Identifying genetic variants influencing human brain structures may reveal new biological mechanisms underlying cognition and neuropsychiatric illness. The volume of the hippocampus is a biomarker of incipient Alzheimer's disease1,2 and is reduced in schizophrenia3, major depression4 and mesial temporal lobe epilepsy5. Whereas many brain imaging phenotypes are highly heritable6,7, identifying and replicating genetic influences has been difficult, as small effects and the high costs of magnetic resonance imaging (MRI) have led to underpowered studies. Here we report genome-wide association meta-analyses and replication for mean bilateral hippocampal, total brain and intracranial volumes from a large multinational consortium. The intergenic variant rs7294919 was associated with hippocampal volume (12q24.22; N = 21,151; P = 6.70 × 10−16) and the expression levels of the positional candidate gene TESC in brain tissue. Additionally, rs10784502, located within HMGA2, was associated with intracranial volume (12q14.3; N = 15,782; P = 1.12 × 10−12). We also identified a suggestive association with total brain volume at rs10494373 within DDR2 (1q23.3; N = 6,500; P = 5.81 × 10−7).
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Some authors received commercial funding unrelated to the topic of this paper. N.J.v.d.W. received speaking fees from Eli Lilly & Company and Wyeth and served on advisory panels of Eli Lilly & Company, Pfizer, Wyeth and Servier. A.A. received an investigator-initiated unrestricted research grant from Bristol-Myers Squibb and speaker's fees from AstraZeneca, Bristol-Myers Squibb and GlaxoSmithKline. H.J.G. received external research support from the German Research Foundation, the Federal Ministry of Education and Research Germany, speaker's honoraria from Bristol-Myers Squibb, Eli Lilly & Company, Novartis, Eisai, Boehringer Ingelheim and Servier and travel funds from Janssen-Cilag, Eli Lilly & Company, Novartis, AstraZeneca, Lundbeck and the SALUS–Institute for Trend-Research and Therapy Evaluation in Mental Health. M.N. received research grants from the Federal Ministry of Education and Research, Germany, the German Research Foundation, BioRad Laboratories, Siemens AG, Zeitschrift für Laboratoriumsmedizin, Bruker Daltronics, Abbott, Jurilab Kuopio, Roche Diagnostics, Instand and Becton Dickinson. H.V. received external research support via research grants from Hofmann La Roche, the Humboldt Foundation, the Federal Ministry of Education and Research (Germany) and the German Research Foundation. M.W. is on the following scientific advisory boards: Lilly, Araclon and Institut Catala de Neurociencies Aplicades, the Gulf War Veterans Illnesses Advisory Committee, VACO, Biogen Idec and Pfizer. M.W. received funding for consulting from Astra Zeneca, Araclon, Medivation/Pfizer, Ipsen, TauRx Therapeutics, Bayer Healthcare, Biogen Idec, Exonhit Therapeutics, SA, Servier, Synarc, Pfizer and Janssen; for travel from NeuroVigil, CHRU–Hopital Roger Salengro, Siemens, AstraZeneca, Geneva University Hospitals, Lilly, the University of California, San Diego–ADNI, Paris University, Institut Catala de Neurociencies Aplicades, the University of New Mexico School of Medicine, Ipsen, Clinical Trials on Alzheimer's Disease (CTAD), Pfizer, AD PD Meeting, Paul Sabatier University, Novartis and Tohoku University; and research support from: Merck, Avid, DoD, VA. M.W. received honoraria from PMDA/ the Japanese Ministry of Health, Labour, and Welfare, Tohoku University, Neuro Vigil, Insitut Catala de Neurociencies Aplicades. M.W. owns stock options for Synarc, Elan. Organizations contributing to the Foundation for the US NIH and thus to the National Institute on Aging (NIA)-funded Alzheimer's Disease Neuroimaging Initiative included Abbott, the Alzheimer's Association, the Alzheimer's Drug Discovery Foundation, Anonymous Foundation, AstraZeneca, Bayer Healthcare, BioClinica (ADNI 2), Bristol-Myers Squibb, the Cure Alzheimer's Fund, Eisai, Elan, Gene Network Sciences, Genentech, GE Healthcare, GlaxoSmithKline, Innogenetics, Johnson & Johnson, Eli Lilly & Company, Medpace, Merck, Novartis, Pfizer, Roche, Schering Plough, Synarc and Wyeth.
