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Pedigree disequilibrium test (PDT) replicates association and linkage between DRD4 and ADHD in multigenerational and extended pedigrees from a genetic isolate

Molecular Psychiatry volume 9, pages 252–259 (2004)Cite this article

Abstract

Association/linkage between dopamine D4 receptor (DRD4) polymorphisms and attention-deficit/hyperactivity disorder (ADHD) has been suggested by case–control- and nuclear-family-based studies. Here, we present a candidate gene analysis for DRD4 using 14 extended and multigenerational families segregating ADHD derived from the ‘Paisa’ community of Antioquia, Colombia, a genetic isolate. Two DRD4 polymorphisms (a 120 bp tandem duplication at the promoter and a 48 bp-VNTR at exon 3), reported associated to ADHD, were genotyped. Parametric and non-parametric linkage analyses, and a family-based association test (FBAT), the pedigree disequilibrium test (PDT), were applied to search for evidence of association/linkage. Two-point LOD scores were significantly negative, with values ranging from −3.21 (P=0.011158) to −7.66 (P=0.000091 at θ=0). Non-parametrical analysis resulted in nonsignificant evidence for linkage. The PDT showed a moderate trend toward significance of association/linkage between the 7-repeat (7R) allele at the 48 bp VNTR and ADHD (P=0.0578). Furthermore, the haplotype analysis shows a significant association/linkage of the 7R-240 bp haplotype (P=0.0467) with ADHD. Results suggest that either a moderate DRD4 genetic effect, or linkage disequilibrium of DRD4 with an ADHD disease locus in the vicinity or the linkage to a phenotypic component of the ADHD spectrum could be underlying this association/linkage. These results provide further evidence for the association of ADHD to genetic variation in or near to DRD4 and replicate the previously reported association between ADHD and the 7R allele.

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Acknowledgements

We are grateful to the Colombian families who participated in this research and for two anonymous reviewers whose comments significantly improved this paper. We also thank John Compton and Sherri Bale for their support in the molecular genotyping. This research was financed by the Intramural Research Programs of the National Human Genome Research Institute and National Institute of Mental Health and partly by COLCIENCIAS, Grant 1115-04-12010.

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Authors and Affiliations

  1. National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA

    M Arcos-Burgos, D Konecki, K Berg, J Bailey-Wilson & M Muenke

  2. Population Genetics, Mutacarcinogenesis and Genetic Epidemiology Group, University of Antioquia, Medellín, Colombia

    M Arcos-Burgos

  3. National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA

    F X Castellanos & J L Rapoport

  4. New York University Child Study Center, New York, NY, USA

    F X Castellanos

  5. Neurosciences Group, University of Antioquia, Medellín, Colombia

    F Lopera, D Pineda & J D Palacio

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Arcos-Burgos, M., Castellanos, F., Konecki, D. et al. Pedigree disequilibrium test (PDT) replicates association and linkage between DRD4 and ADHD in multigenerational and extended pedigrees from a genetic isolate. Mol Psychiatry 9, 252–259 (2004). https://doi.org/10.1038/sj.mp.4001396

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