Genomic analysis of intracranial and subcortical brain volumes yields polygenic scores accounting for variation across ancestries

Luis M García-Marín^#^{1

2}, Adrian I Campos^#^{1

3}, Santiago Diaz-Torres^{2

4}, Jill A Rabinowitz⁵, Zuriel Ceja^{1

2}, Brittany L Mitchell^{1

2}, Katrina L Grasby^{1

2}, Jackson G Thorp¹, Ingrid Agartz^{6

7

8}, Saud Alhusaini^{9

10}, David Ames^{11

12}, Philippe Amouyel^{13

14

15

16}, Ole A Andreassen^{6

17

18}, Konstantinos Arfanakis^{19

20}, Alejandro Arias-Vasquez²¹, Nicola J Armstrong²², Lavinia Athanasiu^{17

23}, Mark E Bastin²⁴, Alexa S Beiser^{25

26}, David A Bennett^{19

27}, Joshua C Bis²⁸, Marco P M Boks²⁹, Dorret I Boomsma³⁰, Henry Brodaty³¹, Rachel M Brouwer³⁰, Jan K Buitelaar³², Ralph Burkhardt^{33

34}, Wiepke Cahn^{35

36}, Vince D Calhoun³⁷, Owen T Carmichael³⁸, Mallar Chakravarty^{39

40}, Qiang Chen⁴¹, Christopher R K Ching⁴², Sven Cichon^{43

44

45}, Benedicto Crespo-Facorro⁴⁶, Fabrice Crivello⁴⁷, Anders M Dale⁴⁸, George Davey Smith^{49

50}, Eco J C de Geus⁵¹, Philip L De Jager⁵², Greig I de Zubicaray⁵³, Stéphanie Debette^{54

55}, Charles DeCarli⁵⁶, Chantal Depondt⁵⁷, Sylvane Desrivières⁵⁸, Srdjan Djurovic^{59

60}, Stefan Ehrlich⁶¹, Susanne Erk^{62

63}, Thomas Espeseth^{64

65}, Guillén Fernández⁶⁶, Irina Filippi⁶⁷, Simon E Fisher^{68

69}, Debra A Fleischman^{19

70}, Evan Fletcher⁷¹, Myriam Fornage⁷², Andreas J Forstner^{43

73}, Clyde Francks^{66

68

74}, Barbara Franke^{32

75}, Tian Ge⁷⁶, Aaron L Goldman⁴¹, Hans J Grabe⁷⁷, Robert C Green⁷⁸, Oliver Grimm^{79

80}, Nynke A Groenewold⁸¹, Oliver Gruber⁸², Vilmundur Gudnason^{83

84}, Asta K Håberg^{85

86}, Unn K Haukvik^{87

88}, Andreas Heinz^{62

88}, Derrek P Hibar⁸⁹, Saima Hilal⁹⁰, Jayandra J Himali^{25

26

91

92

93}, Beng-Choon Ho⁹⁴, David F Hoehn⁹⁵, Pieter J Hoekstra^{96

97}, Edith Hofer^{98

99}, Wolfgang Hoffmann^{100

101}, Avram J Holmes¹⁰², Georg Homuth¹⁰³, Norbert Hosten¹⁰⁴, M Kamran Ikram¹⁰⁵, Jonathan C Ipser¹⁰⁶, Clifford R Jack Jr¹⁰⁷, Neda Jahanshad⁴², Erik G Jönsson^{17

108}, Rene S Kahn³⁶, Ryota Kanai¹⁰⁹, Marieke Klein^{66

75}, Maria J Knol¹¹⁰, Lenore J Launer¹¹¹, Stephen M Lawrie¹¹², Stephanie Le Hellard⁶⁰, Phil H Lee^{113

114

115}, Hervé Lemaître¹¹⁶, Shuo Li^{25

26}, David C M Liewald¹¹⁷, Honghuang Lin¹¹⁸, W T Longstreth Jr^{119

120}, Oscar L Lopez¹²¹, Michelle Luciano¹²², Pauline Maillard⁷¹, Andre F Marquand⁶⁶, Nicholas G Martin¹, Jean-Luc Martinot¹²³, Karen A Mather³¹, Venkata S Mattay⁴¹, Katie L McMahon¹²⁴, Patrizia Mecocci^{125

126}, Ingrid Melle¹⁷, Andreas Meyer-Lindenberg¹²⁷, Nazanin Mirza-Schreiber^{128

129}, Yuri Milaneschi^{130

131

132

133}, Thomas H Mosley¹³⁴, Thomas W Mühleisen^{43

135

136}, Bertram Müller-Myhsok¹³⁷, Susana Muñoz Maniega²⁴, Matthias Nauck^{138

139}, Kwangsik Nho^{140

141}, Wiro J Niessen¹⁴², Markus M Nöthen⁷³, Paul A Nyquist^{143

144}, Jaap Oosterlaan^{145

146

147}, Massimo Pandolfo^{148

149}, Tomas Paus^{150

151}, Zdenka Pausova^{152

153}, Brenda W J H Penninx¹³⁰, G Bruce Pike¹⁵⁴, Bruce M Psaty^{28

120

155}, Benno Pütz¹⁵⁶, Simone Reppermund^{31

157}, Marcella D Rietschel¹⁵⁸, Shannon L Risacher^{140

141}, Nina Romanczuk-Seiferth^{159

160}, Rafael Romero-Garcia^{161

162}, Gennady V Roshchupkin^{110

163}, Jerome I Rotter¹⁶⁴, Perminder S Sachdev^{31

165}, Philipp G Sämann⁹⁵, Arvin Saremi⁴², Muralidharan Sargurupremraj^{54

91}, Andrew J Saykin^{140

141}, Lianne Schmaal^{166

167}, Helena Schmidt¹⁶⁸, Reinhold Schmidt¹⁶⁹, Peter R Schofield^{170

171}, Markus Scholz^{34

172}, Gunter Schumann^{62

162

173

174}, Emanuel Schwarz¹²⁷, Li Shen¹⁷⁵, Jean Shin¹⁷⁶, Sanjay M Sisodiya^{177

178}, Albert V Smith^{83

179}, Jordan W Smoller⁷⁶, Hilkka S Soininen¹⁸⁰, Vidar M Steen^{60

181}, Dan J Stein¹⁸², Jason L Stein¹⁸³, Sophia I Thomopoulos⁴², Arthur W Toga¹⁸⁴, Diana Tordesillas-Gutiérrez^{185

