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      Synaptic processes and immune-related pathways implicated in Tourette syndrome

      research-article
      1 , 2 , 3 , 4 , 5 , 4 , 5 , 6 , 2 , 2 , 7 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 13 , 14 , 15 , 16 , 17 , 17 , 18 , 19 , 19 , 20 , 20 , 21 , 22 , 22 , 23 , 24 , 24 , 25 , 26 , 27 , 24 , 25 , 26 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 49 , 50 , 4 , 5 , 2 , 3 , 51 , 50 , 4 , 5 , 52 , 2 , 3 , 53 , 54 , , on behalf of the Tourette Association of America International Consortium for Genetics, 16 , 32 , 35 , 28 , 33 , 4 , 5 , 50 , 7 , 50 , 11 , 4 , 5 , 17 , 8 , 7 , 4 , 5 , 6 , 2 , 20 , 55 , 56 , 30 , 34 , 52 , 31 , 2 , 3 , 51 , 34 , 2 , 39 , 12 , 15 , 2 , 3 , 53 , 17 , 57 , 4 , 5 , 2 , 3 , the Gilles de la Tourette GWAS Replication Initiative, 13 , 14 , 21 , 28 , 33 , 23 , 24 , 24 , 25 , 26 , 19 , 13 , 58 , 52 , 9 , 22 , 18 , 54 , 29 , 12 , 15 , 2 , 3 , 53 , 14 , 13 , 10 , 1 , 22 , 59 , 24 , 25 , 26 , 60 , the Tourette International Collaborative Genetics Study, 41 , 61 , 42 , 43 , 20 , 62 , 40 , 63 , 64 , 65 , 66 , 49 , 67 , 68 , 43 , 69 , 70 , 71 , 20 , 72 , 73 , 44 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 49 , 48 , 45 , and the Psychiatric Genomics Consortium Tourette Syndrome Working Group, 13 , 14 , 16 , 21 , 32 , 35 , 41 , 28 , 33 , 42 , 4 , 5 , 50 , 7 , 50 , 23 , 24 , 43 , 11 , 20 , 4 , 5 , 40 , 17 , 8 , 24 , 25 , 26 , 19 , 49 , 7 , 43 , 4 , 5 , 6 , 2 , 38 , 20 , 44 , 37 , 30 , 34 , 52 , 31 , 9 , 22 , 2 , 3 , 51 , 18 , 34 , 2 , 54 , 29 , 39 , 12 , 15 , 2 , 3 , 53 , 14 , 17 , 13 , 10 , 4 , 5 , 22 , 49 , 1 , 48 , 36 , 24 , 25 , 26 , 89 , 2 , 3 , 45
      Translational Psychiatry
      Nature Publishing Group UK
      Comparative genomics, Molecular neuroscience

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          Abstract

          Tourette syndrome (TS) is a neuropsychiatric disorder of complex genetic architecture involving multiple interacting genes. Here, we sought to elucidate the pathways that underlie the neurobiology of the disorder through genome-wide analysis. We analyzed genome-wide genotypic data of 3581 individuals with TS and 7682 ancestry-matched controls and investigated associations of TS with sets of genes that are expressed in particular cell types and operate in specific neuronal and glial functions. We employed a self-contained, set-based association method (SBA) as well as a competitive gene set method (MAGMA) using individual-level genotype data to perform a comprehensive investigation of the biological background of TS. Our SBA analysis identified three significant gene sets after Bonferroni correction, implicating ligand-gated ion channel signaling, lymphocytic, and cell adhesion and transsynaptic signaling processes. MAGMA analysis further supported the involvement of the cell adhesion and trans-synaptic signaling gene set. The lymphocytic gene set was driven by variants in FLT3, raising an intriguing hypothesis for the involvement of a neuroinflammatory element in TS pathogenesis. The indications of involvement of ligand-gated ion channel signaling reinforce the role of GABA in TS, while the association of cell adhesion and trans-synaptic signaling gene set provides additional support for the role of adhesion molecules in neuropsychiatric disorders. This study reinforces previous findings but also provides new insights into the neurobiology of TS.

