Whole-exome sequencing identifies genes associated with Tourette's disorder in multiplex families

Abstract

Tourette's Disorder (TD) is a neurodevelopmental disorder (NDD) that affects about 0.7% of the population and is one of the most heritable NDDs. Nevertheless, because of its polygenic nature and genetic heterogeneity, the genetic etiology of TD is not well understood. In this study, we combined the segregation information in 13 TD multiplex families with high-throughput sequencing and genotyping to identify genes associated with TD. Using whole-exome sequencing and genotyping array data, we identified both small and large genetic variants within the individuals. We then combined multiple types of evidence to prioritize candidate genes for TD, including variant segregation pattern, variant function prediction, candidate gene expression, protein-protein interaction network, candidate genes from previous studies, etc. From the 13 families, 71 strong candidate genes were identified, including both known genes for NDDs and novel genes, such as HtrA Serine Peptidase 3 (HTRA3), Cadherin-Related Family Member 1 (CDHR1), and Zinc Finger DHHC-Type Palmitoyltransferase 17 (ZDHHC17). The candidate genes are enriched in several Gene Ontology categories, such as dynein complex and synaptic membrane. Candidate genes and pathways identified in this study provide biological insight into TD etiology and potential targets for future studies.

Figure 1.. Overall study design.

WES: whole-exome sequencing; SNP: single nucleotide polymorphism; AF: allele frequency; CNV: copy number variant; GO: gene ontology; PPI: protein-protein interaction.

Figure 2.. Information used for variant and gene prioritization.

Detailed description of the “Annotation” fields can be found in the Supplemental Methods and Table 2. PPI: Protein-protein interaction; GO: Gene Ontology; pLI: probability of being loss-of-function intolerant score; mis_z: Z score for the deviation of observed counts from the expected number of missense mutations; TPM: Transcript Per Million.

Figure 3.. Protein-protein interaction (PPI) networks.

(A) PPI network of the 71 TD top candidate genes. Only genes that can be connected are shown. (B) PPI networks of the 71 TD top candidate genes not in (A). Other NDD_all genes were added as intermediate nodes if they interact with more than one TD top candidate genes. For intermediate nodes, only interactions with top candidate genes were included. (C) PPI network formed by NDD_all genes identified in axoneme (GO:0005930). (D) PPI networks formed by NDD_all genes in synaptic membrane (GO:0097060). To simplify the network, interactions between non-candidate genes were removed. PPI networks were defined by three databases, ConsensusPathDB, STRING, and GIANT_v2. Genes were colored by the gene lists (see Methods for details).