Polygenic risk score-based phenome-wide association study identifies novel associations for Tourette syndrome

Abstract

Tourette Syndrome (TS) is a complex neurodevelopmental disorder characterized by vocal and motor tics lasting more than a year. It is highly polygenic in nature with both rare and common previously associated variants. Epidemiological studies have shown TS to be correlated with other phenotypes, but large-scale phenome wide analyses in biobank level data have not been performed to date. In this study, we used the summary statistics from the latest meta-analysis of TS to calculate the polygenic risk score (PRS) of individuals in the UK Biobank data and applied a Phenome Wide Association Study (PheWAS) approach to determine the association of disease risk with a wide range of phenotypes. A total of 57 traits were found to be significantly associated with TS polygenic risk, including multiple psychosocial factors and mental health conditions such as anxiety disorder and depression. Additional associations were observed with complex non-psychiatric disorders such as Type 2 diabetes, heart palpitations, and respiratory conditions. Cross-disorder comparisons of phenotypic associations with genetic risk for other childhood-onset disorders (e.g.: attention deficit hyperactivity disorder [ADHD], autism spectrum disorder [ASD], and obsessive-compulsive disorder [OCD]) indicated an overlap in associations between TS and these disorders. ADHD and ASD had a similar direction of effect with TS while OCD had an opposite direction of effect for all traits except mental health factors. Sex-specific PheWAS analysis identified differences in the associations with TS genetic risk between males and females. Type 2 diabetes and heart palpitations were significantly associated with TS risk in males but not in females, whereas diseases of the respiratory system were associated with TS risk in females but not in males. This analysis provides further evidence of shared genetic and phenotypic architecture of different complex disorders.

Tourette syndrome research highlights from 2022

“…Jain and colleagues used previous TS GWAS summary statistics ( Tsetsos et al . 2023 ) to calculate the TS Polygenic Risk Score (PRS) on individuals in the UK Biobank and then performed a Phenome Wide Association Study (PheWAS) to assess the association of TS genetic risk with a wide range of phenotypes (n = 2242) ( Jain et al . 2023 ).…”

Genome-wide Association Study Points to Novel Locus for Gilles de la Tourette Syndrome

“…However, this work can motivate future studies that may have significant clinical impact, like for instance patient stratification according to genetic risk to inform clinical practice or drug discovery based on genetic loci that are identified through genetic association. Our recently described phenomewide association analysis of TS genetic risk and a large number of clinical traits available in the UKBB represents one further step towards clinically related discoveries (60).…”

Complex interplay of neurodevelopmental disorders (NDDs), fractures, and osteoporosis: a mendelian randomization study

“…Attention Deficit Hyperactivity Disorder (ADHD), Autism Spectrum Disorder (ASD), and Tourette Syndrome (TS) are prominent Neurodevelopmental disorders(NDDs)often co-occurring and impactingsocial and emotional aspects [1]. Observational studies reveal higher fracture risks among adults with these conditions compared to those without [2].…”

“…Simultaneously, cross-disease investigations have uncovered significant overlap in the phenotypic traits associated with the genetic risk shared by ADHD, ASD, and TS [1]. Grounded in the characteristic features of inattention, hyperactivity, and impulsivity commonly observed in individuals with ADHD, previous research provides a compelling basis for postulating causal links between ADHD, ASD, TS and the occurrence of fractures and osteoporosis.…”