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

Abstract

Previously, we had reported a genome-wide scan for attention-deficit/hyperactivity disorder (ADHD) in 102 families with affected sibs of German ancestry; the highest multipoint LOD score of 4.75 was obtained on chromosome 5p13 (parametric HLOD analysis under a dominant model) near the dopamine transporter gene (DAT1). We genotyped 30 single nucleotide polymorphisms (SNPs) in this candidate gene and its 5 0 region in 329 families (including the 102 initial families) with 523 affected offspring. We found that (1) SNP rs463379 was significantly associated with ADHD upon correction for multiple testing (P = 0.0046); (2) the global P-value for association of haplotypes was significant for block two upon correction for all (n = 3) tested blocks (P = 0.0048); (3) within block two we detected a nominal P = 0.000034 for one specific marker combination. This CGC haplotype showed relative risks of 1.95 and 2.43 for heterozygous and homozygous carriers, respectively; and (4) finally, our linkage data and the genotype-IBD sharing test (GIST) suggest that genetic variation at the DAT1 locus explains our linkage peak and that rs463379 (P < 0.05) is the only SNP of the above haplotype that contributed to the linkage signal. In sum, we have accumulated evidence that genetic variation at the DAT1 locus underlies our ADHD linkage peak on chromosome 5; additionally solid association for a single SNP and a haplotype were shown. Future studies are required to assess if variation at this locus also explains other positive linkage results obtained for chromosome 5p.

A high-density SNP linkage scan with 142 combined subtype ADHD sib pairs identifies linkage regions on chromosomes 9 and 16

“…Based on our previous investigation, we decided to specifically reanalyze the two suggestive linkage loci in a stratified sample without the 18 Israeli families. 13 Interestingly, the linkage signal on chromosome 16 increased and passed the provisional significance criteria for linkage, with a LOD score of 3.82. Our further simulations demonstrated that this increase was statistically significant (P = 0.035).…”

“…If there is locus-specific genetic heterogeneity where the allele frequencies of the linked locus are significantly different between countries, it might be advantageous to test for linkage with a stratified sample based on a priori knowledge. 30 Given that we found a certain level of background genetic heterogeneity in the IMAGE sample which was reflected by significant allele frequency differences between the Israeli samples and the rest of the IMAGE samples in our previous investigation of 51 ADHD candidate genes, 13 we repeated the same nonparametric linkage analysis without the 18 Israeli families. As shown in Table 2, the suggestive linkage peak on chromosome 16 increased above the provisional criteria of significant linkage while the peak on chromosome 9 decreased.…”

“…8,11,12 Although as yet no genes explaining any of the linkage findings have been reported in the published literature, one study suggested that genetic variation of the dopamine transporter gene (DAT1) might explain linkage on chromosome 5p. 13 In the current study we contribute to linkage findings from affected sibling pair studies of ADHD, using a sample of 142 Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) combined subtype ADHD proband-sibling pairs, ascertained by the International Multi-centre ADHD Genetics (IMAGE) project. 1,6 Using a panel of highly informative single nucleotide polymorphisms (SNPs) our main aim was to identify genetic linkage regions using a sample ascertained with a relatively homogeneous phenotype.…”

The Pharmacogenomic Era: Promise for Personalizing Attention Deficit Hyperactivity Disorder Therapy

“…In contrast, genome-wide investigations require no a priori hypotheses related to specific genes, but scan the entire genome in an attempt to identify areas harboring genes that contribute some effect on outcome. Several genome-wide scans have identified regions linked with ADHD risk [7,54], including fine mapping by one group to DAT1 (55). Genome-wide approaches also have potential utility in pharmacogenetic investigations.…”

Genome-wide copy number variation analysis in attention-deficit/hyperactivity disorder: association with neuropeptide Y gene dosage in an extended pedigree

“…2 Although the substantial heritability of ADHD is documented in numerous family, twin and adoption studies, with estimates up to 80%, genome-wide linkage scans and candidate gene studies have failed to reliably identify ADHD-associated genes. 3 Hebebrand and co-workers 4 reported evidence for a risk haplotype at the dopamine transporter (DAT/SLC6A3) locus based on a linkage scan and subsequent finemapping of chromosome 5p13. A linkage analysis of eight extended families with high density of ADHD using a B50 K single-nucleotide polymorphism (SNP) array-based genotyping assay by our group validated previously reported findings and also revealed several novel susceptibility loci.…”