186}, Julian N Trollor^{31

187}, Maria C Valdes-Hernandez²⁴, Dennis van T Ent¹⁸⁸, Hans van Bokhoven^{32

189}, Dennis van der Meer^{17

190}, Nic J A van der Wee¹⁹¹, Javier Vázquez-Bourgon^{192

193

194}, Dick J Veltman¹³⁰, Meike W Vernooij^{110

163}, Arno Villringer^{195

196}, Louis N Vinke¹⁹⁷, Henry Völzke¹⁰¹, Henrik Walter⁶³, Joanna M Wardlaw^{24

198}, Daniel R Weinberger^{41

143

199

200

201}, Michael W Weiner^{202

203

204}, Wei Wen³¹, Lars T Westlye^{17

64}, Eric Westman²⁰⁵, Tonya White²⁰⁶, A Veronica Witte^{195

196}, Christiane Wolf⁹⁵, Jingyun Yang^{19

27}, Marcel P Zwiers³², M Arfan Ikram¹¹⁰, Sudha Seshadri^{26

91}, Paul M Thompson⁴², Claudia L Satizabal^{26

207

208}, Sarah E Medland^{1

2

53

209}, Miguel E Rentería^{210

211}

Affiliations

¹ Brain and Mental Health Program, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
² School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia.
³ Institute for Molecular Biosciences, The University of Queensland, Brisbane, Queensland, Australia.
⁴ Population Health Program, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
⁵ Department of Psychiatry, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ, USA.
⁶ Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
⁷ Department of Psychiatric Research, Diakonhjemmet Hospital, Oslo, Norway.
⁸ Department of Clinical Neuroscience, Karolinska Institutet and Stockholm Health Care Services, Stockholm, Sweden.
⁹ Department of Neurology, Alpert Medical School of Brown University, Providence, RI, USA.
¹⁰ Molecular and Cellular Therapeutics Department, Royal College of Surgeons in Ireland, Dublin, Ireland.
¹¹ Academic Unit Psychiatry of Old Age, University of Melbourne, Melbourne, Victoria, Australia.
¹² National Ageing Research Institute, Parkville, Victoria, Australia.
¹³ Universite Lille, U1167-RID-AGE-LabEx DISTALZ-Risk Factors and Molecular Determinants of Aging Diseases, Lille, France.
¹⁴ Institut National de la Santé et de la Recherche Médicale, Lille, France.
¹⁵ Centre Hospitalier Universitaire de Lille Department of Public Health, Lille, France.
¹⁶ Institut Pasteur de Lille UMR1167, Lille, France.
¹⁷ Centre for Precision Psychiatry, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
¹⁸ KG Jebsen Centre for Neurodevelopmental Disorders, University of Oslo, Oslo, Norway.
¹⁹ Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
²⁰ Department of Biomedical Engineering, Illinois Institute of Technology, Chicago, IL, USA.
²¹ Departments of Psychiatry and Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
²² Department of Mathematics and Statistics, Curtin University, Perth, Western Australia, Australia.
²³ CoE NORMENT, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
²⁴ Centre for Clinical Brain Sciences and Edinburgh Imaging, University of Edinburgh, Edinburgh, UK.
²⁵ Department of Biostatistics, School of Public Health, Boston University, Boston, MA, USA.
²⁶ Framingham Heart Study, Chobanian and Avedisian Boston University School of Medicine, Boston, MA, USA.
²⁷ Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA.
²⁸ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
²⁹ Brain Center University Medical Center Utrecht, Utrecht, The Netherlands.
³⁰ Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, VU Amsterdam, Amsterdam, The Netherlands.
³¹ Centre for Healthy Brain Ageing (CHeBA), Discipline of Psychiatry and Mental Health, School of Clinical Medicine, University of New South Wales, Sydney, New South Wales, Australia.
³² Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
³³ Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Regensburg, Regensburg University, Regensburg, Germany.
³⁴ LIFE Research Center for Civilization Diseases, University of Leipzig, Leipzig, Germany.
³⁵ Department of Psychiatry, University Medical Center Utrecht, Utrecht, The Netherlands.
³⁶ Altrecht Mental Health Institute, Utrecht, The Netherlands.
³⁷ Tri-institutional Center for Translational Research in Neuroimaging and Data Science (TReNDS)-Georgia State, Georgia Tech and Emory University, Atlanta, GA, USA.
³⁸ Pennington Biomedical Research Center, Baton Rouge, LA, USA.
³⁹ Cerebral Imaging Centre, Douglas Research Centre, Montreal, Quebec, Canada.
⁴⁰ Department of Psychiatry, McGill University, Montreal, Quebec, Canada.
⁴¹ Lieber Institute for Brain Development, Baltimore, MD, USA.
⁴² Laboratory of Neuro Imaging, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Marina del Rey, CA, USA.
⁴³ Institute of Neuroscience and Medicine (INM-1), Research Center Jülich, Jülich, Germany.
⁴⁴ Department of Biomedicine, University of Basel, Basel, Switzerland.
⁴⁵ Medical Genetics, Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland.
⁴⁶ HU Virgen del Rocio, Instituto de Investigacion Biomedica IBIS-CSIC, Universidad de Sevilla, CIBERSAM, Sevilla, Spain.
⁴⁷ CNRS, IMN, UMR 5293, University of Bordeaux, Bordeaux, France.
⁴⁸ Center for Multimodal Imaging and Genetics, La Jolla, CA, USA.
⁴⁹ MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
⁵⁰ Population Health Sciences, University of Bristol, Bristol, UK.
⁵¹ Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
⁵² Center for Translational and Computational Neuroimmunology, Department of Neurology, Columbia University Irving Medical Center, New York City, NY, USA.
⁵³ School of Psychology and Counselling, Queensland University of Technology, Brisbane, Queensland, Australia.
⁵⁴ INSERM U1219, Bordeaux Population Health Research Center, University of Bordeaux, Bordeaux, France.
⁵⁵ Department of Neurology, Institute of Neurodegenerative Diseases, Bordeaux University Hospital, Bordeaux, France.
⁵⁶ Imaging of Dementia and Aging Laboratory, Department of Neurology, University of California, Davis, Sacramento, CA, USA.
⁵⁷ Department of Neurology, Hôpital Universitaire de Bruxelles, Université Libre de Bruxelles, Brussels, Belgium.
⁵⁸ Social, Genetic, and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
⁵⁹ Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
⁶⁰ Department of Clinical Science, University of Bergen, Bergen, Norway.
⁶¹ Translational Developmental Neuroscience Section, Division of Psychological and Social Medicine and Developmental Neurosciences, Faculty of Medicine, TU Dresden, Dresden, Germany.
⁶² German Center of Mental Health (DZPG), Partner Site Berlin/Potsdam, Berlin, Germany.
⁶³ Department of Psychiatry and Psychotherapy, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
⁶⁴ Department of Psychology, University of Oslo, Oslo, Norway.
⁶⁵ Department of Psychology, Oslo New University College, Oslo, Norway.
