Polymorphism of Estrogen Receptor Genes and Its Interactions With Neurodevelopmental Genes in Attention Deficit Hyperactivity Disorder Among Chinese Han Descent

Abstract

Objective Attention deficit hyperactivity disorder (ADHD) is a polygenic neurodevelopmental disorder with significant gender differences. The sexual dimorphism of ADHD may be associated with estrogen acting through estrogen receptors (ESR). This study investigates the impact of <i>ESR</i> gene polymorphism and its interactions with neurodevelopmental genes on ADHD susceptibility.Methods The study compared genotyping data of single nucleotide polymorphisms in <i>ESR1</i> and <i>ESR2</i> in 1,035 ADHD cases and 962 controls. The gene-gene interactions between <i>ESR</i> genes and three neurodevelopmental genes (brain-derived neurotrophic factor [<i>BDNF</i>], synaptosomal-associated protein of 25 kDa gene [<i>SNAP25</i>], and cadherin-13 [<i>CDH13<i></i></i>]) in ADHD were investigated using generalized multifactor dimensionality reduction and verified by logistic regression analysis.Results The G allele of rs960070/<i>ESR2</i> (empirical p=0.0076) and the A allele of rs8017441/<i>ESR2</i> (empirical p=0.0426) were found significantly higher in ADHD cases than in the controls but not in male or female subgroups. Though no difference was found in all subjects or females, the A allele of rs9340817/<i>ESR1</i> (empirical p=0.0344) was found significantly higher in ADHD cases than controls in males. We also found genetic interaction models between <i>ESR2</i> gene, neurodevelopmental genes and ADHD susceptibility in males (<i>ESR2</i> rs960070/<i>BDNF</i> rs6265/<i>BDNF</i> rs2049046/<i>SNAP25</i> rs362987/<i>CDH13</i> rs6565113) and females (<i>ESR2<i></i></i> rs960070/<i>BDNF<i></i></i> rs6265/<i>BDNF</i> rs2049046) separately, though it was negative in overall subjects.Conclusion The <i>ESR</i> gene polymorphism associates with ADHD among Chinese Han children, with interactions between <i>ESR<i></i></i> genes and neurodevelopmental genes potentially influencing the susceptibility of ADHD.