Interaction between lead and noradrenergic genotypes affects neurocognitive functions in attention-deficit/hyperactivity disorder: a case control study

Abstract

Background We aimed to evaluate neurocognitive functions associated with blood lead levels and their relationship with the interactions between lead and dopaminergic or noradrenergic genotypes in youths with attention-deficit/hyperactivity disorder (ADHD).Methods A total of 267 youths with ADHD and 101 healthy controls (aged 5 to 18 years) participated in this study. A semi-structured interview, the Korean Kiddie Schedule for Affective Disorders and Schizophrenia–Present and Lifetime version (K-SADS-PL), was conducted for psychiatric diagnostic evaluation. Blood lead levels were measured, and their interaction with dopaminergic or noradrenergic genotypes for ADHD, namely 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. Path analysis model was used to identify mediating effects of neurocognitive functions on blood lead levels and ADHD symptoms.Results 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=0.004). Blood lead levels showed a positive correlation with scores on omission errors of CPT (r=0.16, p=0.01) and on the hyperactivity-impulsivity subscale of ADHD-RS (r=0.14, p=0.03). In the multivariable linear regression model, blood lead levels were associated with CPT omission errors (B=0.14, p=0.02). Regarding the effects of lead on ADHD symptoms, hyperactivity-impulsivity was mediated by omission errors of CPT. An interaction effect was detected between ADRA2A genotype and lead levels on omission errors (B=0.12, p=0.04).Conclusions 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.