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      Polygenic risk score-based phenome-wide association study identifies novel associations for Tourette syndrome

      research-article
      1 , 2 , 3 , 1 , 4 , 5 , 6 , 7 , 8 , 1 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 25 , 26 , 27 , 28 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 30 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , The Psychiatric Genomics Consortium Tourette Syndrome Working Group (PGC-TS), The EMTICS collaborative group, 57 , The TS-EUROTRAIN Network, 58 , 4 , 5 , 59 , 57 , 2 , 3 , , 1 ,
      Translational Psychiatry
      Nature Publishing Group UK
      Genomics, Psychiatric disorders

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          Abstract

          Tourette Syndrome (TS) is a complex neurodevelopmental disorder characterized by vocal and motor tics lasting more than a year. It is highly polygenic in nature with both rare and common previously associated variants. Epidemiological studies have shown TS to be correlated with other phenotypes, but large-scale phenome wide analyses in biobank level data have not been performed to date. In this study, we used the summary statistics from the latest meta-analysis of TS to calculate the polygenic risk score (PRS) of individuals in the UK Biobank data and applied a Phenome Wide Association Study (PheWAS) approach to determine the association of disease risk with a wide range of phenotypes. A total of 57 traits were found to be significantly associated with TS polygenic risk, including multiple psychosocial factors and mental health conditions such as anxiety disorder and depression. Additional associations were observed with complex non-psychiatric disorders such as Type 2 diabetes, heart palpitations, and respiratory conditions. Cross-disorder comparisons of phenotypic associations with genetic risk for other childhood-onset disorders (e.g.: attention deficit hyperactivity disorder [ADHD], autism spectrum disorder [ASD], and obsessive-compulsive disorder [OCD]) indicated an overlap in associations between TS and these disorders. ADHD and ASD had a similar direction of effect with TS while OCD had an opposite direction of effect for all traits except mental health factors. Sex-specific PheWAS analysis identified differences in the associations with TS genetic risk between males and females. Type 2 diabetes and heart palpitations were significantly associated with TS risk in males but not in females, whereas diseases of the respiratory system were associated with TS risk in females but not in males. This analysis provides further evidence of shared genetic and phenotypic architecture of different complex disorders.

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          Most cited references38

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          • Article: found

          Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression

          Major depressive disorder (MDD) is a common illness accompanied by considerable morbidity, mortality, costs, and heightened risk of suicide. We conducted a genome-wide association (GWA) meta-analysis based in 135,458 cases and 344,901 control, We identified 44 independent and significant loci. The genetic findings were associated with clinical features of major depression, and implicated brain regions exhibiting anatomical differences in cases. Targets of antidepressant medications and genes involved in gene splicing were enriched for smaller association signal. We found important relations of genetic risk for major depression with educational attainment, body mass, and schizophrenia: lower educational attainment and higher body mass were putatively causal whereas major depression and schizophrenia reflected a partly shared biological etiology. All humans carry lesser or greater numbers of genetic risk factors for major depression. These findings help refine and define the basis of major depression and imply a continuous measure of risk underlies the clinical phenotype.
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            • Article: found

            Identification of common genetic risk variants for autism spectrum disorder

            Autism spectrum disorder (ASD) is a highly heritable and heterogeneous group of neurodevelopmental phenotypes diagnosed in more than 1% of children. Common genetic variants contribute substantially to ASD susceptibility, but to date no individual variants have been robustly associated with ASD. With a marked sample-size increase from a unique Danish population resource, we report a genome-wide association meta-analysis of 18,381 individuals with ASD and 27,969 controls that identified five genome-wide-significant loci. Leveraging GWAS results from three phenotypes with significantly overlapping genetic architectures (schizophrenia, major depression, and educational attainment), we identified seven additional loci shared with other traits at equally strict significance levels. Dissecting the polygenic architecture, we found both quantitative and qualitative polygenic heterogeneity across ASD subtypes. These results highlight biological insights, particularly relating to neuronal function and corticogenesis, and establish that GWAS performed at scale will be much more productive in the near term in ASD.
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              Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder

              Attention deficit/hyperactivity disorder (ADHD) is a highly heritable childhood behavioral disorder affecting 5% of children and 2.5% of adults. Common genetic variants contribute substantially to ADHD susceptibility, but no variants have been robustly associated with ADHD. We report a genome-wide association meta-analysis of 20,183 individuals diagnosed with ADHD and 35,191 controls that identifies variants surpassing genome-wide significance in 12 independent loci, finding important new information about the underlying biology of ADHD. Associations are enriched in evolutionarily constrained genomic regions and loss-of-function intolerant genes and around brain-expressed regulatory marks. Analyses of three replication studies: a cohort of individuals diagnosed with ADHD, a self-reported ADHD sample and a meta-analysis of quantitative measures of ADHD symptoms in the population, support these findings while highlighting study-specific differences on genetic overlap with educational attainment. Strong concordance with GWAS of quantitative population measures of ADHD symptoms supports that clinical diagnosis of ADHD is an extreme expression of continuous heritable traits.
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                Author and article information

                Contributors
                lea.k.davis@vumc.org
                ppaschou@purdue.edu
                Journal
                Transl Psychiatry
                Transl Psychiatry
                Translational Psychiatry
                Nature Publishing Group UK (London )
                2158-3188
                23 February 2023
                23 February 2023
                2023
                : 13
                : 69
                Affiliations
                [1 ]GRID grid.169077.e, ISNI 0000 0004 1937 2197, Department of Biological Sciences, , Purdue University, ; West Lafayette, IN USA
                [2 ]GRID grid.412807.8, ISNI 0000 0004 1936 9916, Division of Genetic Medicine, , Department of Medicine Vanderbilt University Medical Center Nashville, ; Nashville, TN USA
                [3 ]GRID grid.412807.8, ISNI 0000 0004 1936 9916, Vanderbilt Genetics Institute, , Vanderbilt University Medical Center, ; Nashville, TN USA
                [4 ]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
                [5 ]GRID grid.66859.34, ISNI 0000 0004 0546 1623, Stanley Center for Psychiatric Research, , Broad Institute of MIT and Harvard, ; Cambridge, MA USA
                [6 ]GRID grid.169077.e, ISNI 0000 0004 1937 2197, Department of Computer Science, , Purdue University, ; West Lafayette, IN USA
                [7 ]GRID grid.12284.3d, ISNI 0000 0001 2170 8022, Department of Molecular Biology and Genetics, , Democritus University of Thrace, ; Alexandroupolis, Greece
                [8 ]GRID grid.4793.9, ISNI 0000000109457005, 1st Laboratory of Medical Biology-Genetics, School of Medicine, , Aristotle University of Thessaloniki, ; Thessaloniki, Greece
                [9 ]GRID grid.8158.4, ISNI 0000 0004 1757 1969, Child and Adolescent Neurology and Psychiatry, Department of Clinical and Experimental Medicine, , University of Catania, ; Catania, Italy
                [10 ]GRID grid.10423.34, ISNI 0000 0000 9529 9877, Department of Psychiatry, , Social psychiatry and Psychotherapy, Hannover Medical School, ; Hannover, Germany
                [11 ]GRID grid.5254.6, ISNI 0000 0001 0674 042X, Department of Clinical Medicine, Faculty of Health and Medical Sciences, , University of Copenhagen, ; Copenhagen, Denmark
                [12 ]GRID grid.475435.4, Department of Clinical Genetics, Kennedy Center, , Copenhagen University Hospital, Rigshospitalet, ; Copenhagen, Denmark
                [13 ]GRID grid.411900.d, ISNI 0000 0004 0646 8325, Department of Pediatrics, , Herlev University Hospital, ; Herlev, Denmark
                [14 ]GRID grid.411439.a, ISNI 0000 0001 2150 9058, Department of Neurology, , Hôpital de la Pitié-Salpêtrière, ; Paris, France
                [15 ]GRID grid.410718.b, ISNI 0000 0001 0262 7331, Institute for Human Genetics, , University Hospital Essen, ; Essen, Germany
                [16 ]GRID grid.50550.35, ISNI 0000 0001 2175 4109, Assistance Publique Hôpitaux de Paris, Sorbonne University, Faculty of Medicine Hopital Saint Antoine, ; Paris, France
                [17 ]GRID grid.411439.a, ISNI 0000 0001 2150 9058, French Reference Centre for Gilles de la Tourette Syndrome, Groupe Hospitalier Pitié-Salpêtrière, ; Paris, France
                [18 ]Unidad de Trastornos del Movimiento. Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain
                [19 ]GRID grid.418264.d, ISNI 0000 0004 1762 4012, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), ; Madrid, Spain
                [20 ]GRID grid.5477.1, ISNI 0000000120346234, Department of Clinical and health Psychology, , Utrecht University, ; Utrecht, Netherlands
                [21 ]GRID grid.6582.9, ISNI 0000 0004 1936 9748, Institute for Anatomy and Cell Biology, , Ulm University, ; Ulm, Germany
                [22 ]GRID grid.16872.3a, ISNI 0000 0004 0435 165X, EMGO+Institute for Health and Care Research, , VU University Medical Centre, ; Amsterdam, Netherlands
                [23 ]GRID grid.4488.0, ISNI 0000 0001 2111 7257, Department of Child and Adolescent Psychiatry, , Medical Faculty Carl Gustav Carus, TU Dresden, ; Dresden, Germany
                [24 ]GRID grid.13339.3b, ISNI 0000000113287408, Department of Child Psychiatry, , Medical University of Warsaw, ; Warsaw, Poland
                [25 ]GRID grid.13339.3b, ISNI 0000000113287408, Department of Neurology, , Medical University of Warsaw, ; Warsaw, Poland
                [26 ]GRID grid.13339.3b, ISNI 0000000113287408, Department of Bioethics, , Medical University of Warsaw, ; Warsaw, Poland
                [27 ]GRID grid.413454.3, ISNI 0000 0001 1958 0162, Department of Neurogenetics and Functional Genomics, , Mossakowski Medical Research Institute, Polish Academy of Sciences, ; Warsaw, Poland
                [28 ]GRID grid.11804.3c, ISNI 0000 0001 0942 9821, Department of Molecular Biology, Institute of Biochemistry and Molecular Biology, , Semmelweis University, ; Budapest, Hungary
                [29 ]Vadaskert Clinic for Child and Adolescent Psychiatry, Budapest, Hungary
                [30 ]GRID grid.59734.3c, ISNI 0000 0001 0670 2351, Department of Psychiatry, , Icahn School of Medicine at Mount Sinai, ; New York, USA
                [31 ]GRID grid.59734.3c, ISNI 0000 0001 0670 2351, Seaver Autism Center for Research and Treatment, , Icahn School of Medicine at Mount Sinai, ; New York, USA
                [32 ]GRID grid.59734.3c, ISNI 0000 0001 0670 2351, Department of Genetics and Genomic Sciences, , Icahn School of Medicine at Mount Sinai, ; New York, USA
                [33 ]GRID grid.59734.3c, ISNI 0000 0001 0670 2351, Department of Neuroscience, , Icahn School of Medicine at Mount Sinai, ; New York, USA
                [34 ]GRID grid.59734.3c, ISNI 0000 0001 0670 2351, The Mindich Child Health and Development Institute, , Icahn School of Medicine at Mount Sinai, ; New York, USA
                [35 ]GRID grid.59734.3c, ISNI 0000 0001 0670 2351, Friedman Brain Institute, , Icahn School of Medicine at Mount Sinai, ; New York, USA
                [36 ]GRID grid.59734.3c, ISNI 0000 0001 0670 2351, Division of Tics, OCD, and Related Disorders, , Icahn School of Medicine at Mount Sinai, ; New York, USA
                [37 ]GRID grid.10417.33, ISNI 0000 0004 0444 9382, Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, , Radboud University Medical Center, ; New York, Netherlands
                [38 ]GRID grid.421812.c, ISNI 0000 0004 0618 6889, deCODE Genetics/Amgen, ; Reykjavik, Iceland
                [39 ]GRID grid.420061.1, ISNI 0000 0001 2171 7500, Boehringer Ingelheim Pharma GmbH & Co. KG, CNS Research, ; Boehringer, Germany
                [40 ]GRID grid.12136.37, ISNI 0000 0004 1937 0546, Child and Adolescent Psychiatry Department, , Schneider Children’s Medical Centre of Israel, Petah-Tikva. Affiliated to Sackler Faculty of Medicine, Tel Aviv University, ; Tel Aviv, Israel
                [41 ]GRID grid.7841.a, Department of Human Neurosciences, , University La Sapienza of Rome, ; Rome, Italy
                [42 ]GRID grid.483570.d, ISNI 0000 0004 5345 7223, Evelina London Children’s Hospital GSTT, Kings Health Partners AHSC, ; London, UK
                [43 ]GRID grid.451052.7, ISNI 0000 0004 0581 2008, Psychological Medicine, Great Ormond Street Hospital NHS Foundation Trust, ; Great Ormond Street, London, UK
                [44 ]GRID grid.491096.3, Levvel, Academic Center for Child and Adolescent Psychiatry, ; Amsterdam, The Netherlands
                [45 ]GRID grid.509540.d, ISNI 0000 0004 6880 3010, Amsterdam UMC, Department of Child and Adolescent Psychiatry, ; Amsterdam, The Netherlands
                [46 ]GRID grid.410458.c, ISNI 0000 0000 9635 9413, Department of Child and Adolescent Psychiatry and Psychology, , Institute of Neurosciences, Hospital Clinic Universitario, ; Barcelona, Spain
                [47 ]GRID grid.10403.36, ISNI 0000000091771775, Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS), ; Barcelona, Spain
                [48 ]GRID grid.413448.e, ISNI 0000 0000 9314 1427, Centro de Investigacion en Red de Salud Mental (CIBERSAM), Instituto Carlos III, ; Barcelona, Spain
