Pharmacological and autoradiological studies suggest that mu-opioid receptor (OPRM) mediated neurotransmission is involved in the generation of absence seizures. Mutation screening of the human OPRM gene identified a common amino acid substitution polymorphism (Asn40Asp) that differentially modulates the binding affinity of beta-endorphin and signal transduction of the receptor. The present association study tested the candidate gene hypothesis that the Asn40Asp substitution polymorphism in the N-terminal OPRM domain confers genetic susceptibility to idiopathic absence epilepsy (IAE). The genotypes of the Asn40Asp polymorphism were assessed by allele-specific polymerase chain reaction in 72 German IAE patients and in 340 ethnically matched control subjects. The frequency of the Asp40 allele was significantly increased in the IAE patients [f(Asp40) = 0.139] compared to the controls [f(Asp40) = 0.078; chi2 = 5.467, df = 1, P = 0.019; OR = 2.03; 95%-CI: 1.12-3.68]. This allelic association suggests that the functional Asp40 variant of OPRM modulates neuronal excitability underlying the epileptogenesis of IAE.