Genome-wide Association Study identifies two novel loci for Gilles de la Tourette Syndrome

Tsetsos, Fotis; Topaloudi, Apostolia; Jain, Pritesh; Yang, Zhiyu; Yu, Dongmei; Kolovos, Petros; Tümer, Zeynep; Rizzo, Renata; Hartmann, Andreas; Depienne, Christel; Worbe, Yulia; Müller-Vahl, Kirsten; Cath, Daniëlle C.; Boomsma, Dorret I.; Wolańczyk, Tomasz; Żekanowski, Cezary; Barta, Csaba; Nemoda, Zsófia; Tárnok, Zsanett; Padmanabhuni, Shanmukha Sampath; Buxbaum, Joseph D.; Grice, Dorothy E.; Glennon, Jeffrey; Stefánsson, Hreinn; Hengerer, Bastian; Yannaki, Evangelia; Stamatoyannopoulos, J; Benaroya-Milshtein, Noa; Cardona, Francesco; Hedderly, Tammy; Heyman, Isobel; Huyser, Chaim; Mir, Pablo; Morer, Àstrid; Mueller, Norbert; Münchau, Alexander; Plessen, Kerstin J.; Porcelli, Cesare; Roessner, Veit; Walitza, Susanne; Schrag, Anette; Martino, Davide; Tischfield, Jay A.; Heiman, Gary A.; Willsey, A. Jeremy; Dietrich, Andrea; Davis, Lea K.; Crowley, James J.; Mathews, Carol A.; Scharf, Jeremiah M.; Georgitsi, Marianthi; Hoekstra, Pieter J.; Paschou, Peristera

doi:10.1101/2021.12.11.21267560

Cited by 4 publications

(9 citation statements)

References 74 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This could possibly explain the low levels of correlation between TS PRS and the PRS of the other three disorders. We observe a higher number of associations for ADHD and ASD compared to TS and OCD, which could be attributed to the differences in the sample size of the discovery GWAS used for PRS calculation of these disorders 11,[25][26][27] . Finally, our observed associations do not provide information about causality but should be followed up with additional study designs like mendelian randomization in appropriate datasets, or twin studies.…”

Section: Discussionmentioning

confidence: 81%

“…Here, using the summary statistics from the latest GWAS meta-analysis of TS 11 and genomic and phenomic data from the UK Biobank (UKB), we conducted a PRS-based PheWAS for TS, interrogating a wide range of phenotypes including physical and mental health, lifestyle, and socio-demographic factors. Our goal was to uncover phenotypes that may be associated with TS genetic risk and compare to phenotypic associations with genetic risk of other disorders along the impulsivity-compulsivity spectrum that have previously been found to be genetically associated with TS 20,21 .…”

Section: Introductionmentioning

confidence: 99%

“…It is a childhood onset condition with a prevalence of 0.6 -0.8% in school age children and has a population heritability of 70% and SNP-based heritability estimates ranging from 0.21 to 0.58 [2][3][4][5][6] . TS is highly polygenic in nature and multiple genetic variants account for a substantial proportion of phenotypic variance of the condition [6][7][8][9][10][11] .…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

Jain

Topaloudi

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 81%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Jain

Topaloudi

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…Analysis of an even larger GWAS for TS bringing together all major consortia working on TS genetics in a study of more than 12,000 patients is currently underway, promising novel insights into the genetics of TS by uncovering additional genes and pathways that underlie disease risk. Already, intermediate results point to two additional novel candidates for TS ( 79 ).…”

Section: Introductionmentioning

confidence: 99%

“…The following genes were included: ASH1L ( 72 ), CD180 ( 7 ), CDH26 ( 7 ), CELSR3 ( 8 , 70 ), CNTN6 ( 9 ), COL8A1 ( 71 ), CTNNA3 ( 93 ), FLT3 ( 7 ), GABBR2 ( 7 ), GABRG1 ( 7 ), GRIK4 ( 7 ), HCN1 ( 7 ), HDAC9 ( 7 ), HDC ( 74 – 76 ), IL12A ( 7 ), KIF26B ( 72 ), NCAM2 ( 7 ), NCR1 ( 7 ), NLRP7 ( 7 ), NRXN1 ( 9 ), NTM ( 7 ), ROBO2 ( 7 ), SLITRK1 ( 77 , 78 ), WWC1 ( 8 , 70 ). (B) Associations between TS PRS calculated based on the latest TS GWAS meta-analysis ( 79 ) and volume of 14 sub-cortical brain structures in UK Biobank. Each part was measured separately in the left hemisphere and the right hemisphere of the brain.…”

