Genetic correlations and genome-wide associations of cortical structure in general population samples of 22,824 adults

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 Amouyel; 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; ENIGMA consortium; Perminder S Sachdev; William S Kremen; Joanna M Wardlaw; Arno Villringer; Cornelia M van Duijn; Hans J Grabe; William T Longstreth Jr; Myriam Fornage; Tomas Paus; Stephanie Debette; M Arfan Ikram; Helena Schmidt; Reinhold Schmidt; Sudha Seshadri

doi:10.1038/s41467-020-18367-y

Genetic correlations and genome-wide associations of cortical structure in general population samples of 22,824 adults

Nat Commun. 2020 Sep 22;11(1):4796. doi: 10.1038/s41467-020-18367-y.

Authors

Edith Hofer^#^{1

2}, Gennady V Roshchupkin^#^{3

4

5}, Hieab H H Adams^#^{3

5}, Maria J Knol⁵, Honghuang Lin⁶, Shuo Li⁷, Habil Zare^{8

9}, Shahzad Ahmad⁵, Nicola J Armstrong¹⁰, Claudia L Satizabal^{8

11}, Manon Bernard¹², Joshua C Bis¹³, Nathan A Gillespie^{14

15}, Michelle Luciano^{16

17}, Aniket Mishra¹⁸, Markus Scholz^{19

20}, Alexander Teumer²¹, Rui Xia²², Xueqiu Jian²², Thomas H Mosley²³, Yasaman Saba²⁴, Lukas Pirpamer¹, Stephan Seiler^{25

26}, James T Becker²⁷, Owen Carmichael²⁸, Jerome I Rotter²⁹, Bruce M Psaty¹³, Oscar L Lopez²⁷, Najaf Amin⁵, Sven J van der Lee⁵, Qiong Yang⁷, Jayandra J Himali⁷, Pauline Maillard^{25

26}, Alexa S Beiser^{7

11}, Charles DeCarli^{25

26}, Sherif Karama³⁰, Lindsay Lewis³⁰, Mat Harris^{16

31

32

33}, Mark E Bastin^{16

31

32

33}, Ian J Deary^{16

17}, A Veronica Witte^{34

35}, Frauke Beyer^{34

35}, Markus Loeffler^{19

20}, Karen A Mather^{36

37}, Peter R Schofield^{37

38}, Anbupalam Thalamuthu³⁶, John B Kwok^{38

39}, Margaret J Wright^{40

41}, David Ames^{42

43}, Julian Trollor^{36

44}, Jiyang Jiang³⁶, Henry Brodaty^{36

45}, Wei Wen³⁶, Meike W Vernooij^{3

5}, Albert Hofman^{5

46}, André G Uitterlinden⁵, Wiro J Niessen^{3

47}, Katharina Wittfeld^{48

49}, Robin Bülow⁵⁰, Uwe Völker⁵¹, Zdenka Pausova^{12

52}, G Bruce Pike⁵³, Sophie Maingault⁵⁴, Fabrice Crivello⁵⁴, Christophe Tzourio^{18

55}, Philippe Amouyel^{56

57

58}, Bernard Mazoyer⁵⁴, Michael C Neale¹⁴, Carol E Franz⁵⁹, Michael J Lyons⁶⁰, Matthew S Panizzon⁵⁹, Ole A Andreassen⁶¹, Anders M Dale⁶², Mark Logue^{7

63

64}, Katrina L Grasby⁶⁵, Neda Jahanshad⁶⁶, Jodie N Painter⁶⁵, Lucía Colodro-Conde⁶⁵, Janita Bralten^{67

68}, Derrek P Hibar^{66

69}, Penelope A Lind⁶⁵, Fabrizio Pizzagalli⁶⁶, Jason L Stein⁷⁰, Paul M Thompson⁶⁶, Sarah E Medland⁶⁵; ENIGMA consortium; Perminder S Sachdev^{36