ADNI: The ADNI study was supported by the US NIH (U01 AG024904) and the Foundation for the NIH for genotype and phenotype data collection, the NIH (RC2 AG036535-01) for data analysis, the NIA (R01 AG019771-09) for additional data analysis and NCRAD (U24AG021886) for DNA used in part for the GWAS. Data used in preparation of this article were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database (see URLs). As such, the investigators within ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. The ADNI sample wishes to acknowledge the investigators who contributed to the design and implementation of ADNI (see URLs). Data collection and sharing for this project were funded by ADNI (NIH grant U01 AG024904). ADNI is funded by the NIA, the National Institute of Biomedical Imaging and Bioengineering (NIBIB) and through generous contributions from Abbott, AstraZeneca AB, Bayer Schering Pharma AG, Bristol-Myers Squibb, Eisai Global Clinical Development, Elan Corporation, Genentech, GE Healthcare, GlaxoSmithKline, Innogenetics, Johnson & Johnson, Eli Lilly & Company, Medpace, Merck and Cocpany, Novartis AG, Pfizer, F. Hoffman–La Roche, Schering-Plough and Synarc, as well as from nonprofit partners at the Alzheimer's Association and the Alzheimer's Drug Discovery Foundation, with participation from the US Food and Drug Administration (FDA). Private sector contributions to ADNI are facilitated by the Foundation for the NIH (see URLs). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory of Neuro Imaging at the University of California, Los Angeles. This research was also supported by NIH grants (P30 AG010129 and K01 AG030514) and by the Dana Foundation. ADNI was launched in 2003 by the NIA, the NIBIB, the FDA, private pharmaceutical companies and nonprofit organizations as a 5-year public- private partnership. The primary goal of ADNI has been to test whether serial MRI), positron emission tomography (PET), other biological markers and clinical and neuropsychological assessments can be combined to measure the progression of mild cognitive impairment (MCI) and early Alzheimer's disease. Determination of sensitive and specific markers of very early Alzheimer's disease progression is intended to aid researchers and clinicians in developing new treatments and monitoring their effectiveness, as well as lessening the time and cost of clinical trials. The Principal Investigator of this initiative is M.W. Weiner. ADNI is the result of efforts of many coinvestigators from a broad range of academic institutions and private corporations, and subjects have been recruited from over 50 sites across the United States and Canada. The initial goal of ADNI was to recruit 800 adults ages 55 to 90 to participate in the research—approximately 200 cognitively normal older individuals to be followed for 3 years, 400 people with MCI to be followed for 3 years and 200 people with early Alzheimer's disease to be followed for 2 years. For up-to-date information, please visit the ADNI website (see URLs).
BIG: The BIG study wishes to acknowledge S. Kooijman for coordination of sample collection and A. Heister, M. Naber, R. Makkinje, M. Hakobjan and M. Steehouwer for genotyping. The BIG study was supported by a Biobanking and Biomolecular Resources Research Infrastructure Netherlands (BBMRI-NL) complementation grant for brain segmentation and the Netherlands Organisation for Scientific Research (NWO) Horizon Breakthrough grant (grant number 93511010 (to A.A.V.).
Bipolar Family Study: The Bipolar Family Study wishes to thank the Scottish Mental Health Research Network for research assistant support, the Brain Research Imaging Centre Edinburgh (see URLs), a center in the Scottish Funding Council Scottish Imaging Network–A Platform for Scientific Excellence (SINAPSE) Collaboration (see URLs), for image acquisition and the Wellcome Trust Clinical Research Facility for genotyping. Genotyping was supported by the National Alliance for Research on Schizophrenia and Depression (NARSAD) Independent Investigator Award (to A.M.M.), and data collection was supported by the Health Foundation Clinician Scientist Fellowship.
fBIRN: fBIRN wishes to acknowledge D.B. Keator for leading fBIRN neuroinformatics development, B.A. Mueller for image calibration and quality assurance and A. Belger, V.D. Calhoun, G.G. Brown, J.M. Ford, G.H. Glover, R. Kikinis, K. Lim, J. Laurriello, J. Bustillo, G. McCarthy, D.S. O'Leary, B. Rosen, A.W.T. and J.T. Voyvodic for their leadership contributions to fBIRN scanner and sequence calibration, tool development and data collection efforts. The fBIRN study was supported by the US NIH (U24 RR21992) for phenotypic data collection. Genotyping was performed with the support of the grant RBIN04SWHR to F.M. from the Italian Ministry of University and Research.
