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      Structural network alterations in focal and generalized epilepsy assessed in a worldwide ENIGMA study follow axes of epilepsy risk gene expression

      research-article
      1 , , 1 , 1 , 2 , 3 , 3 , 4 , 5 , 6 , 7 , 8 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 15 , 16 , 16 , 17 , 18 , 17 , 18 , 17 , 18 , 18 , 18 , 19 , 20 , 19 , 20 , 20 , 21 , 22 , 23 , 24 , 25 , 22 , 25 , 22 , 25 , 26 , 27 , 28 , 28 , 29 , 28 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 38 , 38 , 11 , 39 , 40 , 39 , 41 , 42 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 49 , 49 , 50 , 51 , 51 , 52 , 52 , 53 , 54 , 36 , 37 , 55 , 36 , 37 , 36 , 37 , 22 , 56 , 36 , 37 , 57 , 58 , 53 , 57 , 1 ,
      Nature Communications
      Nature Publishing Group UK
      Epilepsy, Network models

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          Abstract

          Epilepsy is associated with genetic risk factors and cortico-subcortical network alterations, but associations between neurobiological mechanisms and macroscale connectomics remain unclear. This multisite ENIGMA-Epilepsy study examined whole-brain structural covariance networks in patients with epilepsy and related findings to postmortem epilepsy risk gene expression patterns. Brain network analysis included 578 adults with temporal lobe epilepsy (TLE), 288 adults with idiopathic generalized epilepsy (IGE), and 1328 healthy controls from 18 centres worldwide. Graph theoretical analysis of structural covariance networks revealed increased clustering and path length in orbitofrontal and temporal regions in TLE, suggesting a shift towards network regularization. Conversely, people with IGE showed decreased clustering and path length in fronto-temporo-parietal cortices, indicating a random network configuration. Syndrome-specific topological alterations reflected expression patterns of risk genes for hippocampal sclerosis in TLE and for generalized epilepsy in IGE. These imaging-transcriptomic signatures could potentially guide diagnosis or tailor therapeutic approaches to specific epilepsy syndromes.

          Abstract

          Epilepsy is a brain network disorder with associated genetic risk factors. Here, the authors show that spatial patterns of transcriptomic vulnerability co-vary with structural brain network alterations in focal and generalized epilepsy.

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          PLINK: a tool set for whole-genome association and population-based linkage analyses.

          Whole-genome association studies (WGAS) bring new computational, as well as analytic, challenges to researchers. Many existing genetic-analysis tools are not designed to handle such large data sets in a convenient manner and do not necessarily exploit the new opportunities that whole-genome data bring. To address these issues, we developed PLINK, an open-source C/C++ WGAS tool set. With PLINK, large data sets comprising hundreds of thousands of markers genotyped for thousands of individuals can be rapidly manipulated and analyzed in their entirety. As well as providing tools to make the basic analytic steps computationally efficient, PLINK also supports some novel approaches to whole-genome data that take advantage of whole-genome coverage. We introduce PLINK and describe the five main domains of function: data management, summary statistics, population stratification, association analysis, and identity-by-descent estimation. In particular, we focus on the estimation and use of identity-by-state and identity-by-descent information in the context of population-based whole-genome studies. This information can be used to detect and correct for population stratification and to identify extended chromosomal segments that are shared identical by descent between very distantly related individuals. Analysis of the patterns of segmental sharing has the potential to map disease loci that contain multiple rare variants in a population-based linkage analysis.
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            An Integrated Encyclopedia of DNA Elements in the Human Genome

            Summary The human genome encodes the blueprint of life, but the function of the vast majority of its nearly three billion bases is unknown. The Encyclopedia of DNA Elements (ENCODE) project has systematically mapped regions of transcription, transcription factor association, chromatin structure, and histone modification. These data enabled us to assign biochemical functions for 80% of the genome, in particular outside of the well-studied protein-coding regions. Many discovered candidate regulatory elements are physically associated with one another and with expressed genes, providing new insights into the mechanisms of gene regulation. The newly identified elements also show a statistical correspondence to sequence variants linked to human disease, and can thereby guide interpretation of this variation. Overall the project provides new insights into the organization and regulation of our genes and genome, and an expansive resource of functional annotations for biomedical research.
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              An automated labeling system for subdividing the human cerebral cortex on MRI scans into gyral based regions of interest.

