title: The possible involvement of genetic variants of NET1 in the etiology of attention-deficit/hyperactivity disorder comorbid with oppositional defiant disorder.
abstract: BACKGROUND
  Attention-deficit/hyperactivity disorder (ADHD) and oppositional defiant disorder (ODD) often coexist and shared some genetic influences. Evidence from the existing literature indicated that comorbid with ODD may increase the heterogeneity of ADHD genetics. Our present study sought to investigate the role of norepinephrine transporter gene (NET1) for ADHD comorbid with ODD.
  
  
  METHODS
  Six single nucleotide polymorphisms (SNPs) of NET1 were genotyped for a total of 1,815 ADHD cases, including 587 subjects (32.3%) with ODD. Chi-square tests were conducted for pseudo case-control study comparing allelic and genotypic distributions between ADHD with and without ODD. Among them, there were 1,249 probands together with their parents composing trios for family-based association studies using transmission disequilibrium tests (TDTs). In addition, 1,337 ADHD probands have detailed information of ODD symptoms and were included for quantitative analyses with genotypes using analyses of covariance (ANCOVA). To consider the overlap and correlation of other comorbidities with ODD and eliminate their potential confounding effect, we further repeated above analyses for 'pure ADHD+ODD' versus 'ADHD-only' after excluding other comorbidities except for ODD.
  
  
  RESULTS
  The pseudo case-control study showed different allelic and genotypic distributions of SNP rs3785143 between ADHD with ODD and those without ODD. Family-based association tests indicated overtransmission of the T allele of rs3785143 in ADHD with ODD trios, but no biased transmission in those without ODD. ANCOVA showed association between genotypes of rs3785143 with ODD symptoms in ADHD probands, especially with 'Argumentative/Defiant Behavior (ADB)' dimension after controlling gender, age, clinical subtypes and intelligence. Above association still existed after removing the samples with other comorbidities.
  
  
  CONCLUSIONS
  NET1 was associated with comorbidity of ODD and ODD symptoms in ADHD probands. Our findings emphasize the importance of considering the comorbidity of ODD in ADHD genetic studies, especially ADHD with ADB. However, further replication in independent sample or different populations is still needed.
authors.affiliation: Peking University Sixth Hospital, Institute of Mental Health, Beijing, China; Key Laboratory of Mental Health, Ministry of Health (Peking University), Beijing, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Liu
authors.forename: Jia
authors.initials: J
authors.lastname: Cheng
authors.forename: Haimei
authors.initials: H
authors.lastname: Li
authors.forename: Li
authors.initials: L
authors.lastname: Yang
authors.forename: Qiujin
authors.initials: Q
authors.lastname: Qian
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000293:Adolescent; D000328:Adult; D001289:Attention Deficit Disorder with Hyperactivity / Q000453:epidemiology / Q000235:genetics*; D019958:Attention Deficit and Disruptive Behavior Disorders / Q000453:epidemiology / Q000235:genetics*; D002648:Child; D015897:Comorbidity; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D008297:Male; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000235:genetics*; D010290:Parents; D020641:Polymorphism, Single Nucleotide
chemical_list: D050484:Norepinephrine Plasma Membrane Transport Proteins; C493227:SLC6A2 protein, human
keywords: ADHD; NET1; ODD; association