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Genetic Determinants of Cortical Structure (Thickness, Surface Area and Volumes) among Disease Free Adults in the CHARGE Consortium

Edith Hofer, Gennady V. Roshchupkin, Hieab H. H. Adams, Maria J. Knol, Honghuang Lin, Shuo Li, Habil Zare, View ORCID ProfileShahzad Ahmad, Nicola J. Armstrong, View ORCID ProfileClaudia L. Satizabal, Manon Bernard, Joshua C. Bis, Nathan A. Gillespie, Michelle Luciano, Aniket Mishra, Markus Scholz, View ORCID ProfileAlexander Teumer, Rui Xia, Xueqiu Jian, Thomas H. Mosley, Yasaman Saba, Lukas Pirpamer, Stephan Seiler, James T. Becker, Owen Carmichael, Jerome I. Rotter, Bruce M. Psaty, Oscar L. Lopez, Najaf Amin, Sven J. van der Lee, Qiong Yang, Jayandra J. Himali, Pauline Maillard, Alexa S. Beiser, Charles DeCarli, Sherif Karama, Lindsay Lewis, Mat Harris, Mark E. Bastin, Ian J. Deary, A.Veronica Witte, Frauke Beyer, Markus Loeffler, Karen A. Mather, View ORCID ProfilePeter R. Schofield, Anbupalam Thalamuthu, View ORCID ProfileJohn B. Kwok, Margaret J. Wright, David Ames, Julian Trollor, Jiyang Jiang, Henry Brodaty, Wei Wen, Meike W Vernooij, Albert Hofman, André G. Uitterlinden, Wiro J. Niessen, Katharina Wittfeld, Robin Bülow, Uwe Völker, Zdenka Pausova, G. Bruce Pike, Sophie Maingault, Fabrice Crivello, View ORCID ProfileChristophe Tzourio, Philippe Amouye, Bernard Mazoyer, Michael C. Neale, Carol E. Franz, Michael J. Lyons, Matthew S. Panizzon, Ole A. Andreassen, Anders M. Dale, Mark Logue, Katrina L. Grasby, Neda Jahanshad, Jodie N. Painter, Lucía Colodro-Conde, Janita Bralten, Derrek P. Hibar, Penelope A. Lind, Fabrizio Pizzagalli, Jason L. Stein, Paul M. Thompson, Sarah E. Medland
doi: https://doi.org/10.1101/409649
Edith Hofer
1Clinical Division of Neurogeriatrics, Department of Neurology, Medical University of Graz, Graz, Austria
2Institute for Medical Informatics, Statistics and Documentation, Medical University of Graz, Graz, Austria
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Gennady V. Roshchupkin
3Department of Radiology and Nuclear Medicine, Erasmus MC, Rotterdam, The Netherlands
4Department of Medical Informatics, Erasmus MC, Rotterdam, The Netherlands
5Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands
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Hieab H. H. Adams
3Department of Radiology and Nuclear Medicine, Erasmus MC, Rotterdam, The Netherlands
5Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands
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Maria J. Knol
5Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands
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Honghuang Lin
6Section of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, Boston, MA, USA
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Shuo Li
7Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA
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Habil Zare
8Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, UT Health San Antonio, San Antonio, USA
9Department of Cell Systems & Anatomy, The University of Texas Health Science Center, San Antonio, Texas, USA
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Shahzad Ahmad
5Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands
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Nicola J. Armstrong
10Mathematics and Statistics, Murdoch University, Perth, Australia
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Claudia L. Satizabal
30Department of Epidemiology and Biostatistics, Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, UT Health San Antonio, San Antonio, USA
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Manon Bernard
11Hospital for Sick Children, Toronto, Canada
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Joshua C. Bis
12Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA
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Nathan A. Gillespie
13Virginia Institute for Psychiatric and Behavior Genetics, Virginia Commonwealth University, VA, USA
14QIMR Berghofer Medical Research Institute, QLD, Australia
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Michelle Luciano
15Centre for Cognitive Epidemiology and Cognitive Ageing, University of Edinburgh, Edinburgh, UK
16Department of Psychology, University of Edinburgh, Edinburgh, UK
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Aniket Mishra
17University of Bordeaux, Bordeaux Population Health Research Center, INSERM UMR 1219, Bordeaux, France
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Markus Scholz
18Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany
19LIFE Research Center for Civilization Diseases, University of Leipzig, Leipzig, Germany
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Alexander Teumer
20Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany
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Rui Xia
21Institute of Molecular Medicine and Human Genetics Center, University of Texas Health Science Center at Houston, Houston, TX, USA
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Xueqiu Jian
21Institute of Molecular Medicine and Human Genetics Center, University of Texas Health Science Center at Houston, Houston, TX, USA
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Thomas H. Mosley
22Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA
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Yasaman Saba
23Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Medical University of Graz, Graz, Austria
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Lukas Pirpamer
1Clinical Division of Neurogeriatrics, Department of Neurology, Medical University of Graz, Graz, Austria
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Stephan Seiler
24Imaging of Dementia and Aging (IDeA) Laboratory, Department of Neurology, University of California-Davis, Davis, CA, USA
25Department of Neurology and Center for Neuroscience, University of California at Davis, Sacramento, CA, USA
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James T. Becker
26Departments of Psychiatry, Neurology, and Psychology, University of Pittsburgh, Pittsburgh, PA, USA
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Owen Carmichael
27Pennington Biomedical Research Center, Baton Rouge, LA, USA
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Jerome I. Rotter
28Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute and Pediatrics at Harbor-UCLA Medical Center, Torrance, CA, USA
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Bruce M. Psaty
29Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology and Health Services, University of Washington, Seattle, WA, USA
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Oscar L. Lopez
26Departments of Psychiatry, Neurology, and Psychology, University of Pittsburgh, Pittsburgh, PA, USA
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Najaf Amin
5Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands
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Sven J. van der Lee
5Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands
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Qiong Yang
7Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA
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Jayandra J. Himali
7Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA
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Pauline Maillard
24Imaging of Dementia and Aging (IDeA) Laboratory, Department of Neurology, University of California-Davis, Davis, CA, USA
25Department of Neurology and Center for Neuroscience, University of California at Davis, Sacramento, CA, USA
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Alexa S. Beiser
7Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA
31Department of Neurology, Boston University School of Medicine, Boston, MA, USA
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Charles DeCarli
24Imaging of Dementia and Aging (IDeA) Laboratory, Department of Neurology, University of California-Davis, Davis, CA, USA
25Department of Neurology and Center for Neuroscience, University of California at Davis, Sacramento, CA, USA
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Sherif Karama
32McGill University, Montreal Neurological Institute, Montreal, Canada
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Lindsay Lewis
32McGill University, Montreal Neurological Institute, Montreal, Canada
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Mat Harris
15Centre for Cognitive Epidemiology and Cognitive Ageing, University of Edinburgh, Edinburgh, UK
33Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK
66Brain Research Imaging Centre, University of Edinburgh, Edinburgh, UK
67Scottish Imaging Network, A Platform for Scientific Excellence (SINAPSE) Collaboration, Department of Neuroimaging Sciences, The University of Edinburgh, Edinburgh, UK
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Mark E. Bastin
15Centre for Cognitive Epidemiology and Cognitive Ageing, University of Edinburgh, Edinburgh, UK
33Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK
66Brain Research Imaging Centre, University of Edinburgh, Edinburgh, UK
67Scottish Imaging Network, A Platform for Scientific Excellence (SINAPSE) Collaboration, Department of Neuroimaging Sciences, The University of Edinburgh, Edinburgh, UK
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Ian J. Deary
15Centre for Cognitive Epidemiology and Cognitive Ageing, University of Edinburgh, Edinburgh, UK
16Department of Psychology, University of Edinburgh, Edinburgh, UK
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A.Veronica Witte
34Department of Neurology, Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany
35Faculty of Medicine, CRC 1052 Obesity Mechanisms, University of Leipzig, Leipzig, Germany
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Frauke Beyer
34Department of Neurology, Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany
35Faculty of Medicine, CRC 1052 Obesity Mechanisms, University of Leipzig, Leipzig, Germany
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Markus Loeffler
18Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany
19LIFE Research Center for Civilization Diseases, University of Leipzig, Leipzig, Germany
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Karen A. Mather
36Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, Australia
37Neuroscience Research Australia, Sydney, Australia
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Peter R. Schofield
37Neuroscience Research Australia, Sydney, Australia
38School of Medical Sciences, University of New South Wales, Sydney, Australia
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Anbupalam Thalamuthu
36Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, Australia
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John B. Kwok
39Brain and Mind Centre - The University of Sydney, Camperdown, NSW, Australia
38School of Medical Sciences, University of New South Wales, Sydney, Australia
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Margaret J. Wright
40Queensland Brain Institute, The University of Queensland, St Lucia, QLD, Australia
41Centre for Advanced Imaging, The University of Queensland, St Lucia, QLD, Australia
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David Ames
42National Ageing Research Institute, Royal Melbourne Hospital, Victoria, Australia
43Academic Unit for Psychiatry of Old Age, University of Melbourne, St George’s Hospital, Kew, Australia
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Julian Trollor
36Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, Australia
44Department of Developmental Disability Neuropsychiatry, School of Psychiatry, University of New South Wales, Sydney, Australia
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Jiyang Jiang
36Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, Australia
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Henry Brodaty
45Dementia Centre for Research Collaboration, University of New South Wales, Sydney, NSW, Australia
36Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, Australia
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Wei Wen
36Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, Australia
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Meike W Vernooij
3Department of Radiology and Nuclear Medicine, Erasmus MC, Rotterdam, The Netherlands
5Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands
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Albert Hofman
46Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
5Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands
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André G. Uitterlinden
5Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands
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Wiro J. Niessen
47Imaging Physics, Faculty of Applied Sciences, Delft University of Technology, The Netherlands
3Department of Radiology and Nuclear Medicine, Erasmus MC, Rotterdam, The Netherlands
