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Nat Genet. 2019 Nov;51(11):1624-1636. doi: 10.1038/s41588-019-0511-y. Epub 2019 Oct 21.

Genetic architecture of subcortical brain structures in 38,851 individuals.

Satizabal CL1,2,3,4, Adams HHH5,6,7, Hibar DP8, White CC9,10, Knol MJ5, Stein JL8,11,12, Scholz M13,14, Sargurupremraj M15, Jahanshad N8, Roshchupkin GV5,6,16, Smith AV17,18,19, Bis JC20, Jian X21, Luciano M22, Hofer E23,24, Teumer A25, van der Lee SJ5, Yang J26,27, Yanek LR28, Lee TV29, Li S30, Hu Y31, Koh JY32, Eicher JD33, Desrivières S34, Arias-Vasquez A35,36,37,38, Chauhan G15,39, Athanasiu L40,41, Rentería ME42, Kim S43,44,45, Hoehn D46, Armstrong NJ47, Chen Q48, Holmes AJ49,50, den Braber A51,52,53,54, Kloszewska I55, Andersson M56,57, Espeseth T40,58, Grimm O59, Abramovic L60, Alhusaini S61,62, Milaneschi Y63, Papmeyer M64,65, Axelsson T66, Ehrlich S50,67,68, Roiz-Santiañez R69,70,71, Kraemer B72, Håberg AK73,74, Jones HJ75,76,77, Pike GB78,79, Stein DJ80,81, Stevens A68, Bralten J36,38, Vernooij MW5,6, Harris TB82, Filippi I83, Witte AV84,85, Guadalupe T86,87, Wittfeld K88,89, Mosley TH90, Becker JT91,92,93, Doan NT41, Hagenaars SP22, Saba Y94, Cuellar-Partida G95, Amin N5, Hilal S96,97, Nho K43,44,45, Mirza-Schreiber N46,98, Arfanakis K26,99,100, Becker DM28, Ames D101,102, Goldman AL48, Lee PH50,103,104,105,106, Boomsma DI51,52,53,107, Lovestone S108,109, Giddaluru S110,111, Le Hellard S110,111, Mattheisen M112,113,114,115,116, Bohlken MM60, Kasperaviciute D117,118, Schmaal L119,120, Lawrie SM64, Agartz I41,115,121, Walton E67,122, Tordesillas-Gutierrez D71,123, Davies GE124, Shin J125, Ipser JC80, Vinke LN126, Hoogman M36,38, Jia T34, Burkhardt R14,127, Klein M36,38, Crivello F128, Janowitz D88, Carmichael O129, Haukvik UK40,130, Aribisala BS131,132, Schmidt H94, Strike LT95,133, Cheng CY32,134, Risacher SL44,45, Pütz B46, Fleischman DA26,27,135, Assareh AA136, Mattay VS48,137,138, Buckner RL50,139, Mecocci P140, Dale AM141,142,143,144,145, Cichon S146,147,148, Boks MP60, Matarin M117,149,150, Penninx BWJH63, Calhoun VD151,152,153, Chakravarty MM154,155, Marquand AF38,156, Macare C34, Kharabian Masouleh S84,157, Oosterlaan J158,159, Amouyel P160,161,162,163, Hegenscheid K164, Rotter JI165, Schork AJ166,167, Liewald DCM22, de Zubicaray GI168,169, Wong TY32,170, Shen L171, Sämann PG46, Brodaty H136,172, Roffman JL50, de Geus EJC51,52,53,107, Tsolaki M173, Erk S174, van Eijk KR175, Cavalleri GL176, van der Wee NJA177,178, McIntosh AM22,64, Gollub RL50,68,103, Bulayeva KB179, Bernard M125, Richards JS35,38,180, Himali JJ181,182,30, Loeffler M13,14, Rommelse N37,38,183, Hoffmann W89,184, Westlye LT40,41, Valdés Hernández MC131,185, Hansell NK95,133, van Erp TGM186,187, Wolf C188, Kwok JBJ189,190,191, Vellas B192,193, Heinz A194, Olde Loohuis LM195, Delanty N61,196, Ho BC197, Ching CRK8,198, Shumskaya E36,38,156, Singh B199, Hofman A5,200, van der Meer D40,41,201, Homuth G202, Psaty BM20,203,204,205, Bastin ME131,185, Montgomery GW206, Foroud TM45,207, Reppermund S136,208, Hottenga JJ51,52,53,107, Simmons A209,210,211, Meyer-Lindenberg A59, Cahn W60, Whelan CD8,61, van Donkelaar MMJ36,38, Yang Q30, Hosten N164, Green RC103,212, Thalamuthu A136, Mohnke S174, Hulshoff Pol HE60, Lin H181,213, Jack CR Jr214, Schofield PR190,215, Mühleisen TW148,216,217, Maillard P199, Potkin SG218, Wen W136, Fletcher E199, Toga AW219, Gruber O72, Huentelman M167, Davey Smith G76, Launer LJ82, Nyberg L56,57,220, Jönsson EG41,115, Crespo-Facorro B70,71, Koen N80,81, Greve DN68,221, Uitterlinden AG5,222, Weinberger DR48,137,223,224,225, Steen VM110,111, Fedko IO51,52,107, Groenewold NA80, Niessen WJ6,16,226, Toro R227, Tzourio C228, Longstreth WT Jr204,229, Ikram MK5,230, Smoller JW50,103,105,106, van Tol MJ231, Sussmann JE64, Paus T232,233,234, Lemaître H83, Schroeter ML14,84,235, Mazoyer B128, Andreassen OA40,41, Holsboer F46,236, Depondt C237, Veltman DJ63, Turner JA152,153,238, Pausova Z125, Schumann G34, van Rooij D35,38,180, Djurovic S110,239, Deary IJ22, McMahon KL168,169, Müller-Myhsok B46,240,241, Brouwer RM60, Soininen H242,243, Pandolfo M237, Wassink TH197, Cheung JW8, Wolfers T36,38, Martinot JL83, Zwiers MP38,156, Nauck M244,245, Melle I40,41, Martin NG95, Kanai R246,247,248, Westman E249, Kahn RS60,250, Sisodiya SM117,118, White T6,251, Saremi A8, van Bokhoven H36,38, Brunner HG36,38,252,253, Völzke H25,245, Wright MJ133,254, van 't Ent D51,52,53,107, Nöthen MM147,255, Ophoff RA195,256, Buitelaar JK35,38,183, Fernández G35,38, Sachdev PS136,257, Rietschel M59, van Haren NEM60,251, Fisher SE38,87, Beiser AS181,182,30, Francks C38,87, Saykin AJ44,45,207, Mather KA136,190, Romanczuk-Seiferth N194, Hartman CA180, DeStefano AL181,30, Heslenfeld DJ258, Weiner MW259,260, Walter H174, Hoekstra PJ180, Nyquist PA28, Franke B36,37,38, Bennett DA26,27, Grabe HJ88,89, Johnson AD33, Chen C96,97, van Duijn CM5,261, Lopez OL92,93, Fornage M21,262, Wardlaw JM22,185,263, Schmidt R23, DeCarli C264, De Jager PL9,10, Villringer A84,85, Debette S182,15,228, Gudnason V18,19, Medland SE95, Shulman JM29,265,266,267, Thompson PM8, Seshadri S181,182, Ikram MA268,269.

Author information

1
Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, UT Health San Antonio, San Antonio, TX, USA. satizabal@uthscsa.edu.
2
Department of Population Health Sciences, UT Health San Antonio, San Antonio, TX, USA. satizabal@uthscsa.edu.
3
The Framingham Heart Study, Framingham, MA, USA. satizabal@uthscsa.edu.
4
Department of Neurology, Boston University School of Medicine, Boston, MA, USA. satizabal@uthscsa.edu.
