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

Area of Science:

• Genetics
• Neuroscience
• Psychiatry

Background:

• Tic disorders (TDs) impose a significant burden, yet their genetic underpinnings remain incompletely understood.
• Family history is a primary risk factor, underscoring the need to identify genetic contributors to TD etiology.
• Current treatments for TDs offer modest outcomes, necessitating advanced research into their causes.

Purpose of the Study:

• To conduct a large-scale genome-wide association study (GWAS) meta-analysis to identify genetic risk variants for tic disorders (TDs).
• To characterize the genetic architecture of TDs through post-GWAS analyses, including gene-based and enrichment studies.
• To explore genetic correlations between TDs and other psychiatric disorders.

Main Methods:

• A genome-wide association study (GWAS) meta-analysis was performed on 9619 cases and 981,048 controls of European ancestry.
• Replication analysis was attempted using an independent deCODE genetics GWAS dataset.
• Post-GWAS analyses included gene-based tests, heritability estimation, and enrichment analyses in specific cell types and gene sets.

Main Results:

• A genome-wide significant hit (rs79244681) in MCHR2-AS1 was identified but not replicated.
• Significant genetic heritability (13.8%) was observed, with BCL11B, NDFIP2, and RBM26 identified as significant genes.
• TD risk was enriched in genes expressed in the cortico-striato-thalamo-cortical circuit and specific brain cell types, including medium spiny neurons.
• Polygenic risk for TD was enriched in loss-of-function intolerant genes and neurodevelopmental disorder genes.
• Significant genetic correlations were found between TDs and multiple psychiatric disorders.

Conclusions:

• The current genome-wide association study (GWAS) was underpowered for high-confidence, replicable locus discovery.
• Results indicate that common genetic variants contributing to TDs are likely to be discovered with increased sample sizes.
• The study provides valuable insights into the genetic architecture of TDs and their relationship with other psychiatric conditions.