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

Item Type:Article
Title:Association and linkage of allelic variants of the dopamine transporter gene in ADHD
Creators Name:Friedel, S. and Saar, K. and Sauer, S. and Dempfle, A. and Walitza, S. and Renner, T. and Romanos, M. and Freitag, C. and Seitz, C. and Palmason, H. and Scherag, A. and Windemuth-Kieselbach, C. and Schimmelmann, B.G. and Wewetzer, C. and Meyer, J. and Warnke, A. and Lesch, K.P. and Reinhardt, R. and Herpertz-Dahlmann, B. and Linder, M. and Hinney, A. and Remschmidt, H. and Schaefer, H. and Konrad, K. and Huebner, N. and Hebebrand, J.
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' 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.
Keywords:Attention-Deficit/Hyperactivity Disorder, Haplotype, DAT1, SLC6A3
Source:Molecular Psychiatry
Publisher:Nature Publishing Group
Page Range:923-933
Date:October 2007
Official Publication:https://doi.org/10.1038/sj.mp.4001986
PubMed:View item in PubMed

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