Journal article
De Novo Coding Variants Are Strongly Associated with Tourette Disorder
Neuron (Cambridge, Mass.), Vol.94(3), pp.486-499.e9
05/03/2017
DOI: 10.1016/j.neuron.2017.04.024
PMCID: PMC5769876
PMID: 28472652
Abstract
Whole-exome sequencing (WES) and de novo variant detection have proven a powerful approach to gene discovery in complex neurodevelopmental disorders. We have completed WES of 325 Tourette disorder trios from the Tourette International Collaborative Genetics cohort and a replication sample of 186 trios from the Tourette Syndrome Association International Consortium on Genetics (511 total). We observe strong and consistent evidence for the contribution of de novo likely genedisrupting (LGD) variants (rate ratio [RR] 2.32, p = 0.002). Additionally, de novo damaging variants (LGD and probably damaging missense) are over-represented in probands (RR 1.37, p = 0.003). We identify four likely risk genes with multiple de novo damaging variants in unrelated probands: WWC1 (WW and C2 domain containing 1), CELSR3 (Cadherin EGF LAG seven-pass G-type receptor 3), NIPBL (Nipped-B-like), and FN1 (fibronectin 1). Overall, we estimate that de novo damaging vari-ants in approximately 400 genes contribute risk in 12% of clinical cases.
Details
- Title: Subtitle
- De Novo Coding Variants Are Strongly Associated with Tourette Disorder
- Creators
- A. Jeremy Willsey - University of California, San FranciscoThomas V. Fernandez - Yale UniversityDongmei Yu - Harvard UniversityRobert A. King - Yale UniversityAndrea Dietrich - University Medical Center GroningenJinchuan Xing - Rutgers, The State University of New JerseyStephan J. Sanders - Univ Calif San Francisco, Dept Psychiat, UCSF Weill Inst Neurosci, San Francisco, CA 94143 USAJeffrey D. Mandell - University of California, San FranciscoAlden Y. Huang - University of California, Los AngelesPetra Richer - Sewanee: The University of the SouthLouw Smith - University of California, San FranciscoShan Dong - University of California, San FranciscoKaitlin E. Samocha - Harvard UniversityBenjamin M. Neale - Harvard UniversityGiovanni Coppola - University of California, Los AngelesCarol A. Mathews - University of FloridaJay A. Tischfield - Rutgers, The State University of New JerseyJeremiah M. Scharf - VA Boston Healthcare SystemMatthew W. State - University of California, San FranciscoGary A. Heiman - Rutgers, The State University of New JerseyTourette International Collaborative Genetics (TIC Genetics)Tourette Syndrome Association International Consortium for Genetics (TSAICG)
- Contributors
- Samuel Kuperman (Contributor) - University of Iowa, Psychiatry
- Resource Type
- Journal article
- Publication Details
- Neuron (Cambridge, Mass.), Vol.94(3), pp.486-499.e9
- Publisher
- Elsevier
- DOI
- 10.1016/j.neuron.2017.04.024
- PMID
- 28472652
- PMCID
- PMC5769876
- ISSN
- 0896-6273
- eISSN
- 1097-4199
- Number of pages
- 23
- Grant note
- Fundacion Mutua Madrilena; Instituto de Salud Carlos III Overlook International Fund CVI-02526; CTS-7685 / Consejeria de Economia, Innovacion, Ciencia y Empresa de la Junta de Andalucia DFG: MU 1692/3-1; MU1692/4-1; SFB 936 / Deutsche Forschungsgemeinschaft; German Research Foundation (DFG) R01MH092290 / NATIONAL INSTITUTE OF MENTAL HEALTH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Mental Health (NIMH) Fundacion Alicia Koplowitz UL TR001102 / Harvard Clinical and Translational Science Center U01GM115486 / NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of General Medical Sciences (NIGMS) PI10/01674; PI13/01461 / Instituto de Salud Carlos III; European Commission R01MH092290; R01MH092291; R01MH092292; R01MH092293; R01MH092513; R01MH092516; R01MH092520; R01MH092289; K08MH099424; K23MH085057 / National Institute of Mental Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Mental Health (NIMH) Jaques and Gloria Gossweiler Foundation UL1TR001102 / NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Center for Advancing Translational Sciences (NCATS) U01NS40024-09S1; K02 NS085048 / National Institute of Neurological Disorders and Stroke; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Neurological Disorders & Stroke (NINDS) Informatics Starter Grant from the PhRMA Foundation K02NS085048 / NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Neurological Disorders & Stroke (NINDS) New Jersey Center for Tourette Syndrome and Associated Disorders (NJCTS) Tourette Association of America NIHR Great Ormond Street Hospital Biomedical Research Centre (GOSH BRC) Sociedad Andaluza de Neurologia PI-0741/2010; PI-0437-2012; PI-0471-2013 / Consejeria de Salud y Bienestar Social de la Junta de Andalucia
- Language
- English
- Date published
- 05/03/2017
- Academic Unit
- Psychiatry
- Record Identifier
- 9984293754302771
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