Metanalysis of genome-wide association studies for panic disorder suggest pathways and mechanisms of pathogenesis

Panic disorder (PD) is characterized by abrupt surges of intense fear and distress. There is evidence for a genetic component in this disorder. We ran a meta-analysis of genome-wide association studies of patients with PD, and found 25 single-nucleotide polymorphisms that were associated with the disorder. Causal gene prediction based on these polymorphisms uncovered 20 hits. Exploratory analyses suggested that these genes formed interactor networks, which was enriched in signaling pathways associated with immune and inflammatory responses, as well as growth factors and other developmental mediators. A subset of genes is enriched in limbic regions of the human brain and in microglia and myelinating oligodendrocytes of mice. While these genes were not associated with relevant neurobehavioral phenotypes in mutant mice, expression levels of several causal genes in the amygdala, prefrontal cortex, hippocampus, hypothalamus, and adrenal gland of recombinant mouse strains was associated with endophenotypes of fear conditioning. Drug repositioning prediction was unsuccessful, but this does not discard these genes and pathways as targets for investigational drugs. In general, ASB3 , EIF2S2, RASGRF2 , and TRMT2B (and its coded proteins) emerged as interesting targets for mechanistic research on PD. These exploratory findings point towards hypotheses of pathogenesis and neuropharmacology that need to be further investigated.