              In this study, we have assessed the validity and reliability of an automated labeling system that we have developed for subdividing the human cerebral cortex on magnetic resonance images into gyral based regions of interest (ROIs). Using a dataset of 40 MRI scans we manually identified 34 cortical ROIs in each of the individual hemispheres. This information was then encoded in the form of an atlas that was utilized to automatically label ROIs. To examine the validity, as well as the intra- and inter-rater reliability of the automated system, we used both intraclass correlation coefficients (ICC), and a new method known as mean distance maps, to assess the degree of mismatch between the manual and the automated sets of ROIs. When compared with the manual ROIs, the automated ROIs were highly accurate, with an average ICC of 0.835 across all of the ROIs, and a mean distance error of less than 1 mm. Intra- and inter-rater comparisons yielded little to no difference between the sets of ROIs. These findings suggest that the automated method we have developed for subdividing the human cerebral cortex into standard gyral-based neuroanatomical regions is both anatomically valid and reliable. This method may be useful for both morphometric and functional studies of the cerebral cortex as well as for clinical investigations aimed at tracking the evolution of disease-induced changes over time, including clinical trials in which MRI-based measures are used to examine response to treatment.
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                Author and article information

                Contributors
                sara.lariviere@mail.mcgill.ca
                boris.bernhardt@mcgill.ca
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                27 July 2022
                27 July 2022
                2022
                : 13
                : 4320
                Affiliations
                [1 ]GRID grid.14709.3b, ISNI 0000 0004 1936 8649, Multimodal Imaging and Connectome Analysis Laboratory, McConnell Brain Imaging Centre, Montreal Neurological Institute and Hospital, , McGill University, ; Montreal, QC Canada
                [2 ]GRID grid.8385.6, ISNI 0000 0001 2297 375X, Institute for Neuroscience and Medicine (INM-1), , Forschungszentrum Jülich, ; Jülich, Germany
                [3 ]GRID grid.411489.1, ISNI 0000 0001 2168 2547, Neuroscience Research Center, , University Magna Græcia, ; Catanzaro, CZ Italy
                [4 ]GRID grid.411489.1, ISNI 0000 0001 2168 2547, Institute of Neurology, , University Magna Græcia, ; Catanzaro, CZ Italy
                [5 ]GRID grid.9486.3, ISNI 0000 0001 2159 0001, Institute of Neurobiology, , Universidad Nacional Autónoma de México, ; Querétaro, México
                [6 ]GRID grid.10025.36, ISNI 0000 0004 1936 8470, Institute of Systems, Molecular and Integrative Biology, , University of Liverpool, ; Liverpool, UK
                [7 ]GRID grid.416928.0, ISNI 0000 0004 0496 3293, Walton Centre NHS Foundation Trust, ; Liverpool, UK
                [8 ]GRID grid.411087.b, ISNI 0000 0001 0723 2494, Department of Neurology, , University of Campinas–UNICAMP, Campinas, ; São Paulo, Brazil
                [9 ]GRID grid.189967.8, ISNI 0000 0001 0941 6502, Department of Neurology, , Emory University, ; Atlanta, GA USA
                [10 ]GRID grid.259828.c, ISNI 0000 0001 2189 3475, Department of Neurology, , Medical University of South Carolina, ; Charleston, SC USA
                [11 ]GRID grid.411984.1, ISNI 0000 0001 0482 5331, Department of Neurology, , University of Medicine Göttingen, ; Göttingen, Germany
                [12 ]GRID grid.5603.0, Institute of Diagnostic Radiology and Neuroradiology, , Functional Imaging Unit, University Medicine Greifswald, ; Greifswald, Germany
                [13 ]GRID grid.5603.0, Department of Neurology, , University Medicine Greifswald, ; Greifswald, Germany
                [14 ]GRID grid.5603.0, Institute of Diagnostic Radiology and Neuroradiology, , University Medicine Greifswald, ; Greifswald, Germany
                [15 ]GRID grid.411656.1, ISNI 0000 0004 0479 0855, Support Center for Advanced Neuroimaging (SCAN), , University Institute of Diagnostic and Interventional Neuroradiology, University Hospital Bern, ; Bern, Switzerland
                [16 ]GRID grid.428620.a, Department of Neurology and Epileptology, , Hertie Institute for Clinical Brain Research, University of Tübingen, ; Tübingen, Germany
                [17 ]GRID grid.1002.3, ISNI 0000 0004 1936 7857, Department of Neuroscience, Central Clinical School, Alfred Hospital, , Monash University, Melbourne, ; Melbourne, VIC Australia
