Human subcortical brain asymmetries in 15,847 people worldwide reveal effects of age and sex

Tulio Guadalupe, Samuel R. Mathias, Theo G.M. vanErp, Christopher D. Whelan, Marcel P. Zwiers, Yoshinari Abe, Lucija Abramovic, Ingrid Agartz, Ole A. Andreassen, Alejandro Arias-Vásquez, Benjamin S. Aribisala, Nicola J. Armstrong, Volker Arolt, Eric Artiges, Rosa Ayesa-Arriola, Vatche G. Baboyan, Tobias Banaschewski, Gareth Barker, Mark E. Bastin, Bernhard T. BauneJohn Blangero, Arun L.W. Bokde, Premika S.W. Boedhoe, Anushree Bose, Silvia Brem, Henry Brodaty, Uli Bromberg, Samantha Brooks, Christian Büchel, Jan Buitelaar, Vince D. Calhoun, Dara M. Cannon, Anna Cattrell, Yuqi Cheng, Patricia J. Conrod, Annette Conzelmann, Aiden Corvin, Benedicto Crespo-Facorro, Fabrice Crivello, Udo Dannlowski, Greig I. de Zubicaray, Sonja M.C. de Zwarte, Ian J. Deary, Sylvane Desrivières, Nhat Trung Doan, Gary Donohoe, Erlend S. Dørum, Stefan Ehrlich, Thomas Espeseth, Guillén Fernández, Herta Flor, Jean Paul Fouche, Vincent Frouin, Masaki Fukunaga, Jürgen Gallinat, Hugh Garavan, Michael Gill, Andrea Gonzalez Suarez, Penny Gowland, Hans J. Grabe, Dominik Grotegerd, Oliver Gruber, Saskia Hagenaars, Ryota Hashimoto, Tobias U. Hauser, Andreas Heinz, Derrek P. Hibar, Pieter J. Hoekstra, Martine Hoogman, Fleur M. Howells, Hao Hu, Hilleke E. Hulshoff Pol, Chaim Huyser, Bernd Ittermann, Neda Jahanshad, Erik G. Jönsson, Sarah Jurk, Rene S. Kahn, Sinead Kelly, Bernd Kraemer, Harald Kugel, Jun Soo Kwon, Herve Lemaitre, Klaus Peter Lesch, Christine Lochner, Michelle Luciano, Andre F. Marquand, Nicholas G. Martin, Ignacio Martínez-Zalacaín, Jean Luc Martinot, David Mataix-Cols, Karen Mather, Colm McDonald, Katie L. McMahon, Sarah E. Medland, José M. Menchón, Derek W. Morris, Omar Mothersill, Susana Munoz Maniega, Benson Mwangi, Takashi Nakamae, Tomohiro Nakao, Janardhanan C. Narayanaswaamy, Frauke Nees, Jan E. Nordvik, A. Marten H. Onnink, Nils Opel, Roel Ophoff, Marie Laure Paillère Martinot, Dimitri Papadopoulos Orfanos, Paul Pauli, Tomáš Paus, Luise Poustka, Janardhan Yc Reddy, Miguel E. Renteria, Roberto Roiz-Santiáñez, Annerine Roos, Natalie A. Royle, Perminder Sachdev, Pascual Sánchez-Juan, Lianne Schmaal, Gunter Schumann, Elena Shumskaya, Michael N. Smolka, Jair C. Soares, Carles Soriano-Mas, Dan J. Stein, Lachlan T. Strike, Roberto Toro, Jessica A. Turner, Nathalie Tzourio-Mazoyer, Anne Uhlmann, Maria Valdés Hernández, Odile A. van den Heuvel, Dennis van der Meer, Neeltje E.M. van Haren, Dick J. Veltman, Ganesan Venkatasubramanian, Nora C. Vetter, Daniella Vuletic, Susanne Walitza, Henrik Walter, Esther Walton, Zhen Wang, Joanna Wardlaw, Wei Wen, Lars T. Westlye, Robert Whelan, Katharina Wittfeld, Thomas Wolfers, Margaret J. Wright, Jian Xu, Xiufeng Xu, Je Yeon Yun, Jing Jing Zhao, Barbara Franke, Paul M. Thompson, David C. Glahn, Bernard Mazoyer, Simon E. Fisher, Clyde Francks*

