Novel genetic loci associated with hippocampal volume

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Abstract

The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes ( ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease ( r _g=−0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness.

Abstract

The hippocampus in mammalian brain varies in size across individuals. Here, Hibar and colleagues perform a genome-wide association meta-analysis to find six genetic loci with significant association to hippocampus volume.

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Most cited references 32

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Functional organization of the hippocampal longitudinal axis.

Bryan Strange, Menno P Witter, Ed Lein … (2014)

The precise functional role of the hippocampus remains a topic of much debate. The dominant view is that the dorsal (or posterior) hippocampus is implicated in memory and spatial navigation and the ventral (or anterior) hippocampus mediates anxiety-related behaviours. However, this 'dichotomy view' may need revision. Gene expression studies demonstrate multiple functional domains along the hippocampal long axis, which often exhibit sharply demarcated borders. By contrast, anatomical studies and electrophysiological recordings in rodents suggest that the long axis is organized along a gradient. Together, these observations suggest a model in which functional long-axis gradients are superimposed on discrete functional domains. This model provides a potential framework to explain and test the multiple functions ascribed to the hippocampus.

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Subcortical brain volume abnormalities in 2028 individuals with schizophrenia and 2540 healthy controls via the ENIGMA consortium

T van Erp, D Hibar, J Rasmussen … (2015)

The profile of brain structural abnormalities in schizophrenia is still not fully understood, despite decades of research using brain scans. To validate a prospective meta-analysis approach to analyzing multicenter neuroimaging data, we analyzed brain MRI scans from 2028 schizophrenia patients and 2540 healthy controls, assessed with standardized methods at 15 centers worldwide. We identified subcortical brain volumes that differentiated patients from controls, and ranked them according to their effect sizes. Compared with healthy controls, patients with schizophrenia had smaller hippocampus (Cohen's d=−0.46), amygdala (d=−0.31), thalamus (d=−0.31), accumbens (d=−0.25) and intracranial volumes (d=−0.12), as well as larger pallidum (d=0.21) and lateral ventricle volumes (d=0.37). Putamen and pallidum volume augmentations were positively associated with duration of illness and hippocampal deficits scaled with the proportion of unmedicated patients. Worldwide cooperative analyses of brain imaging data support a profile of subcortical abnormalities in schizophrenia, which is consistent with that based on traditional meta-analytic approaches. This first ENIGMA Schizophrenia Working Group study validates that collaborative data analyses can readily be used across brain phenotypes and disorders and encourages analysis and data sharing efforts to further our understanding of severe mental illness.

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Knowing where and getting there: a human navigation network.

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The neural basis of navigation by humans was investigated with functional neuroimaging of brain activity during navigation in a familiar, yet complex virtual reality town. Activation of the right hippocampus was strongly associated with knowing accurately where places were located and navigating accurately between them. Getting to those places quickly was strongly associated with activation of the right caudate nucleus. These two right-side brain structures function in the context of associated activity in right inferior parietal and bilateral medial parietal regions that support egocentric movement through the virtual town, and activity in other left-side regions (hippocampus, frontal cortex) probably involved in nonspatial aspects of navigation. These findings outline a network of brain areas that support navigation in humans and link the functions of these regions to physiological observations in other mammals.

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Author and article information

Journal

Journal ID (nlm-ta): Nat Commun

Journal ID (iso-abbrev): Nat Commun

Title: Nature Communications

Publisher: Nature Publishing Group

ISSN (Electronic): 2041-1723

Publication date (Electronic): 18 January 2017

Publication date Collection: 2017

Volume: 8

Electronic Location Identifier: 13624

Affiliations

[1 ]Imaging Genetics Center, USC Mark and Mary Stevens Neuroimaging & Informatics Institute, Keck School of Medicine of University of Southern California , Los Angeles, California 90292, USA

[2 ]Department of Epidemiology, Erasmus University Medical Center , 3015 CE Rotterdam, The Netherlands

[3 ]Department of Radiology and Nuclear Medicine, Erasmus MC , 3015 CE Rotterdam, The Netherlands

[4 ]INSERM Unit U1219, University of Bordeaux , 33076 Bordeaux, France

[5 ]Department of Genetics & UNC Neuroscience Center, University of North Carolina (UNC) , Chapel Hill, North Carolina, 27599, USA

[6 ]Department of Neurology, Clinical Division of Neurogeriatrics, Medical University Graz , Auenbruggerplatz 22, 8036 Graz, Austria

[7 ]Institute of Medical Informatics, Statistics and Documentation, Medical University Graz , Auenbruggerplatz 22, 8036 Graz, Austria