5
Department of Epidemiology, Erasmus MC, Rotterdam, the Netherlands.
6
Department of Radiology and Nuclear Medicine, Erasmus MC, Rotterdam, the Netherlands.
7
Department of Clinical Genetics, Erasmus MC, Rotterdam, the Netherlands.
8
Imaging Genetics Center, USC Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
9
Cell Circuits Program, Broad Institute, Cambridge, MA, USA.
10
Center for Translational and Computational Neuroimmunology, Department of Neurology, Columbia University Medical Center, New York, NY, USA.
11
Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
12
UNC Neuroscience Center, University of North Carolina, Chapel Hill, NC, USA.
13
Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.
14
LIFE: The Leipzig Research Center for Civilization Diseases, University of Leipzig, Leipzig, Germany.
15
University of Bordeaux, Inserm, Bordeaux Population Health Research Center, Team VINTAGE, UMR 1219, Bordeaux, France.
16
Department of Medical Informatics, Erasmus MC, Rotterdam, the Netherlands.
17
Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA.
18
Faculty of Medicine, University of Iceland, Reykjavík, Iceland.
19
Icelandic Heart Association, Kopavogur, Iceland.
20
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
21
The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA.
22
Department of Psychology, Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.
23
Clinical Division of Neurogeriatrics, Department of Neurology, Medical University of Graz, Graz, Austria.
24
Institute for Medical Informatics, Statistics and Documentation, Medical University of Graz, Graz, Austria.
25
Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
26
Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
27
Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA.
28
GeneSTAR Research Program, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
29
Department of Neurology, Baylor College of Medicine, Houston, TX, USA.
30
Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
31
Department of Genetics, Harvard Medical School, Boston, MA, USA.
32
Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore.
33
Division of Intramural Research, Population Sciences Branch, National Heart, Lung and Blood Institute, Framingham, MA, USA.
34
MRC-SGDP Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
35
Department of Cognitive Neuroscience, Radboud University Medical Center, Nijmegen, the Netherlands.
36
Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.
37
Department of Psychiatry, Radboud University Medical Center, Nijmegen, the Netherlands.
38
Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, the Netherlands.
39
Centre for Brain Research, Indian Institute of Science, Bangalore, India.
40
CoE NORMENT, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
41
CoE NORMENT, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
42
Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
43
Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA.
44
Center for Neuroimaging, Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA.
45
Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA.
46
Max Planck Institute of Psychiatry, Munich, Germany.
47
Mathematics and Statistics, Murdoch University, Perth, Western Australia, Australia.
48
Lieber Institute for Brain Development, Baltimore, MD, USA.
49
Department of Psychology, Yale University, New Haven, CT, USA.
50
Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.
51
Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
52
Netherlands Twin Register, Vrije Universiteit, Amsterdam, the Netherlands.
53
Amsterdam Neuroscience, Amsterdam, the Netherlands.
54
Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, VU Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands.
55
Medical University of Lodz, Lodz, Poland.
56
Department of Integrative Medical Biology, Umeå University, Umeå, Sweden.
57
Umeå Centre for Functional Brain Imaging (UFBI), Umeå University, Umeå, Sweden.
58
Department of Psychology, University of Oslo, Oslo, Norway.
59
Central Institute of Mental Health, Medical Faculty Mannheim, University Heidelberg, Mannheim, Germany.
60
Department of Psychiatry, UMC Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
61
The Royal College of Surgeons in Ireland, Dublin, Ireland.
62
Department of Neurology, Yale School of Medicine, New Haven, CT, USA.
63
Department of Psychiatry, Amsterdam Neuroscience, VU University Medical Center, Amsterdam, the Netherlands.
64
Division of Psychiatry, Royal Edinburgh Hospital, University of Edinburgh, Edinburgh, UK.
65
Division of Systems Neuroscience of Psychopathology, Translational Research Center, University Hospital of Psychiatry, University of Bern, Bern, Switzerland.