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          Most cited references68

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          • Article: not found

          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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            Is Open Access

            Second-generation PLINK: rising to the challenge of larger and richer datasets

            PLINK 1 is a widely used open-source C/C++ toolset for genome-wide association studies (GWAS) and research in population genetics. However, the steady accumulation of data from imputation and whole-genome sequencing studies has exposed a strong need for even faster and more scalable implementations of key functions. In addition, GWAS and population-genetic data now frequently contain probabilistic calls, phase information, and/or multiallelic variants, none of which can be represented by PLINK 1's primary data format. To address these issues, we are developing a second-generation codebase for PLINK. The first major release from this codebase, PLINK 1.9, introduces extensive use of bit-level parallelism, O(sqrt(n))-time/constant-space Hardy-Weinberg equilibrium and Fisher's exact tests, and many other algorithmic improvements. In combination, these changes accelerate most operations by 1-4 orders of magnitude, and allow the program to handle datasets too large to fit in RAM. This will be followed by PLINK 2.0, which will introduce (a) a new data format capable of efficiently representing probabilities, phase, and multiallelic variants, and (b) extensions of many functions to account for the new types of information. The second-generation versions of PLINK will offer dramatic improvements in performance and compatibility. For the first time, users without access to high-end computing resources can perform several essential analyses of the feature-rich and very large genetic datasets coming into use.
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              Principal components analysis corrects for stratification in genome-wide association studies.

              Population stratification--allele frequency differences between cases and controls due to systematic ancestry differences-can cause spurious associations in disease studies. We describe a method that enables explicit detection and correction of population stratification on a genome-wide scale. Our method uses principal components analysis to explicitly model ancestry differences between cases and controls. The resulting correction is specific to a candidate marker's variation in frequency across ancestral populations, minimizing spurious associations while maximizing power to detect true associations. Our simple, efficient approach can easily be applied to disease studies with hundreds of thousands of markers.
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                Author and article information

