The Influence of Schizophrenia-Related Neuregulin-1 Polymorphisms on Sensorimotor Gating in Healthy Males

Background: Neuregulin-1 (NRG1) variations have been shown to modulate schizophrenia candidate endophenotypes related to brain structure and function. The objective of this cross-sectional genetic association study was to determine the relationship of six core single-nucleotide polymorphisms within the NRG1 gene identified as promising schizophrenia risk genes (rs6994992, SNP8NRG221132, SNP8NRG241930, rs3924999, rs2439272 and rs10503929) to prepulse inhibition (PPI) of the acoustic startle reflex, a well validated schizophrenia endophenotype. Methods: PPI was tested in a highly homogeneous study entry cohort (n = 445) of carefully screened healthy, young male army conscripts originating from the Greek LOGOS project (Learning on Genetics of Schizophrenia Spectrum). The QTPHASE from the UNPHASED package was used for the association analysis of each single-nucleotide polymorphisms or haplotype data. Results: Reduced PPI, particularly at 75-dB_120-msec and 85-dB_60-msec trials, was related to the SNP8NRG241930 G allele and especially the rs6994992 T allele and rs2439272 C allele. Haplotype analysis followed up by risk versus no-risk groups Analysis of variance confirmed that the rs10503929 and rs3924999 SNPs were also associated with PPI reductions, when combined with rs2439272. Conclusions: We provide solid evidence for a role of NRG1 risk genotype variations in PPI reductions in a large and demographically and genetically highly homogeneous cohort of healthy young males. These results further validate NRG1 as a candidate gene for the schizophrenia and spectrum disorders and improve our understanding of its functional mechanisms within the human brain because they suggest an influence of the gene in the neural substrate mediating sensorimotor gating.