[8 ]QIMR Berghofer Medical Research Institute , Brisbane, Queensland 4006, Australia

[9 ]Cardiovascular Health Research Unit, Department of Medicine, University of Washington , 1730 Minor Avenue/Suite 1360. Seattle, Washington 98101, USA

[10 ]Department of Human Genetics, Radboud University Medical Center , 6525 GA Nijmegen, The Netherlands

[11 ]Department of Psychiatry, Radboud University Medical Center , 6525 GA Nijmegen, The Netherlands

[12 ]Department of Cognitive Neuroscience, Radboud University Medical Center , 6525 GA Nijmegen, The Netherlands

[13 ]Donders Institute for Brain, Cognition and Behaviour, Radboud University , 6525 GA Nijmegen, The Netherlands

[14 ]Academic Medicine Research Institute, Duke-NUS Graduate Medical School , Singapore, 169857, Singapore

[15 ]Singapore Eye Research Institute, Singapore National Eye Centre , Singapore, 168751, Singapore

[16 ]Memory Aging & Cognition Centre (MACC), National University Health System , Singapore, 119228, Singapore

[17 ]Department of Pharmacology, National University of Singapore , Singapore, 119077, Singapore

[18 ]MRC-SGDP Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London , London SE5 8AF, UK

[19 ]Brain Center Rudolf Magnus, Department of Psychiatry, UMC Utrecht , 3584 CX Utrecht, The Netherlands

[20 ]Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University , Montreal, Quebec, Canada H3A 2B4

[21 ]The Royal College of Surgeons in Ireland , 123 St Stephen's Green, Dublin 2, Ireland

[22 ]Department of Integrative Medical Biology and Umeå Center for Functional Brain Imaging, Umeå University , 901 87 Umeå, Sweden

[23 ]Department of Biomedical Engineering, Illinois Institute of Technology , Chicago, Illinois 60616, USA

[24 ]Rush Alzheimer's Disease Center, Rush University Medical Center , Chicago, Illinois 60612, USA

[25 ]Department of Diagnostic Radiology and Nuclear Medicine, Rush University Medical Center , Chicago, Illinois 60616, USA

[26 ]Brain Research Imaging Centre, University of Edinburgh , Edinburgh EH4 2XU, UK

[27 ]Department of Computer Science, Lagos State University , Lagos, P.M.B. 01 LASU, Nigeria

[28 ]Scottish Imaging Network, A Platform for Scientific Excellence (SINAPSE) Collaboration, Department of Neuroimaging Sciences, University of Edinburgh , Edinburgh EH16 4SB, UK

[29 ]Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales , Sydney, New South Wales 2052, Australia

[30 ]Mathematics and Statistics, Murdoch University , Perth, Western Australia, 6150, Australia

[31 ]NORMENT—KG Jebsen Centre, Institute of Clinical Medicine, University of Oslo , 0315 Oslo, Norway

[32 ]NORMENT—KG Jebsen Centre, Division of Mental Health and Addiction, Oslo University Hospital , 0424 Oslo, Norway

[33 ]Department of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala University , Box 1432, SE-751 44 Uppsala, Sweden

[34 ]Dr John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miller School of Medicine , Miami, Florida, 33136, USA

[35 ]John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine , Miami, Florida, 33136, USA

[36 ]Department of Neurology, Boston University School of Medicine , Boston, Massachusetts,02118, USA

[37 ]Department of Biostatistics, Boston University School of Public Health , Boston, Massachusetts 02118 USA

[38 ]Framingham Heart Study , 17 Mount Wayte Avenue, Framingham, Massachusetts 01703 USA

[39 ]Hospital for Sick Children, University of Toronto , Toronto, Ontario, Canada M5G 1X8

[40 ]Taub Institute for Research on Alzheimer's Disease and the Aging Brain; G.H. Sergievsky Center; Department of Neurology. Columbia University Medical Center , 639 West 1168th Street, New York, New York 10032, USA

[41 ]Pennington Biomedical Research Center , Baton Rouge, Louisiana 70808, USA

[42 ]Cerebral Imaging Centre, Douglas Mental Health University Institute , Montreal, Quebec, Canada H4H 1R3

[43 ]Department of Psychiatry and Biomedical Engineering, McGill University , Montreal, Quebec, Canada H3A 2B4

[44 ]Lieber Institute for Brain Development , Baltimore, Maryland 21205, USA

[45 ]Interdepartmental Neuroscience Graduate Program, UCLA School of Medicine , Los Angeles, California 90095, USA