                [49 ]GRID grid.5252.0, ISNI 0000 0004 1936 973X, Department of Psychiatry and Psychotherapy, , University Hospital, LMU Munich, ; Munich, Germany
                [50 ]GRID grid.4562.5, ISNI 0000 0001 0057 2672, Institute of Systems Motor Science, , University of Lübeck, ; Lübeck, Germany
                [51 ]GRID grid.425848.7, ISNI 0000 0004 0639 1831, Child and Adolescent Mental Health Centre, Mental Health Services, , Capital Region of Denmark and University of Copenhagen, ; Copenhagen, Denmark
                [52 ]GRID grid.8515.9, ISNI 0000 0001 0423 4662, Division of Child and Adolescent Psychiatry, Department of Psychiatry, , Lausanne University Hospital, ; Lausanne, Switzerland
                [53 ]ASL BA, Maternal and Childood Department, Adolescence and Childhood Neuropsychiatry Unit, Bari, Italy
                [54 ]GRID grid.7400.3, ISNI 0000 0004 1937 0650, Department of Child and Adolescent Psychiatry and Psychotherapy, , University of Zurich, ; Zurich, Switzerland
                [55 ]GRID grid.83440.3b, ISNI 0000000121901201, Department of Clinical and Movement Neurosciences, UCL Institute of Neurology, , University College London, ; London, UK
                [56 ]GRID grid.22072.35, ISNI 0000 0004 1936 7697, Department of Clinical Neurosciences, , Cumming School of Medicine & Hotchkiss Brain Institute, University of Calgary, ; Calgary, AB Canada
                [57 ]GRID grid.4494.d, ISNI 0000 0000 9558 4598, University of Groningen, University Medical Center Groningen, Department of Child and Adolescent Psychiatry, ; Groningen, the Netherlands
                [58 ]GRID grid.15276.37, ISNI 0000 0004 1936 8091, Department of Psychiatry and Genetics Institute, , University of Florida College of Medicine, ; Florida, USA
                [59 ]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
                Author information
                http://orcid.org/0000-0002-7181-7419
                http://orcid.org/0000-0002-4777-5802
                http://orcid.org/0000-0002-7212-9554
                http://orcid.org/0000-0003-1656-302X
                http://orcid.org/0000-0002-7099-7972
                http://orcid.org/0000-0002-1873-7081
                http://orcid.org/0000-0001-7332-8494
                http://orcid.org/0000-0002-4350-8838
                http://orcid.org/0000-0002-9550-7730
                http://orcid.org/0000-0002-2493-0232
                http://orcid.org/0000-0001-8898-8313
                http://orcid.org/0000-0002-7811-9795
                http://orcid.org/0000-0002-5467-054X
                http://orcid.org/0000-0001-8757-3124
                http://orcid.org/0000-0003-2208-7058
                Article
                2341
                10.1038/s41398-023-02341-5
                9950421
                36823209
                6250a331-ccc1-49f6-a50d-ca28008f7f65
                © The Author(s) 2023

                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
                : 5 September 2022
                : 23 January 2023
                : 27 January 2023
                Funding
                Funded by: FundRef https://doi.org/10.13039/100000001, National Science Foundation (NSF);
                Award ID: 1715202
                Award ID: 2006929
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/100000065, U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS);
                Award ID: R01NS105746
                Award ID: R01NS105746
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/100000025, U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH);
                Award ID: R01MH126213
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/501100001659, Deutsche Forschungsgemeinschaft (German Research Foundation);
                Funded by: KNAW Academy Professor Award (PAH/6635)
                Funded by: FundRef https://doi.org/10.13039/501100004281, Narodowe Centrum Nauki (National Science Centre);
                Award ID: UMO-2016/23/B/NZ2/03030
                Award ID: UMO-2016/23/B/NZ2/03030
                Award Recipient :
                Funded by: Employee of Boehringer Ingelheim Pharma
                Funded by: U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)
                Categories
                Article
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                © The Author(s) 2023

                Clinical Psychology & Psychiatry
                genomics,psychiatric disorders
                Clinical Psychology & Psychiatry
                genomics, psychiatric disorders

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