GDNF gene is associated with tourette syndrome in a family study

Abstract

Background Tourette syndrome is a disorder characterized by persistent motor and vocal tics, and frequently accompanied by the comorbidities attention deficit hyperactivity disorder and obsessive-compulsive disorder. Impaired synaptic neurotransmission has been implicated in its pathogenesis. Our aim was to investigate the association of 28 candidate genes, including genes related to synaptic neurotransmission and neurotrophic factors, with Tourette syndrome. Methods We genotyped 506 polymorphisms in a discovery cohort from the United States composed of 112 families and 47 unrelated singletons with Tourette syndrome (201 cases and 253 controls). Genes containing significant polymorphisms were imputed to fine-map the signal(s) to potential causal variants. Allelic analyses in Tourette syndrome cases were performed to check the role in attention deficit hyperactivity disorder and obsessive-compulsive disorder comorbidities. Target polymorphisms were further studied in a replication cohort from southern Spain composed of 37 families and three unrelated singletons (44 cases and 73 controls). Results The polymorphism rs3096140 in glial cell line–derived neurotrophic factor gene (GDNF) was significant in the discovery cohort after correction (P = 1.5 × 10−4). No linkage disequilibrium was found between rs3096140 and other functional variants in the gene. We selected rs3096140 as target polymorphism, and the association was confirmed in the replication cohort (P = 0.01). No association with any comorbidity was found. Conclusions As a conclusion, a common genetic variant in GDNF is associated with Tourette syndrome. A defect in the production of GDNF could compromise the survival of parvalbumin interneurons, thus altering the excitatory/inhibitory balance in the corticostriatal circuitry. Validation of this variant in other family cohorts is necessary.

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 ].…”

Refractory Gilles de la Tourette Syndrome—Many Pieces That Define the Puzzle

“…These include dopaminergic neurotransmission (9,10) as well as glutaminergic (11,12), serotoninergic (13), GABA-ergic (14)(15)(16), or endocannabinoid (17,18) neurotransmission. In addition, a significant number of genetic variants have also been identified [SLITRK1 (19)(20)(21), DRD2 (22), DRD3 (23), AADAC (24), ADORA (25), BTBD9 (26), CNR1 (18), GDNF (27), KCNJ5 (28), IL1RN (29), PNKD (30), and HDC (31,32), to give only some examples]. The first genome-wide association study (GWAS) (33) in GTS demonstrated a combined genetic background for GTS and OCD.…”

Investigation of a Possible Role for the Histidine Decarboxylase Gene in Tourette Syndrome in the Chinese Han Population: A Family-Based Study

“…Most individuals, upwards of 45%–60%, are also affected by a co-morbidity such as obsessive compulsive disorder (OCD), attention deficit hyperactivity disorder (ADHD), depression, or autism[ 1 ]. Although the disorders originating from TS sometimes lessen with age, the co-morbid symptoms may continue until adolescence and even adulthood [ 2 , 3 ]. Therefore, the occurrence of multiple conditions may present a challenge to the complicated pathogenesis of TS.…”