Overall we partially confirmed our predictions and when comp

Overall, we partially confirmed our predictions, and, when compared to the other existing dataset exploring the interaction among CRFR1, FAAH, and anxiety, our data are somewhat confirmatory. Demers and colleagues (Demers et al., 2016) found one (protective) CRFR1 minor allele (rs110402) and the (less risky) FAAH AA or AC S63845 were associated with increased anxiety disorder diagnosis; they did not measure baseline cortisol. However, if the individuals in the Demers study were non-minor at CRFR1 rs7209436 and rs242924, then their participants would match our results of FAAH AA or AC being riskier for anxiety in individuals who were not carriers of all three minor alleles. But, the sample populations in the two studies were not identical. In our sample, it is important to note that individuals were not clinically anxious, and our anxiety scores represent natural variation in state (current) anxiety in a population; whereas the individuals in the Demers et al. study met DSM-5 criteria for anxiety disorder. However, data suggest that state, trait, and clinical anxiety are related and therefore biomarkers related to one of these measures may be relevant for all of them. For example, state anxiety increases after stress (Ackerl et al., 2002) and this is true for individuals high and low for trait anxiety (Jezova et al., 2004; Roelofs et al., 2007), thus is it plausible that baseline cortisol at the time of state anxiety measure and genotypes related to anxiety and stress responsiveness would be associated with both state and trait anxiety. Moreover, state and trait anxiety are highly correlated (Spielberger, 1983) and individuals with higher levels of anxiety sensitivity are more at-risk for clinical anxiety disorders (Naragon-Gainey, 2010). Nonetheless, it is possible that biomarkers of state anxiety and those for trait or pathological anxiety differ.
Acknowledgements Project FRONTIER is currently funded by TTUHSC Garrison Institute on Aging; the TTUHSC F. Marie Hall Institute for Rural and Community Health participated in previous management of Project FRONTIER. This research was partially funded by the National Science Foundation (PRISM; NSF Grant No. 1035096) and by the TTU Center for Active Learning and Undergraduate Engagement (CALUE; now TRUE). We thank the PRISM PIs (Drs. G. Brock Williams, Sophia Jang, Nancy McIntyre, Jaclyn Canas-Carrell, and Jerry Dwyer), Dr. James Carr, Dr. Andrew Littlefield, Jessica Spott, Jerylme Robins, Dr. P. Hemachandra Reddy, and the Garrison Institute on Aging for their support. We extend a special thank you to Dr. Linda Yin for her support and wisdom, and for her exceptional work on, and dedication to, the Project FRONTIER biobank. Lastly, we would like to thank two anonymous reviewers for their helpful comments and critiques of an earlier version of this manuscript.
Fatty-acid amide hydrolase (FAAH) is the major catabolic enzyme for a range of bioactive lipids called fatty-acid amides (FAAs)., These FAAs include -acyl ethanolamines, such as anandamide (AEA), that act as endogenous ligands for cannabinoid receptors (i.e. endocannabinoids). Other substrates of FAAH include palmitoylethanolamide (PEA), oleoylethanolamine (OEA), and -acyl-taurines. 2-Arachidonoylglycerol (2-AG) is another related endocannabinoid and FAA, but is metabolised mostly by monoacylglycerol lipase (MAGL). AEA has roles in nociception, fear-extinction memory, anxiety, and depression., knockout mice have elevated brain concentrations of AEA, display an analgesic phenotype in response to acute thermal stimuli, and show reduced pain in formalin and carrageenan inflammatory models., FAAH is therefore an attractive drug target for treating pain, anxiety, and depression, although recent clinical trials with FAAH inhibitors were unsuccessful., The human gene contains a commonly carried hypomorphic single-nucleotide polymorphism (SNP) (C385A; rs324420; C allele frequency 74%, A 26%) that significantly reduces the activity of the FAAH enzyme. Genetic association studies have investigated the link between this and other SNPs and pain sensitivity., , Notably, homozygous carriers of the hypomorphic SNP (A allele) in a cohort of women undergoing breast cancer surgery were less sensitive to cold pain and had a reduced need for postoperative analgesia. Furthermore, a mouse knock-in model of the human SNP showed that both the mouse and human SNP carriers display enhanced fear-extinction learning and decreased anxiety-linked behaviours. Here, we describe a pain-insensitive patient with a non-anxious disposition presenting with a novel genetic disorder associated with loss of function of .