Reward-related traits as a possible path through which dopaminergic genetic variation confers psychopathology risk: a mediation analysis
Rewards are essential for human behavior as they guarantee our survival (i.e., by eating and drinking water) and influence our positive emotional experiences, motivation, and learning processes (Wise, 2002). Nonetheless, people with high or low reward approach motivation might be more vulnerable to developing psychiatric conditions. This is based on the numerous observations of such reward-related traits being associated with different psychiatric conditions (Zald & Treadway, 2017). For this reason, alterations within the reward system have been considered of transdiagnostic importance. The reward system has even been put forward as one of the transdiagnostic neurobiological substrates for psychopathology in the National Institute of Mental Health’s Research Domain Criteria (RDoc; Insel et al., 2010).
A way of conceptualizing reward-related traits is Gray’s behavioral approach system (BAS; Gray, 1981), which regulates approach motivation to attain rewards. The BAS has been largely used as a framework for understanding individual differences in reward approach motivation that are associated with psychopathology. The most common conceptualizations divide the BAS into three aspects/subscales that are all related to approach behavior but differ in what motivates the approach. Responsiveness relates to approach behavior that is motivated by rewards. Drive relates to the perseverance in pursuing a reward once selected. The last aspect, fun-seeking, relates to the motivation to seek new and intense rewards. Prior research, including our own recent work on the TRAILS data (Cardoso Melo et al., submitted), showed some evidence for high reward approach motivation in attention-deficit/hyperactivity disorder (ADHD), disruptive behavior disorders (DBD), substance use disorders (SUD), and anxiety disorders (Barker et al., 2019; Bruin, 2011; Franken et al., 2006; Loxton & Dawe, 2001; Mitchell & Nelson-Gray, 2006). In contrast, major depressive disorder (MDD) has been associated with low reward approach motivation (Katz et al., 2020). Even though research based on reward-related traits in autism spectrum disorders (ASD) is scarce, some studies have described low reward approach motivation in ASD as well (Larson et al., 2010; Schiltz et al., 2018).
Despite these examples of how these reward-related traits are relevant for psychiatry, many questions remain unanswered as most studies have been of cross-sectional nature. The most critical open question is whether extreme levels of reward approach motivation are merely symptoms of psychopathology or play a causal role in the onset and course of psychiatric conditions. However, establishing causality based on observational research is difficult, and should include evidence from different perspectives and approaches (i.e., triangulation (Lawlor, Tilling & Davey Smith, 2016)). One first step to further this field was to study the potential predictive role of reward-related traits longitudinally. In our previous study (Cardoso Melo et al., submitted), we observed that reward-related traits measured at age 13 predicted the future course of attention problems and hyperactivity, reactive and proactive aggressive problems, anxiety problems, smoking, alcohol use, and cannabis use over a 12-year follow-up. This provides some evidence for a potential causal role as a long-lasting predictive role has been established.
Another step forward to establishing a potential causal relationship of extreme levels of reward approach motivation is to turn to genetics. One approach would be to investigate the genetics of candidate underlying biological systems in relation to reward-related traits. Extreme levels of reward approach motivation are thought to be the outcome of dysregulated dopaminergic neurotransmission (see Arias-Carrion et al., 2010 for a review). Therefore, for reward-related traits, the biological system is the dopaminergic neurotransmission pathway. In addition to a link with reward-related traits, previous studies have also linked genetic variation in the dopaminergic neurotransmission pathway to psychopathology. For instance, recent gene-set association analyses revealed significant associations between dopaminergic genes and ADHD, ASD, and MDD (Cabana-Dominguez et al., 2021; Mota et al., 2020). Additionally, review studies have described many dopaminergic candidate genes associated with psychiatric disorders (Hoenicka et al., 2007; Lacerda-Pinheiro et al., 2014). However, the behavioral mechanisms through which variation in the dopaminergic neurotransmission pathway confers risk to psychopathology remain unclear.
In light of this evidence, reward-related traits may be a possible path through which dopaminergic genetic variation confers psychopathology risk. Using data from the Lifelines cohort, we propose to test this potential causal pathway hypothesis by:
1. Testing whether the association between dopaminergic genetic risk scores and psychopathological problems is mediated by reward-related traits