[46 ]Lille University, Inserm, CHU Lille, Institut Pasteur de Lille, U1167—RID-AGE—Risk factors and molecular determinants of aging-related diseases , F-59000 Lille, France

[47 ]IMN UMR5293, GIN, CNRS, CEA, University of Bordeaux , 146 rue Léo Saignat, 33076 Bordeaux, France

[48 ]Biological Psychology, Amsterdam Neuroscience, Vrije Universiteit & Vrije Universiteit Medical Center , 1081 BT Amsterdam, The Netherlands

[49 ]Division of Psychological and Social Medicine and Developmental Neurosciences, Faculty of Medicine, TU Dresden , 01307 Dresden, Germany

[50 ]Department of Psychiatry, Massachusetts General Hospital , Boston, Massachusetts 02114, USA

[51 ]Martinos Center for Biomedical Imaging, Massachusetts General Hospital , Charlestown, Massachusetts 02129, USA

[52 ]NORMENT—KG Jebsen Centre for Psychosis Research, Department of Clinical Science, University of Bergen , 5021 Bergen, Norway

[53 ]Dr Einar Martens Research Group for Biological Psychiatry, Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital , 5021 Bergen, Norway

[54 ]Department of Neurology, Johns Hopkins University School of Medicine , Baltimore, Maryland 21287, USA

[55 ]Central Institute of Mental Health, Medical Faculty Mannheim, University Heidelberg , 68159 Mannheim, Germany

[56 ]Department of Data Science, University of Mississippi Medical Center , Jackson, Mississippi, 39216, USA

[57 ]Language and Genetics Department, Max Planck Institute for Psycholinguistics , 6525 XD Nijmegen, The Netherlands

[58 ]International Max Planck Research School for Language Sciences , 6525 XD Nijmegen, The Netherlands

[59 ]Department of Child and Adolescent Psychiatry, Faculty of Medicine of the TU Dresden , 01307 Dresden, Germany

[60 ]Department of Research and Development, Diakonhjemmet Hospital , 0319 Oslo, Norway

[61 ]Max Planck Institute of Psychiatry , 80804 Munich, Germany

[62 ]Department of Psychology, Yale University , New Haven, Connecticut 06520, USA

[63 ]Department of Psychiatry, University Medicine Greifswald , 17489 Greifswald, Germany

[64 ]UCL Institute of Neurology, London, United Kingdom and Epilepsy Society , Bucks, SL9 0RJ, UK

[65 ]Department of Medicine, Imperial College London , London SW7 2AZ, UK

[66 ]Center for Neuroimaging, Radiology and Imaging Sciences, Indiana University School of Medicine , Indianapolis, Indiana 46202, USA

[67 ]Center for Computational Biology and Bioinformatics, Indiana University School of Medicine , Indianapolis, Indiana 46202, USA

[68 ]Indiana Alzheimer Disease Center, Indiana University School of Medicine , Indianapolis, Indiana 46202, USA

[69 ]Section for Experimental Psychopathology and Neuroimaging, Department of General Psychiatry, Heidelberg University , Heidelberg, 69120, Germany

[70 ]Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital , Boston, Massachusetts 02114, USA

[71 ]Harvard Medical School , Boston, Massachusetts 02115, USA

[72 ]Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard , Boston, Massachusetts 02141, USA

[73 ]Lurie Center for Autism, Massachusetts General Hospital, Harvard Medical School , Lexington, Massachusetts, 02421, USA

[74 ]Centre for Cognitive Ageing and Cognitive Epidemiology, Psychology, University of Edinburgh , Edinburgh EH8 9JZ, UK

[75 ]Donders Centre for Cognitive Neuroimaging, Radboud University , Nijmegen, 6525 EN, The Netherlands

[76 ]Reta Lila Weston Institute and Department of Molecular Neuroscience, UCL Institute of Neurology , London WC1N 3BG, UK

[77 ]Department of Biomedicine, Aarhus University , DK-8000 Aarhus, Denmark

[78 ]The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH , DK-8000 Aarhus and Copenhagen, Denmark

[79 ]Center for integrated Sequencing, iSEQ, Aarhus University , DK-8000 Aarhus, Denmark

[80 ]Department of Psychiatry, Yale University , New Haven, Connecticut 06511, USA

[81 ]Olin Neuropsychiatric Research Center , Hartford, Connecticut 06114, USA

[82 ]Department of Psychiatry, EMGO Institute for Health and Care Research and Neuroscience Campus Amsterdam, VU University Medical Center/GGZ inGeest , 1081 HL Amsterdam, The Netherlands

[83 ]Human Genetics Branch, National Institute of Mental Health Intramural Research Program , 35 Convent Drive, Rm 1A202, Bethesda, Maryland 20892-3719, USA

[84 ]Department of Neurology, Department of Anesthesia/Critical Care Medicine, Department of Neurosurgery, Johns Hopkins , USA600 N. Wolfe St, Baltimore, Maryland 21287, USA

[85 ]Center for Neurobehavioral Genetics, University of California , Los Angeles, California 90095, USA

[86 ]Department of Clinical Neuropsychology, VU University Amsterdam , Amsterdam, 1081 HV, The Netherlands

[87 ]Division of Psychiatry, Royal Edinburgh Hospital, University of Edinburgh , Edinburgh EH10 5HF, UK

[88 ]Division of Systems Neuroscience of Psychopathology, Translational Research Center, University Hospital of Psychiatry, University of Bern , Bern, 3060, Switzerland

[89 ]Department of Medical and Molecular Genetics, King's College London , London SE1 9RT, UK

[90 ]The Jenner Institute Laboratories, University of Oxford , Oxford OX3 7DQ, UK

[91 ]Karakter Child and Adolescent Psychiatry University Center , Nijmegen, 6525 GC, The Netherlands

[92 ]Department of Medicine and Psychiatry, University Hospital Marqués de Valdecilla, School of Medicine, University of Cantabria-IDIVAL , 39008 Santander, Spain

[93 ]CIBERSAM (Centro Investigación Biomédica en Red Salud Mental) , Santander, 39011, Spain

[94 ]Psychosis Research Group, Department of Psychiatry & Trinity Translational Medicine Institute, Trinity College , Dublin, Dublin 2, Ireland

[95 ]Centre for Clinical Brain Sciences, University of Edinburgh , Edinburgh EH16 4SB, UK

[96 ]Department of Neurology, University of Miami, Miller School of Medicine , Miami, Florida, 33136, USA

[97 ]Department of Epidemiology and Public Health Sciences, University of Miami, Miller School of Medicine , Miami, Florida, 33136, USA

[98 ]Orygen, The National Centre of Excellence in Youth Mental Health , Melbourne, Victoria, 3502, Australia

[99 ]Centre for Youth Mental Health, The University of Melbourne , Melbourne, Victoria, 3502, Australia

[100 ]Department of Psychiatry, Neuroscience Campus Amsterdam, VU University Medical Center , 1007 MB Amsterdam, The Netherlands

[101 ]Multimodal Imaging Laboratory, Department of Neurosciences, University of California , San Diego, California 92093, USA

[102 ]Department of Cognitive Sciences, University of California , San Diego, California 92161, USA

[103 ]Icelandic Heart Association , Kopavogur, 201, Iceland

[104 ]Faculty of Medicine, University of Iceland , Reykjavik, 101, Iceland

[105 ]Department of Psychiatry, Icahn School of Medicine at Mount Sinai , New York, New York, 10029, USA

[106 ]Queensland Brain Institute, University of Queensland , Brisbane, Queensland 4072, Australia

[107 ]Institute for Community Medicine, University Medicine Greifswald , 17489 Greifswald, Germany

[108 ]Neuroimaging Unit, Technological Facilities. Valdecilla Biomedical Research Institute IDIVAL , Santander, Cantabria, 39011, Spain

[109 ]Institut Pasteur , 75015 Paris, France

[110 ]Department of Genetics, King Faisal Specialist Hospital and Research Centre , Riyadh 11211, Saudi Arabia

[111 ]Department of Cardiology, Leiden University Medical Center , Leiden, 2300RC, The Netherlands

[112 ]GeneSTAR Research Center, Department of Medicine, Johns Hopkins University School of Medicine , 1830 E Monument St Suite 8028, Baltimore, Maryland 21287, USA

[113 ]Department of Radiology, Leiden University Medical Center , Leiden, 2300RC, The Netherlands

[114 ]Department of Psychiatry, University of Groningen, University Medical Center Groningen , Groningen, 9700RB, The Netherlands

[115 ]Brain Center Rudolf Magnus, Human Neurogenetics Unit, UMC Utrecht , 3584 CG Utrecht, The Netherlands

[116 ]Department of Psychiatry and Human Behavior, University of California-Irvine , Irvine, California 92617, USA

[117 ]Department of Psychology, Georgia State University , Atlanta, Georgia 30302, USA

[118 ]NORMENT—KG Jebsen Centre, Department of Psychology, University of Oslo , 0317 Oslo, Norway

[119 ]Department of Medicine, University of Mississippi Medical Center , Jackson, Mississippi, 39216, USA