71}, William S Kremen⁵⁹, Joanna M Wardlaw^{16

31

32

33}, Arno Villringer^{34

72}, Cornelia M van Duijn^{5

73}, Hans J Grabe^{48

49}, William T Longstreth Jr⁷⁴, Myriam Fornage²², Tomas Paus^{75

76}, Stephanie Debette^{11

18

77}, M Arfan Ikram^{3

5

78}, Helena Schmidt²⁴, Reinhold Schmidt⁷⁹, Sudha Seshadri^{80

81}

Collaborators

ENIGMA consortium:
Katrina L Grasby, Neda Jahanshad, Jodie N Painter, Lucía Colodro-Conde, Janita Bralten, Derrek P Hibar, Penelope A Lind, Fabrizio Pizzagalli, Christopher R K Ching, Mary Agnes B McMahon, Natalia Shatokhina, Leo C P Zsembik, Ingrid Agartz, Saud Alhusaini, Marcio A A Almeida, Dag Alnæs, Inge K Amlien, Micael Andersson, Tyler Ard, Nicola J Armstrong, Allison Ashley-Koch, Manon Bernard, Rachel M Brouwer, Elizabeth E L Buimer, Robin Bülow, Christian Bürger, Dara M Cannon, Mallar Chakravarty, Qiang Chen, Joshua W Cheung, Baptiste Couvy-Duchesne, Anders M Dale, Shareefa Dalvie, Tânia K de Araujo, Greig I de Zubicaray, Sonja M C de Zwarte, Anouk den Braber, Nhat Trung Doan, Katharina Dohm, Stefan Ehrlich, Hannah-Ruth Engelbrecht, Susanne Erk, Chun Chieh Fan, Iryna O Fedko, Sonya F Foley, Judith M Ford, Masaki Fukunaga, Melanie E Garrett, Tian Ge, Sudheer Giddaluru, Aaron L Goldman, Nynke A Groenewold, Dominik Grotegerd, Tiril P Gurholt, Boris A Gutman, Narelle K Hansell, Mathew A Harris, Marc B Harrison, Courtney C Haswell, Michael Hauser, Stefan Herms, Dirk J Heslenfeld, New Fei Ho, David Hoehn, Per Hoffmann, Laurena Holleran, Martine Hoogman, Jouke-Jan Hottenga, Masashi Ikeda, Deborah Janowitz, Iris E Jansen, Tianye Jia, Christiane Jockwitz, Ryota Kanai, Sherif Karama, Dalia Kasperaviciute, Tobias Kaufmann, Sinead Kelly, Masataka Kikuchi, Marieke Klein, Michael Knapp, Annchen R Knodt, Bernd Krämer, Max Lam, Thomas M Lancaster, Phil H Lee, Tristram A Lett, Lindsay B Lewis, Iscia Lopes-Cendes, Michelle Luciano, Fabio Macciardi, Andre F Marquand, Samuel R Mathias, Tracy R Melzer, Yuri Milaneschi, Nazanin Mirza-Schreiber, Jose C V Moreira, Thomas W Mühleisen, Bertram Müller-Myhsok, Pablo Najt, Soichiro Nakahara, Kwangsik Nho, Loes M Olde Loohuis, Dimitri Papadopoulos Orfanos, John F Pearson, Toni L Pitcher, Benno Pütz, Anjanibhargavi Ragothaman, Faisal M Rashid, Ronny Redlich, Céline S Reinbold, Jonathan Repple, Geneviève Richard, Brandalyn C Riedel, Shannon L Risacher, Cristiane S Rocha, Nina Roth Mota, Lauren Salminen, Arvin Saremi, Andrew J Saykin, Fenja Schlag, Lianne Schmaal, Peter R Schofield, Rodrigo Secolin, Chin Yang Shapland, Li Shen, Jean Shin, Elena Shumskaya, Ida E Sønderby, Emma Sprooten, Lachlan T Strike, Katherine E Tansey, Alexander Teumer, Anbupalam Thalamuthu, Sophia I Thomopoulos, Diana Tordesillas-Gutiérrez, Jessica A Turner, Anne Uhlmann, Costanza Ludovica Vallerga, Dennis van der Meer, Marjolein M J van Donkelaar, Liza van Eijk, Theo G M van Erp, Neeltje E M van Haren, Daan van Rooij, Marie-José van Tol, Jan H Veldink, Ellen