De Novo Coding Variants Are Strongly Associated with Tourette Disorder

A Jeremy Willsey; Thomas V Fernandez; Dongmei Yu; Robert A King; Andrea Dietrich; Jinchuan Xing; Stephan J Sanders; Jeffrey D Mandell; Alden Y Huang; Petra Richer; Louw Smith; Shan Dong; Kaitlin E Samocha; Tourette International Collaborative Genetics (TIC Genetics); Tourette Syndrome Association International Consortium for Genetics (TSAICG); Benjamin M Neale; Giovanni Coppola; Carol A Mathews; Jay A Tischfield; Jeremiah M Scharf; Matthew W State; Gary A Heiman

doi:10.1016/j.neuron.2017.04.024

De Novo Coding Variants Are Strongly Associated with Tourette Disorder

Neuron. 2017 May 3;94(3):486-499.e9. doi: 10.1016/j.neuron.2017.04.024.

Authors

A Jeremy Willsey¹, Thomas V Fernandez², Dongmei Yu³, Robert A King², Andrea Dietrich⁴, Jinchuan Xing⁵, Stephan J Sanders⁶, Jeffrey D Mandell¹, Alden Y Huang⁷, Petra Richer⁸, Louw Smith⁶, Shan Dong⁶, Kaitlin E Samocha³; Tourette International Collaborative Genetics (TIC Genetics); Tourette Syndrome Association International Consortium for Genetics (TSAICG); Benjamin M Neale³, Giovanni Coppola⁷, Carol A Mathews⁹, Jay A Tischfield⁵, Jeremiah M Scharf¹⁰, Matthew W State¹¹, Gary A Heiman¹²

Collaborators

Mohamed Abdulkadir, Julia Bohnenpoll, Yana Bromberg, Lawrence W Brown, Keun-Ah Cheon, Barbara J Coffey, Li Deng, Andrea Dietrich, Shan Dong, Lonneke Elzerman, Thomas V Fernandez, Odette Fründt, Blanca Garcia-Delgar, Erika Gedvilaite, Donald L Gilbert, Dorothy E Grice, Julie Hagstrøm, Tammy Hedderly, Gary A Heiman, Isobel Heyman, Pieter J Hoekstra, Hyun Ju Hong, Chaim Huyser, Laura Ibanez-Gomez, Young Key Kim, Young-Shin Kim, Robert A King, Yun-Joo Koh, Sodahm Kook, Samuel Kuperman, Andreas Lamerz, Bennett Leventhal, Andrea G Ludolph, Claudia Lühr da Silva, Marcos Madruga-Garrido, Jeffrey D Mandell, Athanasios Maras, Pablo Mir, Astrid Morer, Alexander Münchau, Tara L Murphy, Cara Nasello, Thaïra J C Openneer, Kerstin J Plessen, Petra Richer, Veit Roessner, Stephan Sanders, Eun-Young Shin, Deborah A Sival, Louw Smith, Dong-Ho Song, Jungeun Song, Matthew W State, Anne Marie Stolte, Nawei Sun, Jay A Tischfield, Jennifer Tübing, Frank Visscher, Michael F Walker, Sina Wanderer, Shuoguo Wang, A Jeremy Willsey, Martin Woods, Jinchuan Xing, Yeting Zhang, Anbo Zhou, Samuel H Zinner, Cathy L Barr, James R Batterson, Cheston Berlin, Ruth D Bruun, Cathy L Budman, Danielle C Cath, Sylvain Chouinard, Giovanni Coppola, Nancy J Cox, Sabrina Darrow, Lea K Davis, Yves Dion, Nelson B Freimer, Marco A Grados, Matthew E Hirschtritt, Alden Y Huang, Cornelia Illmann, Robert A King, Roger Kurlan, James F Leckman, Gholson J Lyon, Irene A Malaty, Carol A Mathews, William M MaMahon, Benjamin M Neale, Michael S Okun, Lisa Osiecki, David L Pauls, Danielle Posthuma, Vasily Ramensky, Mary M Robertson, Guy A Rouleau, Paul Sandor, Jeremiah M Scharf, Harvey S Singer, Jan Smit, Jae-Hoon Sul, Dongmei Yu

Affiliations

¹ Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA 94143, USA; Institute for Neurodegenerative Diseases, UCSF Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA 94143, USA.
² Yale Child Study Center and Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06520, USA.
³ Center for Genomic Medicine, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Psychiatric and Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
⁴ University of Groningen, University Medical Center Groningen, Department of Child and Adolescent Psychiatry, 9713GZ Groningen, the Netherlands.
⁵ Rutgers, the State University of New Jersey, Department of Genetics and the Human Genetics Institute of New Jersey, Piscataway, NJ 08854, USA.
⁶ Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA 94143, USA.
⁷ Department of Neurology, University of California Los Angeles, Los Angeles, California, CA 90095, USA; Department of Psychiatry and Biobehavioral Sciences, University of California Los Angeles, Los Angeles, CA 90095, USA.
⁸ Yale Child Study Center and Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06520, USA; Sewanee: The University of the South, Sewanee, TN 37383, USA.
⁹ Department of Psychiatry, University of Florida School of Medicine, Gainesville, FL 32611, USA.
¹⁰ Center for Genomic Medicine, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Psychiatric and Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. Electronic address: [email protected].
¹¹ Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA 94143, USA. Electronic address: [email protected].
¹² Rutgers, the State University of New Jersey, Department of Genetics and the Human Genetics Institute of New Jersey, Piscataway, NJ 08854, USA. Electronic address: [email protected].

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 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.

Keywords: TIC Genetics; TSAICG; Tourette disorder; Tourette syndrome; de novo variants; gene discovery; whole-exome sequencing.

Publication types

Video-Audio Media

MeSH terms

Adult
Cadherins / genetics*
Cell Cycle Proteins
Child
Cohort Studies
Female
Fibronectins / genetics*
Genetic Predisposition to Disease
Genetic Variation
Humans
Intracellular Signaling Peptides and Proteins / genetics*
Male
Mutation
Odds Ratio
Parents
Phosphoproteins / genetics*
Proteins / genetics*
Receptors, Cell Surface / genetics*
Sequence Analysis, DNA
Tourette Syndrome / genetics*

Substances

Cadherins
Cell Cycle Proteins
Celsr3 protein, human
FN1 protein, human
Fibronectins
Intracellular Signaling Peptides and Proteins
NIPBL protein, human
Phosphoproteins
Proteins
Receptors, Cell Surface
WWC1 protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding