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.

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.

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