Genome-Wide Association Study Meta-Analysis of 9619 Cases With Tic Disorders

Abstract

BACKGROUND: Despite the significant personal and societal burden of tic disorders (TDs), treatment outcomes remain modest, necessitating a deeper understanding of their etiology. Family history is the biggest known risk factor, and identifying risk genes could accelerate progress in the field. METHODS: Expanding upon previous sample size limitations, we added 4800 new TD cases and 971,560 controls and conducted a genome-wide association study (GWAS) meta-analysis with 9619 cases and 981,048 controls of European ancestry. We attempted to replicate the results in an independent deCODE genetics GWAS (885 TD cases and 310,367 controls). To characterize GWAS findings, we conducted several post-GWAS gene-based and enrichment analyses. RESULTS: A genome-wide significant hit (rs79244681, p = 2.27 × 10-8) within MCHR2-AS1 was identified, although it was not replicated. Post-GWAS analyses revealed a 13.8% single nucleotide polymorphism heritability and 3 significant genes: BCL11B, NDFIP2, and RBM26. Common variant risk for TD was enriched within genes preferentially expressed in the cortico-striato-thalamo-cortical circuit (including the putamen, caudate, nucleus accumbens, and Brodmann area 9) and 5 brain cell types (excitatory and inhibitory telencephalon neurons, inhibitory diencephalon and mesencephalon neurons, and hindbrain and medium spiny neurons). TD polygenic risk was enriched within loss-of-function intolerant genes (p = .0017) and high-confidence neurodevelopmental disorder genes (p = .0108). Of 112 genetic correlations, 43 were statistically significant, showing high positive correlations with most psychiatric disorders. Of the 2 single nucleotide polymorphisms previously associated with TDs, one (rs2453763) replicated in an independent subsample of our GWAS (p = .00018). CONCLUSIONS: This GWAS was still underpowered to identify high-confidence, replicable loci, but the results suggest imminent discovery of common genetic variants for TDs.