Association of NPSR1 gene variation and neural activity in patients with panic disorder and agoraphobia and healthy controls

Neuroimage Clin. 2019;24:102029. doi: 10.1016/j.nicl.2019.102029. Epub 2019 Oct 21.


Introduction: The neurobiological mechanisms behind panic disorder with agoraphobia (PD/AG) are not completely explored. The functional A/T single nucleotide polymorphism (SNP) rs324981 in the neuropeptide S receptor gene (NPSR1) has repeatedly been associated with panic disorder and might partly drive function respectively dysfunction of the neural "fear network". We aimed to investigate whether the NPSR1 T risk allele was associated with malfunctioning in a fronto-limbic network during the anticipation and perception of agoraphobia-specific stimuli.

Method: 121 patients with PD/AG and 77 healthy controls (HC) underwent functional magnetic resonance imaging (fMRI) using the disorder specific "Westphal-Paradigm". It consists of neutral and agoraphobia-specific pictures, half of the pictures were cued to induce anticipatory anxiety.

Results: Risk allele carriers showed significantly higher amygdala activation during the perception of agoraphobia-specific stimuli than A/A homozygotes. A linear group x genotype interaction during the perception of agoraphobia-specific stimuli showed a strong trend towards significance. Patients with the one or two T alleles displayed the highest and HC with the A/A genotype the lowest activation in the inferior orbitofrontal cortex (iOFC).

Discussion: The study demonstrates an association of the NPSR1rs324981 genotype and the perception of agoraphobia-specific stimuli. These results support the assumption of a fronto-limbic dysfunction as an intermediate phenotype of PD/AG.

Trial registration: NCT01323556.

Keywords: Agoraphobia; Imaging genetics; NPSR1; Panic disorder; Westphal-Paradigm; fMRI.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Agoraphobia / genetics*
  • Agoraphobia / physiopathology*
  • Agoraphobia / psychology
  • Alleles
  • Anticipation, Psychological
  • Female
  • Frontal Lobe / physiopathology
  • Genetic Variation
  • Genotype
  • Humans
  • Limbic System / physiopathology
  • Magnetic Resonance Imaging
  • Male
  • Nerve Net / physiopathology
  • Panic Disorder / genetics*
  • Panic Disorder / physiopathology*
  • Panic Disorder / psychology
  • Perception
  • Polymorphism, Single Nucleotide
  • Receptors, G-Protein-Coupled / genetics*
  • Risk Assessment


  • NPSR1 protein, human
  • Receptors, G-Protein-Coupled

Associated data