                Contributors
                ppaschou@gmail.com
                Journal
                Transl Psychiatry
                Transl Psychiatry
                Translational Psychiatry
                Nature Publishing Group UK (London )
                2158-3188
                18 January 2021
                18 January 2021
                2021
                : 11
                : 56
                Affiliations
                [1 ]GRID grid.12284.3d, ISNI 0000 0001 2170 8022, Department of Molecular Biology and Genetics, , Democritus University of Thrace, ; Alexandroupolis, Greece
                [2 ]GRID grid.32224.35, ISNI 0000 0004 0386 9924, Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Department of Psychiatry, , Massachusetts General Hospital, ; Boston, MA USA
                [3 ]GRID grid.66859.34, Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, ; Cambridge, MA USA
                [4 ]GRID grid.19006.3e, ISNI 0000 0000 9632 6718, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, , University of California, ; Los Angeles, CA USA
                [5 ]GRID grid.19006.3e, ISNI 0000 0000 9632 6718, Department of Psychiatry and Biobehavioral Sciences, , University of California, ; Los Angeles, CA USA
                [6 ]GRID grid.19006.3e, ISNI 0000 0000 9632 6718, Bioinformatics Interdepartmental Program, , University of California, ; Los Angeles, CA USA
                [7 ]GRID grid.266102.1, ISNI 0000 0001 2297 6811, Department of Psychiatry, UCSF Weill Institute for Neurosciences, , University of California, ; San Francisco, CA USA
                [8 ]GRID grid.32224.35, ISNI 0000 0004 0386 9924, Department of Psychiatry, , Massachusetts General Hospital, ; Boston, MA USA
                [9 ]GRID grid.10423.34, ISNI 0000 0000 9529 9877, Clinic of Psychiatry, Social Psychiatry, and Psychotherapy, , Hannover Medical School, ; Hannover, Germany
                [10 ]GRID grid.10423.34, ISNI 0000 0000 9529 9877, Institute of Human Genetics, , Hannover Medical School, ; Hannover, Germany
                [11 ]McGill University Health Center, University of Montreal, McGill University Health Centre, Montreal, Canada
                [12 ]GRID grid.14709.3b, ISNI 0000 0004 1936 8649, Montreal Neurological Institute, Department of Neurology and Neurosurgery, , McGill University, ; Montreal, Canada
                [13 ]GRID grid.22937.3d, ISNI 0000 0000 9259 8492, Department of Psychiatry and Psychotherapy, , Medical University Vienna, ; Vienna, Austria
                [14 ]Biopsychosocial Corporation, Vienna, Austria
                [15 ]GRID grid.17063.33, ISNI 0000 0001 2157 2938, University Health Network, Youthdale Treatment Centres, and University of Toronto, ; Toronto, Canada
                [16 ]GRID grid.17063.33, ISNI 0000 0001 2157 2938, Krembil Research Institute, University Health Network, , Hospital for Sick Children, and University of Toronto, ; Toronto, Canada
                [17 ]GRID grid.21107.35, ISNI 0000 0001 2171 9311, Johns Hopkins University School of Medicine and the Kennedy Krieger Institute, ; Baltimore, MD USA
                [18 ]GRID grid.10388.32, ISNI 0000 0001 2240 3300, Institute of Human Genetics, University Hospital Bonn, , University of Bonn Medical School, ; Bonn, Germany
                [19 ]GRID grid.5718.b, ISNI 0000 0001 2187 5445, Department of Child and Adolescent Psychiatry, Psychosomatics, and Psychotherapy, University Hospital Essen, , University of Duisburg-Essen, ; Essen, Germany
                [20 ]GRID grid.47100.32, ISNI 0000000419368710, Yale Child Study Center and the Department of Psychiatry, , Yale University School of Medicine, ; New Haven, CT USA
                [21 ]GRID grid.11804.3c, ISNI 0000 0001 0942 9821, Institute of Medical Chemistry, Molecular Biology, and Pathobiochemistry, , Semmelweis University, ; Budapest, Hungary
                [22 ]Vadaskert Child and Adolescent Psychiatric Hospital, Budapest, Hungary