*Corresponding author for this work

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Abstract

The two hemispheres of the human brain differ functionally and structurally. Despite over a century of research, the extent to which brain asymmetry is influenced by sex, handedness, age, and genetic factors is still controversial. Here we present the largest ever analysis of subcortical brain asymmetries, in a harmonized multi-site study using meta-analysis methods. Volumetric asymmetry of seven subcortical structures was assessed in 15,847 MRI scans from 52 datasets worldwide. There were sex differences in the asymmetry of the globus pallidus and putamen. Heritability estimates, derived from 1170 subjects belonging to 71 extended pedigrees, revealed that additive genetic factors influenced the asymmetry of these two structures and that of the hippocampus and thalamus. Handedness had no detectable effect on subcortical asymmetries, even in this unprecedented sample size, but the asymmetry of the putamen varied with age. Genetic drivers of asymmetry in the hippocampus, thalamus and basal ganglia may affect variability in human cognition, including susceptibility to psychiatric disorders.

Original languageEnglish
Pages (from-to)1497-1514
Number of pages18
JournalBrain Imaging and Behavior
Volume11
Issue number5
DOIs
Publication statusPublished - 1 Oct 2017
Externally publishedYes

Bibliographical note

Funding Information:
IMAGEN received support from the following sources: the European Union-funded FP6 Integrated Project IMAGEN (Reinforcement-related behaviour in normal brain function and psychopathology) (LSHM-CT-2007-037286), the FP7 projects IMAGEMEND(602450; IMAging GEnetics for MENtal Disorders), AGGRESSOTYPE (602805) and MATRICS (603016), the Innovative Medicine Initiative Project EU-AIMS (115300–2), a Medical Research Council Programme Grant BDevelopmental pathways into adolescent substance abuse^ (93558), the Swedish funding agency FORMAS, the Medical Research Council and the Wellcome Trust (Behavioural and Clinical Neuroscience Institute, University of Cambridge), the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London, the Bundesministeriumfür Bildung und Forschung (BMBF grants 01GS08152; 01EV0711; eMED SysAlc01ZX1311A; Forschungsnetz AERIAL), the Deutsche Forschungsgemeinschaft (DFG grants SM 80/ 7–1, SM 80/7–2, SFB 940/1), the National Institutes of Health, U.S.A. (Axon, Testosterone and Mental Health during Adolescence; RO1 MH085772-01 A1), and by NIH Consortium grant U54 EB020403, supported by a cross-NIH alliance that funds Big Data to Knowledge Centres of Excellence.

Funding Information:
The IMpACT study was supported by a grant from the Brain & Cognition Excellence Program and a Vici grant (to Barbara Franke) of the Netherlands Organization for Scientific Research (NWO, grant numbers 433–09-229 and 016–130-669) and in part by the Netherlands Brain Foundation (grant number, 15F07[2]27)and the and BBMRI-NL (grant CP2010–33). The research leading to these results also received funding from the European Community’s Seventh Framework Programme (FP7/ 2007–2013) under grant agreement no. 602805 (Aggressotype), no. 278948 (TACTICS), and no. 602450 (IMAGEMEND). In addition, the project received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement no 643051 (MiND), the NIH BD2K U54 020403 grant for the ENIGMA Consortium, and from the ECNP Network ADHD across the lifespan.

Funding Information:
CLiNG and HMS studies were partially supported by a research grant from the Competence Network Schizophrenia to Oliver Gruber.

Funding Information:
The Brain Imaging Genetics (BIG) database was established in Nijmegen in 2007. This resource is now part of Cognomics, a joint initiative by researchers of the Donders Centre for Cognitive Neuroimaging, the Human Genetics and Cognitive Neuroscience departments of the Radboud University Medical Center, and the Max Planck Institute for Psycholinguistics. The Cognomics Initiative is supported by the participating departments and centres and by external grants, i.e. the Biobanking and Biomolecular Resources Research Infrastructure (Netherlands) (BBMRI-NL), the Hersenstichting Nederland, and the Netherlands Organisation for Scientific Research (NWO). The research on BIG also receives funding from the European Community‘s Seventh Framework Programme (FP7/2007–2013) under grant agreements #602450 (IMAGEMEND) and #602805 (Aggressotype) and from the National Institutes of Health (NIH) Consortium grant U54 EB020403, supported by a cross-NIH alliance that funds Big Data to Knowledge Centers of Excellence. We would also like to thank Hans van Bokhoven for his contributions to the Cognomics initiative and to all persons who kindly participated in this research. In addition, AF Marquand gratefully acknowledges support from the Language in Interaction project, funded by the NWO under the Gravitation Programme (grant 024.001.006).

