title: Common genetic variants influence human subcortical brain structures.
abstract: The highly complex structure of the human brain is strongly shaped by genetic influences. Subcortical brain regions form circuits with cortical areas to coordinate movement, learning, memory and motivation, and altered circuits can lead to abnormal behaviour and disease. To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume and intracranial volume. These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08 × 10(-33); 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability in human brain development, and may help to determine mechanisms of neuropsychiatric dysfunction.
authors.affiliation: Imaging Genetics Center, Institute for Neuroimaging &Informatics, Keck School of Medicine of the University of Southern California, Los Angeles, California 90292, USA.
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authors.affiliation: 1] Department of Human Genetics, Radboud university medical center, Nijmegen 6500 HB, The Netherlands. [2] Department of Psychiatry, Radboud university medical center, Nijmegen 6500 HB, The Netherlands. [3] Department of Cognitive Neuroscience, Radboud university medical center, Nijmegen 6500 HB, The Netherlands. [4] Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen 6500 GL, The Netherlands.
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authors.affiliation: Imaging Genetics Center, Institute for Neuroimaging &Informatics, Keck School of Medicine of the University of Southern California, Los Angeles, California 90292, USA.
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authors.forename: Katharina
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authors.affiliation: Brain Center Rudolf Magnus, Department of Psychiatry, University Medical Center Utrecht, Utrecht, 3584 CX, The Netherlands.
authors.forename: Lucija
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authors.affiliation: Umeå Centre for Functional Brain Imaging (UFBI), Umeå University, Umeå 901 87, Sweden.
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authors.affiliation: Department of Psychiatry, Neuroscience Campus Amsterdam, VU University Medical Center/GGZ inGeest, Amsterdam 1081 HL, The Netherlands.
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authors.affiliation: Brain Center Rudolf Magnus, Department of Psychiatry, University Medical Center Utrecht, Utrecht, 3584 CX, The Netherlands.
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authors.affiliation: Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal H3A 2B4, Canada.
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authors.forename: Lavinia
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authors.affiliation: NORMENT - KG Jebsen Centre, Institute of Clinical Medicine, University of Oslo, Oslo N-0316, Norway.
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authors.affiliation: 1] Department of Human Genetics, Radboud university medical center, Nijmegen 6500 HB, The Netherlands. [2] Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen 6500 GL, The Netherlands.
authors.forename: Angelien J G A M
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authors.affiliation: Max Planck Institute of Psychiatry, Munich 80804, Germany.
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authors.affiliation: Centre for Cognitive Ageing and Cognitive Epidemiology, Psychology, University of Edinburgh, Edinburgh EH8 9JZ, UK.
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authors.affiliation: Centre for Cognitive Ageing and Cognitive Epidemiology, Psychology, University of Edinburgh, Edinburgh EH8 9JZ, UK.
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authors.affiliation: 1] Department of Human Genetics, Radboud university medical center, Nijmegen 6500 HB, The Netherlands. [2] Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen 6500 GL, The Netherlands.
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authors.affiliation: 1] Department of Human Genetics, Radboud university medical center, Nijmegen 6500 HB, The Netherlands. [2] Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen 6500 GL, The Netherlands.
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authors.affiliation: Max Planck Institute of Psychiatry, Munich 80804, Germany.
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authors.affiliation: 1] Brain Research Imaging Centre, University of Edinburgh, Edinburgh EH4 2XU, UK. [2] Centre for Cognitive Ageing and Cognitive Epidemiology, Psychology, University of Edinburgh, Edinburgh EH8 9JZ, UK. [3] Scottish Imaging Network, A Platform for Scientific Excellence (SINAPSE) Collaboration, Department of Neuroimaging Sciences, University of Edinburgh, Edinburgh EH4 2XU, UK.
authors.forename: Natalie A
authors.initials: NA
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authors.affiliation: 1] Center for Neuroimaging, Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA. [2] Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA. [3] Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
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authors.forename: Emma
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authors.affiliation: 1] Reta Lila Weston Institute and Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK. [2] Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia.
authors.forename: Daniah
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authors.affiliation: 1] Department of Human Genetics, Radboud university medical center, Nijmegen 6500 HB, The Netherlands. [2] Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen 6500 GL, The Netherlands.
authors.forename: Saskia S L
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authors.affiliation: 1] Department of Human Genetics, Radboud university medical center, Nijmegen 6500 HB, The Netherlands. [2] Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen 6500 GL, The Netherlands.
authors.forename: Kimm J E
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authors.affiliation: Department of Child and Adolescent Psychiatry, Faculty of Medicine of the TU Dresden, Dresden 01307 Germany.
