Oligogenic risk score for Gilles de la Tourette syndrome reveals a genetic continuum of tic disorders.

Abstract

Gilles de la Tourette syndrome (GTS) and other tic disorders (TDs) have a substantial genetic component with their heritability estimated at between 60 and 80%. Here we propose an oligogenic risk score of TDs using whole-genome sequencing (WGS) data from a group of Polish GTS patients, their families, and control samples (n = 278). In this study, we first reviewed the literature to obtain a preliminary list of 84 GTS/TD candidate genes. From this list, 10 final risk score genes were selected based on single-gene burden tests (SKAT p < 0.05) between unrelated GTS cases (n = 37) and synthetic control samples based on a database of local allele frequencies. These 10 genes were CHADL, DRD2, MAOA, PCDH10, HTR2A, SLITRK5, SORCS3, KCNQ5, CDH9, and CHD8. Variants in and in the vicinity (± 20 kbp) of the ten risk genes (n = 7654) with a median minor allele frequency in the non-Finnish European population of 0.02 were integrated into an additive classifier. This risk score was then applied to healthy and GTS-affected individuals from 23 families and 100 unrelated healthy samples from the Polish population (AUC-ROC = 0.62, p = 0.02). Application of the algorithm to a group of patients with other tic disorders revealed a continuous increase of the oligogenic score with healthy individuals with the lowest mean, then patients with other tic disorders, then GTS patients, and finally with severe GTS cases with the highest oligogenic score. We have further compared our WGS results with the summary statistics of the Psychiatric Genomics Consortium genome-wide association study (PGC GWAS) of TDs and found no signal overlap except for the CHADL gene locus. Polygenic risk scores from common variants of GTS GWAS show no difference between patient and control groups, except for the comparison between patients with non-GTS TDs and patients with severe GTS. Overall, we leveraged WGS data to construct a GTS/TD risk score based on variants that may cooperatively contribute to the aetiology of these disorders. This study provides evidence that typical and severe adult GTS as well as other tic disorders may exist on a single spectrum in terms of their genetic background.