Evidence of missense mutations on the neuregulin 1 gene affecting function of prepulse inhibition

Background: Neuregulin I (NRG1) is one of the leading candidate genes in schizophrenia. Rodents with NRG1 knock-out showed significantly impaired prepulse inhibition (PPI) in the original report linking NRG1 to schizophrenia. A widely used surrogate measure of psychosis in animal models, PPI is considered a schizophrenia enclophenotype.We hypothesized that if NRG1 influences PPI in rodents,then it should have a similar effect on PPI in humans. Methods: We examined the potential neurophysiological effects of two nonsynonymous single nucleotide polymorphisms located on NRG1 (rs3924999 and rs10503929) on PPI. Genotyping was completed in 430 unrelated individuals, including 244 schizophrenia cases and 186 controls. PPI was available in a subgroup of 113 cases and 63 controls. Results: Rs3924999 genotype was significantly associated with PPI (p =.003): PPI was lowest in the subjects who were homozygous for the minor allele A/A carriers, intermediate in A/G carriers, and highest in homozygous major alleles G/G carriers. The associations persisted within cases (p =.02) and controls (p =.02) analyzed separately. An additive model suggested that rs3924999 alone contributes to 7.9% of the PPI variance. In contrast, rs10503929 genotype was not associated with PPI (p =.85). Schizophrenia patients had reduced PPI compared to control subjects (p =.04). Neither single nucleoticle polymorphism was associated with schizophrenia (all p > 37). However, schizophrenia patients with abnormal PPI may be associated with rs3924999 (p =.05). Conclusions: A missense mutation on rs3924999 of the neuregulin 1 gene may have a functional effect on prepulse inhibition in both schizophrenia and healthy control populations.