Funding Information:
The FBIRN study was supported by the National Center for Research Resources at the National Institutes of Health (grant numbers: NIH 1 U24 RR021992 (Function Biomedical Informatics Research Network) and NIH 1 U24 RR025736–01 (Biomedical Informatics Research Network Coordinating Center; http://www.birncommunity.org). FBIRN data was processed by the UCI High Performance Computing cluster supported by Joseph Farran, Harry Mangalam, and Adam Brenner and the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant UL1 TR000153. FBIRN thanks Mrs. Liv McMillan for overall study coordination.

Funding Information:
The Study of Health in Pomerania (SHIP) is supported by the German Federal Ministry of Education and Research (grants 01ZZ9603, 01ZZ0103 and 01ZZ0403) the Ministry of Cultural Affairs as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania. MRI scans were supported by Siemens Healthcare, Erlangen, Germany. SHIP-LEGEND was supported by the German Research Foundation (GR1912/5–1).

Funding Information:
The HUBIN study was supported by the Swedish Research Council (grant numbers K2009-62X-15077-06-3 and K2012-61X-15077-09-3), the Karolinska Institutet and the Knut and Alice Wallenberg Foundation.

Funding Information:
The infrastructure for the NESDA study (www.nesda.nl) is funded through the Geestkracht program of the Netherlands Organisation for Health Research and Development (Zon-Mw, grant number 10–000-1002 ) and is supported by participating universities (VU University Medical Center, GGZ inGeest, Arkin, Leiden University Medical Center, GGZ Rivierduinen, University Medical Center Groningen) and mental health care organizations, see www.nesda.nl. Lianne Schmaal is supported by The Netherlands Brain Foundation Grant number F2014(1)-24.

Funding Information:
is supported by the NIH BD2K BBig Data to Knowledge^ initiative (U54 020403; PI: Paul Thompson) which is funded by a cross-NIH partnership.

Funding Information:
The Münster Neuroimaging Cohort (MüNC) was supported by grants from the German Research Foundation (DFG; grant FOR 2107; DA1151/5–1 to UD) and Innovative Medizinische Forschung (IMF) of the Medical Faculty of Münster (DA120903 to UD, DA111107 to UD, and DA211012 to UD).

Funding Information:
Sydney MAS and OATS were supported by a National Health and Medical Research Council (NHMRC)/Australian Research Council Strategic Award (Grant 401162); NHMRC Program Grants (350833, 568969) and a Project Grant (1045325). OATS was facilitated through access to the Australian Twin Registry, which is funded by the NHMRC Enabling Grant 310667. Karen Mather is supported by the NHMRC Capacity Building Grant 568940 and an Alzheimer’s Australia Dementia Research Foundation Postdoctoral Fellowship. We would like to thank the Sydney MAS and OATS participants and their respective research teams.

Funding Information:
LBC1936: Data collection was supported by the Disconnected Mind project, funded by Age UK. J.M.W. is partly funded by the Scottish Funding Council as part of the SINAPSE Collaboration. 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 (MR/K026992/1). Funding from the Biotechnology and Biological Sciences Research Council (BBSRC) and MRC is gratefully acknowledged. We thank the study participants. We also thank Catherine Murray for recruitment of the participants and the radiographers and other staff at the Brain Research Imaging Centre.

Funding Information:
QTIM: Australian National Health and Medical Research Council (Project Grants No. 496682 and 1009064 to MJ Wright and Fellowship No. 464914 to IB Hickie), US National Institute of Child Health and Human Development (RO1HD050735 to MJ Wright), and US National Institute on Drug Abuse (R00DA023549 to NA Gillespie). Baptiste Couvy-Duchesne is supported by a University of Queensland International PhD scholarship. We are grateful to the twins for their generosity of time and willingness to participate in our studies. We thank research assistants Marlene Grace, Ann Eldridge, Richard Parker, Lenore Sullivan, Lorelle Nunn, Kerrie Mcaloney, Kori Johnson, Aaron Quiggle, and Natalie Garden, radiographers Matthew Meredith, Peter Hobden, Kate Borg, Aiman Al Najjar, and Anita Burns for acquisition of the scans, and David Smyth, Anthony Conciotrorre, Daniel Park, and David Butler for IT support.