GOBS: The GOBS study was supported by the US NIH (MH0708143 and MH083824 to D.C.G., MH078111 and MH59490 to J.B., C06 RR13556 and C06 RR017515). P.K. was also supported by an NIH grant (EB006395).
IMAGEN: IMAGEN is funded by the European Commission Framework Programme 6 (FP-6) Integrated Project IMAGEN (PL037286), the European Commission Framework Programme 7 (FP-7) Project Alzheimer's Disease, Alcoholism, Memory, Schizophrenia (ADAMS), the FP-7 Innovative Medicine Initiative Project European Autism Interventions (AIMS), the UK Department of Health National Institute of Health Research (NIHR)–Biomedical Research Centre Mental Health program and the MRC programme grant Developmental Pathways into Adolescent Substance Abuse (93558).
ImaGene: ImaGene wishes to acknowledge J. Lee and J. Lane for processing the blood samples, The Easton Consortium for Alzheimer's Disease Drug Discovery and Biomarker Development and the Alzheimer's Disease Research Center (ADRC) funded by the NIA at the University of California, Los Angeles (AG16570).
LBC1936: We thank the participants in LBC1936. We thank C. Murray, A.J. Gow, S.E. Harris, M. Luciano, P. Redmond, E. Sandeman, I. Gerrish, J. Boyd-Ellison, N. Leslie, A. Howden and C. Scott for data collection and preparation. This project is funded by the Age UK's Disconnected Mind programme and also by Research Into Ageing (251 and 285). The entire genome association part of the study was funded by the Biotechnology and Biological Sciences Research Council (BBSRC) (BB/F019394/1). Analysis of brain images was funded by UK MRC grants (G1001401 and 8200). The work was undertaken by The University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross council Lifelong Health and Wellbeing Initiative (G0700704/84698). Imaging was performed at the Brain Research Imaging Centre, Edinburgh, a center in the SINAPSE Collaboration. Funding from BBSRC, the Engineering and Physical Sciences Research Council (EPSRC), the Economic and Social Research Council (ESRC) and the MRC and Scottish Funding Council through the SINAPSE Collaboration is gratefully acknowledged. L.M.L. is the beneficiary of a postdoctoral grant from the AXA Research Fund.
MooDS: This work was funded by the German Federal Ministry of Education and Research (BMBF) in the National Genome Research Network (NGFN-plus) through the MooDs grant Molecular Causes of Major Mood Disorders and Schizophrenia (coordinator M.M.N.). Additional funding for genotyping was provided by a NARSAD Distinguished Investigator award to A.M.-L.
MPIP: The MPIP Munich Morphometry Sample comprises images acquired as part of the Munich Antidepressant Response Signature Study and the Recurrent Unipolar Depression (RUD) Case-Control Study performed at the MPIP and control subjects acquired at the Department of Psychiatry at the Ludwig-Maximilians-University. We wish to acknowledge A. Olynyik and radiographers R. Schirmer, E. Schreiter and R. Borschke for image acquisition and data preparation. We thank D.P. Auer for local study management in the initial phase of the RUD study. We are grateful to GlaxoSmithKline for providing the genotypes of the RUD Case-Control Sample. We thank the staff of the Center of Applied Genotyping (CAGT) for generating the genotypes of the MARS cohort. The study is supported by a grant from the Exzellenz-Stiftung of the Max Planck Society. This work has also been funded by the BMBF in the framework of the National Genome Research Network (NGFN) (FKZ 01GS0481).
NCNG: We would like to thank the personnel involved in recruitment and data collection and, in particular, P. Due-Tønnessen for clinical assessment of the MRI images. The NCNG study was supported by Research Council of Norway grants (154313/V50 and 177458/V50). The NCNG GWAS was financed by grants from the Bergen Research Foundation, the University of Bergen, the Research Council of Norway (FUGE; Psykisk Helse), Helse Vest Regionalt Helseforetak (RHF) and the Dr Einar Martens Fund.
NESDA-NTR: Funding was obtained from the NWO (MagW/ZonMW 904-61-090; 985-10-002; 904-61-193; 480-04-004; 400-05-717, Addiction-31160008; 911-09-032; SPI 56-464-14192 and Geestkracht Program, 10-000-1002), the Center for Medical Systems Biology (CMSB; NWO Genomics), NBIC/BioAssist/RK/2008.024, BBMRI-NL, Biobanking and Biomolecular Resources Research Infrastructure, the VU University, the EMGO Institute for Health and Care Research and Neuroscience Campus Amsterdam, the European Science Foundation (EU/QLRT-2001-01254), the European Community's FP7 (HEALTH-F4-2007-201413), the European Science Council (ERC) Genetics of Mental Illness (230374), Rutgers University Cell and DNA Repository (cooperative agreement NIMH U24 MH068457-06), the US NIH (R01D0042157-01A) and the Genetic Association Information Network (a public-private partnership between the NIH and Pfizer, Affymetrix and Abbott Laboratories).
NIMH-IRP: This study was supported by funding from the Intramural Research Program of the National Institute of Mental Health (NIMH) from the NIH and the US Department of Health and Human Services (K99 MH085098 to G.L., 1ZIA MH002810 to F.J.M. and 1ZIA MH002790 to W.C.D.). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US government.
QTIM: We are extremely grateful to the twins for their participation, the radiographers at the Centre for Advanced Imaging at the University of Queensland for image acquisition and the many research assistants and support staff at the Queensland Institute of Medical Research for twin recruitment and daily management, and we especially thank K. Johnson for MRI scanning and processing, A. Henders for DNA processing and preparation and S. Gordon for quality control and management of the genotypes. Phenotyping was funded by the US National Institute of Child Health and Human Development (R01 HD050735) and the Australian National Health and Medical Research Council (NHMRC) (project grant 496682). Genotyping was funded by the NHMRC (Medical Bioinformatics Genomics Proteomics Program, 389891). G.M. was supported by an NHMRC Fellowship (613667), and G.Z. was supported by Australian Research Council (ARC) Future Fellowship (FT0991634). S.E.M. is funded by an ARC Future Fellowship (FT110100548). J.L.S. was supported by the Achievement Rewards for College Scientists foundation and the US NIMH (F31 MH087061). D.P.H. is partially supported by a National Science Foundation (NSF) Graduate Research Fellowhip Program (GRFP) grant (DGE-0707424). P.T. was also supported by the NIH (grants U01 AG024904, AG040060, EB008432, P41 RR013642, HD050735, AG036535, AG020098 and EB008281).
SYS: The Saguenay Youth Study Group wishes to thank the following individuals for their contribution in acquiring and analyzing the data: N. Arbour, M.-È. Bouchard, A. Houde, A. Gauthier and H. Simard for the recruitment and assessment of participating families, M. Bérubé, S. Masson, S. Castonguay and M.-J. Morin for MRI acquisition and E. Ding and N. Qiu for MR data management. We thank J. Mathieu for the medical follow up of participants in whom we detected any medically relevant abnormalities. We are grateful to all families for participating in the study. The Saguenay Youth Study Group is supported by the Canadian Institutes of Health Research, the Heart and Stroke Foundation of Quebec and the Canadian Foundation for Innovation. For more information, please see the study website (see URLs).
SHIP: The Study of Health in Pomerania (SHIP) is supported by the German Federal Ministry of Education and Research (grants 01ZZ9603, 01ZZ0103 and 01ZZ0403) and the German Research Foundation (DFG; GR 1912/5-1). Genome-wide data and MRI scans were supported by the Federal Ministry of Education and Research (grant 03ZIK012) and a joint grant from Siemens Healthcare, Erlangen, Germany, and the Federal State of Mecklenburg–West Pomerania. The University of Greifswald is a member of the Center of Knowledge Interchange program of the Siemens AG. We thank all staff members and participants of the SHIP study, as well as all of the genotyping staff for generating the SHIP SNP data set. The genetic data analysis workflow was created using the Software InforSense. Genetic data were stored using the database Caché (InterSystems).
