Association of dopamine gene variants, emotion dysregulation and ADHD in autism spectrum disorder
Introduction
Children with autism spectrum disorder (ASD) experience a wide range of psychiatric symptoms consistent with emotion dysregulation (EMD), such as depression, anxiety, anger, and irritability, as well as attention-deficit hyperactivity disorder (ADHD; Gadow et al., 2006, Gadow et al., 2005). These symptoms are associated with high rates of social and academic impairment (Kaat, Gadow, & Lecavalier, 2013), but little is known about pathogenic variables that may contribute to their co-occurrence with ASD. EMD and ADHD in children with ASD are phenomenologically similar in many ways to comparable symptoms and disorders in non-ASD youth (Gadow et al., 2008a, Gadow et al., 2006, Gadow et al., 2012, Guttmann-Steinmetz et al., 2009, Guttmann-Steinmetz et al., 2010), and this suggests that research about the latter may inform the former (e.g., Cohen et al., 2011, Gadow et al., 2013, Guerini et al., 2011).
Dopamine, brain regions rich in dopamine receptors, and genes involved in dopamine metabolism and signaling are all shown to be involved in emotion regulation and dysregulation (Alcaro et al., 2007, Badgaiyan et al., 2009, Beiderbeck et al., 2012, Garcia-Garcia et al., 2010, Levita et al., 2002, Opmeer et al., 2010, Salgado-Pineda et al., 2005), including depression (Klimek et al., 2002, Meyer et al., 2001, Roy et al., 1992), as well as ADHD (Levy, 1991, Wender, 1971). For example, the 9/10 variable number tandem repeat (VNTR) in the 3′-untranslated region (UTR) of the dopamine transporter (DAT) gene (DAT1/SLC6A3) was found to be associated with depression (Felten, Montag, Markett, Walter, & Reuter, 2011), anxiety (Gadow, Roohi, DeVincent, & Hatchwell, 2008), and processing negative emotional stimuli (Garcia-Garcia et al., 2010). It also evidences modest association with ADHD (Gizer, Ficks, & Waldman, 2009) as do other DAT1 variants including a VNTR on intron8 and the single nucleotide polymorphism (SNP) rs27072, but effect sizes across studies are generally heterogeneous. Researchers have recently established regulatory functions for the DAT1 intron8 5/6 repeat VNTR and rs27072 variants (Pinsonneault et al., 2011) as well as SNP (rs2283265) in the dopamine D2 receptor gene (DRD2) (Zhang et al., 2007), which enables a focused approach to gene-behavior associations founded on strong evidence for genetic influence in dopaminergic signaling.
Although research findings suggest that (a) dysregulation of dopamine metabolism or signaling is likely implicated in the etiology of EMD and ADHD, and (b) specific functional dopaminergic gene variants may modulate symptom severity, little is known of their relation with comparable symptoms in children with ASD. The primary objective of the present study was to explore potential relations of the aforementioned dopamine gene variants with severity of EMD and ADHD symptoms in children with ASD. This seemed reasonable because both spectra are common in children with ASD and often co-occur in ASD samples (suggesting shared pathogenic mechanisms). We also considered whether DAT1 intron8 and DRD2 rs2283265 jointly led to a non-additive association with symptom severity because prior work has documented a functional epistatic interaction (Sullivan et al., 2013).
Section snippets
Participants
Participants were recruited from referrals to a university hospital developmental disabilities specialty clinic located on Long Island, New York. All youth (N = 110) between 4 and 14 years old with the prerequisite measures and a diagnosis of ASD were included in the present study. Demographic characteristics were as follows: age (M = 7.5 ± 2.6), gender (86% male), ethnicity (91% Caucasian), socioeconomic status assessed with Hollingshead's (1975) index of occupational and educational social status (M
Emotion dysregulation
DAT1 intron8 polymorphism was associated with parents’ ratings of EMD, with youth homozygous for the 6-repeat allele exhibiting more severe symptoms than 5-6 heterozygotes (Table 1). The association was somewhat stronger co-varying severity of ADHD symptoms, F = 7.81, p = .006, ηp2 = .077. Secondary analyses indicated that intron8 genotype was significant for subdomains of EMD (untransformed scores): depression (F = 5.81, p = .018, ηp2 = .059) and generalized anxiety (F = 6.47, p = .013, ηp2 = .065).
Discussion
Findings of this study suggest that dopaminergic gene variants may be modulators of EMD and ADHD symptoms in children with ASD. Specifically, there was a moderate-strength (ηp2 = .063) association of the DAT1 intron8 VNTR with parent-rated EMD. Children with lower activity 6–6 repeat genotype had more severe symptoms than 5–6 heterozygotes. Of particular interest is the breadth of associations to include generalized anxiety, depression, and anger/irritability, and a moderate-strength (ηp2 = .110)
Study strengths, limitations, and future directions
The strengths of this study include limiting the sample to children within a relatively restricted age range, assessment of symptom phenotypes with a psychometrically sound and validated measure, and focus on a small number of gene variants previously shown to (a) regulate expression of DAT1 and DRD2 (Pinsonneault et al., 2011, Zhang et al., 2007), key players in dopaminergic signaling, and (b) be associated with EMD or ADHD in prior research with non-ASD individuals. However, generalization of
Conclusion
Research conducted in several different countries indicates that most children with ASD have EMD or ADHD symptoms that are severe enough to impair social or academic functioning. Our results suggest that at least some regulatory dopaminergic gene variants may modulate the severity of these co-occurring symptoms, but they are tentative pending replication in larger, independent samples.
Source of funding
This study was supported in part by the Matt and Debra Cody Center for Autism and Developmental Disorders, charitable contributions, and a grant from the National Institute of Health General Medical Sciences U01 GM092655 (WS).
Conflicts of interest
Dr. Gadow is shareholder in Checkmate Plus, publisher of the Child Symptom Inventory-4. For the remaining authors, none were declared.
Acknowledgments
The authors wish to thank Dr. John Pomeroy, Stony Brook University (Department of Pediatrics) for supervising the clinical diagnoses and Dr. Carla DeVincent, Stony Brook University (Department of Radiology) for managing data collection.
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