ABSTRACT: Abstract Background: Prepulse inhibition (PPI) is a measure of sensorimotor gating shown to be disrupted in schizophrenia. Since dysfunctions of the catecholamine signaling in the cortical circuitry has been associated with reduced PPI, associations between PPI and gene mutations involved in these signaling pathways need to be investigated. The catechol-O-methyltransferase (COMT) Val158Met single nucleotide polymorphism (SNP), which leads to lower COMT enzyme activity in dorsolateral prefrontal cortex of Met/Met carriers, has been shown to modulate PPI disruptions, with higher PPI associated with greater Met load in healthy subjects and schizophrenia patients. Interaction effects with functional SNPs on other catecholamine-related genes, namely norepinephrine transporter (NET), dopamine transporter (DAT), monoamine oxidase A (MAOA), and D2 receptor (DRD2), will shed more light on the specific way in which Val158Met SNP might influence PPI. The current study investigates (1) the association of the Val158Met SNP with PPI; and (2) interaction effects between the Val158Met SNP and other catecholamine-related SNPs. Methods: The Marine Resiliency Study (MRS) is a longitudinal study involving 2593 male active duty Marines recruited in Southern California, and participating in the study before deployment (1 month), and after deployment (1 week, 3 and 6 months). Acoustic startle reflex and PPI were measured on all visits after deployment however only the first visit data will be presented here. Exclusion criteria included low signal to noise, recent traumatic brain injury, poor hearing, inadequate habituation, and non-Caucasian ethnicity. 1193 subjects were included in the final analysis. Results: Following a 2-way ANOVA with the Val158Met SNP (rs4680) as between-subject and interstimulus interval (ISI) as within-subject factors, and controlling for population admixture, no main effect or interaction on PPI was found. For each of the other catecholamine-related SNPs, 3-way ANOVAs with ISI as within-subject factor and Val158Met SNP and the other candidate SNP as between-subject factors were conducted. For the DAT SNP (rs27072), a significant Val158Met SNP × DAT SNP × ISI interaction was found. However, this interaction effect does not survive correction for multiple comparisons and was found only for the ISI = 30?ms condition, not for the other 2 (60?ms and 120?ms), suggesting a type I error. Neither main effect nor interaction with Val158Met SNP was found for the DRD2 (rs1800497), MAOA (rs6323), and NET (rs28386840) SNPs. Conclusion: Despite sufficient power and sample size in the current study, the association between the Val158Met SNP and PPI reported in previous human studies has not been replicated. Also, no interaction effect was found between Val158Met and other candidate SNPs that influence catecholamine signaling. Further investigation will determine if the Val158Met effects on PPI are modulated by trauma history.
