TS is a highly heritable neurodevelopmental disorder with a strong polygenic component.  Here, we report the largest TS genome-wide association study (GWAS) to date, consisting of 4,819 European-ancestry cases and 9,488 ancestry-matched controls from three international TS genetics consortia.

To identify common variants associated with Tourette syndrome (TS) and to use genome-wide ancestry-adjusted TS polygenic risk scores (aPRS) to examine the genetic relationship between TS, other tic disorders, and tic severity.

A multi-center case-control GWAS was conducted followed by ancestry-stratified meta-analysis. TS diagnoses were determined using DSM-5 criteria; a subset of cases underwent in-depth phenotyping, including assessment of worst-ever tic severity using the Yale Global Tic Severity Scale.  Analyses of TS aPRS prediction of tic spectrum disorder status and worst-ever tic severity were performed using logistic and linear regression models.

In the final meta-analysis, one locus, rs2504235 on chromosome 13, lying within an intron of FLT3, surpassed the genome-wide significant threshold (SNP, p=2.1x10^-8; Gene, p=8.9x10^-7); however, this locus was not replicated in an independent population-based Icelandic sample (706 TS cases and 6,068 screened controls).  LD Score regression and linear mixed model analyses both confirmed a high TS SNP-based heritability. Expression of TS-associated genes was preferentially enriched in human dorsolateral prefrontal cortex (BA9)(p=1.2x10^-4).   TS aPRS significantly predicted TS (p=5.3x10^-9) and tic spectrum disorder (p=4.2x10^-4) status in the independent population-based sample with a gradient of TS risk between the two disorders.  Lastly, in cases with affected relatives, TS aPRS significantly correlated with worst-ever tic severity (p=0.026).

This study demonstrates that TS and other tic disorders exist along a spectrum of shared genetic risk, and that altered gene expression within cortico-striatal circuits may underlie the molecular pathogenesis of these disorders.  With significant increases in sample size, TS aPRS could potentially be used to predict future tic severity and tic persistence into adulthood.