⁶⁶ Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
⁶⁷ INSERM U1299, Paris Saclay University, Gif-sur-Yvette, France.
⁶⁸ Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands.
⁶⁹ Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, The Netherlands.
⁷⁰ Department of Psychiatry and Behavioral Sciences, Rush University Medical Center, Chicago, IL, USA.
⁷¹ Department of Neurology, University of California, Davis, Davis, CA, USA.
⁷² Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA.
⁷³ Institute of Human Genetics, University of Bonn, School of Medicine and University Hospital Bonn, Bonn, Germany.
⁷⁴ Department of Cognitive Neuroscience, Radboud University Medical Center, Nijmegen, The Netherlands.
⁷⁵ Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
⁷⁶ Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
⁷⁷ Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany.
⁷⁸ Department of Medicine (Genetics), Mass General Brigham and Harvard Medical School, Boston, MA, USA.
⁷⁹ Central Institute of Mental Health, Mannheim, Germany.
⁸⁰ Goethe-University Frankfurt, Frankfurt, Germany.
⁸¹ Department of Psychiatry and Mental Health, Neuroscience Institute, University of Cape Town, Cape Town, South Africa.
⁸² Section for Experimental Psychopathology and Neuroimaging, Department of General Psychiatry, Heidelberg University, Heidelberg, Germany.
⁸³ Icelandic Heart Association, Kopavogur, Iceland.
⁸⁴ Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
⁸⁵ Department of Neuromedicine and Movement, NTNU Science, Trondheim, Norway.
⁸⁶ MiDT National Research Center, Department of Research, St Olavs Hospital, Trondheim, Norway.
⁸⁷ Norwegian Centre for Mental Health Research (NORMENT), Department of Mental Health and Addiction, University of Oslo, Oslo, Norway.
⁸⁸ Centre for Forensic Psychiatry Research, Oslo University Hospital, Oslo, Norway.
⁸⁹ Product Development, Genentech, Inc., South San Francisco, CA, USA.
⁹⁰ Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore City, Singapore.
⁹¹ Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, University of Texas Health Sciences Center, San Antonio, TX, USA.
⁹² Department of Population Health Sciences, UT Health Science Center San Antonio, San Antonio, TX, USA.
⁹³ Department of Neurology, Boston University School of Medicine, Boston, MA, USA.
⁹⁴ Department of Psychiatry, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
⁹⁵ Max Planck Institute of Psychiatry, Munich, Germany.
⁹⁶ Department of Child and Adolescent Psychiatry, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
⁹⁷ Accare Child Study Center, Groningen, The Netherlands.
⁹⁸ Division of Neurogeriatrics, Department of Neurology, Medical University of Graz, Graz, Austria.
⁹⁹ Institute for Medical Informatics, Statistics and Documentation, Medical University of Graz, Graz, Austria.
¹⁰⁰ German Centre for Neurodegenerative Diseases (DZNE)-Site Rostock/Greifswald, Greifswald, Germany.
¹⁰¹ Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
¹⁰² Department of Psychiatry, Brain Health Institute, Rutgers University, Piscataway, NJ, USA.
¹⁰³ Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
¹⁰⁴ Department of Radiology, University Clinic Greifswald, Greifswald, Germany.
¹⁰⁵ Departments of Epidemiology and Neurology, Erasmus MC, Rotterdam, The Netherlands.
¹⁰⁶ Department of Psychiatry and Mental Health, Neuroscience Institute, Groote Schuur Hospital, University of Cape Town, Cape Town, South Africa.
¹⁰⁷ Department of Radiology, Mayo Clinic, Rochester, MN, USA.
¹⁰⁸ Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet and Stockholm Health Care Sciences, Stockholm Region, Stockholm, Sweden.
¹⁰⁹ Araya, Inc, Tokyo, Japan.
¹¹⁰ Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
¹¹¹ Intramural Research Program, National Institute on Aging, Baltimore, MD, USA.
¹¹² Division of Psychiatry, University of Edinburgh, Edinburgh, UK.
¹¹³ Center for Genomic Medicine, Mass General Brigham, Boston, MA, USA.
¹¹⁴ Department of Psychiatry, Harvard Medical School, Boston, MA, USA.
¹¹⁵ Stanley Center for Psychiatry, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹¹⁶ Groupe d'Imagerie Neurofonctionnelle, Institut des Maladies Neurodégénératives, UMR 5293, CNRS, Université de Bordeaux, Bordeaux, France.
¹¹⁷ PPLS, University of Edinburgh, Edinburgh, UK.
¹¹⁸ Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA.
¹¹⁹ Department of Neurology, University of Washington, Seattle, WA, USA.
¹²⁰ Department of Epidemiology, University of Washington, Seattle, WA, USA.
¹²¹ Departments of Neurology and Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
¹²² Department of Psychology, University of Edinburgh, Edinburgh, UK.
¹²³ Université Paris-Saclay, Institut National de la Santé et de la Recherche Médicale, INSERM U1299 'Trajectoires développementales Psychiatrie', Ecole Normale Supérieure Paris-Saclay, CNRS UMR 9010, Université Paris Cité, Centre Borelli, Gif sur Yvette, France.
¹²⁴ School of Clinical Sciences, Queensland University of Technology, Brisbane, Queensland, Australia.
¹²⁵ Institute of Gerontology and Geriatrics, Department of Medicine and Surgery, University of Perugia, Perugia, Italy.
¹²⁶ Clinical Geriatrics, NVS Department, Karolinska Institute, Huddinge, Sweden.
¹²⁷ Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
¹²⁸ Institute of Neurogenomics, Helmholtz Munich, Neuherberg, Germany.
¹²⁹ Neurogenetic Systems Analysis Group, Institute of Neurogenomics, Helmholtz Munich, Neuherberg, Germany.
¹³⁰ Department of Psychiatry, Amsterdam UMC location Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
¹³¹ Amsterdam Public Health, Mental Health Program, Amsterdam, The Netherlands.
¹³² Amsterdam Neuroscience, Mood, Anxiety, Psychosis, Sleep and Stress Program, Amsterdam, The Netherlands.
¹³³ Amsterdam Neuroscience, Complex Trait Genetics Program, Amsterdam, The Netherlands.
¹³⁴ MIND Center, Jackson, MS, USA.
¹³⁵ Cécile and Oskar Vogt Institute for Brain Research, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
¹³⁶ Department of Biomedicine, University Hospital Basel and University of Basel, Basel, Switzerland.
¹³⁷ Statistics Genetics Group, Max Planck Institute of Psychiatry, Munich, Germany.
¹³⁸ Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany.
¹³⁹ German Centre for Cardiovascular Research (DZHK), Partner Site Greifswald, Greifswald, Germany.
¹⁴⁰ Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA.
¹⁴¹ Indiana Alzheimer's Disease Research Center, Indiana University School of Medicine, Indianapolis, IN, USA.
¹⁴² University Medical Center Groningen, Groningen, The Netherlands.
