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

Abstract

20Panic disorder (PD) is characterized by abrupt surges of intense fear and distress. There is evidence 21 for a genetic component in this disorder. We ran a meta-analysis of genome-wide association studies 22 of patients with PD, and found 25 single-nucleotide polymorphisms that were associated with the 23 disorder. Causal gene prediction based on these polymorphisms uncovered 20 hits. Exploratory 24 analyses suggested that these genes formed interactor networks, which was enriched in signaling 25 pathways associated with immune and inflammatory responses, as well as growth factors and other 26 developmental mediators. A subset of genes is enriched in limbic regions of the human brain and in 27 microglia and myelinating oligodendrocytes of mice. While these genes were not associated with 28 relevant neurobehavioral phenotypes in mutant mice, expression levels of several causal genes in 29 the amygdala, prefrontal cortex, hippocampus,, hypothalamus, and adrenal gland of recombinant 30 mouse strains was associated with endophenotypes of fear conditioning. Drug repositioning 31 prediction was unsuccessful, but this does not discard these genes and pathways as targets for 32 investigational drugs. In general, ASB3, EIF2S2, RASGRF2, and TRMT2B (and its coded proteins) 33 emerged as interesting targets for mechanistic research on PD. These exploratory findings point 34 towards hypotheses of pathogenesis and neuropharmacology that need to be further investigated. 35

Diverse avenues of research support the transmethylation theory of psychosis: implications for neuroprotection

“…The correlation between homocysteine and SAH levels was reported to be r = 0.413 [29]. SAH exerts feedback inhibition to decrease the activity of Nmethyltransferases (NMTs) that utilize SAM, i.e., catechol-O-methyltransferase (COMT) [30,31] and phenylethanolamine NMT (PNMT) [32], potentially leading to a buildup of dopamine, norepinephrine and epinephrine. In this regard, Silva et al [33] found that a polymorphism in the gene SAH hydrolase (AHCY), which breaks down SAH, was significantly associated with, panic disorder, an endophenotype of psychosis, and Bönig et al [34] presented data showing that elevation of SAH is one of the important factors in the psychosis associated with SAM depletion.…”

“…Obeid and Herrmann [291] suggested that because betaine is effective in mitigating CNS consequences of high homocysteine levels, it is very likely that the transport mechanism for homocysteine identified by others in synaptosomes [292] contributes to its transport, while Büdy et al [293] demonstrated that homocysteine is indeed transported by the large neutral amino-acid transport (LAT) proteins in endothelial membranes, and also present in the BBB, thereby explaining the efficacy of betaine for psychotic symptoms via its peripheral action. The advantage of betaine for an optimal outcome is that its methyl groups, unlike those generated by 5-methyl-THF, are not involved in the synthesis of epinephrine [32], N-methyldopamine (Figure 2) nor N-methyl-salsolinol [74].…”