Poster #46 - Reward Processing/Drive as a Mechanism of Polygenic Risk for Attention-Deficit/Hyperactivity Disorder

• In Event: 3-206 - Poster Session 13
  In Poster Session: PS 13 Section - Developmental Disabilities

Integrative Statement

Background:
Genetic influences play a key role in the etiology of attention-deficit/hyperactivity disorder (ADHD), accounting for up to 88% of its variance (Larsson, Chang, D’Onofrio, & Lichtenstein, 2014). Genome-wide association study (GWAS) findings have identified many genes of individually small effects that influence ADHD, indicating its polygenic architecture (Demontis et al., 2017). However, little is known about the etiological processes that lie between these genes and the disorder. Identifying the risk pathways between genes and disorders (i.e., endophenotypes; Gottesman & Gould, 2003) may uncover more targetable mechanisms for intervention.
Disruptions in reward processing has been implicated as a plausible risk factor for ADHD (Luman, Oosterlaan, & Sergeant, 2005), where individuals with ADHD are more responsive to rewards than controls (Sonuga-Barke, 2011). Individuals with ADHD are also more likely to engage in more risky behaviors relative to controls (Faregh & Derevensky, 2010; Humphreys & Lee, 2011). Additionally, the relationship between impaired executive functions (EF; Welsh & Pennington, 1988) and ADHD has been well-replicated (Willcutt, et al., 2005). Because candidate genes for ADHD have been previously shown to covary with these processes (e.g., Forbes et al., 2009; Barnes et al., 2011), the current study will use a more powerful polygenic framework to examine whether reward responsivity, risk taking, and EF are endophenotypes for ADHD.

Methods:
Data were from 209 kindergarten children and their parents (mean age=6.02 years; SD=.43). Polygenic risk scores (PRS) for ADHD were computed using meta-analytic GWAS summary statistics for ADHD (N=20,183 ADHD cases; N=35,191 controls; Demontis et al., 2017). Parents rated their child’s reward responsivity and drive from the SPSRQ-C (Colder & O’Connor, 2004), global executive composite from the BRIEF-2 (Gioia, Isquith, Guy, & Kenworthy, 2015), and total ADHD symptoms from the Vanderbilt Assessment Scale (NICHQ, 2002). Children completed a computerized measure of risk-taking (i.e., Balloon Emotional Learning Task; Humphreys, Lee, & Tottenham, 2013) during a laboratory visit. A multiple mediation model (Hayes, 2018) examined the indirect and direct effects of PRS for ADHD through the effects of three mediators (i.e., reward responsivity/drive, risk taking, and EF) while covarying for child sex and household income.

Results:
The total effect of PRS on ADHD was significant (b=.078, s.e.=.028, p=.006). The direct effect of PRS on ADHD remained significant (b=.052, s.e.=.020, p=.010). However, the 95% confidence interval for the specific indirect effect of PRS on ADHD through SPSRQ-C reward responsivity/drive was above zero (95% CIs=.0002, .0132). There was no evidence of an indirect effect of PRS on ADHD through the effects of either risk taking or global EF.

Conclusions:
Using a polygenic framework, this study found novel evidence of reward responsivity/drive as a key mechanism of risk between PRS and ADHD, while also controlling for risk taking and EF. Our findings support the notion that reward-related processes may be key targets for interventions concerning children with ADHD, especially given that disruptions in these pathways likely covary with genes for ADHD as well. Future work will examine these associations longitudinally to provide causal evidence of this association.

Authors

• Emily Hilton, University of Wisconsin - Madison
  Presenting Author

• James J. Li, University of Wisconsin-Madison
  Non-Presenting Author