                [23 ]Institute of Human Genetics, University Hospital Essen, University Duisburg-Essen, Essen, Germany
                [24 ]GRID grid.462844.8, ISNI 0000 0001 2308 1657, Sorbonne Universités, UPMC Université Paris 06, ; UMR S 1127, CNRS UMR 7225 ICM Paris, France
                [25 ]GRID grid.411439.a, ISNI 0000 0001 2150 9058, French Reference Centre for Gilles de la Tourette Syndrome, , Groupe Hospitalier Pitié-Salpêtrière, ; Paris, France
                [26 ]GRID grid.411439.a, ISNI 0000 0001 2150 9058, Assistance Publique–Hôpitaux de Paris, Department of Neurology, , Groupe Hospitalier Pitié-Salpêtrière, ; Paris, France
                [27 ]GRID grid.412370.3, ISNI 0000 0004 1937 1100, Assistance Publique Hôpitaux de Paris, Hopital Saint Antoine, ; Paris, France
                [28 ]GRID grid.257060.6, ISNI 0000 0001 2284 9943, Zucker School of Medicine at Hofstra/Northwell, ; Hempstead, NY USA
                [29 ]GRID grid.8158.4, ISNI 0000 0004 1757 1969, Child Neuropsychiatry, Department of Clinical and Experimental Medicine, , University of Catania, ; Catania, Italy
                [30 ]GRID grid.420001.7, ISNI 0000 0000 9813 9625, Jervis Clinic, NYS Institute for Basic Research in Developmental Disabilities (IBR), ; Staten Island, NY USA
                [31 ]GRID grid.223827.e, ISNI 0000 0001 2193 0096, Department of Psychiatry, , University of Utah, ; Salt Lake City, UT USA
                [32 ]GRID grid.239559.1, ISNI 0000 0004 0415 5050, Children’s Mercy Hospital, ; Kansas City, MO USA
                [33 ]GRID grid.4494.d, ISNI 0000 0000 9558 4598, Department of Psychiatry, , University Medical Center Groningen and Rijksuniversity Groningen, and Drenthe Mental Health Center, ; Groningen, the Netherlands
                [34 ]GRID grid.430508.a, ISNI 0000 0004 4911 114X, Department of Neurology, Norman Fixel Institute for Neurological Diseases, , University of Florida Health, ; Gainesville, FL USA
                [35 ]GRID grid.29857.31, ISNI 0000 0001 2097 4281, Pennsylvania State University College of Medicine, ; Hershey, PA USA
                [36 ]GRID grid.267468.9, ISNI 0000 0001 0695 7223, Marquette University and University of Wisconsin-Milwaukee, ; Milwaukee, WI USA
                [37 ]GRID grid.410445.0, ISNI 0000 0001 2188 0957, Tripler Army Medical Center and University of Hawaii John A. Burns School of Medicine, ; Honolulu, HI USA
                [38 ]GRID grid.39382.33, ISNI 0000 0001 2160 926X, Parkinson’s Disease Center and Movement Disorders Clinic, Department of Neurology, , Baylor College of Medicine, ; Houston, TX USA
                [39 ]GRID grid.83440.3b, ISNI 0000000121901201, Division of Psychiatry, Department of Neuropsychiatry, , University College London, ; London, UK
                [40 ]GRID grid.24827.3b, ISNI 0000 0001 2179 9593, Division of Pediatric Neurology, Cincinnati Children’s Hospital Medical Center; Department of Pediatrics, , University of Cincinnati, ; Cincinnati, USA
                [41 ]GRID grid.239552.a, ISNI 0000 0001 0680 8770, Children’s Hospital of Philadelphia, ; Philadelphia, PA USA
                [42 ]GRID grid.26790.3a, ISNI 0000 0004 1936 8606, Department of Psychiatry and Behavioral Sciences, , University of Miami Miller School of Medicine, ; Miami, FL USA
                [43 ]Department of Child and Adolescent Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
                [44 ]GRID grid.214572.7, ISNI 0000 0004 1936 8294, University of Iowa Carver College of Medicine, ; Iowa City, IA USA
                [45 ]GRID grid.34477.33, ISNI 0000000122986657, Department of Pediatrics, , University of Washington, ; Seattle, WA USA
                [46 ]GRID grid.15090.3d, ISNI 0000 0000 8786 803X, Department of Psychiatry and Psychotherapy, , University Hospital Bonn, ; Bonn, Germany
                [47 ]GRID grid.262863.b, ISNI 0000 0001 0693 2202, SUNY Downstate Medical Center Brooklyn, ; Brooklyn, NY USA
