# Impact of NPSR1 gene variation on the neural correlates of phasic and sustained fear in spider phobia—an imaging genetics and independent replication approach

## TL;DR

This study explores how a specific gene variant affects brain activity and fear responses in people with spider phobia, using brain scans and treatment outcomes.

## Contribution

The study provides new evidence linking the NPSR1 gene variant to altered ACC activation during fear processing in spider phobia.

## Key findings

- T-allele carriers showed lower ACC activation compared to AA homozygotes during fear processing.
- The effect was replicated in a smaller sample for sustained fear with a medium effect size.
- No significant association was found between the gene variant and symptom reduction after treatment.

## Abstract

The functional neuropeptide S receptor 1 (NPSR1) gene A/T variant (rs324981) is associated with fear processing. We investigated the impact of NPSR1 genotype on fear processing and on symptom reduction following treatment in individuals with spider phobia. A replication approach was applied [discovery sample: Münster (MS) nMS = 104; replication sample Würzburg (WZ) nWZ = 81]. Participants were genotyped for NPSR1 rs324981 [T-allele carriers (risk) versus AA homozygotes (no-risk)]. A sustained and phasic fear paradigm was applied during functional magnetic resonance imaging. A one-session virtual reality exposure treatment was conducted. Change of symptom severity from pre to post treatment and within session fear reduction were assessed. T-allele carriers in the discovery sample displayed lower anterior cingulate cortex (ACC) activation compared to AA homozygotes independent of condition. For sustained fear, this effect was replicated within a small cluster and medium effect size. No association with symptom reduction was found. Within-session fear reduction was negatively associated with ACC activation in T-allele carriers in the discovery sample. NPSR1 rs324981 genotype might be associated with fear processing in the ACC in spider phobia. Interpretation as potential risk-increasing function of the NPSR1 rs324981 T-allele via impaired top-down control of limbic structures remains speculative. Potential association with symptom reduction warrants further research.