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Differential effects of DRD4 and DAT1 genotype on fronto-striatal gray matter volumes in a sample of subjects with attention deficit hyperactivity disorder, their unaffected siblings, and controls

Molecular Psychiatry volume 10, pages 678–685 (2005)Cite this article

Abstract

Genetic influences on behavior are complex and, as such, the effect of any single gene is likely to be modest. Neuroimaging measures may serve as a biological intermediate phenotype to investigate the effect of genes on human behavior. In particular, it is possible to constrain investigations by prior knowledge of gene characteristics and by including samples of subjects where the distribution of phenotypic variance is both wide and under heritable influences. Here, we use this approach to show a dissociation between the effects of two dopamine genes that are differentially expressed in the brain. We show that the DAT1 gene, a gene expressed predominantly in the basal ganglia, preferentially influences caudate volume, whereas the DRD4 gene, a gene expressed predominantly in the prefrontal cortex, preferentially influences prefrontal gray matter volume in a sample of subjects including subjects with ADHD, their unaffected siblings, and healthy controls. This demonstrates that, by constraining our investigations by prior knowledge of gene expression, including samples in which the distribution of phenotypic variance is wide and under heritable influences, and by using intermediate phenotypes, such as neuroimaging, we may begin to map out the pathways by which genes influence behavior.

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Acknowledgements

We gratefully acknowledge all the families that participated in this study, Jacqueline Jansen and Chantal Kemner for their role in subject recruitment, René Mandl for technical assistance, Richard Sinke, Ruben van‘t Slot and Steven Bakker for their help in preparation and shipment of the DNA samples, and Jim Swanson for helpful discussions. This work was supported in part by grants from the Netherlands Organisation for Scientific Research (NWO) and the Dutch brain foundation (Hersenstichting Nederland) to SD.

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Authors and Affiliations

  1. Department of Child and Adolescent Psychiatry, Rudolf Magnus Institute for Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands

    S Durston & H van Engeland

  2. Sackler Institute for Developmental Psychobiology, Weill Medical College of Cornell University, New York, NY, USA

    S Durston, J A Fossella, B J Casey & A Galvan

  3. Department of Psychiatry, Rudolf Magnus Institute for Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands

    H E Hulshoff Pol, H G Schnack & R S Kahn

  4. Academic Center for Child and Adolescent Psychiatry, Groningen, The Netherlands

    M P Steenhuis & R B Minderaa

  5. Department of Psychiatry, Medical Center Nijmegen, Nijmegen, The Netherlands

    J K Buitelaar

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  1. S Durston
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Correspondence to S Durston.

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Durston, S., Fossella, J., Casey, B. et al. Differential effects of DRD4 and DAT1 genotype on fronto-striatal gray matter volumes in a sample of subjects with attention deficit hyperactivity disorder, their unaffected siblings, and controls. Mol Psychiatry 10, 678–685 (2005). https://doi.org/10.1038/sj.mp.4001649

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