De Novo Coding Variants Are Strongly Associated with Tourette Disorder
Willsey AJ., Fernandez TV., Yu D., King RA., Dietrich A., Xing J., Sanders SJ., Mandell JD., Huang AY., Richer P., Smith L., Dong S., Samocha KE., Abdulkadir M., Bohnenpoll J., Bromberg Y., Brown LW., Cheon KA., Coffey BJ., Deng L., Elzerman L., Fründt O., Garcia-Delgar B., Gedvilaite E., Gilbert DL., Grice DE., Hagstrøm J., Hedderly T., Heiman GA., Heyman I., Hoekstra PJ., Hong HJ., Huyser C., Ibanez-Gomez L., Kim YK., Kim YS., Koh YJ., Kook S., Kuperman S., Lamerz A., Leventhal B., Ludolph AG., Lühr da Silva C., Madruga-Garrido M., Maras A., Mir P., Morer A., Münchau A., Murphy TL., Nasello C., Openneer TJC., Plessen KJ., Roessner V., Shin EY., Sival DA., Song DH., Song J., State MW., Stolte AM., Sun N., Tischfield JA., Tübing J., Visscher F., Walker MF., Wanderer S., Wang S., Woods M., Zhang Y., Zhou A., Zinner SH., Barr CL., Batterson JR., Berlin C., Bruun RD., Budman CL., Cath DC., Chouinard S., Coppola G., Cox NJ., Darrow S., Davis LK., Dion Y., Freimer NB., Grados MA., Hirschtritt ME., Illmann C., Leckman JF., Lyon GJ., Malaty IA., Mathews CA., MaMahon WM., Neale BM., Okun MS., Osiecki L., Pauls DL., Posthuma D., Ramensky V., Robertson MM., Rouleau GA., Sandor P.
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]