Verhoef, Esther Walton, Mingyuan Wang, Yunpeng Wang, Joanna M Wardlaw, Wei Wen, Lars T Westlye, Christopher D Whelan, Stephanie H Witt, Katharina Wittfeld, Christiane Wolf, Thomas Wolfers, Clarissa L Yasuda, Dario Zaremba, Zuo Zhang, Alyssa H Zhu, Marcel P Zwiers, Eric Artiges, Amelia A Assareh, Rosa Ayesa-Arriola, Aysenil Belger, Christine L Brandt, Gregory G Brown, Sven Cichon, Joanne E Curran, Gareth E Davies, Franziska Degenhardt, Bruno Dietsche, Srdjan Djurovic, Colin P Doherty, Ryan Espiritu, Daniel Garijo, Yolanda Gil, Penny A Gowland, Robert C Green, Alexander N Häusler, Walter Heindel, Beng-Choon Ho, Wolfgang U Hoffmann, Florian Holsboer, Georg Homuth, Norbert Hosten, Clifford R Jack Jr, MiHyun Jang, Andreas Jansen, Knut Kolskår, Sanne Koops, Axel Krug, Kelvin O Lim, Jurjen J Luykx, Daniel H Mathalon, Karen A Mather, Venkata S Mattay, Sarah Matthews, Jaqueline Mayoral Van Son, Sarah C McEwen, Ingrid Melle, Derek W Morris, Bryon A Mueller, Matthias Nauck, Jan E Nordvik, Markus M Nöthen, Daniel S O'Leary, Nils Opel, Marie -Laure Paillère Martinot, G Bruce Pike, Adrian Preda, Erin B Quinlan, Varun Ratnakar, Simone Reppermund, Vidar M Steen, Fábio R Torres, Dick J Veltman, James T Voyvodic, Robert Whelan, Tonya White, Hidenaga Yamamori, Marina K M Alvim, David Ames, Tim J Anderson, Ole A Andreassen, Alejandro Arias-Vasquez, Mark E Bastin, Bernhard T Baune, John Blangero, Dorret I Boomsma, Henry Brodaty, Han G Brunner, Randy L Buckner, Jan K Buitelaar, Juan R Bustillo, Wiepke Cahn, Vince Calhoun, Xavier Caseras, Svenja Caspers, Gianpiero L Cavalleri, Fernando Cendes, Aiden Corvin, Benedicto Crespo-Facorro, John C Dalrymple-Alford, Udo Dannlowski, Eco J C de Geus, Ian J Deary, Norman Delanty, Chantal Depondt, Sylvane Desrivières, Gary Donohoe, Thomas Espeseth, Guillén Fernández, Simon E Fisher, Herta Flor, Andreas J Forstner, Clyde Francks, Barbara Franke, David C Glahn, Randy L Gollub, Hans J Grabe, Oliver Gruber, Asta K Håberg, Ahmad R Hariri, Catharina A Hartman, Ryota Hashimoto, Andreas Heinz, Manon H J Hillegers, Pieter J Hoekstra, Avram J Holmes, L Elliot Hong, William D Hopkins, Hilleke E Hulshoff Pol, Terry L Jernigan, Erik G Jönsson, René S Kahn, Martin A Kennedy, Tilo T J Kircher, Peter Kochunov, John B J Kwok, Stephanie Le Hellard, Nicholas G Martin, Jean -Luc Martinot, Colm McDonald, Katie L McMahon, Andreas Meyer-Lindenberg, Rajendra A Morey, Lars Nyberg, Jaap Oosterlaan, Roel A Ophoff, Tomáš Paus, Zdenka Pausova, Brenda W J H Penninx, Tinca J C Polderman, Danielle Posthuma, Marcella Rietschel, Joshua L Roffman, Laura M Rowland, Perminder S Sachdev, Philipp G Sämann, Gunter Schumann, Kang Sim, Sanjay M Sisodiya, Jordan W Smoller, Iris E Sommer, Beate St Pourcain, Dan J Stein, Arthur W Toga, Julian N Trollor, Nic J A Van der Wee, Dennis van 't Ent, Henry Völzke, Henrik Walter, Bernd Weber, Daniel R Weinberger, Margaret J Wright, Juan Zhou, Jason L Stein, Paul M Thompson, Sarah E Medland