¹⁴³ Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
¹⁴⁴ General Internal Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA.
¹⁴⁵ Clinical Neuropsychology Section, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
¹⁴⁶ Emma Children's Hospital, University Medical Centers Amsterdam, Amsterdam, The Netherlands.
¹⁴⁷ Amsterdam Reproduction and Development Research Institute, Amsterdam, The Netherlands.
¹⁴⁸ Université Libre de Bruxelles, Brussels, Belgium.
¹⁴⁹ Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.
¹⁵⁰ Departments of Psychiatry and Neuroscience, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada.
¹⁵¹ Centre Hospitalier Universitaire Sainte-Justine, University of Montreal, Montreal, Quebec, Canada.
¹⁵² Hospital for Sick Children, Toronto, Ontario, Canada.
¹⁵³ Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
¹⁵⁴ Departments of Radiology and Clinical Neurosciences, Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
¹⁵⁵ Department of Health Systems and Population Health, Seattle, WA, USA.
¹⁵⁶ Translational Psychiatry, Munich, Germany.
¹⁵⁷ Department of Developmental Disability Neuropsychiatry, Discipline of Psychiatry and Mental Health, School of Clinical Medicine, University of New South Wales, Sydney, New South Wales, Australia.
¹⁵⁸ Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Faculty of Medicine Mannheim, University of Heidelberg, Mannheim, Germany.
¹⁵⁹ Department of Psychiatry and Neuroscience, Charité-Universitätsmedizin Berlin, Berlin, Germany.
¹⁶⁰ Department of Psychology, Clinical Psychology and Psychotherapy, MSB Medical School Berlin, Berlin, Germany.
¹⁶¹ Departamento de Fisiología Médica y Biofísica, Instituto de Biomedicina de Sevilla (IBiS) HUVR/CSIC/Universidad de Sevilla/CIBERSAM, ISCIII, Sevilla, Spain.
¹⁶² Department of Psychiatry, University of Cambridge, Cambridge, UK.
¹⁶³ Department of Radiology and Nuclear Medicine, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
¹⁶⁴ The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
¹⁶⁵ Neuropsychiatric Institute, The Prince of Wales Hospital, Randwick, New South Wales, Australia.
¹⁶⁶ Centre for Youth Mental Health, The University of Melbourne, Parkville, Victoria, Australia.
¹⁶⁷ Orygen, Parkville, Victoria, Australia.
¹⁶⁸ Institute of Molecular Biology and Biochemistry, Gottfried Schatz Center for Signaling, Metabolism and Aging, Medical University Graz, Graz, Austria.
¹⁶⁹ Department of Neurology, Medical University Graz Austria, Graz, Austria.
¹⁷⁰ Neuroscience Research Australia, Sydney, New South Wales, Australia.
¹⁷¹ School of Biomedical Sciences, University of New South Wales, Sydney, New South Wales, Australia.
¹⁷² Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.
¹⁷³ Centre for Population Neuroscience and Stratified Medicine (PONS), ISTBI, Fudan University, Shanghai, PR China.
¹⁷⁴ PONS Centre, Department of Psychiatry, CCM, Charite Unversitaetsmedizin Berlin, Berlin, Germany.
¹⁷⁵ Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹⁷⁶ The Hospital for Sick Children, Departments of Physiology and Nutritional Sciences, University of Toronto, Toronto, Ontario, Canada.
¹⁷⁷ Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, UK.
¹⁷⁸ Chalfont Centre for Epilepsy, Chalfont St Peter, UK.
¹⁷⁹ Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA.
¹⁸⁰ Department of Neurology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland.
¹⁸¹ Dr. Einar Martens Research Group for Biological Psychiatry, Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway.
¹⁸² SAMRC Research Unit on Risk and Resilience in Mental Disorders, Department of Psychiatry and Neuroscience Institute, University of Cape Town, Cape Town, South Africa.
¹⁸³ Department of Genetics and UNC Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹⁸⁴ Laboratory of Neuro Imaging, USC Stevens Neuroimaging and Informatics Institute, Keck School of Medicine of USC, University of Southern California, Los Angeles, CA, USA.
¹⁸⁵ Instituto de Física de Cantabria (CSIC-UC), Santander, Spain.
¹⁸⁶ Department of Radiology, Marqués de Valdecilla University Hospital, Valdecilla Biomedical Research Institute IDIVAL, Santander, Spain.
¹⁸⁷ The National Centre of Excellence in Intellectual Disability Health, Faculty of Medicine and Health, University of New South Wales, Sydney, New South Wales, Australia.
¹⁸⁸ Department of Biological Psychology and Netherlands Twin Register, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
¹⁸⁹ Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
¹⁹⁰ School of Mental Health and Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, The Netherlands.
¹⁹¹ Department of Psychiatry, Leiden University Medical Center, Leiden, The Netherlands.
¹⁹² Department of Psychiatry, University Hospital Marqués de Valdecilla-IDIVAL, Santander, Spain.
¹⁹³ Departamento de Medicina y Psiquiatría, Universidad de Cantabria, Santander, Spain.
¹⁹⁴ Centro de Investigación Biomédica en Red en Salud Mental (CIBERSAM), Sevilla, Spain.
¹⁹⁵ Department of Neurology, Max Planck Institute for Human, Cognitive and Brain Sciences, Leipzig, Germany.
¹⁹⁶ Cognitive Neurology, University of Leipzig Medical Center, Leipzig, Germany.
¹⁹⁷ Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.
¹⁹⁸ UK Dementia Research Institute Centre, University of Edinburgh, Edinburgh, UK.
¹⁹⁹ Department of Psychiatry, Johns Hopkins School of Medicine, Baltimore, MD, USA.
²⁰⁰ Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD, USA.
²⁰¹ Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA.
²⁰² University of California, San Francisco, San Francisco, CA, USA.
²⁰³ Northern California Institute for Research and Education (NCIRE), San Francisco, CA, USA.
²⁰⁴ Veterans Administration Medical Center, San Francisco, CA, USA.
²⁰⁵ Division of Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society (NVS), Karolinska Institutet, Huddinge, Sweden.
²⁰⁶ Section on Social and Cognitive Developmental Neuroscience, National Institute of Mental Health, Bethesda, MD, USA.
²⁰⁷ Department of Population Health Sciences and Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, UT Health San Antonio, San Antonio, TX, USA.
²⁰⁸ Department of Neurology, Boston University Chobanian and Avedisian School of Medicine, Boston, MA, USA.
²⁰⁹ School of Psychology, The University of Queensland, Brisbane, Queensland, Australia.
²¹⁰ Brain and Mental Health Program, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia. miguel.renteria@qimrberghofer.edu.au.
²¹¹ School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia. miguel.renteria@qimrberghofer.edu.au.