                [18 ]GRID grid.1008.9, ISNI 0000 0001 2179 088X, Departments of Medicine and Radiology, The Royal Melbourne Hospital, , The University of Melbourne, ; Parkville, VIC Australia
                [19 ]GRID grid.413363.0, ISNI 0000 0004 1769 5275, Neurology Unit, OCB Hospital, , Azienda Ospedaliera-Universitaria, ; Modena, Italy
                [20 ]GRID grid.7548.e, ISNI 0000000121697570, Department of Biomedical, Metabolic and Neural Science, , University of Modena and Reggio Emilia, ; Modena, Italy
                [21 ]Primary Care Department, Azienda Sanitaria Locale di Modena, Modena, Italy
                [22 ]GRID grid.4912.e, ISNI 0000 0004 0488 7120, Department of Molecular and Cellular Therapeutics, , The Royal College of Surgeons in Ireland, ; Dublin, Ireland
                [23 ]GRID grid.47100.32, ISNI 0000000419368710, Department of Neurology, , Yale University School of Medicine, ; New Haven, CT USA
                [24 ]GRID grid.416409.e, ISNI 0000 0004 0617 8280, Department of Neurology, , St James’ Hospital, ; Dublin, Ireland
                [25 ]GRID grid.437854.9, ISNI 0000 0004 0452 5752, FutureNeuro SFI Research Centre, ; Dublin, Ireland
                [26 ]GRID grid.410705.7, ISNI 0000 0004 0628 207X, Epilepsy Center, Neuro Center, , Kuopio University Hospital, Member of the European Reference Network for Rare and Complex Epilepsies EpiCARE, ; Kuopio, Finland
                [27 ]GRID grid.9668.1, ISNI 0000 0001 0726 2490, Faculty of Health Sciences, School of Medicine, Institute of Clinical Medicine, , University of Eastern Finland, ; Kuopio, Finland
                [28 ]GRID grid.1008.9, ISNI 0000 0001 2179 088X, Florey Institute of Neuroscience and Mental Health, , University of Melbourne, ; Melbourne, VIC 3010 Australia
                [29 ]GRID grid.8404.8, ISNI 0000 0004 1757 2304, Neuroradiology Research Program, Meyer Children Hospital of Florence, , University of Florence, ; Florence, Italy
                [30 ]GRID grid.1006.7, ISNI 0000 0001 0462 7212, Transitional and Clinical Research Institute, , Newcastle University, ; Newcastle upon Tyne, UK
                [31 ]GRID grid.46072.37, ISNI 0000 0004 0612 7950, Contol and Intelligent Processing Center of Excellence (CIPCE), School of Electrical and Computer Engineering, , University of Tehran, ; Tehran, Iran
                [32 ]GRID grid.239864.2, ISNI 0000 0000 8523 7701, Departments of Research Administration and Radiology, , Henry Ford Health System, ; Detroit, MI USA
                [33 ]GRID grid.239864.2, ISNI 0000 0000 8523 7701, Department of Neurology, , Henry Ford Health System, ; Detroit, MI USA
                [34 ]GRID grid.12955.3a, ISNI 0000 0001 2264 7233, Cognitive Science Department, , Xiamen University, ; Xiamen, China
                [35 ]GRID grid.410356.5, ISNI 0000 0004 1936 8331, Division of Neurology, Department of Medicine, , Queen’s University, ; Kingston, ON Canada
                [36 ]GRID grid.83440.3b, ISNI 0000000121901201, Department of Clinical and Experimental Epilepsy, , UCL Institute of Neurology, ; London, UK
                [37 ]GRID grid.452379.e, ISNI 0000 0004 0386 7187, Chalfont Centre for Epilepsy, ; Bucks, UK
                [38 ]GRID grid.4777.3, ISNI 0000 0004 0374 7521, Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry & Biomedical Science, , Queens University Belfast, ; Belfast, UK
                [39 ]GRID grid.413181.e, ISNI 0000 0004 1757 8562, Child Neurology Unit and Laboratories, Neuroscience Department, , Children’s Hospital A. Meyer-University of Florence, ; Florence, Italy
                [40 ]GRID grid.413181.e, ISNI 0000 0004 1757 8562, Functional and Epilepsy Neurosurgery Unit, Neurosurgery Department, , Children’s Hospital A. Meyer-University of Florence, ; Florence, Italy
                [41 ]The Welsh Epilepsy Unit, Department of Neurology, University Hospital of Whales, Cardiff, UK
                [42 ]GRID grid.5600.3, ISNI 0000 0001 0807 5670, Cardiff University Brain Research Imaging Centre (CUBRIC), College of Biomedical Sciences, Cardiff University, ; Cardiff, UK
                [43 ]GRID grid.15090.3d, ISNI 0000 0000 8786 803X, Department of Epileptology, , University of Bonn Medical Center, ; Bonn, Germany
                [44 ]GRID grid.7839.5, ISNI 0000 0004 1936 9721, Epilepsy Center Frankfurt Rhine-Main, Department of Neurology, , Goethe-University Frankfurt, ; Frankfurt am Main, Germany
                [45 ]GRID grid.7839.5, ISNI 0000 0004 1936 9721, Center for Personalized Translational Epilepsy Research (CePTER), , Goethe-University Frankfurt, ; Frankfurt am Main, Germany
