Variation in an Iron Metabolism Gene Moderates the Association Between Blood Lead Levels and Attention-Deficit/Hyperactivity Disorder in Children

Abstract

Although attention-deficit/hyperactivity disorder (ADHD) is a heritable neurodevelopmental condition, there is also considerable scientific and public interest in environmental modulators of its etiology. Exposure to neurotoxins is one potential source of perturbation of neural, and hence psychological, development. Exposure to lead in particular has been widely investigated and is correlated with neurodevelopmental outcomes, including ADHD. To investigate whether this effect is likely to be causal, we used a Mendelian randomization design with a functional gene variant. In a case-control study, we examined the association between ADHD symptoms in children and blood lead level as moderated by variants in the hemochromatosis (HFE) gene. The HFE gene regulates iron uptake and secondarily modulates lead metabolism. Statistical moderation was observed: The magnitude of the association of blood lead with symptoms of ADHD was altered by functional HFE genotype, which is consistent with a causal hypothesis.

Lead exposure and child maltreatment as models for how to conceptualize early‐in‐life risk factors for violence

“…Nevertheless, a recent genome-wide association study of sensitivity to lead exposure in fruit flies also has found pronounced sex differences, such that none of the genes that conferred sensitivity to lead on activity level in females were overlapping with those identified in males (Zhou et al, 2016). Note that the interaction between C282Y and blood lead level was not a significant predictor of children's symptoms of conduct disorder and oppositional defiant disorder in this study (Nigg et al, 2016).…”

“…Thus, in HFE , a change from cysteine to thymine at amino acid position 282 (C282Y) and from histidine to aspartic acid at amino position 63 (H63D) causes a shortage of the HFE protein and, ultimately, increased iron uptake in the gut (Hanson, Imperatore, & Burke, ). Consistent with the likelihood that individuals who carry the C282Y mutations absorb more lead do than wild‐type carriers, lead exposure in the normal range was more strongly associated with symptoms of hyperactivity‐impulsivity according to parents and teachers for youth (6‐ to 17‐year‐olds) who carried the mutation than for youth who carried the wild‐type version of the gene (Nigg, Elmore, Natarajan, Friderici, & Nikolas, ). This interaction effect was detected more reliably in boys than in girls, although the sample of girls was smaller than that of boys (Nigg et al., ).…”

“…Consistent with the likelihood that individuals who carry the C282Y mutations absorb more lead do than wild‐type carriers, lead exposure in the normal range was more strongly associated with symptoms of hyperactivity‐impulsivity according to parents and teachers for youth (6‐ to 17‐year‐olds) who carried the mutation than for youth who carried the wild‐type version of the gene (Nigg, Elmore, Natarajan, Friderici, & Nikolas, ). This interaction effect was detected more reliably in boys than in girls, although the sample of girls was smaller than that of boys (Nigg et al., ). Nevertheless, a recent genome‐wide association study of sensitivity to lead exposure in fruit flies also has found pronounced sex differences, such that none of the genes that conferred sensitivity to lead on activity level in females were overlapping with those identified in males (Zhou et al., ).…”

Research Review: Environmental exposures, neurodevelopment, and child mental health – new paradigms for the study of brain and behavioral effects

“…At the morphological level, prenatal lead exposure delays structural development of the fetal cortex (Bull, McCauley, Taylor, & Croften, 1983), and affects differentiation and synaptogenesis (Regan, 1989). Although it is more difficult to study potentially causal mechanisms in human studies, Mendelian randomization as mentioned earlier lends further weight to the causal evidence linking lead exposure to neurobehavioral outcomes in children (Nigg, Elmore, Natarajan, Friderici, & Nikolas, 2016).…”

Where Do Epigenetics and Developmental Origins Take the Field of Developmental Psychopathology?

“…Nigg et al (in press) reported that child genotype on the HFE gene (human hemochromatosis protein gene; 6p22.2) moderated the strength of association of children’s blood lead level with their teacher-rated hyperactivity symptoms. This was observed at blood lead levels that are typical in the U.S. population (about 1ug/dL), suggesting these effects may be widespread.…”