title: 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. © 2015 Wiley Periodicals, Inc.
authors.affiliation: Faculty of Science, Radboud University, Nijmegen, the Netherlands.
authors.forename: Elena
authors.initials: E
authors.lastname: Sokolova
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.|Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, the Netherlands.
authors.forename: Martine
authors.initials: M
authors.lastname: Hoogman
authors.affiliation: Faculty of Science, Radboud University, Nijmegen, the Netherlands.
authors.forename: Perry
authors.initials: P
authors.lastname: Groot
authors.affiliation: Faculty of Science, Radboud University, Nijmegen, the Netherlands.
authors.forename: Tom
authors.initials: T
authors.lastname: Claassen
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.|Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, the Netherlands.|Department of Cognitive Neuroscience, Radboud University Medical Center, Nijmegen, the Netherlands.|Department of Psychiatry, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Alejandro Arias
authors.initials: AA
authors.lastname: Vasquez
authors.affiliation: Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, the Netherlands.|Department of Cognitive Neuroscience, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Jan K
authors.initials: JK
authors.lastname: Buitelaar
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.|Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, the Netherlands.|Department of Psychiatry, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Barbara
authors.initials: B
authors.lastname: Franke
authors.affiliation: Faculty of Science, Radboud University, Nijmegen, the Netherlands.
authors.forename: Tom
authors.initials: T
authors.lastname: Heskes
keywords: ADHD; Causal discovery; dopamine transporter; reward anticipation