[120 ]FMRIB Centre, University of Oxford , Oxford OX3 9DU, UK

[121 ]German Center for Neurodegenerative Diseases (DZNE) Rostock/Greifswald , 17487 Greifswald, Germany

[122 ]University of Wuerzburg, Department of Psychiatry, Psychosomatics and Psychotherapy , Wuerzburg, 97080, Germany

[123 ]Department of Neurological Sciences, Rush University Medical Center , Chicago, Illinois 60612, USA

[124 ]Biospective Inc, Montreal, Quebec, Canada , 6100 Avenue Royalmount, Montréal, Québec, Canada H4P 2R2

[125 ]Department of Clinical Neuroscience, Centre for Psychiatric Research, Karolinska Institutet , SE-171 77 Stockholm, Sweden

[126 ]South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine , Brownsville/Edinburg/San Antonio, Texas, 78250, USA

[127 ]Department of Genetics, Perelman School of Medicine, University of Pennsylvania , Philadelphia, Pennsylvania 19104, USA

[128 ]Department of Biomedical and Health Informatics, The Children's Hospital of Philadelphia , Philadelphia, Pennsylvania 29104, USA

[129 ]National Ageing Research Institute, Royal Melbourne Hospital , Melbourne, Victoria 3052, Australia

[130 ]Academic Unit for Psychiatry of Old Age, University of Melbourne , Melbourne, Victoria 3101, Australia

[131 ]Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health , Bethesda, Maryland 20892, USA

[132 ]Departments of Psychiatry, Neurology, and Psychology, University of Pittsburgh , 3501 Forbes Ave., Suite 830, Pittsburgh, Pennsylvania 15213, USA

[133 ]Dementia Collaborative Research Centre—Assessment and Better Care, University of New South Wales , Sydney, New South Wales 2052, Australia

[134 ]Department of Clinical Genetics and GROW School for Oncology and Developmental Biology, Maastricht University Medical Center , 6200 MD Maastricht, The Netherlands

[135 ]Department of Psychology, Center for Brain Science, Harvard University , Cambridge, Massachusetts 02138, USA

[136 ]Department of Evolution and Genetics, Dagestan State University , Makhachkala 367000, Dagestan, Russia

[137 ]The Mind Research Network & LBERI , Albuquerque, New Mexico 87106, USA

[138 ]Department of ECE, University of New Mexico , Albuquerque, New Mexico 87131, USA

[139 ]Centre for Neuroimaging & Cognitive Genomics (NICOG), Clinical Neuroimaging Laboratory, NCBES Galway Neuroscience Centre, College of Medicine Nursing and Health Sciences, National University of Ireland Galway , H91 TK33 Galway, Ireland

[140 ]Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore , Singapore, 119077, Singapore

[141 ]Division of Medical Genetics, Department of Biomedicine, University of Basel , 4031 Basel, Switzerland

[142 ]Institute of Human Genetics, University of Bonn , 53127 Bonn, Germany

[143 ]Institute of Neuroscience and Medicine (INM-1), Research Centre Jülich , 52425 Jülich, Germany

[144 ]Center for Multimodal Imaging and Genetics, University of California , San Diego, California 92093, USA

[145 ]Departments of Neurosciences, Radiology, Psychiatry, and Cognitive Science, University of California , San Diego, California 92093, USA

[146 ]Avera Institute for Human Genetics , Sioux Falls, South Dakota 57108, USA

[147 ]Department of Gerontology and Geriatrics, Leiden University Medical Center , Leiden, 2300RC, The Netherlands

[148 ]Program in Translational NeuroPsychiatric Genomics, Departments of Neurology & Psychiatry, Brigham and Women's Hospital , Boston, Massachusetts, 02115, USA

[149 ]Harvard Medical School , Boston, Massachusetts, 02115, USA

[150 ]Program in Medical and Population Genetics, Broad Institute , Cambridge, Massachusetts, 02142, USA

[151 ]Broad Institute , Cambridge, Massachusetts, 02142, USA

[152 ]Faculty of Health and Institute of Health and Biomedical Innovation, Queensland University of Technology (QUT) , Brisbane, Queensland 4059, Australia

[153 ]Department of Neurology, Bordeaux University Hospital , Bordeaux, 33076, France

[154 ]Imaging of Dementia and Aging (IDeA) Laboratory, Department of Neurology and Center for Neuroscience, University of California at Davis , 4860 Y Street, Suite 3700, Sacramento, California 95817, USA