Affiliations

¹ Clinical Division of Neurogeriatrics, Department of Neurology, Medical University of Graz, Graz, Austria.
² Institute for Medical Informatics, Statistics and Documentation, Medical University of Graz, Graz, Austria.
³ Department of Radiology and Nuclear Medicine, Erasmus MC, Rotterdam, The Netherlands.
⁴ Department of Medical Informatics, Erasmus MC, Rotterdam, The Netherlands.
⁵ Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands.
⁶ Section of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
⁷ Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
⁸ Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, UT Health San Antonio, San Antonio, USA.
⁹ Department of Cell Systems & Anatomy, The University of Texas Health Science Center, San Antonio, TX, USA.
¹⁰ Mathematics and Statistics, Murdoch University, Perth, Australia.
¹¹ Department of Neurology, Boston University School of Medicine, Boston, MA, USA.
¹² Hospital for Sick Children, Toronto, ON, Canada.
¹³ Cardiovascular Health Research Unit, Department of Medicine, Epidemiology and Health Services, University of Washington, Seattle, WA, USA.
¹⁴ Virginia Institute for Psychiatric and Behavior Genetics, Virginia Commonwealth University, Richmond, VA, USA.
¹⁵ QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.
¹⁶ Centre for Cognitive Epidemiology and Cognitive Ageing, University of Edinburgh, Edinburgh, UK.
¹⁷ Department of Psychology, University of Edinburgh, Edinburgh, UK.
¹⁸ University of Bordeaux, Bordeaux Population Health Research Center, INSERM UMR 1219, Bordeaux, France.
¹⁹ Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.
²⁰ LIFE Research Center for Civilization Diseases, University of Leipzig, Leipzig, Germany.
²¹ Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
²² Institute of Molecular Medicine and Human Genetics Center, University of Texas Health Science Center at Houston, Houston, TX, USA.
²³ Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA.
²⁴ Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Medical University of Graz, Graz, Austria.
²⁵ Imaging of Dementia and Aging (IDeA) Laboratory, Department of Neurology, University of California-Davis, Davis, CA, USA.
²⁶ Department of Neurology and Center for Neuroscience, University of California at Davis, Sacramento, CA, USA.
²⁷ Departments of Psychiatry, Neurology, and Psychology, University of Pittsburgh, Pittsburgh, PA, USA.
²⁸ Pennington Biomedical Research Center, Baton Rouge, LA, USA.
²⁹ Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute and Pediatrics at Harbor-UCLA Medical Center, Torrance, CA, USA.
³⁰ McGill University, Montreal Neurological Institute, Montreal, QC, Canada.
³¹ Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.
³² Brain Research Imaging Centre, University of Edinburgh, Edinburgh, UK.
³³ Scottish Imaging Network, A Platform for Scientific Excellence (SINAPSE) Collaboration, Department of Neuroimaging Sciences, The University of Edinburgh, Edinburgh, UK.
³⁴ Department of Neurology, Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany.
³⁵ Faculty of Medicine, CRC 1052 Obesity Mechanisms, University of Leipzig, Leipzig, Germany.
³⁶ Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, Australia.
³⁷ Neuroscience Research Australia, Sydney, Australia.
³⁸ School of Medical Sciences, University of New South Wales, Sydney, Australia.
³⁹ Brain and Mind Centre - The University of Sydney, Camperdown, NSW, Australia.
⁴⁰ Queensland Brain Institute, The University of Queensland, St Lucia, QLD, Australia.
⁴¹ Centre for Advanced Imaging, The University of Queensland, St Lucia, QLD, Australia.
⁴² National Ageing Research Institute, Royal Melbourne Hospital, Parkvill, VIC, Australia.
⁴³ Academic Unit for Psychiatry of Old Age, University of Melbourne, St George's Hospital, Kew, VIC, Australia.
⁴⁴ Department of Developmental Disability Neuropsychiatry, School of Psychiatry, University of New South Wales, Sydney, NSW, Australia.
⁴⁵ Dementia Centre for Research Collaboration, University of New South Wales, Sydney, NSW, Australia.
⁴⁶ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁴⁷ Imaging Physics, Faculty of Applied Sciences, Delft University of Technology, Delft, The Netherlands.
