A biologically-informed polygenic score identifies endophenotypes and clinical conditions associated with the insulin receptor function on specific brain regionsResearch in context
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, addi...
| Main Authors: | , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2019-04-01
|
| Series: | EBioMedicine |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396419301963 |
| id |
doaj-0a930b227bbe495788b5d17b8ed4a14e |
|---|---|
| record_format |
Article |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
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 |
| spellingShingle |
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 A biologically-informed polygenic score identifies endophenotypes and clinical conditions associated with the insulin receptor function on specific brain regionsResearch in context EBioMedicine |
| author_facet |
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 |
| author_sort |
Shantala A. Hari Dass |
| title |
A biologically-informed polygenic score identifies endophenotypes and clinical conditions associated with the insulin receptor function on specific brain regionsResearch in context |
| title_short |
A biologically-informed polygenic score identifies endophenotypes and clinical conditions associated with the insulin receptor function on specific brain regionsResearch in context |
| title_full |
A biologically-informed polygenic score identifies endophenotypes and clinical conditions associated with the insulin receptor function on specific brain regionsResearch in context |
| title_fullStr |
A biologically-informed polygenic score identifies endophenotypes and clinical conditions associated with the insulin receptor function on specific brain regionsResearch in context |
| title_full_unstemmed |
A biologically-informed polygenic score identifies endophenotypes and clinical conditions associated with the insulin receptor function on specific brain regionsResearch in context |
| title_sort |
biologically-informed polygenic score identifies endophenotypes and clinical conditions associated with the insulin receptor function on specific brain regionsresearch in context |
| publisher |
Elsevier |
| series |
EBioMedicine |
| issn |
2352-3964 |
| publishDate |
2019-04-01 |
| description |
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 |
| url |
http://www.sciencedirect.com/science/article/pii/S2352396419301963 |
| work_keys_str_mv |
AT shantalaaharidass abiologicallyinformedpolygenicscoreidentifiesendophenotypesandclinicalconditionsassociatedwiththeinsulinreceptorfunctiononspecificbrainregionsresearchincontext AT kathrynmccracken abiologicallyinformedpolygenicscoreidentifiesendophenotypesandclinicalconditionsassociatedwiththeinsulinreceptorfunctiononspecificbrainregionsresearchincontext AT irinapokhvisneva abiologicallyinformedpolygenicscoreidentifiesendophenotypesandclinicalconditionsassociatedwiththeinsulinreceptorfunctiononspecificbrainregionsresearchincontext AT lawrencemchen abiologicallyinformedpolygenicscoreidentifiesendophenotypesandclinicalconditionsassociatedwiththeinsulinreceptorfunctiononspecificbrainregionsresearchincontext AT elikagarg abiologicallyinformedpolygenicscoreidentifiesendophenotypesandclinicalconditionsassociatedwiththeinsulinreceptorfunctiononspecificbrainregionsresearchincontext AT thaottnguyen abiologicallyinformedpolygenicscoreidentifiesendophenotypesandclinicalconditionsassociatedwiththeinsulinreceptorfunctiononspecificbrainregionsresearchincontext AT zihanwang abiologicallyinformedpolygenicscoreidentifiesendophenotypesandclinicalconditionsassociatedwiththeinsulinreceptorfunctiononspecificbrainregionsresearchincontext AT barbarabarth abiologicallyinformedpolygenicscoreidentifiesendophenotypesandclinicalconditionsassociatedwiththeinsulinreceptorfunctiononspecificbrainregionsresearchincontext AT moeinyaqubi abiologicallyinformedpolygenicscoreidentifiesendophenotypesandclinicalconditionsassociatedwiththeinsulinreceptorfunctiononspecificbrainregionsresearchincontext AT lisammcewen abiologicallyinformedpolygenicscoreidentifiesendophenotypesandclinicalconditionsassociatedwiththeinsulinreceptorfunctiononspecificbrainregionsresearchincontext AT julielmacisaac abiologicallyinformedpolygenicscoreidentifiesendophenotypesandclinicalconditionsassociatedwiththeinsulinreceptorfunctiononspecificbrainregionsresearchincontext AT josiediorio abiologicallyinformedpolygenicscoreidentifiesendophenotypesandclinicalconditionsassociatedwiththeinsulinreceptorfunctiononspecificbrainregionsresearchincontext AT michaelskobor abiologicallyinformedpolygenicscoreidentifiesendophenotypesandclinicalconditionsassociatedwiththeinsulinreceptorfunctiononspecificbrainregionsresearchincontext AT kieranjodonnell abiologicallyinformedpolygenicscoreidentifiesendophenotypesandclinicalconditionsassociatedwiththeinsulinreceptorfunctiononspecificbrainregionsresearchincontext AT michaeljmeaney abiologicallyinformedpolygenicscoreidentifiesendophenotypesandclinicalconditionsassociatedwiththeinsulinreceptorfunctiononspecificbrainregionsresearchincontext AT patriciapsilveira