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Katharina Wittfeld
48German Center for Neurodegenerative Diseases (DZNE), Site Rostock/ Greifswald, Germany
49Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Germany
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Robin Bülow
50Institute for Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, Greifswald, Germany
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Uwe Völker
51Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany
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Zdenka Pausova
11Hospital for Sick Children, Toronto, Canada
52Departments of Physiology and Nutritional Sciences, University of Toronto, Toronto, Canada
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G. Bruce Pike
53Departments of Radiology and Clinial Neurosciences, University of Calgary, Calgary, Canada
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Sophie Maingault
54University of Bordeaux, Institut des Maladies NeurodégénrativesUMR5293, CEA, CNRS, University of Bordeaux, Bordeaux, France
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Fabrice Crivello
54University of Bordeaux, Institut des Maladies NeurodégénrativesUMR5293, CEA, CNRS, University of Bordeaux, Bordeaux, France
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Christophe Tzourio
17University of Bordeaux, Bordeaux Population Health Research Center, INSERM UMR 1219, Bordeaux, France
76Pole de santé publique, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France
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Philippe Amouye
77Centre Hospitalier Universitaire de Bordeaux, France; Inserm U1167, Lille, France
78Department of Epidemiology and Public Health, Pasteur Institute of Lille, Lille, France
79Department of Public Health, Lille University Hospital, Lille, France
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Bernard Mazoyer
54University of Bordeaux, Institut des Maladies NeurodégénrativesUMR5293, CEA, CNRS, University of Bordeaux, Bordeaux, France
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Michael C. Neale
13Virginia Institute for Psychiatric and Behavior Genetics, Virginia Commonwealth University, VA, USA
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Carol E. Franz
55Department of Psychiatry, University of California San Diego, CA, USA
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Michael J. Lyons
56Department of Psychological and Brain Sciences, Boston University, Boston, MA, USA
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Matthew S. Panizzon
55Department of Psychiatry, University of California San Diego, CA, USA
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Ole A. Andreassen
74NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo and Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway
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Anders M. Dale
75Departments of Radiology and Neurosciences, University of California, San Diego, La Jolla, CA, USA
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Mark Logue
57National Center for PTSD at Boston VA Healthcare System, Boston, MA, USA
58Department of Psychiatry and Department of Medicine-Biomedical Genetics Section, Boston University School of Medicine, Boston MA, USA
7Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA
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Katrina L. Grasby
59Psychiatric Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia
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Neda Jahanshad
60Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine of USC, University of Southern California, Los Angeles, CA, USA
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Jodie N. Painter
59Psychiatric Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia
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Lucía Colodro-Conde
59Psychiatric Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia
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Janita Bralten
61Department of Human Genetics, Radboud university medical center, Nijmegen, The Netherlands
62Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, The Netherlands
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Derrek P. Hibar
60Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine of USC, University of Southern California, Los Angeles, CA, USA
63Neuroscience Biomarkers, Janssen Research and Development, LLC, San Diego, USA
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Penelope A. Lind
59Psychiatric Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia
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Fabrizio Pizzagalli
60Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine of USC, University of Southern California, Los Angeles, CA, USA
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Jason L. Stein
64Department of Genetics & UNC Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, USA
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Paul M. Thompson
60Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine of USC, University of Southern California, Los Angeles, CA, USA
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Sarah E. Medland
59Psychiatric Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia
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  • Abstract
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Abstract

Cortical thickness, surface area and volumes (MRI cortical measures) vary with age and cognitive function, and in neurological and psychiatric diseases. We examined heritability, genetic correlations and genome-wide associations of cortical measures across the whole cortex, and in 34 anatomically predefined regions. Our discovery sample comprised 22,824 individuals from 20 cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the United Kingdom Biobank. Significant associations were replicated in the Enhancing Neuroimaging Genetics through Meta-analysis (ENIGMA) consortium, and their biological implications explored using bioinformatic annotation and pathway analyses. We identified genetic heterogeneity between cortical measures and brain regions, and 160 genome-wide significant associations pointing to wnt/β-catenin, TGF-β and sonic hedgehog pathways. There was enrichment for genes involved in anthropometric traits, hindbrain development, vascular and neurodegenerative disease and psychiatric conditions. These data are a rich resource for studies of the biological mechanisms behind cortical development and aging.

