De Novo Coding Variants Are Strongly Associated with Tourette Disorder
Open accessAbstract
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 gene-disrupting (LGD) variants (rate ratio [RR] 2.32, p = 0.002). Additionally, de novo damaging variants (LGD and probably damaging missense) are overrepresented 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 variants in approximately 400 genes contribute risk in 12% of clinical cases. VIDEO ABSTRACT.
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A role for de novo gene-disrupting and missense variants has been established in Tourette syndrome.
“In TS, a role for de novo gene disrupting and missense variants has been established (Willsey et al., 2017)”
From Defining the genetic, genomic, cellular, and diagnostic architectures of psychiatric disorders (2019) · cites this paper as Willsey et al., 2017
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References 98 · Cited by 187
Research works printed but not linked: 2
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- Authors
- Willsey, A. J., Fernandez, T. V., Yu, D., King, R. A., Dietrich, A., Xing, J., Sanders, S. J., Mandell, J. D., Huang, A. Y., Richer, P., Smith, L., Dong, S., Samocha, K. E., Neale, B. M., Coppola, G., Mathews, C. A., Tischfield, J. A., Scharf, J. M., State, M. W., Heiman, G. A., Abdulkadir, M., Bohnenpoll, J., Bromberg, Y., Brown, L. W., Cheon, K.-A., Coffey, B. J., Deng, L., Dietrich, A., Dong, S., Elzerman, L., Fernandez, T. V., Fründt, O., Garcia-Delgar, B., Gedvilaite, E., Gilbert, D. L., Grice, D. E., Hagstrøm, J., Hedderly, T., Heiman, G. A., Heyman, I., Hoekstra, P. J., Hong, H. J., Huyser, C., Ibanez-Gomez, L., Kim, Y. K., Kim, Y.-S., King, R. A., Koh, Y.-J., Kook, S., Kuperman, S., Lamerz, A., Leventhal, B., Ludolph, A. G., Lühr da Silva, C., Madruga-Garrido, M., Mandell, J. D., Maras, A., Mir, P., Morer, A., Münchau, A., Murphy, T. L., Nasello, C., Openneer, T. J. C., Plessen, K. J., Richer, P., Roessner, V., Sanders, S., Shin, E.-Y., Sival, D. A., Smith, L., Song, D.-H., Song, J., State, M. W., Stolte, A. M., Sun, N., Tischfield, J. A., Tübing, J., Visscher, F., Walker, M. F., Wanderer, S., Wang, S., Willsey, A. J., Woods, M., Xing, J., Zhang, Y., Zhou, A., Zinner, S. H., Barr, C. L., Batterson, J. R., Berlin, C., Bruun, R. D., Budman, C. L., Cath, D. C., Chouinard, S., Coppola, G., Cox, N. J., Darrow, S., Davis, L. K., Dion, Y., Freimer, N. B., Grados, M. A., Hirschtritt, M. E., Huang, A. Y., Illmann, C., King, R. A., Kurlan, R., Leckman, J. F., Lyon, G. J., Malaty, I. A., Mathews, C. A., MaMahon, W. M., Neale, B. M., Okun, M. S., Osiecki, L., Pauls, D. L., Posthuma, D., Ramensky, V., Robertson, M. M., Rouleau, G. A., Sandor, P., Scharf, J. M., Singer, H. S., Smit, J., Sul, J.-H., & Yu, D.
- Affiliations
- Harvard University (US)
- ORCID
- Samocha, Kaitlin E.
- Abdulkadir, Mohamed
- Bromberg, Yana
- Brown, Lawrence W.
- Cheon, Keun-Ah
- Coffey, Barbara J.
- Gedvilaite, Erika
- Grice, Dorothy E.
- Hagstrøm, Julie
- Hedderly, Tammy
- Heyman, Isobel
- Hoekstra, Pieter J.
- Hong, Hyun Ju
- Huyser, Chaim
- Ibanez-Gomez, Laura
- Koh, Yun-Joo
- Kook, Sodahm
- Ludolph, Andrea G.
- Maras, Athanasios
- Mir, Pablo
- Münchau, Alexander
- Murphy, Tara L.
- Nasello, Cara
- Openneer, Thaïra J.C.
- Roessner, Veit
- Shin, Eun-Young
- Song, Dong-Ho
- Song, Jungeun
- Sun, Nawei
- Zhang, Yeting
- Zhou, Anbo
- Zinner, Samuel H.
- Barr, Cathy L.
- Budman, Cathy L.
- Cox, Nancy J.
- Darrow, Sabrina
- Davis, Lea K.
- Dion, Yves
- Grados, Marco A.
- Hirschtritt, Matthew E.
- Leckman, James F.
- Lyon, Gholson J.
- Malaty, Irene A.
- Okun, Michael S.
- Osiecki, Lisa
- Pauls, David L.
- Ramensky, Vasily
- Rouleau, Guy A.
- Sandor, Paul
- Singer, Harvey S.
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2017-05
- Volume
- 94
- Issue
- 3
- Pages
- 486-499.e9
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC5769876
- OpenAlex
- W2610487679
- Cited by
- 187
- References
- 98
- Citations by year
- 2026: 10 · 2025: 23 · 2024: 17 · 2023: 23 · 2022: 28 · 2021: 28 · 2020: 10 · 2019: 22 · 2018: 14 · 2017: 12
- FWCI
- 19.62
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 367 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion, other-oa)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Rutgers University Community Repository (Rutgers University) (submittedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (submittedVersion, other-oa)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Funders
- NIMH Repository and Genomics Resource (U24MH068457)
- National Institute of Mental Health (R01MH092290, R01MH092291, R01MH092292, R01MH092293, R01MH092513, R01MH092516, R01MH092520, R01MH092289, K08MH099424, K23MH085057)
- National Institute of Neurological Disorders and Stroke (U01NS40024-09S1, K02 NS085048)
- Harvard Clinical and Translational Science Center (UL TR001102)
- Tourette Association of America
- New Jersey Center for Tourette Syndrome and Associated Disorders
- Overlook International Fund
- Instituto de Salud Carlos III (PI10/01674, PI13/01461)
- Consejería de Economía, Innovación, Ciencia y Empresa de la Junta de Andalucía (CVI-02526, CTS-7685)
- Consejería de Salud y Bienestar Social de la Junta de Andalucía (PI-0741/2010, PI-0437-2012, PI-0471-2013)
- Sociedad Andaluza de Neurología
- Fundación Alicia Koplowitz
- Fundación Mutua Madrileña
- the Jaques and Gloria Gossweiler Foundation
- Deutsche Forschungsgemeinschaft (MU 1692/3-1, MU 1692/4-1, SFB 936)
- NIHR Great Ormond Street Hospital Biomedical Research Centre
- PhRMA Foundation
- Topics
- Social Sciences › Psychology › Clinical Psychology › Obsessive-Compulsive Spectrum Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- Tourette syndrome, de novo mutations, neurodevelopmental disorders, WWC1, CELSR3, NIPBL, FN1, risk genes, trios, exome sequencing, gene discovery
- MeSH terms
- Adult, Child, Female, Fibronectins, Tourette Syndrome, Humans, Male, Mutation, Parents, Phosphoproteins, Proteins, Receptors, Cell Surface, Genetic Variation, Cohort Studies, Cadherins, Odds Ratio, Sequence Analysis, DNA, Cell Cycle Proteins, Genetic Predisposition to Disease, Intracellular Signaling Peptides and Proteins
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