abiologicallyinformedpolygenicscoreidentifiesendophenotypesandclinicalconditionsassociatedwiththeinsulinreceptorfunctiononspecificbrainregionsresearchincontext AT shantalaaharidass biologicallyinformedpolygenicscoreidentifiesendophenotypesandclinicalconditionsassociatedwiththeinsulinreceptorfunctiononspecificbrainregionsresearchincontext AT kathrynmccracken biologicallyinformedpolygenicscoreidentifiesendophenotypesandclinicalconditionsassociatedwiththeinsulinreceptorfunctiononspecificbrainregionsresearchincontext AT irinapokhvisneva biologicallyinformedpolygenicscoreidentifiesendophenotypesandclinicalconditionsassociatedwiththeinsulinreceptorfunctiononspecificbrainregionsresearchincontext AT lawrencemchen biologicallyinformedpolygenicscoreidentifiesendophenotypesandclinicalconditionsassociatedwiththeinsulinreceptorfunctiononspecificbrainregionsresearchincontext AT elikagarg biologicallyinformedpolygenicscoreidentifiesendophenotypesandclinicalconditionsassociatedwiththeinsulinreceptorfunctiononspecificbrainregionsresearchincontext AT thaottnguyen biologicallyinformedpolygenicscoreidentifiesendophenotypesandclinicalconditionsassociatedwiththeinsulinreceptorfunctiononspecificbrainregionsresearchincontext AT zihanwang biologicallyinformedpolygenicscoreidentifiesendophenotypesandclinicalconditionsassociatedwiththeinsulinreceptorfunctiononspecificbrainregionsresearchincontext AT barbarabarth biologicallyinformedpolygenicscoreidentifiesendophenotypesandclinicalconditionsassociatedwiththeinsulinreceptorfunctiononspecificbrainregionsresearchincontext AT moeinyaqubi biologicallyinformedpolygenicscoreidentifiesendophenotypesandclinicalconditionsassociatedwiththeinsulinreceptorfunctiononspecificbrainregionsresearchincontext AT lisammcewen biologicallyinformedpolygenicscoreidentifiesendophenotypesandclinicalconditionsassociatedwiththeinsulinreceptorfunctiononspecificbrainregionsresearchincontext AT julielmacisaac biologicallyinformedpolygenicscoreidentifiesendophenotypesandclinicalconditionsassociatedwiththeinsulinreceptorfunctiononspecificbrainregionsresearchincontext AT josiediorio biologicallyinformedpolygenicscoreidentifiesendophenotypesandclinicalconditionsassociatedwiththeinsulinreceptorfunctiononspecificbrainregionsresearchincontext AT michaelskobor biologicallyinformedpolygenicscoreidentifiesendophenotypesandclinicalconditionsassociatedwiththeinsulinreceptorfunctiononspecificbrainregionsresearchincontext AT kieranjodonnell biologicallyinformedpolygenicscoreidentifiesendophenotypesandclinicalconditionsassociatedwiththeinsulinreceptorfunctiononspecificbrainregionsresearchincontext AT michaeljmeaney biologicallyinformedpolygenicscoreidentifiesendophenotypesandclinicalconditionsassociatedwiththeinsulinreceptorfunctiononspecificbrainregionsresearchincontext AT patriciapsilveira biologicallyinformedpolygenicscoreidentifiesendophenotypesandclinicalconditionsassociatedwiththeinsulinreceptorfunctiononspecificbrainregionsresearchincontext |
| _version_ |
1724968679005749248 |
| spelling |
doaj-0a930b227bbe495788b5d17b8ed4a14e2020-11-25T01:58:42ZengElsevierEBioMedicine2352-39642019-04-0142188202A biologically-informed polygenic score identifies endophenotypes and clinical conditions associated with the insulin receptor function on specific brain regionsResearch in contextShantala A. Hari Dass0Kathryn McCracken1Irina Pokhvisneva2Lawrence M. Chen3Elika Garg4Thao T.T. Nguyen5Zihan Wang6Barbara Barth7Moein Yaqubi8Lisa M. McEwen9Julie L. MacIsaac10Josie Diorio11Michael S. Kobor12Kieran J. O'Donnell13Michael J. Meaney14Patricia P. Silveira15Sackler Institute for Epigenetics & Psychobiology, McGill University, 6875 Boulevard LaSalle, Verdun, QC H4H 1R3, CanadaJohn Abbott College, Sainte-Anne-de-Bellevue, 6875 Boulevard LaSalle, Verdun, QC H4H 1R3, Canada; McGill University, 6875 Boulevard LaSalle, Verdun, QC H4H 1R3, CanadaSackler Institute for Epigenetics & Psychobiology, McGill University, 6875 Boulevard LaSalle, Verdun, QC H4H 1R3, CanadaSackler Institute for Epigenetics & Psychobiology, McGill University, 6875 Boulevard LaSalle, Verdun, QC H4H 1R3, CanadaSackler Institute for Epigenetics & Psychobiology, McGill University, 6875 Boulevard LaSalle, Verdun, QC H4H 1R3, CanadaSackler Institute for Epigenetics & Psychobiology, McGill University, 6875 Boulevard LaSalle, Verdun, QC H4H 1R3, CanadaSackler Institute for Epigenetics & Psychobiology, McGill University, 6875 Boulevard LaSalle, Verdun, QC H4H 1R3, CanadaMcGill University, 6875 Boulevard LaSalle, Verdun, QC H4H 1R3, CanadaMcGill University, 6875 Boulevard LaSalle, Verdun, QC H4H 1R3, CanadaCentre 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, CanadaCentre 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, CanadaSackler Institute for Epigenetics & Psychobiology, McGill University, 6875 Boulevard LaSalle, Verdun, QC H4H 1R3, CanadaCentre 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, CanadaDepartment 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, CanadaDepartment 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, SingaporeDepartment 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 diseasehttp://www.sciencedirect.com/science/article/pii/S2352396419301963 |