BACKGROUND: Pharmacologic and animal studies have strongly implicated the norepinephrine transporter (NET) in the pathophysiology of attention-deficit/hyperactivity disorder (ADHD). We conducted a family-based study, with stratification based on sex and subtype, to test the association between 30 tag single-nucleotide polymorphisms (SNPs) within the gene encoding NET (SLC6A2) and ADHD. METHODS: Family-based association tests were conducted with the categorical diagnosis of ADHD, as well as quantitative phenotypes of clinical relevance (Conners Global Index for Teachers and Parents, and Child Behavior Checklist measures). Sliding window haplotype analysis was conducted with screening based on conditional power using PBAT. RESULTS: A previously reported association with rs3785143 was confirmed in this study. Further, extensive association was observed with haplotype blocks, with a differential pattern observed based on sex and subtype. The 5' region of the gene (encompassing haplotype block 1 and including a functional promoter SNP, rs28386840) showed an association with ADHD in girls (irrespective of subtype). A different region of the gene (distributed around haplo-type block 2) was associated with distinct behavioural phenotypes in boys. These findings are correlated with previously reported functional studies of gene variants in SLC6A2. LIMITATIONS: The most important limitation of the study is the small size of the groups resulting from the stratification based on sex followed by subtype. CONCLUSION: The results obtained in this family-based study suggest that haplotype blocks within different regions of SLC6A2 show differential association with the disorder based on sex and subtype. These associations may have been masked in previous studies when tests were conducted with pooled samples.
BACKGROUND: Pharmacologic and animal studies have strongly implicated the norepinephrine transporter (NET) in the pathophysiology of attention-deficit/hyperactivity disorder (ADHD). We conducted a family-based study, with stratification based on sex and subtype, to test the association between 30 tag single-nucleotide polymorphisms (SNPs) within the gene encoding NET (SLC6A2) and ADHD. METHODS: Family-based association tests were conducted with the categorical diagnosis of ADHD, as well as quantitative phenotypes of clinical relevance (Conners Global Index for Teachers and Parents, and Child Behavior Checklist measures). Sliding window haplotype analysis was conducted with screening based on conditional power using PBAT. RESULTS: A previously reported association with rs3785143 was confirmed in this study. Further, extensive association was observed with haplotype blocks, with a differential pattern observed based on sex and subtype. The 5' region of the gene (encompassing haplotype block 1 and including a functional promoter SNP, rs28386840) showed an association with ADHD in girls (irrespective of subtype). A different region of the gene (distributed around haplo-type block 2) was associated with distinct behavioural phenotypes in boys. These findings are correlated with previously reported functional studies of gene variants in SLC6A2. LIMITATIONS: The most important limitation of the study is the small size of the groups resulting from the stratification based on sex followed by subtype. CONCLUSION: The results obtained in this family-based study suggest that haplotype blocks within different regions of SLC6A2 show differential association with the disorder based on sex and subtype. These associations may have been masked in previous studies when tests were conducted with pooled samples.
Authors: W Retz; M Rösler; C Kissling; S Wiemann; R Hünnerkopf; A Coogan; J Thome; C Freitag Journal: J Neural Transm (Vienna) Date: 2007-11-12 Impact factor: 3.575
Authors: Vincenzo De Luca; Pierandrea Muglia; Umesh Jain; James L Kennedy Journal: Am J Med Genet B Neuropsychiatr Genet Date: 2004-01-01 Impact factor: 3.568
Authors: J W Kim; J Biederman; C L McGrath; A E Doyle; E Mick; J Fagerness; S Purcell; J W Smoller; P Sklar; S V Faraone Journal: Mol Psychiatry Date: 2007-09-18 Impact factor: 15.992
Authors: H M Fentress; R Klar; J J Krueger; T Sabb; S N Redmon; N M Wallace; J K Shirey-Rice; M K Hahn Journal: Genes Brain Behav Date: 2013-10-09 Impact factor: 3.449
Authors: Li Yang; Qiujin Qian; Lu Liu; Haimei Li; Stephen V Faraone; Yufeng Wang Journal: J Neural Transm (Vienna) Date: 2012-12-25 Impact factor: 3.575
Authors: Helen L Sigurdardottir; Georg S Kranz; Christina Rami-Mark; Gregory M James; Thomas Vanicek; Gregor Gryglewski; Alexander Kautzky; Marius Hienert; Tatjana Traub-Weidinger; Markus Mitterhauser; Wolfgang Wadsak; Marcus Hacker; Dan Rujescu; Siegfried Kasper; Rupert Lanzenberger Journal: Hum Brain Mapp Date: 2015-12-17 Impact factor: 5.038