Concordance of genetic variation that increases risk for Tourette Syndrome and that influences its underlying neurocircuitry

Abstract

There have been considerable recent advances in understanding the genetic architecture of Tourette Syndrome (TS) as well as its underlying neurocircuitry. However, the mechanisms by which genetic variation that increases risk for TS—and its main symptom dimensions—influence relevant brain regions are poorly understood. Here we undertook a genome-wide investigation of the overlap between TS genetic risk and genetic influences on the volume of specific subcortical brain structures that have been implicated in TS. We obtained summary statistics for the most recent TS genome-wide association study (GWAS) from the TS Psychiatric Genomics Consortium Working Group (4644 cases and 8695 controls) and GWAS of subcortical volumes from the ENIGMA consortium (30,717 individuals). We also undertook analyses using GWAS summary statistics of key symptom factors in TS, namely social disinhibition and symmetry behaviour. SNP effect concordance analysis (SECA) was used to examine genetic pleiotropy—the same SNP affecting two traits—and concordance—the agreement in single nucelotide polymorphism (SNP) effect directions across these two traits. In addition, a conditional false discovery rate (FDR) analysis was performed, conditioning the TS risk variants on each of the seven subcortical and the intracranial brain volume GWAS. Linkage disequilibrium score regression (LDSR) was used as validation of the SECA method. SECA revealed significant pleiotropy between TS and putamen (p = 2 × 10⁻⁴) and caudate (p = 4 × 10⁻⁴) volumes, independent of direction of effect, and significant concordance between TS and lower thalamic volume (p = 1 × 10⁻³). LDSR lent additional support for the association between TS and thalamus volume (p = 5.85 × 10⁻²). Furthermore, SECA revealed significant evidence of concordance between the social disinhibition symptom dimension and lower thalamus volume (p = 1 × 10⁻³), as well as concordance between symmetry behaviour and greater putamen volume (p = 7 × 10⁻⁴). Conditional FDR analysis further revealed novel variants significantly associated with TS (p < 8 × 10⁻⁷) when conditioning on intracranial (rs2708146, q = 0.046; and rs72853320, q = 0.035) and hippocampal (rs1922786, q = 0.001) volumes, respectively. These data indicate concordance for genetic variation involved in disorder risk and subcortical brain volumes in TS. Further work with larger samples is needed to fully delineate the genetic architecture of these disorders and their underlying neurocircuitry.