^# Contributed equally.

PMID: 39433889
PMCID: PMC12088653 (available on 2025-11-01)
DOI: 10.1038/s41588-024-01951-z

Genomic analysis of intracranial and subcortical brain volumes yields polygenic scores accounting for variation across ancestries

Luis M García-Marín et al. Nat Genet. 2024 Nov.

. 2024 Nov;56(11):2333-2344.

doi: 10.1038/s41588-024-01951-z. Epub 2024 Oct 21.

Authors

Affiliations

¹ Brain and Mental Health Program, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
² School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia.
³ Institute for Molecular Biosciences, The University of Queensland, Brisbane, Queensland, Australia.
⁴ Population Health Program, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
⁵ Department of Psychiatry, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ, USA.
⁶ Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
⁷ Department of Psychiatric Research, Diakonhjemmet Hospital, Oslo, Norway.
⁸ Department of Clinical Neuroscience, Karolinska Institutet and Stockholm Health Care Services, Stockholm, Sweden.
⁹ Department of Neurology, Alpert Medical School of Brown University, Providence, RI, USA.
¹⁰ Molecular and Cellular Therapeutics Department, Royal College of Surgeons in Ireland, Dublin, Ireland.
¹¹ Academic Unit Psychiatry of Old Age, University of Melbourne, Melbourne, Victoria, Australia.
¹² National Ageing Research Institute, Parkville, Victoria, Australia.
¹³ Universite Lille, U1167-RID-AGE-LabEx DISTALZ-Risk Factors and Molecular Determinants of Aging Diseases, Lille, France.
¹⁴ Institut National de la Santé et de la Recherche Médicale, Lille, France.
¹⁵ Centre Hospitalier Universitaire de Lille Department of Public Health, Lille, France.
¹⁶ Institut Pasteur de Lille UMR1167, Lille, France.
¹⁷ Centre for Precision Psychiatry, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
¹⁸ KG Jebsen Centre for Neurodevelopmental Disorders, University of Oslo, Oslo, Norway.
¹⁹ Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
²⁰ Department of Biomedical Engineering, Illinois Institute of Technology, Chicago, IL, USA.
²¹ Departments of Psychiatry and Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
²² Department of Mathematics and Statistics, Curtin University, Perth, Western Australia, Australia.
²³ CoE NORMENT, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
²⁴ Centre for Clinical Brain Sciences and Edinburgh Imaging, University of Edinburgh, Edinburgh, UK.
²⁵ Department of Biostatistics, School of Public Health, Boston University, Boston, MA, USA.
²⁶ Framingham Heart Study, Chobanian and Avedisian Boston University School of Medicine, Boston, MA, USA.
²⁷ Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA.
²⁸ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
²⁹ Brain Center University Medical Center Utrecht, Utrecht, The Netherlands.
³⁰ Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, VU Amsterdam, Amsterdam, The Netherlands.
³¹ Centre for Healthy Brain Ageing (CHeBA), Discipline of Psychiatry and Mental Health, School of Clinical Medicine, University of New South Wales, Sydney, New South Wales, Australia.
³² Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
³³ Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Regensburg, Regensburg University, Regensburg, Germany.
³⁴ LIFE Research Center for Civilization Diseases, University of Leipzig, Leipzig, Germany.
³⁵ Department of Psychiatry, University Medical Center Utrecht, Utrecht, The Netherlands.
³⁶ Altrecht Mental Health Institute, Utrecht, The Netherlands.
³⁷ Tri-institutional Center for Translational Research in Neuroimaging and Data Science (TReNDS)-Georgia State, Georgia Tech and Emory University, Atlanta, GA, USA.
³⁸ Pennington Biomedical Research Center, Baton Rouge, LA, USA.
³⁹ Cerebral Imaging Centre, Douglas Research Centre, Montreal, Quebec, Canada.
⁴⁰ Department of Psychiatry, McGill University, Montreal, Quebec, Canada.
⁴¹ Lieber Institute for Brain Development, Baltimore, MD, USA.
⁴² Laboratory of Neuro Imaging, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Marina del Rey, CA, USA.
⁴³ Institute of Neuroscience and Medicine (INM-1), Research Center Jülich, Jülich, Germany.
⁴⁴ Department of Biomedicine, University of Basel, Basel, Switzerland.
⁴⁵ Medical Genetics, Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland.
⁴⁶ HU Virgen del Rocio, Instituto de Investigacion Biomedica IBIS-CSIC, Universidad de Sevilla, CIBERSAM, Sevilla, Spain.
⁴⁷ CNRS, IMN, UMR 5293, University of Bordeaux, Bordeaux, France.
⁴⁸ Center for Multimodal Imaging and Genetics, La Jolla, CA, USA.
⁴⁹ MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
⁵⁰ Population Health Sciences, University of Bristol, Bristol, UK.
⁵¹ Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
⁵² Center for Translational and Computational Neuroimmunology, Department of Neurology, Columbia University Irving Medical Center, New York City, NY, USA.
⁵³ School of Psychology and Counselling, Queensland University of Technology, Brisbane, Queensland, Australia.
⁵⁴ INSERM U1219, Bordeaux Population Health Research Center, University of Bordeaux, Bordeaux, France.
⁵⁵ Department of Neurology, Institute of Neurodegenerative Diseases, Bordeaux University Hospital, Bordeaux, France.
⁵⁶ Imaging of Dementia and Aging Laboratory, Department of Neurology, University of California, Davis, Sacramento, CA, USA.
⁵⁷ Department of Neurology, Hôpital Universitaire de Bruxelles, Université Libre de Bruxelles, Brussels, Belgium.
⁵⁸ Social, Genetic, and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
⁵⁹ Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
⁶⁰ Department of Clinical Science, University of Bergen, Bergen, Norway.
⁶¹ Translational Developmental Neuroscience Section, Division of Psychological and Social Medicine and Developmental Neurosciences, Faculty of Medicine, TU Dresden, Dresden, Germany.
⁶² German Center of Mental Health (DZPG), Partner Site Berlin/Potsdam, Berlin, Germany.
⁶³ Department of Psychiatry and Psychotherapy, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
⁶⁴ Department of Psychology, University of Oslo, Oslo, Norway.
⁶⁵ Department of Psychology, Oslo New University College, Oslo, Norway.
⁶⁶ Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
⁶⁷ INSERM U1299, Paris Saclay University, Gif-sur-Yvette, France.
⁶⁸ Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands.
⁶⁹ Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, The Netherlands.
