Associations Between Behavior Problems and Dopaminergic Variants in High- and Low-Risk Siblings

Background:  Children with autism spectrum disorder (ASD), as well as their younger siblings (high-risk siblings), exhibit substantial heterogeneity in behaviors.  Children’s behavior problems have important implications both for children with ASD and their families.  High levels of internalizing and externalizing behavior problems have been reported in both children with ASD (Mahan & Matson, 2011; Maskey, Warnell, Parr, Couteur, & McConachie, 2013) and in their high-risk siblings (Fisman et al., 1996; Rodrigue, Geffken, & Morgan, 1993; Verte, Roeyers, & Buysse, 2003).  In children with ASD, behavior problems are also associated with the severity of ASD symptomatology (Pearson et al., 2006), as well as broader family factors such parent stress and depression (Davis & Carter, 2008; Ekas & Whitman, 2010).  In typically developing children and children with ASD, dopaminergic variants have been associated with behavioral difficulties.  As behavior problems may be particularly relevant to ASD symptomatology and family emotional factors in high-risk siblings, identifying common genetic variants associated with behavior problems would enable potential early identification of behavioral targets for early intervention.

Objectives:  Examine the role of dopaminergic variants associated with behavior problems, DRD4 and DRD2, in externalizing and internalizing problems at three years in siblings at high and low risk for ASD.

Methods:  High-risk (n=37) and low-risk (n=27) siblings were genotyped for DRD4 and DRD2.  A dopamine gene score was created for each child, ranging from 0-2, indicating the number of alleles associated with lower dopaminergic functioning (7-repeat allele of DRD4 and A allele of DRD2).  At 36 months, parents reported behavior problems (Externalizing and Internalizing Problems) using the Child Behavior Checklist (CBCL).

Results:  Regression models were constructed for CBCL Externalizing and Internalizing Problems to assess effects of the dopamine score, risk group status, and their interaction.  For Externalizing Problems (see Figure 1), neither status, b=-0.55, t=-1.37, p=.89, nor dopamine score, b=-3.95, t=-1.20, p=.24, were significant predictors.  There was a dopamine score*status interaction effect, b=8.97, t=2.06, p=.045, suggesting a moderating role for status.  For Internalizing Problems (see Figure 2), neither status, b=-2.71, t=-0.79, p=.43, nor dopamine score, b=-4.35, t=-1.55, p=.13, were significant predictors.  There was a dopamine score*status interaction effect, b=11.73, t=3.17, p=.003, again suggesting a moderating role for status.

Conclusions:  Associations between dopaminergic functioning and behavior problems were moderated by risk group.  Lower dopaminergic functioning (indexed by higher dopamine gene scores) was associated with higher levels of behavior problems (externalizing and internalizing) at three years in high-risk siblings.  Low-risk siblings exhibited the opposite pattern, suggesting differential susceptibility.  In the presence of familial risk for ASD, lower dopaminergic function was associated with increased behavior problems.  Knowledge of common genetic variants associated with ASD-relevant behaviors may aid in identifying those high-risk siblings at greatest risk for difficulties relevant to ASD-related outcomes and family functioning. Those high-risk siblings at greatest genetic risk represent an appropriate target for prophylactic early intervention.