A genome-wide scan for attention-deficit/hyperactivity disorder in 155 German sib-pairs

Abstract

Three groups have previously performed genome scans in attention-deficit/hyperactivity disorder (ADHD); linkage to chromosome 5p13 was detected in all of the respective studies. In the current study, we performed a whole-genome scan with 102 German families with two or more offspring who currently fulfilled the diagnostic criteria for ADHD. Including subsequent fine mapping on chromosome 5p, a total of 523 markers were genotyped. The highest nonparametric multipoint LOD score of 2.59 (empirical genome-wide significance 0.1) was obtained for chromosome 5p at 17 cM (according to the Marshfield map). Subsequent analyses revealed (a) a higher LOD score of 3.37 at 39 cM for a quantitative severity score based on symptoms of inattention than for hyperactivity/impulsivity (LOD score of 1.11 at 59 cM), and (b) an HLOD of 4.75 (empirical genome-wide significance 0.001) based on a parametric model assuming dominant inheritance. The locus of the solute carrier 6A3 (SLC6A3; dopamine transporter 1; DAT1) localizes to 5p15.33; the gene has repeatedly been implicated in the etiology of ADHD. However, in our sample the DAT1 VNTR did not show association with ADHD. We additionally identified nominal evidence for linkage to chromosomes 6q, 7p, 9q, 11 q, 12q and 17p, which had also been identified in previous scans. Despite differences in ethnicity, ascertainment and phenotyping schemes, linkage results in ADHD appear remarkably consistent.

The analysis of 51 genes in DSM-IV combined type attention deficit hyperactivity disorder: association signals in DRD4, DAT1 and 16 other genes

“…11 To date, there have been four published genome linkage scans of ADHD; three affected sibling pair studies and one of 16 multiplex pedigrees. [12][13][14][15][16][17][18] These studies have highlighted a number of potential linkage regions for further exploration, although there is as yet no clear consensus across the various data sets and no genes have been identified that account for linkage signals. Several of the linkage regions overlap in two or more of these studies, including regions of chromosomes 5p, 6q, 7p, 11q, 12q and 17p, suggesting that one or more loci of moderately large effect may exist.…”

Association and linkage of allelic variants of the dopamine transporter gene in ADHD

“…In our previously reported genome-wide scan for ADHD, parametric heterogeneity LOD (HLOD) analysis under a dominant model yielded the highest multipoint LOD score of 4.75 on chromosome 5p13. 3 A metaanalysis of genome-wide linkage data on 424 sib pairs affected with ADHD from two previously published genome-wide scans 4-6 also suggests a common risk locus at 5p13. 7 To date, the best-known candidate gene for ADHD located on distal chromosome 5p is the dopamine transporter gene (DAT1, SLC6A3).…”

“…(2) Stimulants, effective in the treatment of the core symptoms of ADHD, are known to interact with DAT1; 14 striatal DAT1 availability is lowered effectively in children and adults with ADHD by methylphenidate in clinical doses. 9,11 (3) Complete disruption of the DAT1 gene in mice (Dat1-knockout (KO) mice) alters DA tone and signaling and leads to spontaneous locomotor activity in novel environment and lack of locomotor habituation; [15][16][17] furthermore, Dat1-KO mice show deficits in learning, memory and social interactions leading to the hypothesis that Dat1-KO mice represent a model for ADHD. 18,19 The DAT1 gene, encoding 620 amino acids, comprises 15 exons that span more than 52 kb of genomic DNA on human chromosome 5p15.33.…”

“…3 To increase the statistical power to detect a genetic association, we enlarged our sample to 329 families comprising at least one offspring with ADHD. Here we report the fine mapping of DAT1 and family-based association studies for 30 SNPs and haplotypes covering the 5 0 region, the coding sequence (CDS) and the 3 0 flanking region.…”

“…We provide evidence for association of a DAT1 SNP and DAT1 haplotypes with ADHD and show that this association presumably underlies our previously reported linkage peak on chromosome 5p. 3 …”