⁷⁰ Department of Psychiatry and Behavioral Sciences, Rush University Medical Center, Chicago, IL, USA.
⁷¹ Department of Neurology, University of California, Davis, Davis, CA, USA.
⁷² Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA.
⁷³ Institute of Human Genetics, University of Bonn, School of Medicine and University Hospital Bonn, Bonn, Germany.
⁷⁴ Department of Cognitive Neuroscience, Radboud University Medical Center, Nijmegen, The Netherlands.
⁷⁵ Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
⁷⁶ Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
⁷⁷ Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany.
⁷⁸ Department of Medicine (Genetics), Mass General Brigham and Harvard Medical School, Boston, MA, USA.
⁷⁹ Central Institute of Mental Health, Mannheim, Germany.
⁸⁰ Goethe-University Frankfurt, Frankfurt, Germany.
⁸¹ Department of Psychiatry and Mental Health, Neuroscience Institute, University of Cape Town, Cape Town, South Africa.
⁸² Section for Experimental Psychopathology and Neuroimaging, Department of General Psychiatry, Heidelberg University, Heidelberg, Germany.
⁸³ Icelandic Heart Association, Kopavogur, Iceland.
⁸⁴ Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
⁸⁵ Department of Neuromedicine and Movement, NTNU Science, Trondheim, Norway.
⁸⁶ MiDT National Research Center, Department of Research, St Olavs Hospital, Trondheim, Norway.
⁸⁷ Norwegian Centre for Mental Health Research (NORMENT), Department of Mental Health and Addiction, University of Oslo, Oslo, Norway.
⁸⁸ Centre for Forensic Psychiatry Research, Oslo University Hospital, Oslo, Norway.
⁸⁹ Product Development, Genentech, Inc., South San Francisco, CA, USA.
⁹⁰ Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore City, Singapore.
⁹¹ Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, University of Texas Health Sciences Center, San Antonio, TX, USA.
⁹² Department of Population Health Sciences, UT Health Science Center San Antonio, San Antonio, TX, USA.
⁹³ Department of Neurology, Boston University School of Medicine, Boston, MA, USA.
⁹⁴ Department of Psychiatry, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
⁹⁵ Max Planck Institute of Psychiatry, Munich, Germany.
⁹⁶ Department of Child and Adolescent Psychiatry, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
⁹⁷ Accare Child Study Center, Groningen, The Netherlands.
⁹⁸ Division of Neurogeriatrics, Department of Neurology, Medical University of Graz, Graz, Austria.
⁹⁹ Institute for Medical Informatics, Statistics and Documentation, Medical University of Graz, Graz, Austria.
¹⁰⁰ German Centre for Neurodegenerative Diseases (DZNE)-Site Rostock/Greifswald, Greifswald, Germany.
¹⁰¹ Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
¹⁰² Department of Psychiatry, Brain Health Institute, Rutgers University, Piscataway, NJ, USA.
¹⁰³ Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
¹⁰⁴ Department of Radiology, University Clinic Greifswald, Greifswald, Germany.
¹⁰⁵ Departments of Epidemiology and Neurology, Erasmus MC, Rotterdam, The Netherlands.
¹⁰⁶ Department of Psychiatry and Mental Health, Neuroscience Institute, Groote Schuur Hospital, University of Cape Town, Cape Town, South Africa.
¹⁰⁷ Department of Radiology, Mayo Clinic, Rochester, MN, USA.
¹⁰⁸ Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet and Stockholm Health Care Sciences, Stockholm Region, Stockholm, Sweden.
¹⁰⁹ Araya, Inc, Tokyo, Japan.
¹¹⁰ Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
¹¹¹ Intramural Research Program, National Institute on Aging, Baltimore, MD, USA.
¹¹² Division of Psychiatry, University of Edinburgh, Edinburgh, UK.
¹¹³ Center for Genomic Medicine, Mass General Brigham, Boston, MA, USA.
¹¹⁴ Department of Psychiatry, Harvard Medical School, Boston, MA, USA.
¹¹⁵ Stanley Center for Psychiatry, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹¹⁶ Groupe d'Imagerie Neurofonctionnelle, Institut des Maladies Neurodégénératives, UMR 5293, CNRS, Université de Bordeaux, Bordeaux, France.
¹¹⁷ PPLS, University of Edinburgh, Edinburgh, UK.
¹¹⁸ Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA.
¹¹⁹ Department of Neurology, University of Washington, Seattle, WA, USA.
¹²⁰ Department of Epidemiology, University of Washington, Seattle, WA, USA.
¹²¹ Departments of Neurology and Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
¹²² Department of Psychology, University of Edinburgh, Edinburgh, UK.
¹²³ Université Paris-Saclay, Institut National de la Santé et de la Recherche Médicale, INSERM U1299 'Trajectoires développementales Psychiatrie', Ecole Normale Supérieure Paris-Saclay, CNRS UMR 9010, Université Paris Cité, Centre Borelli, Gif sur Yvette, France.
¹²⁴ School of Clinical Sciences, Queensland University of Technology, Brisbane, Queensland, Australia.
¹²⁵ Institute of Gerontology and Geriatrics, Department of Medicine and Surgery, University of Perugia, Perugia, Italy.
¹²⁶ Clinical Geriatrics, NVS Department, Karolinska Institute, Huddinge, Sweden.
¹²⁷ Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
¹²⁸ Institute of Neurogenomics, Helmholtz Munich, Neuherberg, Germany.
¹²⁹ Neurogenetic Systems Analysis Group, Institute of Neurogenomics, Helmholtz Munich, Neuherberg, Germany.
¹³⁰ Department of Psychiatry, Amsterdam UMC location Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
¹³¹ Amsterdam Public Health, Mental Health Program, Amsterdam, The Netherlands.
¹³² Amsterdam Neuroscience, Mood, Anxiety, Psychosis, Sleep and Stress Program, Amsterdam, The Netherlands.
¹³³ Amsterdam Neuroscience, Complex Trait Genetics Program, Amsterdam, The Netherlands.
¹³⁴ MIND Center, Jackson, MS, USA.
¹³⁵ Cécile and Oskar Vogt Institute for Brain Research, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
¹³⁶ Department of Biomedicine, University Hospital Basel and University of Basel, Basel, Switzerland.
¹³⁷ Statistics Genetics Group, Max Planck Institute of Psychiatry, Munich, Germany.
¹³⁸ Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany.
¹³⁹ German Centre for Cardiovascular Research (DZHK), Partner Site Greifswald, Greifswald, Germany.
¹⁴⁰ Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA.
¹⁴¹ Indiana Alzheimer's Disease Research Center, Indiana University School of Medicine, Indianapolis, IN, USA.
¹⁴² University Medical Center Groningen, Groningen, The Netherlands.
¹⁴³ Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
¹⁴⁴ General Internal Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA.
