Abstract
BackgroundLead is known to be associated with attention-deficit/hyperactivity disorder (ADHD) even at low concentrations. We aimed to evaluate neurocognitive functions associated with lead in the blood and the interactions between lead and dopaminergic or noradrenergic pathway-related genotypes in youths with ADHD.MethodsA total of 259 youths with ADHD and 96 healthy controls (aged 5–18 years) enrolled in this study. The Korean Kiddie Schedule for Affective Disorders and Schizophrenia–Present and Lifetime version was conducted for psychiatric diagnostic evaluation. Blood lead levels were measured, and their interaction with dopaminergic or noradrenergic genotypes for ADHD; namely, the dopamine transporter (DAT1), dopamine receptor D4 (DRD4), and alpha-2A-adrenergic receptor (ADRA2A) genotypes were investigated. All participants were assessed using the ADHD Rating Scale-IV (ADHD-RS). Participants also completed the continuous performance test (CPT) and Stroop Color-Word Test (SCWT). Analysis of covariance was used for comparison of blood lead levels between ADHD and control groups. A multivariable linear regression model was used to evaluate the associations of blood lead levels with the results of ADHD-RS, CPT, and SCWT; adjusted for intelligence quotient (IQ), age, and sex. A path analysis model was used to identify the mediating effects of neurocognitive functions on the effects of blood lead on ADHD symptoms. To evaluate the effect of the interaction between blood lead and genes on neuropsychological functions, hierarchical regression analyses were performed.ResultsThere was a significant difference in blood lead levels between the ADHD and control groups (1.4 ± 0.5 vs. 1.3 ± 0.5 μg/dL, p = .005). Blood lead levels showed a positive correlation with scores on omission errors(r = .158, p = .003) and response time variability (r = .136, p = .010) of CPT. In the multivariable linear regression model, blood lead levels were associated with omission errors (B = 3.748, p = .045). Regarding the effects of lead on ADHD symptoms, hyperactivity-impulsivity was mediated by omission errors. An interaction effect was detected between ADRA2A DraI genotype and lead levels on omission errors (B = 5.066, p = .041).ConclusionsOur results indicate that neurocognitive functions at least partly mediate the association between blood lead levels and ADHD symptoms, and that neurocognitive functions are affected by the interaction between blood lead levels and noradrenergic genotype.
Highlights
Lead is known to be associated with attention-deficit/hyperactivity disorder (ADHD) even at low concentrations
There was a significant difference in blood lead levels between the ADHD and control groups (1.4 ± 0.5 vs. 1.3 ± 0.5 μg/dL, p = .005)
Our results indicate that neurocognitive functions at least partly mediate the association between blood lead levels and ADHD symptoms, and that neurocognitive functions are affected by the interaction between blood lead levels and noradrenergic genotype
Summary
Lead is known to be associated with attention-deficit/hyperactivity disorder (ADHD) even at low concentrations. Attention-deficit/hyperactivity disorder (ADHD) occurs in 5% of children [1] and is characterized by symptoms of hyperactivity, impulsivity, and inattention leading to functional impairments in social activities, performance at school, and family relationships [2]. Many candidate genes, including dopaminergic, serotonergic, and noradrenergic pathway-related genes, are reported to be associated with ADHD [5, 6]. Genes in the dopaminergic pathway, such as the dopamine transporter (DAT1) and dopamine D4 receptor (DRD4), are most commonly reported as having positive associations with ADHD [6]. Recent imaging studies have focused on these two genes [8] Noradrenergic genes, such as the alpha-2A adrenergic receptor gene (ADRA2A), have been studied in the context of their relationship with symptoms and executive functions in ADHD [9, 10]
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