66
Department of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
67
Division of Psychological and Social Medicine and Developmental Neurosciences, Faculty of Medicine, TU Dresden, Dresden, Germany.
68
Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA, USA.
69
Department of Psychiatry, University Hospital Marqués de Valdecilla, School of Medicine, University of Cantabria-IDIVAL, Santander, Spain.
70
Department of Medicine, University Hospital Marqués de Valdecilla, School of Medicine, University of Cantabria-IDIVAL, Santander, Spain.
71
Centro Investigación Biomédica en Red Salud Mental, Santander, Spain.
72
Section for Experimental Psychopathology and Neuroimaging, Department of General Psychiatry, Heidelberg University, Heidelberg, Germany.
73
Department of Neuroscience, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
74
Department of Radiology, St. Olav's Hospital, Trondheim University Hospital, Trondheim, Norway.
75
Centre for Academic Mental Health, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
76
MRC Integrative Epidemiology Unit, Bristol Medical School, University of Bristol, Bristol, UK.
77
NIHR Bristol Biomedical Research Centre, University Hospitals Bristol NHS Foundation Trust and University of Bristol, Bristol, UK.
78
Department of Radiology, University of Calgary, Calgary, Alberta, Canada.
79
Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada.
80
Department of Psychiatry and Mental Health, University of Cape Town, Cape Town, South Africa.
81
South African Medical Research Council Unit on Risk and Resilience in Mental Disorders, Cape Town, South Africa.
82
Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Intramural Research Program, National Institutes of Health, Bethesda, MD, USA.
83
INSERM, Research Unit 1000 'Neuroimaging and Psychiatry', Paris Saclay University and Paris Descartes University-DIGITEO Labs, Gif sur Yvette, France.
84
Department of Neurology, Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany.
85
Faculty of Medicine, CRC 1052 'Obesity Mechanisms', University of Leipzig, Leipzig, Germany.
86
International Max Planck Research School for Language Sciences, Nijmegen, the Netherlands.
87
Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen, the Netherlands.
88
Department of Psychiatry, University Medicine Greifswald, Greifswald, Germany.
89
German Center for Neurodegenerative Diseases, Greifswald, Germany.
90
Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA.
91
Department of Psychology, University of Pittsburgh, Pittsburgh, PA, USA.
92
Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA.
93
Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA.
94
Research Unit-Genetic Epidemiology, Gottfried Schatz Research Centre for Cell Signaling, Metabolism and Aging, Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria.
95
QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
96
Department of Pharmacology, National University of Singapore, Singapore, Singapore.
97
Memory Aging and Cognition Center, National University Health System, Singapore, Singapore.
98
Institute of Neurogenomics, Helmholtz Zentrum München, German Research Centre for Environmental Health, Neuherberg, Germany.
99
Department of Biomedical Engineering, Illinois Institute of Technology, Chicago, IL, USA.
100
Department of Diagnostic Radiology and Nuclear Medicine, Rush University Medical Center, Chicago, IL, USA.
101
Academic Unit for Psychiatry of Old Age, University of Melbourne, Melbourne, Victoria, Australia.
102
National Ageing Research Institute, Royal Melbourne Hospital, Melbourne, Victoria, Australia.
103
Harvard Medical School, Boston, MA, USA.
104
Lurie Center for Autism, Massachusetts General Hospital, Harvard Medical School, Lexington, MA, USA.
105
Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
106
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Boston, MA, USA.
107
Amsterdam Public Health Research Institute, VU Medical Center, Amsterdam, the Netherlands.
108
Department of Psychiatry, University of Oxford, Oxford, UK.
109
NIHR Dementia Biomedical Research Unit, King's College London, London, UK.
110
NORMENT, Department of Clinical Science, University of Bergen, Bergen, Norway.
111
Dr Einar Martens Research Group for Biological Psychiatry, Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.
112
Centre for integrated Sequencing, Aarhus University, Aarhus, Denmark.
113
Department of Biomedicine, Aarhus University, Aarhus, Denmark.
114
The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Aarhus, Denmark.
115
Department of Clinical Neuroscience, Centre for Psychiatric Research, Karolinska Institutet, Stockholm, Sweden.
116
Stockholm Health Care Services, Stockholm County Council, Stockholm, Sweden.
117
UCL Queen Square Institute of Neurology, London, UK.
118
Chalfont Centre for Epilepsy, Bucks, UK.
119
Centre for Youth Mental Health, The University of Melbourne, Melbourne, Victoria, Australia.
120
Orygen, The National Centre of Excellence in Youth Mental Health, Melbourne, Victoria, Australia.
121
Department of Research and Development, Diakonhjemmet Hospital, Oslo, Norway.
122
Department of Psychology, University of Bath, Bath, UK.
123
Neuroimaging Unit, Technological Facilities, Valdecilla Biomedical Research Institute IDIVAL, Santander, Spain.
124
Avera Institute for Human Genetics, Sioux Falls, SD, USA.
125
Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
126
Center for Systems Neuroscience, Boston University, Boston, MA, USA.
127
Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Regensburg, Regensburg, Germany.
128
Neurodegeneratives Diseases Institute, CNRS UMR 5293, Université de Bordeaux, Bordeaux, France.
129
Pennington Biomedical Research Center, Baton Rouge, LA, USA.
130
Department of Adult Psychiatry, Institute for Clinical Medicine, University of Oslo, Oslo, Norway.
131
Brain Research Imaging Centre, University of Edinburgh, Edinburgh, UK.
132
Department of Computer Science, Lagos State University, Ojo, Nigeria.
133
Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia.
134
Ophthalmology and Visual Sciences Academic Clinical Program (Eye ACP), Duke-NUS Medical School, Singapore, Singapore.
135
Department of Behavioral Sciences, Rush University Medical Center, Chicago, IL, USA.
136
Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, New South Wales, Australia.
137
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
138
Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
139
Department of Psychology, Center for Brain Science, Harvard University, Cambridge, MA, USA.
140
Section of Gerontology and Geriatrics, Department of Medicine, University of Perugia, Perugia, Italy.
141
Center for Multimodal Imaging and Genetics, University of California, San Diego, San Diego, CA, USA.
142
Department of Cognitive Sciences, University of California, San Diego, San Diego, CA, USA.
143
Department of Neurosciences, University of California. San Diego, San Diego, CA, USA.
144
Department of Psychiatry, University of California, San Diego, San Diego, CA, USA.
145
Department of Radiology, University of California, San Diego, San Diego, CA, USA.
146
Division of Medical Genetics, Department of Biomedicine, University of Basel, Basel, Switzerland.
147
Institute of Human Genetics, University of Bonn, Bonn, Germany.
148
Institute for Neuroscience and Medicine: Structural and Functional Organisation of the Brain (INM-1), Research Centre Jülich, Jülich, Germany.
149
Reta Lila Weston Institute, UCL Institute of Neurology, London, UK.
150
Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
151
Department of ECE, University of New Mexico, Albuquerque, NM, USA.
152
The Mind Research Network and LBERI, Albuquerque, NM, USA.
153
Tri-institutional Center for Translational Research in Neuroimaging and Data Science, Georgia State University, Atlanta, GA, USA.
154
Cerebral Imaging Centre, Douglas Mental Health University Institute, Montreal, Québec, Canada.
155
Departments of Psychiatry and Biological and Biomedical Engineering, McGill University, Montreal, Québec, Canada.
156
Donders Centre for Cognitive Neuroimaging, Radboud University, Nijmegen, the Netherlands.
157
Institute for Neuroscience and Medicine: Brain and Behaviour (INM-7), Research Centre Jülich, Jülich, Germany.
158
Clinical Neuropsychology Section, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
159
Emma Neuroscience Group, Department of Pediatrics, Emma Children's Hospital, Amsterdam Reproduction & Development, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.