¹⁴⁵ Clinical Neuropsychology Section, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
¹⁴⁶ Emma Children's Hospital, University Medical Centers Amsterdam, Amsterdam, The Netherlands.
¹⁴⁷ Amsterdam Reproduction and Development Research Institute, Amsterdam, The Netherlands.
¹⁴⁸ Université Libre de Bruxelles, Brussels, Belgium.
¹⁴⁹ Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.
¹⁵⁰ Departments of Psychiatry and Neuroscience, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada.
¹⁵¹ Centre Hospitalier Universitaire Sainte-Justine, University of Montreal, Montreal, Quebec, Canada.
¹⁵² Hospital for Sick Children, Toronto, Ontario, Canada.
¹⁵³ Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
¹⁵⁴ Departments of Radiology and Clinical Neurosciences, Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
¹⁵⁵ Department of Health Systems and Population Health, Seattle, WA, USA.
¹⁵⁶ Translational Psychiatry, Munich, Germany.
¹⁵⁷ Department of Developmental Disability Neuropsychiatry, Discipline of Psychiatry and Mental Health, School of Clinical Medicine, University of New South Wales, Sydney, New South Wales, Australia.
¹⁵⁸ Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Faculty of Medicine Mannheim, University of Heidelberg, Mannheim, Germany.
¹⁵⁹ Department of Psychiatry and Neuroscience, Charité-Universitätsmedizin Berlin, Berlin, Germany.
¹⁶⁰ Department of Psychology, Clinical Psychology and Psychotherapy, MSB Medical School Berlin, Berlin, Germany.
¹⁶¹ Departamento de Fisiología Médica y Biofísica, Instituto de Biomedicina de Sevilla (IBiS) HUVR/CSIC/Universidad de Sevilla/CIBERSAM, ISCIII, Sevilla, Spain.
¹⁶² Department of Psychiatry, University of Cambridge, Cambridge, UK.
¹⁶³ Department of Radiology and Nuclear Medicine, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
¹⁶⁴ The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
¹⁶⁵ Neuropsychiatric Institute, The Prince of Wales Hospital, Randwick, New South Wales, Australia.
¹⁶⁶ Centre for Youth Mental Health, The University of Melbourne, Parkville, Victoria, Australia.
¹⁶⁷ Orygen, Parkville, Victoria, Australia.
¹⁶⁸ Institute of Molecular Biology and Biochemistry, Gottfried Schatz Center for Signaling, Metabolism and Aging, Medical University Graz, Graz, Austria.
¹⁶⁹ Department of Neurology, Medical University Graz Austria, Graz, Austria.
¹⁷⁰ Neuroscience Research Australia, Sydney, New South Wales, Australia.
¹⁷¹ School of Biomedical Sciences, University of New South Wales, Sydney, New South Wales, Australia.
¹⁷² Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.
¹⁷³ Centre for Population Neuroscience and Stratified Medicine (PONS), ISTBI, Fudan University, Shanghai, PR China.
¹⁷⁴ PONS Centre, Department of Psychiatry, CCM, Charite Unversitaetsmedizin Berlin, Berlin, Germany.
¹⁷⁵ Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹⁷⁶ The Hospital for Sick Children, Departments of Physiology and Nutritional Sciences, University of Toronto, Toronto, Ontario, Canada.
¹⁷⁷ Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, UK.
¹⁷⁸ Chalfont Centre for Epilepsy, Chalfont St Peter, UK.
¹⁷⁹ Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA.
¹⁸⁰ Department of Neurology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland.
¹⁸¹ Dr. Einar Martens Research Group for Biological Psychiatry, Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway.
¹⁸² SAMRC Research Unit on Risk and Resilience in Mental Disorders, Department of Psychiatry and Neuroscience Institute, University of Cape Town, Cape Town, South Africa.
¹⁸³ Department of Genetics and UNC Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹⁸⁴ Laboratory of Neuro Imaging, USC Stevens Neuroimaging and Informatics Institute, Keck School of Medicine of USC, University of Southern California, Los Angeles, CA, USA.
¹⁸⁵ Instituto de Física de Cantabria (CSIC-UC), Santander, Spain.
¹⁸⁶ Department of Radiology, Marqués de Valdecilla University Hospital, Valdecilla Biomedical Research Institute IDIVAL, Santander, Spain.
¹⁸⁷ The National Centre of Excellence in Intellectual Disability Health, Faculty of Medicine and Health, University of New South Wales, Sydney, New South Wales, Australia.
¹⁸⁸ Department of Biological Psychology and Netherlands Twin Register, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
¹⁸⁹ Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
¹⁹⁰ School of Mental Health and Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, The Netherlands.
¹⁹¹ Department of Psychiatry, Leiden University Medical Center, Leiden, The Netherlands.
¹⁹² Department of Psychiatry, University Hospital Marqués de Valdecilla-IDIVAL, Santander, Spain.
¹⁹³ Departamento de Medicina y Psiquiatría, Universidad de Cantabria, Santander, Spain.
¹⁹⁴ Centro de Investigación Biomédica en Red en Salud Mental (CIBERSAM), Sevilla, Spain.
¹⁹⁵ Department of Neurology, Max Planck Institute for Human, Cognitive and Brain Sciences, Leipzig, Germany.
¹⁹⁶ Cognitive Neurology, University of Leipzig Medical Center, Leipzig, Germany.
¹⁹⁷ Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.
¹⁹⁸ UK Dementia Research Institute Centre, University of Edinburgh, Edinburgh, UK.
¹⁹⁹ Department of Psychiatry, Johns Hopkins School of Medicine, Baltimore, MD, USA.
²⁰⁰ Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD, USA.
²⁰¹ Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA.
²⁰² University of California, San Francisco, San Francisco, CA, USA.
²⁰³ Northern California Institute for Research and Education (NCIRE), San Francisco, CA, USA.
²⁰⁴ Veterans Administration Medical Center, San Francisco, CA, USA.
²⁰⁵ Division of Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society (NVS), Karolinska Institutet, Huddinge, Sweden.
²⁰⁶ Section on Social and Cognitive Developmental Neuroscience, National Institute of Mental Health, Bethesda, MD, USA.
²⁰⁷ Department of Population Health Sciences and Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, UT Health San Antonio, San Antonio, TX, USA.
²⁰⁸ Department of Neurology, Boston University Chobanian and Avedisian School of Medicine, Boston, MA, USA.
²⁰⁹ School of Psychology, The University of Queensland, Brisbane, Queensland, Australia.
²¹⁰ Brain and Mental Health Program, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia. miguel.renteria@qimrberghofer.edu.au.
²¹¹ School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia. miguel.renteria@qimrberghofer.edu.au.