Section: Introductionmentioning

confidence: 99%

Enhancing neuroimaging genetics through meta-analysis for Tourette syndrome (ENIGMA-TS): A worldwide platform for collaboration

et al. 2022

Self Cite

View full text Add to dashboard Cite

Tourette syndrome (TS) is characterized by multiple motor and vocal tics, and high-comorbidity rates with other neuropsychiatric disorders. Obsessive compulsive disorder (OCD), attention deficit hyperactivity disorder (ADHD), autism spectrum disorders (ASDs), major depressive disorder (MDD), and anxiety disorders (AXDs) are among the most prevalent TS comorbidities. To date, studies on TS brain structure and function have been limited in size with efforts mostly fragmented. This leads to low-statistical power, discordant results due to differences in approaches, and hinders the ability to stratify patients according to clinical parameters and investigate comorbidity patterns. Here, we present the scientific premise, perspectives, and key goals that have motivated the establishment of the enhancing neuroimaging genetics through meta-analysis for TS (ENIGMA-TS). Working group ENIGMA-TS is an international collaborative effort bringing together a large network of investigators aiming to understand brain structure and function in TS and dissect the underlying neurobiology that leads to observed comorbidity patterns and clinical heterogeneity. Previously collected TS neuroimaging data will be analyzed jointly and integrated with genomic data, and also equivalently large and already existing studies of highly comorbid OCD, ADHD, ASD, MDD, and AXD. Our work highlights the power of collaborative efforts and transdiagnostic approaches, and points to the existence of different TS subtypes. ENIGMA-TS will offer large-scale, high-powered studies that will lead to important insights toward understanding brain structure and function and genetic effects in TS and related disorders, and also biomarkers that could help inform improved clinical practice.

show abstract

Oligogenic risk model for Gilles de la Tourette syndrome reveals a genetic continuum of tic disorders

Borczyk

Fichna

Piechota

et al. 2021

Preprint

View full text Add to dashboard Cite

Gilles de la Tourette syndrome (GTS) is a neurodevelopmental disorder from the spectrum of tic disorders (TDs). GTS and other TDs have a substantial genetic component with the heritability estimated at between 60 and 80%. Here we propose an oligogenic risk model of GTS and other TDs using whole-genome sequencing (WGS) data from a group of Polish GTS patients and their families (n=185). The model is based on the overrepresentation of putatively pathogenic coding and non-coding genetic variants in genes selected from a set of 86 genes previously suggested to be associated with GTS. Based on the variant overrepresentation (SKAT test results) between unrelated GTS patients and controls based on gnomAD database allele frequencies five genes (HDC, CHADL, MAOA, NAA11, and PCDH10) were selected for the risk model. Putatively pathogenic variants (n = 98) with the median allele frequency of ~0.04 in and near these genes were used to build an additive classifier which was then validated on the GTS patients and their families. This risk model successfully assigned individuals from 22 families to either healthy or GTS groups (AUC-ROC = 0.6, p < 0.00001). These results were additionally validated using the GTS GWAS data from the Psychiatric Genomic Consortium. To investigate the GTS genetics further we identified 32 genes from the list of 86 genes as candidate genes in 14 multiplex families, including NEGR1 and NRXN with variants overrepresented in multiple families. WGS data allowed the construction of an oligogenic risk model of GTS based on possibly pathogenic variants likely contributing to the risk of GTS and TDs. The model includes putatively deleterious rare and non-coding variants in and near GTS candidate genes that may cooperatively contribute to GTS etiology and provides a novel approach to the analysis of clinical WGS data.

show abstract

Genome-wide Association Study identifies two novel loci for Gilles de la Tourette Syndrome

Cited by 4 publications

References 74 publications

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

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

Enhancing neuroimaging genetics through meta-analysis for Tourette syndrome (ENIGMA-TS): A worldwide platform for collaboration

Oligogenic risk model for Gilles de la Tourette syndrome reveals a genetic continuum of tic disorders

Contact Info

Product

Resources

About