Investigation of gene-environment interactions in relation to tic severity.

Tourette syndrome (TS) is a neuropsychiatric disorder with involvement of genetic and environmental factors. We investigated genetic loci previously implicated in Tourette syndrome and associated disorders in interaction with pre- and perinatal adversity in relation to tic severity using a case-only (N = 518) design. We assessed 98 single-nucleotide polymorphisms (SNPs) selected from (I) top SNPs from genome-wide association studies (GWASs) of TS; (II) top SNPs from GWASs of obsessive-compulsive disorder (OCD), attention-deficit/hyperactivity disorder (ADHD), and autism spectrum disorder (ASD); (III) SNPs previously implicated in candidate-gene studies of TS; (IV) SNPs previously implicated in OCD or ASD; and (V) tagging SNPs in neurotransmitter-related candidate genes. Linear regression models were used to examine the main effects of the SNPs on tic severity, and the interaction effect of these SNPs with a cumulative pre- and perinatal adversity score. Replication was sought for SNPs that met the threshold of significance (after correcting for multiple testing) in a replication sample (N = 678). One SNP (rs7123010), previously implicated in a TS meta-analysis, was significantly related to higher tic severity. We found a gene-environment interaction for rs6539267, another top TS GWAS SNP. These findings were not independently replicated. Our study highlights the future potential of TS GWAS top hits in gene-environment studies.

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

Genetic studies in Tourette syndrome (TS) are characterized by scattered and poorly replicated findings. We aimed to replicate findings from candidate gene and genome-wide association studies (GWAS). Our cohort included 465 probands with chronic tic disorder (93% TS) and both parents from 412 families (some probands were siblings). We assessed 75 single nucleotide polymorphisms (SNPs) in 465 parent-child trios; 117 additional SNPs in 211 trios; and 4 additional SNPs in 254 trios. We performed SNP and gene-based transmission disequilibrium tests and compared nominally significant SNP results with those from a large independent case-control cohort. After quality control 71 SNPs were available in 371 trios; 112 SNPs in 179 trios; and 3 SNPs in 192 trios. 17 were candidate SNPs implicated in TS and 2 were implicated in obsessive-compulsive disorder (OCD) or autism spectrum disorder (ASD); 142 were tagging SNPs from eight monoamine neurotransmitter-related genes (including dopamine and serotonin); 10 were top SNPs from TS GWAS; and 13 top SNPs from attention-deficit/hyperactivity disorder, OCD, or ASD GWAS. None of the SNPs or genes reached significance after adjustment for multiple testing. We observed nominal significance for the candidate SNPs rs3744161 (TBCD) and rs4565946 (TPH2) and for five tagging SNPs; none of these showed significance in the independent cohort. Also, SLC1A1 in our gene-based analysis and two TS GWAS SNPs showed nominal significance, rs11603305 (intergenic) and rs621942 (PICALM). We found no convincing support for previously implicated genetic polymorphisms. Targeted re-sequencing should fully appreciate the relevance of candidate genes.

Pre- and perinatal complications in relation to Tourette syndrome and co-occurring obsessive-compulsive disorder and attention-deficit/hyperactivity disorder.

Pre- and perinatal complications have been implicated in the onset and clinical expression of Tourette syndrome albeit with considerable inconsistencies across studies. Also, little is known about their role in co-occurring obsessive-compulsive disorder (OCD) and attention-deficit/hyperactivity disorder (ADHD) in individuals with a tic disorder. Therefore, we aimed to investigate the role of pre- and perinatal complications in relation to the presence and symptom severity of chronic tic disorder and co-occurring OCD and ADHD using data of 1113 participants from the Tourette International Collaborative Genetics study. This study included 586 participants with a chronic tic disorder and 527 unaffected family controls. We controlled for age and sex differences by creating propensity score matched subsamples for both case-control and within-case analyses. We found that premature birth (OR = 1.72) and morning sickness requiring medical attention (OR = 2.57) were associated with the presence of a chronic tic disorder. Also, the total number of pre- and perinatal complications was higher in those with a tic disorder (OR = 1.07). Furthermore, neonatal complications were related to the presence (OR = 1.46) and severity (b = 2.27) of co-occurring OCD and also to ADHD severity (b = 1.09). Delivery complications were only related to co-occurring OCD (OR = 1.49). We conclude that early exposure to adverse situations during pregnancy is related to the presence of chronic tic disorders. Exposure at a later stage, at birth or during the first weeks of life, appears to be associated with co-occurring OCD and ADHD.

Children and adolescents with Tourette's disorder in the USA versus Argentina: behavioral differences may reflect cultural factors.

To explore behavioral differences as possible cultural factors in presentation of psychiatric comorbidity in two clinically referred, consecutively ascertained samples of youth with Tourette's disorder (TD) from New York and Buenos Aires. Subjects were evaluated between 2002 and 2010 at the Tics and Tourette's Clinical and Research Program at the New York University Child Study Center in New York and the Interdisciplinary Center for Tourette's, Obsessive Compulsive Disorder (OCD) and Associated Disorders (CITTTA)/Institute of Cognitive Psychology (INECO) in Buenos Aires. Demographic, diagnostic, tic severity (Yale Global Tic Severity Scale; YGTSS), clinical (Child Behavior Check List-Parent version; CBCL), and global functioning (Global Assessment of Functioning; GAF) data were compared using descriptive statistics. The sample included 111 subjects ages 6-17 years, who met DSM-IV-TR diagnostic criteria for TD. Findings revealed that the BA sample (n = 35) was significantly older at initial evaluation at the tic specialty clinic, and had higher frequency of oppositional defiant disorder (ODD), mood and non-OCD anxiety disorders than the NY sample (n = 76). There were no differences in gender distribution, age at tic onset or TD diagnosis, tic severity, proportion with current diagnoses of OCD/OC behavior or attention deficit hyperactivity disorder (ADHD), CBCL internalizing, externalizing, or total problems scores, YGTSS scores, or GAF scores. The observed similarities in demographic features, clinical presentation, rates of ADHD and OCD/OCB, and global impairment may reflect similar phenomenology and illness-related characteristics of TD in these referred youth. Differences in age at initial specialty clinic evaluation and rates of ODD, mood and non-OCD anxiety disorders may need further exploration before they may be considered to reflect cultural factors. Because of these limitations (e.g. small sample size), these results can be regarded only as preliminary.