^# Contributed equally.

PMID: 39433889
PMCID: PMC12088653 (available on 2025-11-01)
DOI: 10.1038/s41588-024-01951-z

Abstract

Subcortical brain structures are involved in developmental, psychiatric and neurological disorders. Here we performed genome-wide association studies meta-analyses of intracranial and nine subcortical brain volumes (brainstem, caudate nucleus, putamen, hippocampus, globus pallidus, thalamus, nucleus accumbens, amygdala and the ventral diencephalon) in 74,898 participants of European ancestry. We identified 254 independent loci associated with these brain volumes, explaining up to 35% of phenotypic variance. We observed gene expression in specific neural cell types across differentiation time points, including genes involved in intracellular signaling and brain aging-related processes. Polygenic scores for brain volumes showed predictive ability when applied to individuals of diverse ancestries. We observed causal genetic effects of brain volumes with Parkinson's disease and attention-deficit/hyperactivity disorder. Findings implicate specific gene expression patterns in brain development and genetic variants in comorbid neuropsychiatric disorders, which could point to a brain substrate and region of action for risk genes implicated in brain diseases.

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Conflict of interest statement

Competing interests

I.A. received a speaker’s honorarium from Lundbeck. O.A.A. is a consultant to Cortechs.ai and Precision Health and has received a speaker’s honorarium from Lundbeck, Janssen, Otsuka and Sunovion. H.B. is an Advisory Board Member or Consultant to Biogen, Eisai, Eli Lilly, Roche, Skin2Neuron, Cranbrook Care and Montefiore Homes. C.R.K.C. has received past partial research support from Biogen for work unrelated to the topic of this paper. A.M.D. is the Principal Investigator of a research agreement between General Electric Healthcare and the University of California, San Diego (UCSD); he is a founder of and holds equity in CorTechs Labs and a member of the Scientific Advisory Board of Human Longevity and the Mohn Medical Imaging and Visualization Center in Bergen, Norway. The terms of these arrangements have been reviewed and approved by UCSD in accordance with its conflict of interest policies. B.F. has received educational speaking fees from Medice. H.J.G. has received travel grants and speakers honoraria from Fresenius Medical Care, Neuraxpharm, Servier and Janssen-Cilag, as well as research funding from Fresenius Medical Care. D.P.H. is a full-time employee of Genentech. N.H. is a shareholder in various manufacturers of medical technology. A.M.-L. has received consultant fees from Daimler und Benz Stiftung, EPFL Brain Mind Institute, Fondation FondaMental, Hector Stiftung II, Invisio, Janssen-Cilag GmbH, Lundbeck A/S, Lundbeckfonden, Lundbeck Int. Neuroscience Foundation, Neurotorium, MedinCell, The LOOP Zürich, University Medical Center Utrecht, University of Washington, Verein für Mentales Wohlbefinden and von Behring-Röntgen-Stiftung; speaker fees from Ärztekammer Nordrhein, Caritas, Clarivate, Dt. Gesellschaft für Neurowissenschaftliche Begutachtung, Gentner Verlag, Landesärztekammer Baden-Württemberg, LWL Bochum, Northwell Health, Ruhr University Bochum, Penn State University, Society of Biological Psychiatry, University Prague and Vitos Klinik Rheingau; and editorial and/or author fees from American Association for the Advancement of Science, ECNP, Servier and Thieme Verlag. W.J.N. is the founder of Quantib BV and was the scientific lead of Quantib BV until 31 January 2023. M.M.N. has received fees for membership in an advisory board from HMG Systems Engineering GmbH (Fürth, Germany), for membership in the Medical-Scientific Editorial Office of the Deutsches Ärzteblatt and for serving as a consultant for EVERIS Belgique SPRL in a project of the European Commission (REFORM/SC2020/029), and receives salary payments from Life & Brain GmbH and holds shares in Life & Brain GmbH. All these concerned activities are outside the submitted work. B.M.P. serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. A.J.S. receives support from multiple National Institutes of Health (NIH) grants and has also received support from Avid Radiopharmaceuticals, a subsidiary of Eli Lilly (in-kind contribution of position emission tomography tracer precursor); Bayer Oncology (Scientific Advisory Board); Eisai (Scientific Advisory Board); Siemens Medical Solutions USA (Dementia Advisory Board); NIH National Heart, Lung, and Blood Institute (Multi-Ethnic Study of Atherosclerosis Observational Study Monitoring Board); and Springer Nature Publishing (Editorial Office Support as Editor-in-Chief, Brain Imaging and Behavior). M. Scholz received funding from Pfizer for a project not related to this research. E.S. received speaker fees from bfd buchholz fachinformationsdienst gmbh. P.M.T. receives partial research support from Biogen for research unrelated to this paper. M.W.W. serves on editorial boards for Alzheimer’s & Dementia and the Journal for Prevention of Alzheimer’s Disease. He has served on advisory boards for Acumen Pharmaceutical, Alzheon, Cerecin, Merck Sharp & Dohme and the NC Registry for Brain Health. He also serves on the University of Southern California (USC) Alzheimer’s Clinical Trials Consortium grant that receives funding from Eisai for the AHEAD study; has provided consulting to Boxer Capital, Cerecin, Clario, Dementia Society of Japan, Eisai, Guidepoint, Health and Wellness Partners, Indiana University, LCN Consulting, Merck Sharp & Dohme, NC Registry for Brain Health, Prova Education, T3D Therapeutics, USC and WebMD; has acted as a speaker/lecturer for the China Association for Alzheimer’s Disease and Taipei Medical University, as well as a speaker/lecturer with academic travel funding provided by AD/PD Congress, Cleveland Clinic, CTAD Congress, Foundation of Learning, Health Society (Japan), INSPIRE project, U. Toulouse, Japan Society for Dementia Research, and Korean Dementia Society, Merck Sharp & Dohme, National Center for Geriatrics and Gerontology (Japan) and USC; holds stock options with Alzeca, Alzheon, ALZPath and Anven; and received support for his research from the following funding sources: NIH/National Institute of Neurological Disorders and Stroke/National Institute on Aging, Department of Defense, California Department of Public Health, University of Michigan, Siemens, Biogen, Hillblom Foundation, Alzheimer’s Association, Johnson & Johnson, Kevin and Connie Shanahan, GE, VUmc, Australian Catholic University (Healthy Brain Initiative/Brain Health Registry), The Stroke Foundation, and the Veterans Administration. A.I.C. is currently employed by the Regeneron Genetics Center, a wholly-owned subsidiary of Regeneron Pharmaceuticals, and may hold Regeneron stock or stock options. The other authors declare no competing interests.

Update of

Genomic analysis of intracranial and subcortical brain volumes yields polygenic scores accounting for variation across ancestries.
García-Marín LM, Campos AI, Diaz-Torres S, Rabinowitz JA, Ceja Z, Mitchell BL, Grasby KL, Thorp JG, Agartz I, Alhusaini S, Ames D, Amouyel P, Andreassen OA, Arfanakis K, Vasquez AA, Armstrong NJ, Athanasiu L, Bastin ME, Beiser AS, Bennett DA, Bis JC, Boks MP, Boomsma DI, Brodaty H, Brouwer RM, Buitelaar JK, Burkhardt R, Cahn W, Calhoun VD, Carmichael OT, Chakravarty M, Chen Q, Ching CRK, Cichon S, Crespo-Facorro B, Crivello F, Dale AM, Smith GD, de Geus EJ, De Jager PL, de Zubicaray GI, Debette S, DeCarli C, Depondt C, Desrivières S, Djurovic S, Ehrlich S, Erk S, Espeseth T, Fernández G, Filippi I, Fisher SE, Fleischman DA, Fletcher E, Fornage M, Forstner AJ, Francks C, Franke B, Ge T, Goldman AL, Grabe HJ, Green RC, Grimm O, Groenewold NA, Gruber O, Gudnason V, Håberg AK, Haukvik UK, Heinz A, Hibar DP, Hilal S, Himali JJ, Ho BC, Hoehn DF, Hoekstra PJ, Hofer E, Hoffmann W, Holmes AJ, Homuth G, Hosten N, Ikram MK, Ipser JC, Jack CR Jr, Jahanshad N, Jönsson EG, Kahn RS, Kanai R, Klein M, Knol MJ, Launer LJ, Lawrie SM, Hellard SL, Lee PH, Lemaître H, Li S, Liewald DC, Lin H, Longstreth WT Jr, Lopez OL, Luciano M, Maillard P, Marquand AF, Martin NG, Martinot JL, Mather KA, Mattay VS, … See abstract for full author list ➔ García-Marín LM, et al. medRxiv [Preprint]. 2024 Aug 15:2024.08.13.24311922. doi: 10.1101/2024.08.13.24311922. medRxiv. 2024. Update in: Nat Genet. 2024 Nov;56(11):2333-2344. doi: 10.1038/s41588-024-01951-z. PMID: 39371125 Free PMC article. Updated. Preprint.

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Genomic analysis of intracranial and subcortical brain volumes yields polygenic scores accounting for variation across ancestries

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Genomic analysis of intracranial and subcortical brain volumes yields polygenic scores accounting for variation across ancestries

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