[155 ]Neurology Division, Beaumont Hospital , Dublin 9, Ireland

[156 ]Department of Neurology, Hopital Erasme, Universite Libre de Bruxelles , 1070 Brussels, Belgium

[157 ]Department of Medical Genetics, Oslo University Hospital , 0420 Oslo, Norway

[158 ]Cognitive Genetics and Cognitive Therapy Group, Neuroimaging, Cognition & Genomics Centre (NICOG) & NCBES Galway Neuroscience Centre, School of Psychology and Discipline of Biochemistry, National University of Ireland Galway , H91 TK33, Galway, Ireland

[159 ]Neuropsychiatric Genetics Research Group, Department of Psychiatry and Trinity College Institute of Psychiatry, Trinity College Dublin , Dublin 8, Ireland

[160 ]Janssen Research & Development, LLC , Titusville, New Jersey 08560, USA

[161 ]Charité - Universitätsmedizin Berlin, Campus Charité Mitte, Department of Psychiatry and Psychotherapy , Charitéplatz 1, 10117 Berlin, Germany

[162 ]Intramural Research Program of the National Institute on Aging , Baltimore, Maryland, 21224, USA

[163 ]Department of Neurological Sciences & Department of Behavioral Sciences, Rush University Medical Center , Chicago, Illinois 60616, USA

[164 ]Robertson Centre for Biostatistics, University of Glasgow , Glasgow, G41 4DQ, UK

[165 ]Institute of Molecular Medicine and Human Genetics Center, University of Texas Health Science Center at Houston , Houston, Texas, 77030, USA

[166 ]Medical and Molecular Genetics, Indiana University School of Medicine , Indianapolis, Indiana 46202, USA

[167 ]University of Texas Health Science Center , San Antonio, Texas 78229, USA

[168 ]Division of Cerebral Integration, National Institute for Physiological Sciences , Aichi, 444-8585, Japan

[169 ]Division of Genetics, Department of Medicine, Brigham and Women's Hospital , Boston, Massachusetts 02115, USA

[170 ]Department of Neuroscience, Faculty of Medicine, Norwegian University of Science and Technology (NTNU) , Trondheim, 7491, Norway

[171 ]Department of Radiology, St. Olav's Hospital, Trondheim University Hospital , Trondheim, 7030, Norway

[172 ]Department of Psychiatry, Osaka University Graduate School of Medicine , Osaka 565-0871, Japan

[173 ]Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University , Osaka, 565-0871, Japan

[174 ]Institute of Diagnostic Radiology and Neuroradiology, University Medicine Greifswald , 17489 Greifswald, Germany

[175 ]German Center for Neurodegenerative Diseases (DZNE) , Tübingen, 72076, Germany

[176 ]Department of Psychology, VU University Amsterdam , 1081 BT Amsterdam, The Netherlands

[177 ]Department of Psychiatry, University of Iowa , Iowa City, Iowa 52242, USA

[178 ]Department of Epidemiology, Harvard T.H. Chan School of Public Health , Boston, Massachusetts 02115 USA

[179 ]HMNC Brain Health , Munich, 80539, Germany

[180 ]Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald , 17489 Greifswald, Germany

[181 ]Translational Genomics Research Institute, Neurogenomics Division , 445N Fifth Street, Phoenix, Arizona 85004, USA

[182 ]Department of Psychiatry, Fujita Health University School of Medicine , Toyoake 470-1192, Japan

[183 ]Department of Radiology, Mayo Clinic , Rochester, Minnesota 55905, USA

[184 ]NICHD Brain and Tissue Bank for Developmental Disorders, University of Maryland Medical School , Baltimore, Maryland 21201, USA

[185 ]School of Psychology, University of Sussex , Brighton BN1 9QH, UK

[186 ]Institute of Cognitive Neuroscience, University College London , London WC1N 3AR, UK

[187 ]Department of Neuroinformatics, Araya Brain Imaging , Tokyo, 102-0093, Japan

[188 ]Medical University of Lodz , 90-419 Lodz, Poland

[189 ]Department of Neurology, Mayo Clinic , Rochester, Minnesota, 55905, USA

[190 ]Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine , Baltimore, Maryland, 21228, USA

[191 ]Neuroscience Research Australia , Sydney, New South Wales 2031, Australia

[192 ]School of Medical Sciences, UNSW , Sydney, New South Wales 2052, Australia

[193 ]INSERM UMR 1000 “Neuroimaging and Psychiatry”, Service Hospitalier Frédéric Joliot; University Paris-Sud, Université Paris-Saclay, University Paris Descartes , Maison de Solenn, Paris, 91400, France

