A Case-Control Association Study of Tic/Stereotypic Movement Phenotypes in a Missouri Twin Sample and Polymorphisms in the Dopaminergic and Nicotinic Acetylcholine Receptor Genes

Background: Tics and stereotypic movement disorders (SM) are defined in DSM-IV-TR (American Psychiatric Association, 2000) as clearly separate disorders, sometimes difficult to distinguish. SM represent a continuum of behavior present with the typically developing child population at one end of the spectrum, and extending into autistic disorder and other pervasive developmental disorders (PDDs) at the other end of the spectrum. SM have similar co-morbidity patterns and family history as tics. These similarities between both disorders suggest that they may share the frontal-striatal abnormalities described for Attention-Deficit/Hyperactivity Disorder (ADHD), obsessive compulsive disorder (OCD), and tic disorders, and the genes implicated in these pathways.

Objectives: To investigate the association between a Tic Narrow Phenotype (TNP) & Tic/Stereotypic-Movements-Broad-Phenotype (TSMBP) and the following candidate genes: Dopamine transporter (SLC6A3, also referred to as DAT1), D4 receptor (DRD4) and the Nicotinic acetylcholine receptor CHRNA4 gene.

Methods: Participants from the population-based Missouri Twin Study sample (MOTWIN) were selected.
Measures: Parents and twins completed the Missouri Assessment of Genetics Interview for Children (MAGIC) (Todd et al, 2003) that queries present and past existence of all DSM-IV symptoms of psychopathology. Interviewers had college degrees (psychology or related background) and received a 6-week training course for the MAGIC interview. For this study we used the DSM-IV Tic disorder diagnoses, (transient, chronic, motor and vocal), Tourette syndrome (TS), Stereotypic movements, ADHD, OCD, and related diagnoses. Child Behavior Checklist CBCL/4-18 (Achenbach, 1991) was also completed by the parents. Of 1635 total subjects, 67 were assigned to the TNP which included DSM-IV transient (motor or vocal), chronic (motor or vocal), or Tourette Syndrome from the MAGIC-Parent interview; and 511 twins met criteria for TSMBP which included TNP+SM from MAGIC-Parent interview + 2 CBCL items (Nervous movements and Picks skin rated as 1 or 2). The average age of both phenotypes did not differ (approximately 13 ± 3.2 years).

Results: Cases with TNP and TSMBP had significantly higher co-morbidity for ADHD, OCD, Depression, conduct disorder and oppositional defiant disorder than controls (p<.0001 for each comparison). We found a significant association with rs6090384, a SNP (single nucleotide polymorphism) in exon 2 of the CHRNA4 gene on chromosome 20 (odds ratio 5.6, 95% CI=1.4- 22.6) and TSMBP. No additional associations were found between DAT1 or DRD4 for TSMBP; nor were there any genetic associations found with TNP.

Conclusions: These results provide support for a putative role of a CHRNA4 variant in TSMBP. Replication studies are necessary to confirm these findings.