Attention-deficit/hyperactivity disorder associated with KChIP1 rs1541665 in Kv channels accessory proteins

PLoS One. 2017 Nov 27;12(11):e0188678. doi: 10.1371/journal.pone.0188678. eCollection 2017.

Abstract

Attention-deficit/hyperactivity disorder (ADHD) is an early onset childhood neurodevelopmental disorder with high heritability. A number of genetic risk factors and environment factors have been implicated in the pathogenesis of ADHD. Genes encoding for subtypes of voltage-dependent K channels (Kv) and accessory proteins to these channels have been identified in genome-wide association studies (GWAS) of ADHD. We conducted a two-stage case-control study to investigate the associations between five key genes (KChIP4, KChIP1, DPP10, FHIT, and KCNC1) and the risk of developing ADHD. In the discovery stage comprising 256 cases and 372 controls, KChIP1 rs1541665 and FHIT rs3772475 were identified; they were further genotyped in the validation stage containing 328cases and 431 controls.KChIP1 rs1541665 showed significant association with a risk of ADHD at both stages, with CC vs TT odds ratio (OR) = 1.961, 95% confidence interval (CI) = 1.366-2.497, in combined analyses (P-FDR = 0.007). Moreover, we also found rs1541665 involvement in ADHD-I subtype (OR (95% CI) = 2.341(1.713, 3.282), and Hyperactive index score (P = 0.005) in combined samples.Intriguingly, gene-environmental interactions analysis consistently revealed the potential interactionsof rs1541665 collaboratingwith maternal stress pregnancy (Pmul = 0.021) and blood lead (Padd = 0.017) to modify ADHD risk. In conclusion, the current study provides evidence that genetic variants of Kv accessory proteins may contribute to the susceptibility of ADHD.Further studies with different ethnicitiesare warranted to produce definitive conclusions.

MeSH terms

  • Attention Deficit Disorder with Hyperactivity / genetics*
  • Child
  • Female
  • Gene-Environment Interaction
  • Genetic Predisposition to Disease*
  • Genome-Wide Association Study
  • Humans
  • Kv Channel-Interacting Proteins / genetics*
  • Male
  • Polymorphism, Single Nucleotide / genetics*
  • Risk Factors
  • Surveys and Questionnaires

Substances

  • KCNIP1 protein, human
  • Kv Channel-Interacting Proteins

Grants and funding

This study is supported partially by the National Natural Science Foundation of China (81101016), The Fundamental Research Funds for the Central Universities, HUST (2016 YXMS218) to Dr. Jing Wu.