[194 ]Columbia University Medical Center , New York, New York 10032, USA

[195 ]Laboratory of Genetics, National Institute on Aging, National Institutes of Health , Baltimore, Maryland 21224, USA

[196 ]Departments of Neurology and Psychiatry, University of Pittsburgh , 3501 Forbes Ave., Suite 830, Pittsburgh Pennsylvania 15213, USA

[197 ]Department of Psychiatry, University of Oxford , Oxford OX3 7JX, UK

[198 ]Department of Radiology, Johns Hopkins University School of Medicine , Baltimore, Maryland 21205, USA

[199 ]Centre for Advanced Imaging, University of Queensland , Brisbane, Queensland 4072, Australia

[200 ]Section of Gerontology and Geriatrics, Department of Medicine, University of Perugia , 06132 Perugia, Italy

[201 ]Munich Cluster for Systems Neurology (SyNergy) , 81377 Munich, Germany

[202 ]University of Liverpool, Institute of Translational Medicine , Liverpool L69 3BX, UK

[203 ]Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald , 17489 Greifswald, Germany

[204 ]German Center for Cardiovascular Research (DZHK e.V.), partner site Greifswald , Greifswald, 17475, Germany

[205 ]Department of Statistics & WMG, University of Warwick , Coventry CV4 7AL, UK

[206 ]Department of Medical Informatics Erasmus MC , 3015 CE Rotterdam, The Netherlands

[207 ]Faculty of Applied Sciences, Delft University of Technology , Delft, 2628 CD, The Netherlands

[208 ]Department of Genomics, Life & Brain Center, University of Bonn , 53127 Bonn, Germany

[209 ]Rotman Research Institute, University of Toronto , Toronto, Ontario, Canada M6A 2E1

[210 ]Departments of Psychology and Psychiatry, University of Toronto , Toronto, Ontario, Canada M5T 1R8

[211 ]Child Mind Institute , New York, New York, 10022, USA

[212 ]Departments of Physiology and Nutritional Sciences, University of Toronto , Toronto, Ontario, Canada M5S 3E2

[213 ]Department of Radiology, University of Calgary , Calgary, Alberta, Canada T2N 4N1

[214 ]Department of Clinical Neuroscience, University of Calgary , Calgary, Alberta, Canada T2N 4N1

[215 ]Departments of Epidemiology, Medicine and Health Services, University of Washington, Seattle, WA, USA Group Health Research Institute, Group Health , 1730 Minor Avenue/Suite 1360, Seattle, Washington 98101, USA

[216 ]Department of Developmental Disability Neuropsychiatry, School of Psychiatry, University of New South Wales , Sydney, New South Wales 2052, Australia

[217 ]Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute and Pediatrics at Harbor-UCLA Medical Center , Torrance, California 90502, USA

[218 ]Evelyn F. McKnight Brain Institute, University of Miami, Miller School of Medicine , Miami, Florida, 33136, USA

[219 ]Neuropsychiatric Institute, Prince of Wales Hospital , Randwick, New South Wales 2031, Australia

[220 ]Institute of Molecular Biology and Biochemistry, Medical University Graz , Harrachgasse 21/III, 8010 Graz, Austria

[221 ]Department of Neuroimaging, Institute of Psychiatry, King's College London , London SE5 8AF, UK

[222 ]Biomedical Research Centre for Mental Health, King's College London , London SE5 8AF, UK

[223 ]Biomedical Research Unit for Dementia, King's College London , London SE5 8AF, UK

[224 ]MRC Edinburgh Brain Bank, University of Edinburgh, Academic Department of Neuropathology, Centre for Clinical Brain Sciences , Edinburgh, EH16 4SB UK

[225 ]Institute of Clinical Medicine, Neurology, University of Eastern Finland , FI-70211 Kuopio, Finland

[226 ]Neurocentre Neurology, Kuopio University Hospital , FI-70211 Kuopio, Finland

[227 ]Institute of Cardiovascular and Medical Sciences, Faculty of Medicine, University of Glasgow , Glasgow, G4 0SF, UK

[228 ]Laboratory of Neuro Imaging, Institute for Neuroimaging and Informatics, Keck School of Medicine of the University of Southern California , Los Angeles, California 90033, USA

[229 ]Department of Pathology, Johns Hopkins University , Baltimore, Maryland 21205, USA

[230 ]3rd Department of Neurology, "G. Papanicolaou", Hospital, Aristotle University of Thessaloniki , Thessaloniki, 57010, Greece

[231 ]Univ. Bordeaux, Inserm, Bordeaux Population Health Research Center, UMR1219 , Bordeaux, F-33000, France

