De Novo Sequence and Copy Number Variants Are Strongly Associated with Tourette Disorder and Implicate Cell Polarity in Pathogenesis.

Cell Rep
Authors
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.

Year of Publication
2018
Journal
Cell Rep
Volume
24
Issue
13
Pages
3441-3454.e12
Date Published
2018 Sep 25
ISSN
2211-1247
DOI
10.1016/j.celrep.2018.08.082
PubMed ID
30257206
PubMed Central ID
PMC6475626
Links
Grant list
R01 MH092292 / MH / NIMH NIH HHS / United States
UM1 HG006504 / HG / NHGRI NIH HHS / United States
R01 MH092516 / MH / NIMH NIH HHS / United States
R01 MH092513 / MH / NIMH NIH HHS / United States
R01 MH092291 / MH / NIMH NIH HHS / United States
K08 MH099424 / MH / NIMH NIH HHS / United States
R01 MH092520 / MH / NIMH NIH HHS / United States
R01 MH092289 / MH / NIMH NIH HHS / United States
R01 MH092290 / MH / NIMH NIH HHS / United States
U01 GM115486 / GM / NIGMS NIH HHS / United States
U24 MH068457 / MH / NIMH NIH HHS / United States
R01 MH092293 / MH / NIMH NIH HHS / United States
U24 HG008956 / HG / NHGRI NIH HHS / United States