160
LabEx DISTALZ-U1167, RID-AGE-Risk Factors and Molecular Determinants of Aging-Related Diseases, University of Lille, Lille, France.
161
Inserm U1167, Lille, France.
162
Centre Hospitalier Universitaire Lille, Lille, France.
163
Institut Pasteur de Lille, Lille, France.
164
Institute of Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, Greifswald, Germany.
165
Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute and Pediatrics at Harbor-UCLA Medical Center, Torrance, CA, USA.
166
Institute of Biological Psychiatry, Mental Health Center Sct. Hans, Roskilde, Denmark.
167
Neurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ, USA.
168
Faculty of Health, Queensland University of Technology, Brisbane, Queensland, Australia.
169
Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia.
170
Academic Medicine Research Institute, Duke-NUS Medical School, Singapore, Singapore.
171
Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania, Philadelphia, PA, USA.
172
Dementia Centre for Research Collaboration, UNSW, Sydney, New South Wales, Australia.
173
1st Department of Neurology, AHEPA University Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece.
174
Division of Mind and Brain Research, D, Corporate member of Freie Universität Berliepartment of Psychiatry and Psychotherapy, Charité-Universitätsmedizin Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany.
175
Brain Center Rudolf Magnus, Human Neurogenetics Unit, UMC Utrecht, Utrecht, the Netherlands.
176
Department of Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland.
177
Department of Psychiatry, Leiden University Medical Center, Leiden, the Netherlands.
178
Leiden Institute for Brain and Cognition, Leiden University Medical Center, Leiden, the Netherlands.
179
Department of Evolution and Genetics, Dagestan State University, Makhachkala, Russia.
180
University Medical Center Groningen, Department of Psychiatry, University of Groningen, Groningen, the Netherlands.
181
The Framingham Heart Study, Framingham, MA, USA.
182
Department of Neurology, Boston University School of Medicine, Boston, MA, USA.
183
Karakter Child and Adolescent Psychiatry University Center, Nijmegen, the Netherlands.
184
Section Epidemiology of Health Care and Community Health, Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
185
Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.
186
Clinical Translational Neuroscience Laboratory, Department of Psychiatry and Human Behavior, University of California, Irvine, Irvine, CA, USA.
187
Center for the Neurobiology of Learning and Memory, University of California, Irvine, Irvine, CA, USA.
188
Department of Psychiatry, Psychosomatics and Psychotherapy, University of Wuerzburg, Wuerzburg, Germany.
189
Brain and Mind Centre, University of Sydney, Sydney, New South Wales, Australia.
190
Neuroscience Research Australia, Sydney, New South Wales, Australia.
191
University of New South Wales, Sydney, New South Wales, Australia.
192
Department of Internal Medicine, INSERM U 1027, University of Toulouse, Toulouse, France.
193
Department of Geriatric Medicine, INSERM U 1027, University of Toulouse, Toulouse, France.
194
Department of Psychiatry and Psychotherapy, Charité Universitätsmedizin Berlin, Berlin, Germany.
195
Center for Neurobehavioral Genetics, University of California, Los Angeles, Los Angeles, CA, USA.
196
Neurology Division, Beaumont Hospital, Dublin, Ireland.
197
Department of Psychiatry, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
198
Interdepartmental Neuroscience Graduate Program, UCLA School of Medicine, Los Angeles, CA, USA.
199
Imaging of Dementia and Aging Laboratory, Department of Neurology, University of California, Davis, Davis, CA, USA.
200
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
201
School of Mental Health and Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, the Netherlands.
202
Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
203
Kaiser Permanent Washington Health Research Institute, Seattle, WA, USA.
204
Department of Epidemiology, University of Washington, Seattle, WA, USA.
205
Department of Health Services, University of Washington, Seattle, WA, USA.
206
Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.
207
Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
208
Department of Developmental Disability Neuropsychiatry, School of Psychiatry, UNSW Medicine, Sydney, New South Wales, Australia.
209
Biomedical Research Unit for Dementia, King's College London, London, UK.