[232 ]Department of Internal Medicine, Erasmus MC , 3015 CE Rotterdam, The Netherlands

[233 ]Genentech Inc. , South San Francisco, California 94080, USA

[234 ]Department of Psychiatry and Leiden Institute for Brain and Cognition, Leiden University Medical Center , 2333 ZA Leiden, The Netherlands

[235 ]University of Groningen, University Medical Center Groningen, Department of Neuroscience , 9713 AW Groningen, the Netherlands

[236 ]Department of Internal Medicine and Geriatric Medicine, INSERM U1027, University of Toulouse , Toulouse, 31024, France

[237 ]Department of Psychiatry, Carver College of Medicine, University of Iowa , Iowa City, Iowa 52242, USA

[238 ]Departments of Psychiatry, Neurology, Neuroscience and the Institute of Genetic Medicine, Johns Hopkins University School of Medicine , Baltimore, Maryland 21205, USA

[239 ]Center for Imaging of Neurodegenerative Disease, San Francisco VA Medical Center, University of California , San Francisco, California 94121, USA

[240 ]Department of Neurobiology, Care Sciences and Society, Karolinska Institutet , SE-141 57 Huddinge, Sweden

[241 ]Department of Child and Adolescent Psychiatry/Psychology, Erasmus MC-Sophia Children's Hospital , 3015 CE Rotterdam, The Netherlands

[242 ]Laboratory of Epidemiology & Population Sciences, National Institute on Aging, National Institutes of Health , Bethesda, Maryland 20892, USA

[243 ]Departments of Neurology and Epidemiology, University of Washington , 325 Ninth Avenue, Seattle, Washington 98104-2420, USA

[244 ]Intramural Research Program, NIA, NIH , 7201 Wisconsin Ave, Suite 3C-309, Bethesda, Maryland 20892, USA

[245 ]Department of Neurology, Erasmus MC , Rotterdam 3015 CE, The Netherlands

Author notes

[a ] pthomp@ 123456usc.edu

[b ] m.a.ikram@ 123456erasmusmc.nl

[*]

These authors contributed equally to this work.

[†]

These authors jointly supervised the study

Author information

Marco P. Boks http://orcid.org/0000-0001-6163-7484

Tianye Jia http://orcid.org/0000-0001-5399-2953

Marieke Klein http://orcid.org/0000-0001-8784-5679

Manuel Mattheisen http://orcid.org/0000-0002-8442-493X

Loes M. Olde Loohuis http://orcid.org/0000-0002-3327-7837

Claudia L. Satizabal http://orcid.org/0000-0002-1115-4430

Li Shen http://orcid.org/0000-0002-5443-0503

Alexander Teumer http://orcid.org/0000-0002-8309-094X

Daniah Trabzuni http://orcid.org/0000-0003-4826-9570

Sven J. Van der Lee http://orcid.org/0000-0003-1606-8643

Lars T. Westlye http://orcid.org/0000-0001-8644-956X

Anderson M. Winkler http://orcid.org/0000-0002-4169-9781

Philippe Amouyel http://orcid.org/0000-0001-9088-234X

Ole A. Andreassen http://orcid.org/0000-0002-4461-3568

Henry Brodaty http://orcid.org/0000-0001-9487-6617

Thomas D. Dyer http://orcid.org/0000-0002-5809-1190

Simon E. Fisher http://orcid.org/0000-0002-3132-1996

Ryota Hashimoto http://orcid.org/0000-0002-5941-4238

Beng-Choon Ho http://orcid.org/0000-0003-3976-1555

Andrew M. McIntosh http://orcid.org/0000-0002-0198-4588

Francis J. McMahon http://orcid.org/0000-0002-9469-305X

Thomas E. Nichols http://orcid.org/0000-0002-4516-5103

G. Bruce Pike http://orcid.org/0000-0001-8924-683X

Perminder S. Sachdev http://orcid.org/0000-0002-9595-3220

Andrew J. Saykin http://orcid.org/0000-0002-1376-8532

Peter R. Schofield http://orcid.org/0000-0003-2967-9662

Joanna M. Wardlaw http://orcid.org/0000-0002-9812-6642

Eric Westman http://orcid.org/0000-0002-3115-2977

Barbara Franke http://orcid.org/0000-0003-4375-6572

Article

Publisher Item ID: ncomms13624

DOI: 10.1038/ncomms13624

PMC ID: 5253632

PubMed ID: 28098162

SO-VID: 63f8c3ac-08b1-411a-bb21-cb3a60e53e14

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Date received : 23 August 2016

Date accepted : 18 October 2016

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