TY - JOUR
T1 - De Novo Coding Variants Are Strongly Associated with Tourette Disorder
AU - Tourette International Collaborative Genetics (TIC Genetics)
AU - Tourette Syndrome Association International Consortium for Genetics (TSAICG)
AU - Tourette Syndrome Association International Consortium for Genetics (TSAICG)
AU - Willsey, A. Jeremy
AU - Fernandez, Thomas V.
AU - Yu, Dongmei
AU - King, Robert A.
AU - Dietrich, Andrea
AU - Xing, Jinchuan
AU - Sanders, Stephan J.
AU - Mandell, Jeffrey D.
AU - Huang, Alden Y.
AU - Richer, Petra
AU - Smith, Louw
AU - Dong, Shan
AU - Samocha, Kaitlin E.
AU - Abdulkadir, Mohamed
AU - Bohnenpoll, Julia
AU - Bromberg, Yana
AU - Brown, Lawrence W.
AU - Cheon, Keun Ah
AU - Coffey, Barbara J.
AU - Deng, Li
AU - Elzerman, Lonneke
AU - Fründt, Odette
AU - Garcia-Delgar, Blanca
AU - Gedvilaite, Erika
AU - Gilbert, Donald L.
AU - Grice, Dorothy E.
AU - Hagstrøm, Julie
AU - Hedderly, Tammy
AU - Heiman, Gary A.
AU - Heyman, Isobel
AU - Hoekstra, Pieter J.
AU - Hong, Hyun Ju
AU - Huyser, Chaim
AU - Ibanez-Gomez, Laura
AU - Kim, Young Key
AU - Kim, Young Shin
AU - Koh, Yun Joo
AU - Kook, Sodahm
AU - Kuperman, Samuel
AU - Lamerz, Andreas
AU - Leventhal, Bennett
AU - Ludolph, Andrea G.
AU - Lühr da Silva, Claudia
AU - Madruga-Garrido, Marcos
AU - Maras, Athanasios
AU - Mir, Pablo
AU - Morer, Astrid
AU - Münchau, Alexander
AU - Murphy, Tara L.
AU - Berlin, Cheston
N1 - Funding Information:
This research was also supported in part by an Informatics Starter Grant from the PhRMA Foundation (to Y. Bromberg). 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: Stephanie Enghardt, Yvonne Friedrich, Christiane Michel (Dresden), Jenny Schmalfeld (L?beck), Hanife Kling, and Ariane Saccarello (Ulm); Spain: Mar?a T. C?ceres, F?tima Carrillo, Marta Correa, Pilar G?mez-Garre, and Laura Vargas (Sevilla); the Netherlands: Vivian op de Beek (Amsterdam), Marieke Messchendorp (Groningen), Nicole Driessen, Nadine Schalk (Nijmegen), Noor Tromp (Alkmaar), Els van den Ban (Utrecht), Jolanda Blom, Rudi Bruggemans, and MariAnne Overdijk (Barendrecht); UK: Anup Kharod (London GOSH); USA: Sarah Jacobson (Cincinnati), Angie Cookman (Iowa City), Zoey Shaw (Mount Sinai/NKI), Julia Brillante, Daniela B. Colognori, Joseph Conerty, Alycia Davis, Joanne O'Brien, Carolyn Spiro, Donna Tischfield (Rutgers), Shannon Granillo, and JD Sandhu (Seattle Children's). Finally, we thank Adife Gulhan Ercan-Sencicek (Yale), Xin He (University of Chicago), Kathryn Roeder (CMU), Bernie Devlin (University of Pittsburgh), Helen Willsey (UCSF), the Willsey lab (UCSF), and all who may not have been mentioned.
Publisher Copyright:
© 2017 Elsevier Inc.
PY - 2017/5/3
Y1 - 2017/5/3
N2 - 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 [Figure presented]
AB - 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 [Figure presented]
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U2 - 10.1016/j.neuron.2017.04.024
DO - 10.1016/j.neuron.2017.04.024
M3 - Article
C2 - 28472652
AN - SCOPUS:85018748582
VL - 94
SP - 486-499.e9
JO - Neuron
JF - Neuron
SN - 0896-6273
IS - 3
ER -