Funding Information:
The TCD|NUIG sample was supported by grant funding from the Health Research Board (grant number HRA_POR/2011/100; HRA_ POR/2012/54), Science Foundation ireland (12/IP/1359; 08/IN.1/ B1916), the Wellcome Trust (grant number 072894/2/03/Z) and the Brain and Behavior Research Foundation (grant number 17026), USA.

Funding Information:
The OCD-London dataset was supported by project grant no. 064846 from the Wellcome Trust and a pilot R&D grant from the South London & Maudsley Trust, UK.

Funding Information:
The CIAM and OCD-SU datasets were supported by the Medical Research Council of South Africa .

Funding Information:
The IDIVAL-PAFIP study was supported by Instituto de Salud Carlos III, FIS 00/3095, 01/3129, PI020499, PI060507, PI10/00183, PI14/00639, the SENY Fundació Research Grant CI 2005–0308007, and the Fundación Marqués de Valdecilla API07/011. We thank IDIVAL Neuroimaging Unit for its help in the technical execution of this work.

Funding Information:
The MCIC study was supported by the National Institutes of Health (NIH/NCRR P41RR14075 and R01EB005846 to Vince D. Calhoun), the Department of Energy (DE-FG02-99ER62764), the Mind Research Network, the Morphometry BIRN (1 U24, RR021382A), the Function BIRN (U24RR021992–01, NIH.NCRR MO1 RR025758– 01,1RC1MH089257 and 5P20RR021938/P20GM103472 to Vince D. Calhoun), the Deutsche Forschungsgemeinschaft (research fellowship to Stefan Ehrlich and Esther Walton), and a NARSAD Young Investigator Award (to Stefan Ehrlich).

Funding Information:
The TOP study was supported by the Research Council of Norway (#213837, #217776, #223273), the South-East Norway Health Authority (2013–123), and the KG Jebsen Foundation.

Funding Information:
The NCNG study was supported by the Research Council of Norway (#154313, #177458, and #231286).

Funding Information:
The Barcelona OCD study was supported by project grants no. PI09/01331, PI10/01753, PI10/01003, CP10/00604, PI13/01958 and CIBER-CB06/03/0034 from the Carlos III Health Institute, grant no. 2014SGR1672 from the Agency for Administration of University and Research (AGAUR), and a ‘Miguel Servet’ contract (CP10/00604) from the Carlos III Health Institute to Dr. Soriano-Mas.

Funding Information:
The Osaka study was partially supported by JSPS KAKENHI Grant Number 25293250 and 23659565, MEXT Grant-in-Aid for Scientific Research on Innovative Areas (Comprehensive Brain Science Network) Grant Number 221S0003, and Brain/MINDS, AMED. Part of computations were performed using Research Center for Computational Science, Okazaki, Japan.

Funding Information:
The AMC OCD dataset was supported by grants from ZonMW (grant numbers: 3160007, 91676084, 31160003, 31180002, 31000056, 2812412, 100001002, 100002034), NWO (grant numbers: 90461193, 40007080, 48004004, 40003330), and grants from the Amsterdam Brain Imaging Platform, Neuroscience Campus Amsterdam and the Dutch Brain foundation. The processing with FreeSurfer was performed on the Dutch e-Science Grid through BiG Grid project and COMMIT project Be-Biobanking with imaging for healthcare^, which are funded by the Netherlands Organization for Scientific Research (NWO).

Funding Information:
The NeuroIMAGE study was supported by NIH Grant R01MH62873, NWO Large Investment Grant 1750102007010, and grants from Radboud university medical center, University Medical Center Groningen and Accare, and VU University Amsterdam. This work was also supported by a grant from NWO Brain & Cognition (433–09-242). Further support was received from the European Union FP7 programmes TACTICS (278948) and IMAGEMEND (602450).

Publisher Copyright:
© 2016, The Author(s).

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