                [48 ]GRID grid.266102.1, ISNI 0000 0001 2297 6811, Institute for Neurodegenerative Diseases, UCSF Weill Institute for Neurosciences, , University of California San Francisco, ; San Francisco, CA USA
                [49 ]GRID grid.430387.b, ISNI 0000 0004 1936 8796, Department of Genetics and the Human Genetics Institute of New Jersey, , Rutgers, the State University of New Jersey, ; Piscataway, NJ USA
                [50 ]GRID grid.412807.8, ISNI 0000 0004 1936 9916, Division of Genetic Medicine, Vanderbilt Genetics Institute, , Vanderbilt University Medical Center, ; Nashville, TN USA
                [51 ]GRID grid.32224.35, ISNI 0000 0004 0386 9924, Analytic and Translational Genetics Unit, Department of Medicine, , Massachusetts General Hospital, ; Boston, MA USA
                [52 ]GRID grid.15276.37, ISNI 0000 0004 1936 8091, Department of Psychiatry, Genetics Institute, , University of Florida, ; Gainesville, FL USA
                [53 ]GRID grid.32224.35, ISNI 0000 0004 0386 9924, Department of Neurology, Brigham and Women’s Hospital, and the Department of Neurology, , Massachusetts General Hospital, ; Boston, MA USA
                [54 ]GRID grid.169077.e, ISNI 0000 0004 1937 2197, Department of Biological Sciences, , Purdue University, ; West Lafayette, IN USA
                [55 ]GRID grid.417328.b, ISNI 0000 0000 8945 8587, Atlantic Neuroscience Institute, , Overlook Hospital, ; Summit, NJ USA
                [56 ]GRID grid.47100.32, ISNI 0000000419368710, Yale Child Study Center, , Yale University School of Medicine, ; New Haven, CT USA
                [57 ]GRID grid.16872.3a, ISNI 0000 0004 0435 165X, Department of Psychiatry, , VU UniversityMedical Center, ; Amsterdam, The Netherlands
                [58 ]Center for Mental Health Muldenstrasse, BBRZMed, Linz, Austria
                [59 ]GRID grid.13339.3b, ISNI 0000000113287408, Department of Child Psychiatry, , Medical University of Warsaw, ; 00-001 Warsaw, Poland
                [60 ]GRID grid.412370.3, ISNI 0000 0004 1937 1100, Assistance Publique Hôpitaux de Paris, , Hopital Saint Antoine, ; Paris, France
                [61 ]GRID grid.15444.30, ISNI 0000 0004 0470 5454, Yonsei University College of Medicine, , Yonsei Yoo & Kim Mental Health Clinic, ; Seoul, South Korea
                [62 ]GRID grid.410458.c, ISNI 0000 0000 9635 9413, Department of Child and Adolescent Psychiatry and Psychology, , Institute of Neurosciences, Hospital Clinic Universitari, ; Barcelona, Spain
                [63 ]GRID grid.59734.3c, ISNI 0000 0001 0670 2351, Department of Psychiatry, Friedman Brain Institute, Mindich Child Health and Development Institute, , Icahn School of Medicine at Mount Sinai, ; New York, NY USA
                [64 ]GRID grid.5254.6, ISNI 0000 0001 0674 042X, Child and Adolescent Mental Health Center, Mental Health Services, , Capital Region of Denmark and University of Copenhagen, ; Copenhagen, Denmark
                [65 ]GRID grid.420545.2, Tic and Neurodevelopmental Movements Service (TANDeM), Evelina Children’s Hospital, , Guys and St Thomas’ NHS Foundation Trust, ; London, UK
                [66 ]GRID grid.13097.3c, ISNI 0000 0001 2322 6764, Paediatric Neurosciences, Kings College London, ; London, UK
                [67 ]GRID grid.83440.3b, ISNI 0000000121901201, UCL Great Ormond Street Institute of Child Health, , University College London, ; London, UK
                [68 ]GRID grid.424537.3, ISNI 0000 0004 5902 9895, Psychological and Mental Health Services, Great Ormond Street Hospital for Children NHS Foundation Trust, ; London, UK
                [69 ]GRID grid.491096.3, De Bascule, Academic Centre for Child and Adolescent Psychiatry, ; Amsterdam, The Netherlands
                [70 ]Yonsei Bom Clinic, Seoul, South Korea
                [71 ]GRID grid.266102.1, ISNI 0000 0001 2297 6811, Department of Psychiatry, University of California, San Francisco, ; San Francisco, CA USA
                [72 ]The Korea Institute for Children’s Social Development, Rudolph Child Research Center, Seoul, South Korea
