Measurement and genetics of human subcortical and hippocampal asymmetries in large datasets

Authors

  • Tulio Guadalupe,

    1. Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands
    2. International Max Planck Research School for Language Sciences, Max Planck Insitute for Psycholinguistics, Nijmegen, The Netherlands
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  • Marcel P. Zwiers,

    1. Centre for Cognitive Neuroimaging, Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen, Nijmegen, The Netherlands
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  • Alexander Teumer,

    1. Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany
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  • Katharina Wittfeld,

    1. Department of Psychiatry and Psychotherapy, HELIOS Hospital Stralsund, University Medicine Greifswald, Greifswald, Germany
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  • Alejandro Arias Vasquez,

    1. Department of Human Genetics, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
    2. Department of Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
    3. Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
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  • Martine Hoogman,

    1. Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands
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  • Peter Hagoort,

    1. Centre for Cognitive Neuroimaging, Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen, Nijmegen, The Netherlands
    2. Neurobiology of Language Department, Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands
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  • Guillen Fernandez,

    1. Centre for Cognitive Neuroimaging, Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen, Nijmegen, The Netherlands
    2. Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
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  • Jan Buitelaar,

    1. Department of Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
    2. Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
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  • Katrin Hegenscheid,

    1. Institute of Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, Germany
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  • Henry Völzke,

    1. Institute for Community Medicine, University Medicine Greifswald, Germany
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  • Barbara Franke,

    1. Department of Human Genetics, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
    2. Department of Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
    3. Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
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  • Simon E. Fisher,

    1. Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands
    2. Donders Institute for Brain, Cognition & Behavior, Radboud University Nijmegen, Nijmegen, The Netherlands
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  • Hans J. Grabe,

    1. Department of Psychiatry and Psychotherapy, HELIOS Hospital Stralsund, University Medicine Greifswald, Greifswald, Germany
    2. German Center for Neurodegenerative Diseases (DZNE), Site Rostock/Greifswald, Greifswald, Germany
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  • Clyde Francks

    Corresponding author
    1. Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands
    2. Donders Institute for Brain, Cognition & Behavior, Radboud University Nijmegen, Nijmegen, The Netherlands
    • Correspondence to: Clyde Francks, Max Planck Institute for Psycholinguistics, Wundtlaan 1, Nijmegen 6525 XD, The Netherlands. E-mail: clyde.francks@mpi.nl

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  • Conflict of Interest: No conflicts of interest are declared.

Abstract

Functional and anatomical asymmetries are prevalent features of the human brain, linked to gender, handedness, and cognition. However, little is known about the neurodevelopmental processes involved. In zebrafish, asymmetries arise in the diencephalon before extending within the central nervous system. We aimed to identify genes involved in the development of subtle, left-right volumetric asymmetries of human subcortical structures using large datasets. We first tested the feasibility of measuring left-right volume differences in such large-scale samples, as assessed by two automated methods of subcortical segmentation (FSL|FIRST and FreeSurfer), using data from 235 subjects who had undergone MRI twice. We tested the agreement between the first and second scan, and the agreement between the segmentation methods, for measures of bilateral volumes of six subcortical structures and the hippocampus, and their volumetric asymmetries. We also tested whether there were biases introduced by left-right differences in the regional atlases used by the methods, by analyzing left-right flipped images. While many bilateral volumes were measured well (scan-rescan r = 0.6–0.8), most asymmetries, with the exception of the caudate nucleus, showed lower repeatabilites. We meta-analyzed genome-wide association scan results for caudate nucleus asymmetry in a combined sample of 3,028 adult subjects but did not detect associations at genome-wide significance (P < 5 × 10−8). There was no enrichment of genetic association in genes involved in left-right patterning of the viscera. Our results provide important information for researchers who are currently aiming to carry out large-scale genome-wide studies of subcortical and hippocampal volumes, and their asymmetries. Hum Brain Mapp 35:3277–3289, 2014. © 2013 Wiley Periodicals, Inc.

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