Impact of a Common Genetic Variation Associated With Putamen Volume on Neural Mechanisms of Attention-Deficit/Hyperactivity Disorder

Bing Xu, Tianye Jia, Christine Macare, Tobias Banaschewski, Arun L.W. Bokde, Uli Bromberg, Christian Büchel, Anna Cattrell, Patricia J. Conrod, Herta Flor, Vincent Frouin, Jürgen Gallinat, Hugh Garavan, Penny Gowland, Andreas Heinz, Bernd Ittermann, Jean-Luc Martinot, Marie-Laure Paillère Martinot, Frauke Nees, Dimitri Papadopoulos Orfanos, Tomáš Paus, Luise Poustka, Michael N. Smolka, Henrik Walter, Robert Whelan, Gunter Schumann, Sylvane Desrivières, IMAGEN Consortium, Tobias Banaschewski, Gareth Barker, Arun L.W. Bokde, Uli Bromberg, Christian Büchel, Erin Burke Quinlan, Sylvane Desrivières, Herta Flor, Vincent Frouin, Hugh Garavan, Penny Gowland, Andreas Heinz, Bernd Ittermann, Jean-Luc Martinot, Marie-Laure Paillère Martinot, Eric Artiges, Herve Lemaitre, Frauke Nees, Dimitri Papadopoulos Orfanos, Tomáš Paus, Luise Poustka, Michael N. Smolka, Nora C. Vetter, Sarah Jurk, Eva Mennigen, Henrik Walter, Robert Whelan, Gunter Schumann

In a recent genomewide association study of subcortical brain volumes, a common genetic variation at rs945270 was identified as having the strongest effect on putamen volume, a brain measurement linked to familial risk for attention-deficit/hyperactivity disorder (ADHD). To determine whether rs945270 might be a genetic determinant of ADHD, its effects on ADHD-related symptoms and neural mechanisms of ADHD, such as response inhibition and reward sensitivity, were explored. A large population sample of 1,834 14-year-old adolescents was used to test the effects of rs945270 on ADHD symptoms assessed through the Strengths and Difficulties Questionnaire and region-of-interest analyses of putamen activation by functional magnetic resonance imaging using the stop signal and monetary incentive delay tasks, assessing response inhibition and reward sensitivity, respectively. There was a significant link between rs945270 and ADHD symptom scores, with the C allele associated with lower symptom scores, most notably hyperactivity. In addition, there were sex-specific effects of this variant on the brain. In boys, the C allele was associated with lower putamen activity during successful response inhibition, a brain response that was not associated with ADHD symptoms. In girls, putamen activation during reward anticipation increased with the number of C alleles, most significantly in the right putamen. Remarkably, right putamen activation during reward anticipation tended to negatively correlate with ADHD symptoms. These results indicate that rs945270 might contribute to the genetic risk of ADHD partly through its effects on hyperactivity and reward processing in girls.