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.
Highlights
Attention-deficit/hyperactivity disorder (ADHD) is an early onset childhood neurodevelopmental disorder with a prevalence estimated at 5.9%-7.1% worldwide [1, 2]
All cases were diagnosed ADHD for the first time according to the diagnostic criteria of the DSM-IV [1]; Clinical interviews of at least one parent were conducted by a trained child psychiatrist
We found significant differences in the distribution of maternal stress pregnancy, parental marital status, low birth weight and blood lead level (P = 0.006, P = 0.033, P = 0.018 and P = 0.009 respectively)
Summary
Attention-deficit/hyperactivity disorder (ADHD) is an early onset childhood neurodevelopmental disorder with a prevalence estimated at 5.9%-7.1% worldwide [1, 2]. ADHD is diagnosed approximately three times more frequently in boys than in girls [3]. Attention-deficit/hyperactivity disorder associated with KChIP1 rs1541665 in Kv channels accessory proteins of the disorder are pervasive and developmentally inappropriate inattention, excessive motor activity, impulsivity, and distractibility [4]. Sufferers usually have marked social, academic, occupational and family difficulties, and approximately 30%-50% of them have persisting symptoms as adults [5, 6]. A diagnosis of ADHD conveys a significant risk for other comorbid diseases, such as conduct disorder, learning disorders, mood disorders, and anxiety disorders [6, 7]
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