
Hippocampus / physiopathology
Humans
Male
Phenotype
Polymorphism, Single Nucleotide
Receptor, Insulin / genetics*
Receptor, Insulin / metabolism
Reproducibility of Results

Substances

Receptor, Insulin