⁴⁸ German Center for Neurodegenerative Diseases (DZNE), Site Rostock/Greifswald, Greifswald, Germany.
⁴⁹ Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany.
⁵⁰ Institute for Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, Greifswald, Germany.
⁵¹ Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
⁵² Departments of Physiology and Nutritional Sciences, University of Toronto, Toronto, ON, Canada.
⁵³ Departments of Radiology and Clinial Neurosciences, University of Calgary, Calgary, AB, Canada.
⁵⁴ Institut des Maladies Neurodégénratives UMR5293, CEA, CNRS, University of Bordeaux, Bordeaux, France.
⁵⁵ Pole de santé publique, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France.
⁵⁶ Centre Hospitalier Universitaire de Bordeaux, France; Inserm U1167, Lille, France.
⁵⁷ Department of Epidemiology and Public Health, Pasteur Institute of Lille, Lille, France.
⁵⁸ Department of Public Health, Lille University Hospital, Lille, France.
⁵⁹ Department of Psychiatry, University of California San Diego, San Diego, CA, USA.
⁶⁰ Department of Psychological and Brain Sciences, Boston University, Boston, MA, USA.
⁶¹ NORMENT, 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.
⁶² Departments of Radiology and Neurosciences, University of California, San Diego, La Jolla, CA, USA.
⁶³ National Center for PTSD at Boston VA Healthcare System, Boston, MA, USA.
⁶⁴ Department of Psychiatry and Department of Medicine-Biomedical Genetics Section, Boston University School of Medicine, Boston, MA, USA.
⁶⁵ Psychiatric Genetics, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
⁶⁶ Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine of USC, University of Southern California, Los Angeles, CA, USA.
⁶⁷ Department of Human Genetics, Radboud university medical center, Nijmegen, The Netherlands.
⁶⁸ Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, The Netherlands.
⁶⁹ Neuroscience Biomarkers, Janssen Research and Development, LLC, San Diego, CA, USA.
⁷⁰ Department of Genetics & UNC Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁷¹ Neuropsychiatric Institute, Prince of Wales Hospital, Sydney, NSW, Australia.
⁷² Day Clinic for Cognitive Neurology, University Hospital Leipzig, Leipzig, Germany.
⁷³ Nuffield Department of Population Health, University of Oxford, Oxford, UK.
⁷⁴ Departments of Neurology and Epidemiology, University of Washington, Seattle, WA, USA.
⁷⁵ Bloorview Research Institute, Holland Bloorview Kids Rehabilitation Hospital, Toronto, ON, Canada.
⁷⁶ Departments of Psychology and Psychiatry, University of Toronto, Toronto, ON, Canada.
⁷⁷ CHU de Bordeaux, Department of Neurology, F-33000, Bordeaux, France.
⁷⁸ Department of Neurology, Erasmus MC, Rotterdam, The Netherlands.
⁷⁹ Clinical Division of Neurogeriatrics, Department of Neurology, Medical University of Graz, Graz, Austria. reinhold.schmidt@medunigraz.at.
⁸⁰ Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, UT Health San Antonio, San Antonio, USA. suseshad@bu.edu.
⁸¹ Department of Neurology, Boston University School of Medicine, Boston, MA, USA. suseshad@bu.edu.

^# Contributed equally.

Abstract

Cortical thickness, surface area and volumes vary with age and cognitive function, and in neurological and psychiatric diseases. Here we report heritability, genetic correlations and genome-wide associations of these cortical measures across the whole cortex, and in 34 anatomically predefined regions. Our discovery sample comprises 22,824 individuals from 20 cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank. We identify 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 is 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.

Publication types

Meta-Analysis
Research Support, American Recovery and Reinvestment Act
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Adult
Aged
Aged, 80 and over
Aging / genetics*
Brain*
Chromosome Structures
Cognition
Female
Genome-Wide Association Study*
Genomics
Humans
Male
Mental Disorders / genetics*
Middle Aged
Neurodegenerative Diseases / genetics*
Phenotype
Polymorphism, Single Nucleotide

Abstract

Publication types

MeSH terms

Grants and funding