                [46 ]GRID grid.15090.3d, ISNI 0000 0000 8786 803X, Institute of Experimental Epileptology and Cognition Research, , University Hospital Bonn, ; Bonn, Germany
                [47 ]GRID grid.4989.c, ISNI 0000 0001 2348 0746, Department of Neurology, Hôpital Erasme, , Université Libre de Bruxelles, ; Brussels, Belgium
                [48 ]GRID grid.4989.c, ISNI 0000 0001 2348 0746, Department of Radiology, Hôpital Erasme, , Université Libre de Bruxelles, ; Brussels, Belgium
                [49 ]GRID grid.13097.3c, ISNI 0000 0001 2322 6764, Division of Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, , King’s College London, ; London, UK
                [50 ]GRID grid.137628.9, ISNI 0000 0004 1936 8753, Department of Neurology, , NYU Grossman School of Medicine, ; New York, NY US
                [51 ]GRID grid.419504.d, ISNI 0000 0004 1760 0109, IRCCS Istituto Giannina Gaslini, ; Genova, Italy
                [52 ]GRID grid.5606.5, ISNI 0000 0001 2151 3065, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, , University of Genova, ; Genova, Italy
                [53 ]GRID grid.266100.3, ISNI 0000 0001 2107 4242, Department of Psychiatry, Center for Multimodal Imaging and Genetics, , University of California San Diego, ; La Jolla, CA US
                [54 ]GRID grid.266100.3, ISNI 0000 0001 2107 4242, Department of Neurosciences, Center for Multimodal Imaging and Genetics, , University of California San Diego, ; La Jolla, CA US
                [55 ]GRID grid.83440.3b, ISNI 0000000121901201, Centre for Medical Image Computing, , University College London, ; London, UK
                [56 ]GRID grid.42505.36, ISNI 0000 0001 2156 6853, Imaging Genetics Center, Mark & Mary Stevens Institute for Neuroimaging and Informatics, Keck School of Medicine, , University of Southern California, ; Los Angeles, CA US
                [57 ]GRID grid.14709.3b, ISNI 0000 0004 1936 8649, Neuroimaging of Epilepsy Laboratory, McConnell Brain Imaging Centre, Montreal Neurological Institute and Hospital, , McGill University, ; Montreal, QC Canada
                [58 ]GRID grid.10438.3e, ISNI 0000 0001 2178 8421, Neurology, BIOMORF Dipartment, , University of Messina, ; Messina, Italy
                Author information
                http://orcid.org/0000-0001-5701-1307
                http://orcid.org/0000-0002-4448-8998
                http://orcid.org/0000-0002-2917-1212
                http://orcid.org/0000-0001-7384-3074
                http://orcid.org/0000-0002-7842-3869
                http://orcid.org/0000-0001-9084-7173
                http://orcid.org/0000-0002-6153-8942
                http://orcid.org/0000-0001-5486-6289
                http://orcid.org/0000-0002-8620-966X
                http://orcid.org/0000-0001-7030-2045
                http://orcid.org/0000-0002-7302-6856
                http://orcid.org/0000-0002-9828-5117
                http://orcid.org/0000-0003-0292-6635
                http://orcid.org/0000-0003-2848-621X
                http://orcid.org/0000-0002-8390-2709
                http://orcid.org/0000-0002-6180-7671
                http://orcid.org/0000-0003-0044-4632
                http://orcid.org/0000-0002-6065-1476
                http://orcid.org/0000-0002-9149-8726
                http://orcid.org/0000-0002-8502-4487
                http://orcid.org/0000-0002-1373-0681
                http://orcid.org/0000-0002-8827-7324
                http://orcid.org/0000-0001-9256-6041
                Article
                31730
                10.1038/s41467-022-31730-5
                9329287
                35896547
                5a80bf0c-c251-4143-b81f-34ba4fed5d70
                © The Author(s) 2022

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 22 October 2021
                : 30 June 2022
                Funding
                Funded by: FundRef https://doi.org/10.13039/501100007202, Gouvernement du Canada | Instituts de Recherche en Santé du Canada | CIHR Skin Research Training Centre (Skin Research Training Centre);
                Award ID: FDN-154298
                Award ID: PJT-174995
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/501100002790, Canadian Network for Research and Innovation in Machining Technology, Natural Sciences and Engineering Research Council of Canada (NSERC Canadian Network for Research and Innovation in Machining Technology);
                Award ID: Discovery-1304413
                Award Recipient :
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                epilepsy,network models
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                epilepsy, network models

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