BackgroundTic disorder (TD) is a polygenic neurodevelopmental disorder with high susceptibility. However, identifying high-confidence risk genes has been challenging due to poor replication across multiple studies. MethodsWhole-exome sequencing was performed on 390 TD patients and 372 unaffected individuals in a Chinese Han population. Analysis of variance, burden analysis and in silico prediction were used to identify candidate genes for TD. To facilitate data analysis and to focus on high-confidence genes, we defined a panel of 160 genes as known causal or candidate TD genes from previous studies. Gene enrichment and protein–protein interaction analysis were utilized to detect potential novel TD risk genes. ResultsTotally, 14 variants across 12 known TD candidate genes were considered potential susceptibility variants. Ten variants across 10 known TD candidate genes were identified as potential disease-causing variants. Burden analysis identified variants of 28 known genes were significantly excess in TD patients. In addition, 354 previously unproven TD genes are over-represented in patients. Genes enriched in the PI3K-Akt signaling, sphingolipid metabolism and serotonergic synaptic pathways, as well as those interacting with FN1, were considered potential new candidate genes for TD. ConclusionsThis is the largest WES study focusing on TD patients in a Chinese Han population. Several variants recurring in our cohort were identified as high-confidence risk loci for TD. Moreover, we provided potential new risk genes that may be prioritized for further investigation.