                [73 ]GRID grid.415735.1, ISNI 0000 0004 0621 4536, Kangbuk Samsung Hospital, ; Seoul, South Korea
                [74 ]GRID grid.266102.1, ISNI 0000 0001 2297 6811, Department of Psychiatry, , University of California, San Francisco, ; San Francisco, CA USA
                [75 ]GRID grid.414816.e, ISNI 0000 0004 1773 7922, Sección de Neuropediatría, Instituto de Biomedicina de Sevilla, , Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, ; Seville, Spain
                [76 ]GRID grid.411109.c, ISNI 0000 0000 9542 1158, Hospital Universitario Virgen del Rocío, ; Sevilla, Spain
                [77 ]GRID grid.418264.d, ISNI 0000 0004 1762 4012, Centro de Investigación en Red-Enfermedades Neurodegenerativas (CIBERNED), ; Madrid, Spain
                [78 ]GRID grid.410458.c, ISNI 0000 0000 9635 9413, Department of Child and Adolescent Psychiatry and Psychology, Institute of Neurosciences, , Hospital Clínic Universitari, ; Barcelona, Spain
                [79 ]GRID grid.5841.8, ISNI 0000 0004 1937 0247, Department of Medicine, , University of Barcelona, ; Barcelona, Spain
                [80 ]Centro de Investigación Biomédica en red de Salud Mental (CIBERSAM), Barcelona, Spain
                [81 ]GRID grid.4562.5, ISNI 0000 0001 0057 2672, Institute of Systems Motor Science, , University of Lübeck, ; Lübeck, Germany
                [82 ]GRID grid.425848.7, ISNI 0000 0004 0639 1831, Child and Adolescent Mental Health Centre, Mental Health Services, , Capital Region of Denmark, ; Copenhagen, Denmark
                [83 ]GRID grid.452548.a, ISNI 0000 0000 9817 5300, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, ; Aarhus, Denmark
                [84 ]GRID grid.9851.5, ISNI 0000 0001 2165 4204, Service of Child and Adolescent Psychiatry, Department of Psychiatry, , University Medical Center, University of Lausanne, ; Lausanne, Switzerland
                [85 ]GRID grid.412282.f, ISNI 0000 0001 1091 2917, Department of Child and Adolescent Psychiatry, Faculty of Medicine, , University Hospital Carl Gustav CarusTU Dresden, ; Dresden, Germany
                [86 ]GRID grid.15444.30, ISNI 0000 0004 0470 5454, Yonsei University College of Medicine, , Yonsei Yoo & Kim Mental Health Clinic, ; Seoul, South Korea
                [87 ]GRID grid.15444.30, ISNI 0000 0004 0470 5454, Yonsei University College of Medicine, , Yonsei Yoo & Kim Mental Health Clinic, ; Seoul, South Korea
                [88 ]GRID grid.416665.6, ISNI 0000 0004 0647 2391, National Health Insurance Service Ilsan Hospital, ; Goyang-Si, South Korea
                [89 ]GRID grid.412370.3, ISNI 0000 0004 1937 1100, Assistance Publique Hôpitaux de Paris, Hopital Saint Antoine, ; Paris, France
                Author information
                http://orcid.org/0000-0001-5521-846X
                http://orcid.org/0000-0002-4127-7941
                http://orcid.org/0000-0002-7181-7419
                http://orcid.org/0000-0001-5446-8213
                http://orcid.org/0000-0001-8403-1418
                http://orcid.org/0000-0002-4449-372X
                http://orcid.org/0000-0003-0830-022X
                http://orcid.org/0000-0002-4350-8838
                http://orcid.org/0000-0002-7212-9554
                http://orcid.org/0000-0002-5869-0716
                http://orcid.org/0000-0001-6914-9223
                http://orcid.org/0000-0002-6247-9358
                http://orcid.org/0000-0003-2589-6440
                http://orcid.org/0000-0001-5859-0259
                http://orcid.org/0000-0003-3586-6587
                http://orcid.org/0000-0003-1513-6077
                http://orcid.org/0000-0001-5143-2282
                http://orcid.org/0000-0003-2105-1061
                http://orcid.org/0000-0002-9783-1024
                Article
                1082
                10.1038/s41398-020-01082-z
                7814139
                33462189
                e52314da-9ec3-48ca-8e3d-9fdba8892a1a
                © The Author(s) 2021

