Circulating PACAP peptide and PAC1R genotype as possible transdiagnostic biomarkers for anxiety disorders in women: a preliminary study

Abstract

Research in humans implicates PACAP as a useful biomarker for the severity of psychiatric symptoms in response to psychological stressors, and work in rodent models suggests that PACAP manipulation exerts downstream effects on peripheral hormones and behaviors linked to the stress response, providing a potential therapeutic target. Prior work has also suggested a potential sex difference in PACAP effects due to differential estrogen regulation of this pathway. Therefore, we examined serum PACAP and associated PAC1R genotype in a cohort of males and females with a primary diagnosis of generalized anxiety disorder (GAD) and nonpsychiatric controls. We found that, while circulating hormone levels were not associated with a GAD diagnosis overall (p = 0.19, g = 0.25), PACAP may be associated with GAD in females (p = 0.04, g = 0.33). Additionally, among patients with GAD, the risk genotype identified in the PTSD literature (rs2267735, CC genotype) was associated with higher somatic anxiety symptom severity in females but lower somatic anxiety symptom severity in males , adjusted p = 0.03). Taken together, the associations between the risk genotype, circulating PACAP, and somatic anxiety severity were stronger among females than males. These results indicate a potential underlying biological etiology for sex differences in stress-related anxiety disorders that warrants further study.

Peripheral Biomarkers in DSM-5 Anxiety Disorders: An Updated Overview

“…Neuropeptides' role in ADs have been extensively studied in animal and human samples, underlying their role in the pathophysiology of ADs and as promising new targets for treatment interventions [75,76]. The most important neuropeptides that play a role in the modulation of stress-related behaviors and anxiety are cholecystokinin (CCK) [77][78][79], oxytocin (OXT) [80][81][82][83], substance P [84], neuropeptide Y, galanin [76], pituitary adenylate activator polypeptide (PACAP) [85,86], ghrelin [87], and leptin [88].…”

“…Pituitary Adenylate Cyclase-Activating Polypeptide. A study reported female GAD patients, but not male subjects, to be associated with lower levels of circulating PACAP compared with HCs, as well as with worse anxiety somatic symptoms and insomnia when associated with a specific gene polymorphism (PAC1R CC) [86]. This gender difference could be related to an estrogen response element of the PAC1R allele [85].…”

Probing the VIPR2 Microduplication Linkage to Schizophrenia in Animal and Cellular Models

“…Of note, the behavioral phenotype of PACAPknockout mice varies under different environmental conditions and different genetic backgrounds (mouse strain), and with the specific gene sequences that were deleted in the different PACAP gene knockout models. In humans, the dysregulation of PACAP and the PAC1 receptor has been associated with schizophrenia, depression, and post-traumatic stress disorder (PTSD) (Hashimoto et al, 2007(Hashimoto et al, , 2010Ressler et al, 2011;Mercer et al, 2016;Ross et al, 2020).…”

Pituitary Adenylate Cyclase-Activating Polypeptide in Learning and Memory

“…A single-nucleotide polymorphism (SNP) in the adcyap1r1 gene encoding PAC1R is associated with symptom severity in women, but not men; altered DNA methylation of the same gene is associated with PTSD in both sexes ( Ressler et al, 2002 ; Almli et al, 2013 ). The risk allele for PTSD is also associated with symptom severity in GAD females, but not males ( Ross et al, 2020 ). The SNP is located in an estrogen-response element (ERE), and the nucleotide change interferes with estradiol-estrogen receptor alpha binding the ERE, leading to a decrease in receptor expression ( Mercer et al, 2016 ).…”