Dataset Information

Association of Genetic Variation in the 3'UTR of LHX6, IMMP2L, and AADAC With Tourette Syndrome.

ABSTRACT: Background: Tourette Syndrome (TS) is a neurodevelopmental disorder that presents with motor and vocal tics early in childhood. The aim of this study was to investigate genetic variants in the 3' untranslated region (3'UTR) of TS candidate genes with a putative link to microRNA (miRNA) mediated regulation or gene expression. Methods: We used an in silico approach to identify 32 variants in the 3'UTR of 18 candidate genes putatively changing the binding site for miRNAs. In a sample composed of TS cases and controls (n = 290), as well as TS family trios (n = 148), we performed transmission disequilibrium test (TDT) and meta-analysis. Results: We found positive association of rs3750486 in the LIM homeobox 6 (LHX6) gene (p = 0.021) and rs7795011 in the inner mitochondrial membrane peptidase subunit 2 (IMMP2L) gene (p = 0.029) with TS in our meta-analysis. The TDT showed an over-transmission of the A allele of rs1042201 in the arylacetamide deacetylase (AADAC) gene in TS patients (p = 0.029). Conclusion: This preliminary study provides further support for the involvement of LHX6, IMMP2L, and AADAC genes, as well as epigenetic mechanisms, such as altered miRNA mediated gene expression regulation in the etiology of TS.

SUBMITTER: Pagliaroli L

PROVIDER: S-EPMC7457023 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Association of Genetic Variation in the 3'UTR of LHX6, IMMP2L, and AADAC With Tourette Syndrome.

Pagliaroli Luca L Vereczkei Andrea A Padmanabhuni Shanmukha Sampath SS Tarnok Zsanett Z Farkas Luca L Nagy Peter P Rizzo Renata R Wolanczyk Tomasz T Szymanska Urszula U Kapisyzi Mira M Basha Entela E Koumoula Anastasia A Androutsos Christos C Tsironi Vaia V Karagiannidis Iordanis I Paschou Peristera P Barta Csaba C

Frontiers in neurology 20200814

Background: Tourette Syndrome (TS) is a neurodevelopmental disorder that presents with motor and vocal tics early in childhood. The aim of this study was to investigate genetic variants in the 3' untranslated region (3'UTR) of TS candidate genes with a putative link to microRNA (miRNA) mediated regulation or gene expression. Methods: We used an in silico approach to identify 32 variants in the 3'UTR of 18 candidate genes putatively changing the binding site for miRNAs. In a ...[more]

PMID: 32922348

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Project description:There have been considerable recent advances in understanding the genetic architecture of Tourette syndrome (TS) as well as its underlying neurocircuitry. However, the mechanisms by which genetic variation that increases risk for TS-and its main symptom dimensions-influence relevant brain regions are poorly understood. Here we undertook a genome-wide investigation of the overlap between TS genetic risk and genetic influences on the volume of specific subcortical brain structures that have been implicated in TS. We obtained summary statistics for the most recent TS genome-wide association study (GWAS) from the TS Psychiatric Genomics Consortium Working Group (4644 cases and 8695 controls) and GWAS of subcortical volumes from the ENIGMA consortium (30,717 individuals). We also undertook analyses using GWAS summary statistics of key symptom factors in TS, namely social disinhibition and symmetry behaviour. SNP effect concordance analysis (SECA) was used to examine genetic pleiotropy-the same SNP affecting two traits-and concordance-the agreement in single nucelotide polymorphism (SNP) effect directions across these two traits. In addition, a conditional false discovery rate (FDR) analysis was performed, conditioning the TS risk variants on each of the seven subcortical and the intracranial brain volume GWAS. Linkage disequilibrium score regression (LDSR) was used as validation of the SECA method. SECA revealed significant pleiotropy between TS and putamen (p?=?2?×?10-4) and caudate (p?=?4?×?10-4) volumes, independent of direction of effect, and significant concordance between TS and lower thalamic volume (p?=?1?×?10-3). LDSR lent additional support for the association between TS and thalamus volume (p?=?5.85?×?10-2). Furthermore, SECA revealed significant evidence of concordance between the social disinhibition symptom dimension and lower thalamus volume (p?=?1?×?10-3), as well as concordance between symmetry behaviour and greater putamen volume (p?=?7?×?10-4). Conditional FDR analysis further revealed novel variants significantly associated with TS (p?<?8?×?10-7) when conditioning on intracranial (rs2708146, q?=?0.046; and rs72853320, q?=?0.035) and hippocampal (rs1922786, q?=?0.001) volumes, respectively. These data indicate concordance for genetic variation involved in disorder risk and subcortical brain volumes in TS. Further work with larger samples is needed to fully delineate the genetic architecture of these disorders and their underlying neurocircuitry.

Dataset Information

Association of Genetic Variation in the 3'UTR of LHX6, IMMP2L, and AADAC With Tourette Syndrome.

Publications

Association of Genetic Variation in the 3'UTR of LHX6, IMMP2L, and AADAC With Tourette Syndrome.

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