SHIP-TREND: The authors from SHIP are grateful to M. Stanke for the opportunity to use his Server Cluster for SNP Imputation. This cohort is part of the Community Medicine Research net (CMR) of the University of Greifswald, which is funded by the German Federal Ministry of Education and Research and the German Ministry of Cultural Affairs, as well as by the Social Ministry of the Federal State of Mecklenburg–West Pomerania. CMR encompasses several research projects that share data from the population-based Study of Health in Pomerania (SHIP; see URLs). The work is also supported by the German Research Foundation (DFG; GR 1912/5-1) and the Greifswald Approach to Individualized Medicine (GANI_MED) network funded by the Federal Ministry of Education and Research (grant 03IS2061A). Genome-wide data and MRI scans were supported by the Federal Ministry of Education and Research (grant 03ZIK012) and a joint grant from Siemens Healthcare, Erlangen, Germany, and the Federal State of Mecklenburg–West Pomerania. The University of Greifswald is a member of the Center of Knowledge Interchange program of the Siemens AG.
Superstruct: We thank the investigators and participants who contributed to the brain genomics data collection for Superstruct at Massachusetts General Hospital and Harvard University, with funding from the Simons Foundation, the Howard Hughes Medical Institute and the US NIH (grant MH079799).
TOP: We thank the study participants of TOP and the personnel involved in data collection and logistics, especially T.D. Bjella. This work was supported by the Oslo University Hospital–Ullevål, the Eastern Norway Health Authority (2004-123), the Research Council of Norway (167153/V50, 163070/V50 and 183782/V50), and by Eli Lilly & Company (who covered part of the genotyping costs).
TCD: We wish to express our sincere thanks to all participants and to clinical staff who facilitated patients' involvement. In particular, we acknowledge colleagues from the Trinity College Institute of Neuroscience A. Bodke, J. McGrath, F. Newell, H. Garavan, and J. O'Doherty for their support in sample collection. Collection and analysis of these samples were funded by the Wellcome Trust (072894/z/03/z-Gill) and the Science Foundation Ireland (08/IN.1/B1916_Corvin).
EPIGEN: Work from the London Cohort was supported by research grants from the Wellcome Trust (grant 084730 to S.M.S.), University College London (UCL)/University College London Hospitals (UCLH) Comprehensive Biomedical Research Centre/Specialist Biomedical Research Centres (CBRC/SBRC) (grant 114 to S.M.S.), the European Union Marie Curie Reintegration (to M. Matarin and S.M.S.), the UK NIHR (08-08-SCC), the Comprehensive Local Research Network (CLRN) Flexibility and Sustainability Funding (FSF) (grant CEL1300 to S.M.S.), The Big Lottery Fund, the Wolfson Trust and the Epilepsy Society. This work was undertaken at UCLH/UCL, which received a proportion of funding from the UK Department of Health's NIHR Biomedical Research Centres funding scheme. Work from the Royal College of Surgeons in Ireland was supported by research grants from the Science Foundation Ireland (Research Frontiers Programme award 08/RFP/GEN1538) and Brainwave–the Irish Epilepsy Association. The collection of Belgian subjects was supported by the Fonds National de la Recherche Scientifique (grant FC 63574 / 3.4.620.06 F) and the Fonds Erasme pour la Recherche Médicale at the Université Libre de Bruxelles.
UCL Institute of Neurology Control Brain Tissue Collection: Funding was provided by the UK MRC (grant G0901254), the MRC Sudden Death Brain and Tissue Bank and the Sun Health Research Institute Brain Bank.
UMCU: The UMCU study was supported by the Netherlands Organization for Health Research and Development ZonMw (917.46.370 to H.E.H.) and the US NIMH (MH078075 to R.A.O.).
Supplementary Note, Supplementary Figures 1–44 and Supplementary Tables 1–27
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Scientific Reports (2018)