Abstract
We previously established the contribution of de novo damaging sequence variants to Tourette disorder (TD) through whole-exome sequencing of 511 trios. Here, we sequence an additional 291 TD trios and analyze the combined set of 802 trios. We observe an overrepresentation of de novo damaging variants in simplex, but not multiplex, families; we identify a high-confidence TD risk gene, CELSR3 (cadherin EGF LAG seven-pass G-type receptor 3); we find that the genes mutated in TD patients are enriched for those related to cell polarity, suggesting a common pathway underlying pathobiology; and we confirm a statistically significant excess of de novo copy number variants in TD. Finally, we identify significant overlap of de novo sequence variants between TD and obsessive-compulsive disorder and de novo copy number variants between TD and autism spectrum disorder, consistent with shared genetic risk. Wang et al. expand their earlier exome-sequencing work in TD, adding 291 trios and conducting combined analyses suggesting de novo variants carry more risk in individuals with unaffected parents, establishing de novo structural variants as risk factors, identifying CELSR3 as a risk gene, and implicating cell polarity in pathogenesis.
| Original language | English |
|---|---|
| Journal | Cell Reports |
| Volume | 24 |
| Issue number | 13 |
| Pages (from-to) | 3441-3454.e12 |
| DOIs | |
| Publication status | Published - 25.09.2018 |
| Externally published | Yes |
Funding
We wish to thank the families who have participated in and contributed to this study. We also thank the NIMH Repository and Genomics Resource ( U24MH068457 to J.A.T.) at RUCDR Infinite Biologics for transforming cell lines and providing DNA samples, Liping Wei at Peking University for her support in this project, and Sarah Pyle for graphic design. This study was supported by grants from the National Institute of Mental Health ( R01MH092290 to Lawrence W. Brown, R01MH092291 to Samuel Kuperman, R01MH092292 to Barbara J. Coffey, R01MH092293 to G.A.H. and J.A.T., R01MH092513 to Samuel H. Zinner, R01MH092516 to D.E.G., R01MH092520 to Donald L. Gilbert, R01MH092289 to M.W.S., and K08MH099424 to T.V.F.), from the Human Genetics Institute of New Jersey (to G.A.H. and J.A.T.), and the New Jersey Center for Tourette Syndrome and Associated Disorders (to G.A.H. and J.A.T.). We are also grateful to the NJCTS for facilitating the inception and organization of the TIC Genetics study. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. This study was also supported by the Weill Institute for Neurosciences (Startup Funding to A.J.W.) and the Overlook International Foundation (to M.W.S. and A.J.W.). The Yale Center for Mendelian Genomics ( NIH M#UM1HG006504-05 ) is funded by the National Human Genome Research Institute and the National Heart, Lung, and Blood Institute . The GSP Coordinating Center ( U24 HG008956 ) contributed to cross-program scientific initiatives and provided logistical and general study coordination. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. This work was additionally supported by grants from Spain (to Pablo Mir): the Instituto de Salud Carlos III ( PI10/01674 and PI13/01461 ); the Consejería de Economía, Innovación, Ciencia y Empresa de la Junta de Andalucía ( CVI-02526 and CTS-7685 ); the Consejería de Salud y Bienestar Social de la Junta de Andalucía ( PI-0741/2010 , PI-0437-2012 , and PI-0471-2013 ); the Sociedad Andaluza de Neurología ; the Fundación Alicia Koplowitz ; the Fundación Mutua Madrileña ; and the Jaques and Gloria Gossweiler Foundation , (to Astrid Morer): Alicia Koplowitz Foundation ; grants from Germany (to Astrid Morer): Deutsche Forschungsgemeinschaft (DFG) ( MU 1692/3-1 and MU 1692/4-1 and project C5 of the SFB 936 ); and grants from Sweden: the Swedish Research Council 2015-02424 (to N.D.). This research was also supported in part by an Informatics Starter Grant from the PhRMA Foundation (to Yana Bromberg), the Mindich Child Health and Developmental Institute at the Icahn School of Medicine at Mount Sinai (to D.E.G.), the Seaver Foundation (to D.E.G.), and the Stanley Center for Psychiatric Research (to D.E.G.). All research at Great Ormond Street Hospital NHS Foundation Trust and UCL Great Ormond Street Institute of Child Health is made possible by the NIHR Great Ormond Street Hospital Biomedical Research Centre . The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. We are grateful to all of the families at the participating Simons Simplex Collection (SSC) sites, as well as the principal investigators (A. Beaudet, R. Bernier, J. Constantino, E. Cook, E. Fombonne, D. Geschwind, R. Goin-Kochel, E. Hanson, D. Grice, A. Klin, D. Ledbetter, C. Lord, C. Martin, D. Martin, R. Maxim, J. Miles, O. Ousley, K. Pelphrey, B. Peterson, J. Piggot, C. Saulnier, M. State, W. Stone, J. Sutcliffe, C. Walsh, Z. Warren, and E. Wijsman). We also appreciate obtaining access to whole-exome sequencing, microarray genotyping, and phenotype data on SFARI Base. Approved researchers can obtain the SSC population dataset described in this study by applying at https://base.sfari.org . Finally, we thank all of the individuals involved in recruitment and assessment of the subjects reported in this study: Denmark: Nikoline Frost and Heidi B. Biernat (Copenhagen); Germany: Yvonne Friedrich (Dresden), Daniela Ihlenburg-Schwarz (Hannover), and Jenny Schmalfeld (Lübeck); Spain: Fátima Carrillo, Marta Correa, Pilar Gómez-Garre, and Laura Vargas (Sevilla); the Netherlands: Vivian op de Beek (Amsterdam); Jolanda Blom, Rudi Bruggemans, and MariAnne Overdijk (Barendrecht); and Marieke Messchendorp, Thaïra Openneer, and Anne Marie Stolte (Groningen); UK: Anup Kharod (London GOSH); USA: Sarah Jacobson (Cincinnati), Angie Cookman (Iowa City), Laura Ibanez-Gomez and Zoey Shaw (Mount Sinai/NKI), Shannon Granillo and J.D. Sandhu (Seattle Children’s), and Yanran Wang (Rutgers); and to all who may not have been mentioned.
Research Areas and Centers
- Research Area: Medical Genetics