210
Department of Neuroimaging, Institute of Psychiatry, King's College London, London, UK.
211
Division of Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institute, Stockholm, Sweden.
212
Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
213
Section of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
214
Department of Radiology, Mayo Clinic, Rochester, MN, USA.
215
School of Medical Sciences, UNSW, Sydney, New South Wales, Australia.
216
Department of Biomedicine, University of Basel, Basel, Switzerland.
217
Cécile and Oskar Vogt Institute for Brain Research, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
218
Department of Psychiatry and Human Behavior, University of California, Irvine, Irvine, CA, USA.
219
Laboratory of Neuro Imaging, USC Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA.
220
Radiation Sciences, Umeå University, Umeå, Sweden.
221
Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
222
Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands.
223
Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
224
Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
225
Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
226
Imaging Physics, Faculty of Applied Sciences, Delft University of Technology, Delft, the Netherlands.
227
Institut Pasteur, Paris, France.
228
Department of Neurology, CHU de Bordeaux, Bordeaux, France.
229
Department of Neurology, University of Washington, Seattle, WA, USA.
230
Department of Neurology, Erasmus MC, Rotterdam, the Netherlands.
231
Cognitive Neuroscience Center, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
232
Bloorview Research Institute, Holland Bloorview Kids Rehabilitation Hospital, Toronto, Ontario, Canada.
233
Department of Psychology, University of Toronto, Toronto, Ontario, Canada.
234
Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.
235
Clinic for Cognitive Neurology, University Clinic Leipzig, Leipzig, Germany.
236
HMNC Brain Health, Munich, Germany.
237
Department of Neurology, Hopital Erasme, Universite Libre de Bruxelles, Brussels, Belgium.
238
Department of Psychology, Georgia State University, Atlanta, GA, USA.
239
Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
240
Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
241
Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
242
Institute of Clinical Medicine-Neurology, University of Eastern Finland, Kuopio, Finland.
243
Neurocentre Neurology, Kuopio University Hospital, Kuopio, Finland.
244
Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany.
245
German Center for Cardiovascular Research (partner site Greifswald), Greifswald, Germany.
246
Department of Neuroinformatics, Araya, Tokyo, Japan.
247
Institute of Cognitive Neuroscience, University College London, London, UK.
248
School of Psychology, University of Sussex, Brighton, UK.
249
Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.
250
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
251
Department of Child and Adolescent Psychiatry/Psychology, Erasmus MC-Sophia Children's Hospital, Rotterdam, the Netherlands.
252
Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, the Netherlands.
253
GROW School for Oncology and Developmental Biology, Maastricht, the Netherlands.
254
Centre for Advanced Imaging, University of Queensland, Brisbane, Queensland, Australia.
255
Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
256
Department of Psychiatry, Erasmus Medical Center, Rotterdam, the Netherlands.
257
Neuropsychiatric Institute, Prince of Wales Hospital, Sydney, New South Wales, Australia.
258
Department of Psychology, VU University Amsterdam, Amsterdam, the Netherlands.
259
Center for Imaging of Neurodegenerative Disease, San Francisco VA Medical Center, University of California, San Francisco, San Francisco, CA, USA.
260
Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, USA.
261
Leiden Academic Centre for Drug Research, Leiden University, Leiden, the Netherlands.
262
Human Genetics Center, University of Texas Health Science Center at Houston, Houston, TX, USA.
263
UK Dementia Research Institute, University of Edinburgh, Edinburgh, UK.
264
Department of Neurology, Center for Neuroscience, University of California, Davis, Sacramento, CA, USA.
265
Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA.
266
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
267
Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA.
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Department of Epidemiology, Erasmus MC, Rotterdam, the Netherlands. m.a.ikram@erasmusmc.nl.
269
Department of Radiology and Nuclear Medicine, Erasmus MC, Rotterdam, the Netherlands. m.a.ikram@erasmusmc.nl.

Abstract

Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.

PMID:
31636452
DOI:
10.1038/s41588-019-0511-y

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