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

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

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.