Causal discovery in an adult ADHD data set suggests indirect link between DAT1 genetic variants and striatal brain activation during reward processing

Abstract

Attention-deficit/hyperactivity disorder (ADHD) is a common and highly heritable disorder affecting both children and adults. One of the candidate genes for ADHD is DAT1, encoding the dopamine transporter. In an attempt to clarify its mode of action, we assessed brain activity during the reward anticipation phase of the Monetary Incentive Delay (MID) task in a functional MRI paradigm in 87 adult participants with ADHD and 77 controls (average age 36.5 years). The MID task activates the ventral striatum, where DAT1 is most highly expressed. A previous analysis based on standard statistical techniques did not show any significant dependencies between a variant in the DAT1 gene and brain activation [Hoogman et al. (2013); Neuropsychopharm 23:469-478]. Here, we used an alternative method for analyzing the data, that is, causal modeling. The Bayesian Constraint-based Causal Discovery (BCCD) algorithm [Claassen and Heskes (2012); Proceedings of the 28th Conference on Uncertainty in Artificial Intelligence] is able to find direct and indirect dependencies between variables, determines the strength of the dependencies, and provides a graphical visualization to interpret the results. Through BCCD one gets an opportunity to consider several variables together and to infer causal relations between them. Application of the BCCD algorithm confirmed that there is no evidence of a direct link between DAT1 genetic variability and brain activation, but suggested an indirect link mediated through inattention symptoms and diagnostic status of ADHD. Our finding of an indirect link of DAT1 with striatal activity during reward anticipation might explain existing discrepancies in the current literature. Further experiments should confirm this hypothesis. Ó 2015 Wiley Periodicals, Inc.Key words: ADHD; reward anticipation; Causal discovery; dopamine transporter Barbara Franke, Martine Hoogman, Elena Sokolova, Tom Claassen, Tom Heskes, Alejandro Arias Vasquez, and Perry Groot report no biomedical financial interests or potential conflicts of interest. Jan K. Buitelaar has been for the past 3 years a consultant to/member of advisory board of/ and/or speaker for Janssen Cilag BV, Eli Lilly, and Servier. He is not an employee of any of these companies, and not a stock shareholder of any of these companies. He has no other financial or material support, including expert testimony, patents, royalties. 508Neuropsychiatric Genetics INTRODUCTION Attention-deficit/hyperactivity disorder (ADHD) is an impairing and highly heritable disorder affecting both children and adults. It is characterized by two types of symptoms, hyperactivity/impulsivity and inattention, which can occur separately or combined. ADHD is one of the most common psychiatric disorders in childhood, affecting 5-6% of children [Polanczyk et al., 2007]. Symptoms persist into adulthood in up to 60% of the childhood cases , and the average prevalence of ADHD in the adult population is between 2.5-4.9% [Simon et al., 2009]. Studies show that individuals with ADHD have altered cogniti...

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