                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
                : 27 April 2020
                : 18 September 2020
                : 21 October 2020
                Funding
                Funded by: FT is co-financed by Greece and the European Union (European Social Fund- ESF) through the Operational Programme «Human Resources Development, Education and Lifelong Learning» in the context of the project “Reinforcement of Postdoctoral Researchers - 2nd Cycle” (MIS-5033021), implemented by the State Scholarships Foundation (IKY)
                Funded by: KMV has received financial or material research support from the EU (FP7-HEALTH-2011 No. 278367, FP7-PEOPLE-2012-ITN No. 316978), the German Research Foundation (DFG: GZ MU 1527/3-1), the German Ministry of Education and Research (BMBF: 01KG1421), the National Institute of Mental Health (NIMH), the Tourette Gesellschaft Deutschland e.V., the Else-Kroner-Fresenius-Stiftung, and GW, Almirall, Abide Therapeutics, and Therapix Biosiences and has received consultant’s honoraria from Abide Therapeutics, Tilray, Resalo Vertrieb GmbH, and Wayland Group, speaker’s fees from Tilray and Cogitando GmbH, and royalties from Medizinisch Wissenschaftliche Verlagsgesellschaft Berlin, Elsevier, and Kohlhammer; and is a consultant for Nuvelution TS Pharma Inc., Zynerba Pharmaceuticals, Resalo Vertrieb GmbH, CannaXan GmbH, Therapix Biosiences, Syqe, Nomovo Pharma, and Columbia Care.
                Funded by: MMN has received fees for memberships in Scientific Advisory Boards from the Lundbeck Foundation and the Robert-Bosch-Stiftung, and for membership in the Medical-Scientific Editorial Office of the Deutsches Ärzteblatt. MMN was reimbursed travel expenses for a conference participation by Shire Deutschland GmbH. MMN receives salary payments from Life & Brain GmbH and holds shares in Life & Brain GmbH. All this concerned activities outside the submitted work.
                Funded by: IM has participated in research funded by the Parkinson Foundation, Tourette Association, Dystonia Coalition, AbbVie, Biogen, Boston Scientific, Eli Lilly, Impax, Neuroderm, Prilenia, Revance, Teva but has no owner interest in any pharmaceutical company. She has received travel compensation or honoraria from the Tourette Association of America, Parkinson Foundation, International Association of Parkinsonism and Related Disorders, Medscape, and Cleveland Clinic, and royalties for writing a book with Robert rose publishers.
                Funded by: MSO serves as a consultant for the Parkinson’s Foundation, and has received research grants from NIH, Parkinson’s Foundation, the Michael J. Fox Foundation, the Parkinson Alliance, Smallwood Foundation, the Bachmann-Strauss Foundation, the Tourette Syndrome Association, and the UF Foundation. MSO’s DBS research is supported by: NIH R01 NR014852 and R01NS096008. MSO is PI of the NIH R25NS108939 Training Grant. MSO has received royalties for publications with Demos, Manson, Amazon, Smashwords, Books4Patients, Perseus, Robert Rose, Oxford and Cambridge (movement disorders books). MSO is an associate editor for New England Journal of Medicine Journal Watch Neurology. MSO has participated in CME and educational activities on movement disorders sponsored by the Academy for Healthcare Learning, PeerView, Prime, QuantiaMD, WebMD/Medscape, Medicus, MedNet, Einstein, MedNet, Henry Stewart, American Academy of Neurology, Movement Disorders Society and by Vanderbilt University. The institution and not MSO receives grants from Medtronic, Abbvie, Boston Scientific, Abbott and Allergan and the PI has no financial interest in these grants. MSO has participated as a site PI and/or co-I for several NIH, foundation, and industry sponsored trials over the years but has not received honoraria. Research projects at the University of Florida receive device and drug donations.
                Funded by: DW receives royalties for books on Tourette Syndrome with Guilford Press, Oxford University Press, and Springer Press.
                Funded by: BMN is a member of the scientific advisory board at Deep Genomics and consultant for Camp4 Therapeutics, Takeda Pharmaceutical and Biogen.
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                © The Author(s) 2021

                Clinical Psychology & Psychiatry
                comparative genomics,molecular neuroscience
                Clinical Psychology & Psychiatry
                comparative genomics, molecular neuroscience

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