title: Pedigree disequilibrium test (PDT) replicates association and linkage between DRD4 and ADHD in multigenerational and extended pedigrees from a genetic isolate.
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 theta=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.
authors.affiliation: National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892-1852, USA.
authors.forename: M
authors.initials: M
authors.lastname: Arcos-Burgos
authors.forename: F X
authors.initials: FX
authors.lastname: Castellanos
authors.forename: D
authors.initials: D
authors.lastname: Konecki
authors.forename: F
authors.initials: F
authors.lastname: Lopera
authors.forename: D
authors.initials: D
authors.lastname: Pineda
authors.forename: J D
authors.initials: JD
authors.lastname: Palacio
authors.forename: J L
authors.initials: JL
authors.lastname: Rapoport
authors.forename: K
authors.initials: K
authors.lastname: Berg
authors.forename: J
authors.initials: J
authors.lastname: Bailey-Wilson
authors.forename: M
authors.initials: M
authors.lastname: Muenke
mesh_terms: D000483:Alleles; D001289:Attention Deficit Disorder with Hyperactivity / Q000235:genetics*; D003105:Colombia; D004247:DNA / Q000097:blood / Q000235:genetics; D005091:Exons / Q000235:genetics; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D010375:Pedigree; D011110:Polymorphism, Genetic / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics
chemical_list: D004247:DNA