title: Differential association between the norepinephrine transporter gene and ADHD: role of sex and subtype.
abstract: 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.
  
  
  CONCLUSIONS
  The most important limitation of the study is the small size of the groups resulting from the stratification based on sex followed by subtype.
  
  
  CONCLUSIONS
  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.affiliation: Douglas Hospital Research Centre, Verdun, Que.
authors.forename: Sarojini M
authors.initials: SM
authors.lastname: Sengupta
authors.forename: Natalie
authors.initials: N
authors.lastname: Grizenko
authors.forename: Geeta A
authors.initials: GA
authors.lastname: Thakur
authors.forename: Johanne
authors.initials: J
authors.lastname: Bellingham
authors.forename: Rosherrie
authors.initials: R
authors.lastname: DeGuzman
authors.forename: Sandra
authors.initials: S
authors.lastname: Robinson
authors.forename: Marina
authors.initials: M
authors.lastname: TerStepanian
authors.forename: Anna
authors.initials: A
authors.lastname: Poloskia
authors.forename: S M
authors.initials: SM
authors.lastname: Shaheen
authors.forename: Marie-Eve
authors.initials: ME
authors.lastname: Fortier
authors.forename: Zia
authors.initials: Z
authors.lastname: Choudhry
authors.forename: Ridha
authors.initials: R
authors.lastname: Joober
mesh_terms: D001289:Attention Deficit Disorder with Hyperactivity / Q000235:genetics*; D002648:Child; D039721:Diagnostic and Statistical Manual of Mental Disorders; D005190:Family; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008297:Male; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012727:Sex Characteristics
chemical_list: D050484:Norepinephrine Plasma Membrane Transport Proteins; C493227:SLC6A2 protein, human