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Genetic Determinants of Cortical Structure (Thickness, Surface Area and Volumes) among Disease Free Adults in the CHARGE Consortium
Edith Hofer, Gennady V. Roshchupkin, Hieab H. H. Adams, Maria J. Knol, Honghuang Lin, Shuo Li, Habil Zare, Shahzad Ahmad, Nicola J. Armstrong, Claudia L. Satizabal, Manon Bernard, Joshua C. Bis, Nathan A. Gillespie, Michelle Luciano, Aniket Mishra, Markus Scholz, Alexander Teumer, Rui Xia, Xueqiu Jian, Thomas H. Mosley, Yasaman Saba, Lukas Pirpamer, Stephan Seiler, James T. Becker, Owen Carmichael, Jerome I. Rotter, Bruce M. Psaty, Oscar L. Lopez, Najaf Amin, Sven J. van der Lee, Qiong Yang, Jayandra J. Himali, Pauline Maillard, Alexa S. Beiser, Charles DeCarli, Sherif Karama, Lindsay Lewis, Mat Harris, Mark E. Bastin, Ian J. Deary, A.Veronica Witte, Frauke Beyer, Markus Loeffler, Karen A. Mather, Peter R. Schofield, Anbupalam Thalamuthu, John B. Kwok, Margaret J. Wright, David Ames, Julian Trollor, Jiyang Jiang, Henry Brodaty, Wei Wen, Meike W Vernooij, Albert Hofman, André G. Uitterlinden, Wiro J. Niessen, Katharina Wittfeld, Robin Bülow, Uwe Völker, Zdenka Pausova, G. Bruce Pike, Sophie Maingault, Fabrice Crivello, Christophe Tzourio, Philippe Amouye, Bernard Mazoyer, Michael C. Neale, Carol E. Franz, Michael J. Lyons, Matthew S. Panizzon, Ole A. Andreassen, Anders M. Dale, Mark Logue, Katrina L. Grasby, Neda Jahanshad, Jodie N. Painter, Lucía Colodro-Conde, Janita Bralten, Derrek P. Hibar, Penelope A. Lind, Fabrizio Pizzagalli, Jason L. Stein, Paul M. Thompson, Sarah E. Medland
bioRxiv 409649; doi: https://doi.org/10.1101/409649
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Genetic Determinants of Cortical Structure (Thickness, Surface Area and Volumes) among Disease Free Adults in the CHARGE Consortium
Edith Hofer, Gennady V. Roshchupkin, Hieab H. H. Adams, Maria J. Knol, Honghuang Lin, Shuo Li, Habil Zare, Shahzad Ahmad, Nicola J. Armstrong, Claudia L. Satizabal, Manon Bernard, Joshua C. Bis, Nathan A. Gillespie, Michelle Luciano, Aniket Mishra, Markus Scholz, Alexander Teumer, Rui Xia, Xueqiu Jian, Thomas H. Mosley, Yasaman Saba, Lukas Pirpamer, Stephan Seiler, James T. Becker, Owen Carmichael, Jerome I. Rotter, Bruce M. Psaty, Oscar L. Lopez, Najaf Amin, Sven J. van der Lee, Qiong Yang, Jayandra J. Himali, Pauline Maillard, Alexa S. Beiser, Charles DeCarli, Sherif Karama, Lindsay Lewis, Mat Harris, Mark E. Bastin, Ian J. Deary, A.Veronica Witte, Frauke Beyer, Markus Loeffler, Karen A. Mather, Peter R. Schofield, Anbupalam Thalamuthu, John B. Kwok, Margaret J. Wright, David Ames, Julian Trollor, Jiyang Jiang, Henry Brodaty, Wei Wen, Meike W Vernooij, Albert Hofman, André G. Uitterlinden, Wiro J. Niessen, Katharina Wittfeld, Robin Bülow, Uwe Völker, Zdenka Pausova, G. Bruce Pike, Sophie Maingault, Fabrice Crivello, Christophe Tzourio, Philippe Amouye, Bernard Mazoyer, Michael C. Neale, Carol E. Franz, Michael J. Lyons, Matthew S. Panizzon, Ole A. Andreassen, Anders M. Dale, Mark Logue, Katrina L. Grasby, Neda Jahanshad, Jodie N. Painter, Lucía Colodro-Conde, Janita Bralten, Derrek P. Hibar, Penelope A. Lind, Fabrizio Pizzagalli, Jason L. Stein, Paul M. Thompson, Sarah E. Medland
bioRxiv 409649; doi: https://doi.org/10.1101/409649

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