Meta-Analysis of Tourette Syndrome and Attention Deficit Hyperactivity Disorder Provides Support for a Shared Genetic Basis

Abstract

Gilles de la Tourette Sydrome (TS) is a childhood onset neurodevelopmental disorder, characterized phenotypically by the presence of multiple motor and vocal tics. It is often accompanied by multiple psychiatric comorbidities, with Attention Deficit/Hyperactivity Disorder (ADHD) among the most common. The extensive co-occurrence of the two disorders suggests a shared genetic background. A major step toward the elucidation of the genetic architecture of TS was undertaken by the first TS Genome-wide Association Study (GWAS) reporting 552 SNPs that were moderately associated with TS (p < 1E-3). Similarly, initial ADHD GWAS attempts and meta-analysis were not able to produce genome-wide significant findings, but have provided insight to the genetic basis of the disorder. Here, we examine the common genetic background of the two neuropsychiatric phenotypes, by meta-analyzing the 552 top hits in the TS GWAS with the results of ADHD first GWASs. We identify 19 significant SNPs, with the top four implicated genes being TBC1D7, GUCY1A3, RAP1GDS1, and CHST11. TBCD17 harbors the top scoring SNP, rs1866863 (p:3.23E-07), located in a regulatory region downstream of the gene, and the third best-scoring SNP, rs2458304 (p:2.54E-06), located within an intron of the gene. Both variants were in linkage disequilibrium with eQTL rs499818, indicating a role in the expression levels of the gene. TBC1D7 is the third subunit of the TSC1/TSC2 complex, an inhibitor of the mTOR signaling pathway, with a central role in cell growth and autophagy. The top genes implicated by our study indicate a complex and intricate interplay between them, warranting further investigation into a possibly shared etiological mechanism for TS and ADHD.

Parental Age and Differential Estimates of Risk for Neuropsychiatric Disorders: Findings From the Danish Birth Cohort

“…Similar effects of young parental age on both ADHD and TS/CT are in line with previously recorded shared etiological pathways for these disorders -including both genetic 34,35 and environmental 36,37 risk factors -and frequent co-occurrences observed between these conditions. 38 However, given co-morbidity between ADHD, TS/CT and OCD 38 it was of interest that young age at child's birth had opposite effects on the risk for those disorders.…”

Polygenic Risk Scores Derived From a Tourette Syndrome Genome-wide Association Study Predict Presence of Tics in the Avon Longitudinal Study of Parents and Children Cohort

“…Still one PRS study (4) and three heritability studies suggested a shared genetic background between TS and OCD (6,14,31). Little is known about the possible genetic overlap between TS and ADHD, with one PRS study agreeing with our finding of no overlap (4) and two heritability studies (14,32) suggesting overlap. Lastly, consistent with our findings, Anttila et al (14) did not find evidence for shared genetic risk factors between TS and ASD.…”

Investigation of previously implicated genetic variants in chronic tic disorders: a transmission disequilibrium test approach

“…(d) 12 TS GWAS-based top SNPs, i.e., the top 5 LD-independent SNPs from the first GWAS of TS [ 6 ], 4 top SNPs from the Gilles de la Tourette Syndrome Genome-Wide Association Study Replication Initiative [ 7 ], and the top 3 SNPs from the first cross-disorder GWAS of TS and OCD [ 20 ]; and (e) 17 top SNPs from GWAS studies of OCD [ 21 ], ADHD [ 22 , 23 ], and ASD [ 24 , 25 ]. We did not include the previously implicated TS SNPs rs1894236 ( HDC ), rs1056534 ( TBCD ), rs25531 ( SLC6A4 ), rs25532 ( SLC6A4 ), nor tSNPs covering the possible TS candidate genes DRD4 , Arylacetamide Deacetylase ( AADAC ) [ 26 , 27 ], and Glial Cell Derived Neurotrophic Factor ( GDNF ) [ 27 ], nor 19 SNPs recently implicated in a meta-analysis of TS and ADHD [ 28 ].…”