Association of ADHD, tics, and anxiety with dopamine transporter (DAT1) genotype in autism spectrum disorder.

The core features of autism spectrum disorder (ASD) include deficits in functional language and social skills, as well as repetitive behaviors, all of which vary greatly in severity, complexity, and co-occurrence. The three most common subtypes of ASD are autism (deficits in all three areas), Asperger’s syndrome (primarily social deficits and repetitive behaviors), and PDD-NOS (clinically significant symptoms but sub threshold for autism or Asperger’s syndrome). It is estimated that approximately .6% of the general population has the disorder (Fombonne, 2005), and it is much more common in males than females. As a group, children with ASD exhibit high rates of behavioral disturbance (e.g., Goldstein & Schwebach, 2004; Lee & Ousley, 2006; Leyfer et al., 2006). For example, many meet DSM-IV symptom criteria for attention-deficit/hyperactivity disorder (>50%) (Gadow, DeVincent, & Pomeroy, 2006), anxiety disorder (>50%) (Gadow, DeVincent, Pomeroy, & Azizian, 2005), and motor and vocal tic disorder (>60%) (Gadow & DeVincent, 2005); therefore, co-morbidity is inevitably high. Although these behavioral syndromes appear to be phenomenologically similar to traditional non-ASD psychiatric disorders and often lead to pharmacotherapy and social isolation (Aman, Lam, & Van Bourgondien, 2005) and family stress (Herring et al., 2006), relatively little is known about their etiology (e.g., Brieber et al., 2007; Gadow, DeVincent, & Schneider, in press; Sinzig, Morsch, Bruning, Schmidt, & Lehmkuhl, 2008; Smalley et al., 2002). Traditionally, it has been assumed they were linked in some way to the pathogenesis of ASD and, therefore, genetic studies have logically focused on the core features of ASD (reviewed by Grice & Buxbaum, 2006; Yang & Gill, 2007). Dopamine system genes are likely candidates for the study of behavioral syndromes within the ASD clinical phenotype because they are implicated not only in ASD (e.g., Dawson et al., 2005; Previc, 2007; Toda et al., 2006), but also in its behavioral concomitants, such as ADHD (reviewed by Li, Sham, Owen, & He, 2006), tic disorder (e.g., Singer et al., 2002), and social anxiety (e.g., Sareen et al., 2007). One gene of considerable interest is solute carrier family 6, member 3 (SLC6A3), also known as dopamine transporter gene (DAT1). DAT1 encodes a sodium dependent dopamine transporter that mediates reuptake of the neurotransmitter at the synapse. The 3′-untranslated region of DAT1 contains a 40bp variable number tandem repeat (VNTR), existing in 3 to 13 copies. The 9- and 10-repeat alleles are the two most common variants in Caucasian, Hispanic and African-American samples. Expression studies indicate that the DAT1 VNTR is a functional polymorphism, with significantly higher levels of DAT1 produced from the 10-repeat allele than the 9-repeat allele (Fuke et al., 2001), but findings are mixed (see Brookes et al., 2007). Another dopamine transporter polymorphism of interest is DAT1 DdeI, recently reported to be associated with Tourette syndrome (Yoon et al., 2007). Specifically, a diagnosis of Tourette syndrome was found to be associated with the DAT1 DdeI polymorphism AG versus AA. A number of studies have investigated the relationship between DAT1 polymorphisms and behavioral syndromes in individuals who do not have ASD and have found that the 10-repeat allele or the 10-10 repeat genotype is associated with ADHD(reviewed by Yang et al., 2007), anxiety and tics (Comings et al., 1996; Rowe et al., 1998). Nevertheless, others report that the 9-repeat allele (e.g., Todd et al., 2005; Young et al., 2002) may be a risk factor for ADHD. Lee et al. (2007) have also suggested the possibility that the risk factor for disruptive behavior symptoms, including ADHD, is heterozygosity, i.e., differentially higher levels in heterozygotes (9-10 repeat genotype) versus homozygotes (9-9 or 10-10 repeat genotypes). The present study examined the association between DAT1 genotype and severity of ADHD, social anxiety, and tic symptoms in children with diagnosed ASD. Because a dimensional model of psychopathology has both statistical and conceptual advantages over a categorical model (e.g., Szatmari et al., 2007), we used a validated DSM-IV-referenced behavior rating scale for defining relevant psychiatric symptom dimensions (i.e., component phenotypes and not psychiatric diagnoses). Owing in part to a lack of prior research on behavioral syndromes in ASD, this study is by necessity descriptive (i.e., hypothesis generating and not hypothesis confirming). Based on prior research with non-ASD samples, we predicted that the 10-10 DAT1 genotype would be associated with more severe ADHD, tics, and anxiety symptoms compared with a combined group of all other genotypes. Because it has been hypothesized that ASD is associated with hyperdopaminergic functioning (reviewed by Previc, 2007), it was also conceivable that ASD pathogenic factors might alter these expected outcomes. However, evidence supporting a ‘hyperdopamine model’ of ASD is at best mixed (reviewed by Lam, Aman, & Arnold, 2006). Owing to the fact that parents and teachers often identify different children in the same sample as having ADHD or other clinical phenotypes (Gadow et al., 2004, 2006), we predicted that informant would be an important variable in understanding gene–behavior relations. Lastly, exploratory analyses were conducted to investigate potential gene–ASD symptom associations and the possibility of heterozygosity as a risk genotype for ADHD (see also Comings & MacMurray, 2000).