Abstract
BackgroundPrepulse inhibition (PPI) of the acoustic startle response (ASR) is an operational measure of sensorimotor gating and a promising endophenotype of schizophrenia. We have recently shown that the linked serotonin-2A receptor (5-HT2AR) A-1438 G and T102C polymorphisms modulate PPI in schizophrenia patients. Moreover, it was shown that genetic variation in the catechol-O-methyltransferase (COMT) and the neuregulin-1 (NRG-1) proteins influences PPI in schizophrenia patients and healthy volunteers. Therefore, we aimed to replicate these results and investigated the impact of the related polymorphisms on PPI in healthy human volunteers.MethodsWe analyzed the 5-HT2AR A-1438 G/T102C (rs6311/rs6313), the COMT Val158Met (rs4680), and the NRG-1 Arg38Gln (rs3924999) polymorphisms, assessing startle reactivity, habituation, and PPI of ASR in 107 healthy Caucasian volunteers.ResultsSubjects homozygous for the 5-HT2AR T102C-T/A-1438 G-A allele showed increased PPI levels. In particular, male subjects with the COMT Met158Met-genotype also showed elevated PPI. The NRG-1 Arg38Gln genotype did not have a significant impact on PPI. Startle reactivity was not affected by any of the investigated polymorphisms.ConclusionsWe confirmed in an independent sample of healthy volunteers that PPI is influenced by genetic variation in the 5-HT2AR gene. The influence of the COMT Val158Met genotype on PPI appears to be sex-specific. These results underscore the significance of the serotonin and dopamine systems in the modulation of sensorimotor gating.
Highlights
Prepulse inhibition (PPI) of the acoustic startle response (ASR) is widely used as an operational measure of sensorimotor gating [1]
We showed that the serotonin-2A receptor (5-HT2AR) A-1438G and T102C single nucleotide polymorphisms (SNPs) are associated with PPI in schizophrenia patients [14]
All of these SNPs have at some stage been suggested as susceptibility polymorphisms for schizophrenia (e.g., 16,17) but current meta-analyses do not support their role in aetiology of the disease itself, with the exception of the 5-HT2AR A-1438G polymorphism which may have a small effect on the risk for schizophrenia (SchizophreniaGene: www.schizophreniaforum.org/res/sczgene) [18]
Summary
Prepulse inhibition (PPI) of the acoustic startle response (ASR) is widely used as an operational measure of sensorimotor gating [1]. Roussos et al [12] followed with their finding that the catechol-O-methyltransferase (COMT) Val158Met SNP affects PPI in healthy male volunteers, a discovery which we recently replicated in a mixed-sex sample of schizophrenia patients [13]. We investigated the impact of four SNPs, which were previously linked to sensorimotor gating and schizophrenia, on PPI in a new and independent sample of healthy human volunteers: The linked 5-HT2AR T102C/A-1438G, the COMT Val158Met, and the NRG-1 Arg38Gln polymorphisms. Methods: We analyzed the 5-HT2AR A-1438G/T102C (rs6311/rs6313), the COMT Val158Met (rs4680), and the NRG-1 Arg38Gln (rs3924999) polymorphisms, assessed startle reactivity, habituation, and PPI of ASR in 107 healthy Caucasian volunteers. The influence of the COMT Val158Met genotype on PPI appears gender-specific These results underscore the significance of the serotonin and dopamine systems in the modulation of sensorimotor gating
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