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authors.affiliation: Max Planck Institute of Psychiatry, Munich 80804, Germany.
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authors.affiliation: Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland 20892, USA.
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authors.affiliation: Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney 2052, Australia.
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authors.affiliation: 1] Brain Research Imaging Centre, University of Edinburgh, Edinburgh EH4 2XU, UK. [2] Scottish Imaging Network, A Platform for Scientific Excellence (SINAPSE) Collaboration, Department of Neuroimaging Sciences, University of Edinburgh, Edinburgh EH4 2XU, UK. [3] Centre for Cognitive Ageing and Cognitive Epidemiology, Psychology, University of Edinburgh, Edinburgh EH8 9JZ, UK. [4] Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh EH4 2XU, UK.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Bastin
authors.affiliation: Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney 2052, Australia.
authors.forename: Henry
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authors.lastname: Brodaty
authors.affiliation: N.I. Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow 119333, Russia.
authors.forename: Kazima B
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authors.lastname: Bulayeva
authors.affiliation: Texas Biomedical Research Institute, San Antonio, Texas 78245, USA.
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authors.affiliation: 1] Division of Medical Genetics, Department of Biomedicine, University of Basel, Basel 4055, Switzerland. [2] Institute of Human Genetics, University of Bonn, Bonn, D-53127, Germany. [3] Institute of Neuroscience and Medicine (INM-1), Research Centre Jülich, Jülich, D-52425, Germany. [4] Department of Genomics, Life &Brain Center, University of Bonn, Bonn D-53127, Germany.
authors.forename: Sven
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authors.lastname: Cichon
authors.affiliation: Neuropsychiatric Genetics Research Group and Department of Psychiatry, Trinity College Institute of Psychiatry, Trinity College Dublin, Dublin 2, Ireland.
authors.forename: Aiden
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authors.lastname: Corvin
authors.affiliation: Texas Biomedical Research Institute, San Antonio, Texas 78245, USA.
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authors.initials: JE
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authors.affiliation: Max Planck Institute of Psychiatry, Munich 80804, Germany.
authors.forename: Michael
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authors.affiliation: School of Psychology, University of Queensland, Brisbane 4072, Australia.
authors.forename: Greig I
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authors.affiliation: Biological Psychology, Neuroscience Campus Amsterdam &EMGO Institute for Health and Care Research, VU University &VU Medical Center, Amsterdam 1081 BT, The Netherlands.
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authors.affiliation: Centre for Cognitive Ageing and Cognitive Epidemiology, Psychology, University of Edinburgh, Edinburgh EH8 9JZ, UK.
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authors.affiliation: Reta Lila Weston Institute and Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK.
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authors.affiliation: Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, Osaka 565-0871, Japan.
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authors.affiliation: INSERM U897, University of Bordeaux, Bordeaux 33076, France.
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mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics; D017209:Apoptosis / Q000235:genetics; D001921:Brain / Q000033:anatomy & histology*; D002421:Caudate Nucleus / Q000033:anatomy & histology; D002648:Child; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D056426:Genetic Loci / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics*; D055106:Genome-Wide Association Study; D006624:Hippocampus / Q000033:anatomy & histology; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D009929:Organ Size / Q000235:genetics; D011699:Putamen / Q000033:anatomy & histology; D012727:Sex Characteristics; D012886:Skull / Q000033:anatomy & histology; D055815:Young Adult
chemical_list: C088547:KTN1 protein, human; D008565:Membrane Proteins