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Meta-Analysis
. 2024 Jul 15;96(2):114-124.
doi: 10.1016/j.biopsych.2023.01.023. Epub 2023 Feb 2.

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

Fotis Tsetsos  1 , Apostolia Topaloudi  2 , Pritesh Jain  2 , Zhiyu Yang  2 , Dongmei Yu  3 , Petros Kolovos  1 , Zeynep Tumer  4 , Renata Rizzo  5 , Andreas Hartmann  6 , Christel Depienne  7 , Yulia Worbe  8 , Kirsten R Müller-Vahl  9 , Danielle C Cath  10 , Dorret I Boomsma  11 , Tomasz Wolanczyk  12 , Cezary Zekanowski  13 , Csaba Barta  14 , Zsofia Nemoda  14 , Zsanett Tarnok  15 , Shanmukha S Padmanabhuni  2 , Joseph D Buxbaum  16 , Dorothy Grice  17 , Jeffrey Glennon  18 , Hreinn Stefansson  19 , Bastian Hengerer  20 , Evangelia Yannaki  21 , John A Stamatoyannopoulos  22 , Noa Benaroya-Milshtein  23 , Francesco Cardona  24 , Tammy Hedderly  25 , Isobel Heyman  26 , Chaim Huyser  27 , Pablo Mir  28 , Astrid Morer  29 , Norbert Mueller  30 , Alexander Munchau  31 , Kerstin J Plessen  32 , Cesare Porcelli  33 , Veit Roessner  34 , Susanne Walitza  35 , Anette Schrag  36 , Davide Martino  37 ; PGC TS Working Group; TSAICG; TSGeneSEE Initiative; EMTICS Collaborative Group; TS-EUROTRAIN Network; TIC Genetics Collaborative Group; Jay A Tischfield  38 , Gary A Heiman  38 , A Jeremy Willsey  39 , Andrea Dietrich  40 , Lea K Davis  41 , James J Crowley  42 , Carol A Mathews  43 , Jeremiah M Scharf  44 , Marianthi Georgitsi  45 , Pieter J Hoekstra  46 , Peristera Paschou  47
Collaborators, Affiliations
Meta-Analysis

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

Fotis Tsetsos et al. Biol Psychiatry. .

Abstract

Background: Tourette syndrome (TS) is a childhood-onset neurodevelopmental disorder of complex genetic architecture and is characterized by multiple motor tics and at least one vocal tic persisting for more than 1 year.

Methods: We performed a genome-wide meta-analysis integrating a novel TS cohort with previously published data, resulting in a sample size of 6133 individuals with TS and 13,565 ancestry-matched control participants.

Results: We identified a genome-wide significant locus on chromosome 5q15. Integration of expression quantitative trait locus, Hi-C (high-throughput chromosome conformation capture), and genome-wide association study data implicated the NR2F1 gene and associated long noncoding RNAs within the 5q15 locus. Heritability partitioning identified statistically significant enrichment in brain tissue histone marks, while polygenic risk scoring of brain volume data identified statistically significant associations with right and left thalamus volumes and right putamen volume.

Conclusions: Our work presents novel insights into the neurobiology of TS, thereby opening up new directions for future studies.

Keywords: GWAS; Meta-analysis; NR2F1; Tourette syndrome.

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Conflict of interest statement

Conflicts of interest

The authors report no biomedical financial interests or potential conflicts of interest.

Figures

Figure 1.
Figure 1.
The Manhattan plot for the genome-wide association meta-analysis of Tourette Syndrome with the TS-EUROTRAIN and the TSGWAS2 datasets (6,133 TS cases and 13,565 controls of European descent on 1,955,677 variants) using Han and Eskin’s random effects model (24). The −log10(p) values for the association tests (two-tailed) are shown on the y axis and the chromosomes are ordered on the x axis. One genetic locus on chromosome 5 surpassed the genome-wide significance threshold (p<5×10−8; indicated by the red line). Gray and black differentiate adjacent chromosomes.
Figure 2.
Figure 2.
Genetic correlations with Tourette Syndrome. The genetic correlations were estimated with bivariate LD score regression (21). We showcase the correlations between three TS studies (TS-EUROTRAIN, TS-EUROTRAIN/TSGWAS2 meta-analysis, and TSGWAS2) and 16 psychiatric and neurological traits (see supplementary Table 2 for full list of studies and abbreviations). The number in each square denotes the correlation rg. Two asterisks (**) denote the correlations that were identified as statistically significant after Benjamini-Hochberg FDR correction (a=0.05), while one asterisk (*) shows the correlations with nominal p<0.05.
Figure 3.
Figure 3.
Polygenic Risk Scoring analysis using the TSGWAS2 dataset (7) as discovery and the TS-EUROTRAIN dataset as target. Best fit p-value threshold was determined at p=0.1182 (model fit p=1.26×10−28). Maximum variance explained at the best fit model was estimated by Nagelkerke’s R2 at 3.3%. a) PRS distribution comparison between cases and controls for the best fit model. b) PRS histogram for each p-value bin, including the best fit bin.
See this image and copyright information in PMC

References

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