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  • We found the FAAH CC

    2021-09-22

    We found the FAAH CC genotype only confers risk for anxiety if the CRFR1 minor allele combination is also present. Additionally, the FAAH AA/AC genotype was riskier than the CC if the three CRFR1 minor ornidazole mg were not present. This result is somewhat contrary to our prediction as we hypothesized the FAAH AA/AC and the CRFR1 minor combination would buffer individuals from anxiety both in combination and on their own. While it is unknown why we found this flipped effect of FAAH SNP depending on CRFR1 SNP status, it may be that in response to CRF signaling (which may vary by genotype and/or stress), individuals with higher baseline AEA (those with AA/AC) experience a greater relative drop in AEA compared to the CC individuals that started with less AEA. If the greater drop corresponds to proportionally greater release of inhibition (by decreased binding at more CB1 receptors) it may therefore relate to more glutamatergic output and thus higher BLA activity and increased anxiety. To our knowledge, information on the specific AEA binding dynamics and numbers of CB1 receptors in the BLA among individuals who differ in FAAH genotype is not available. However, data from rodents suggest that the level of CB1 binding is important for signaling - the higher the CB1 agonist concentration, the lower the firing rate of BLA neurons (Pistis et al., 2004), suggesting that a more pronounced decrease in AEA could possible result in greater BLA output. Additionally, recent work highlights the importance of CB1 in understanding the interactions among the EC system, stress, and anxiety. For example, chronic stress, sustained glucocorticoids, and early life stress can decrease CB1 receptor density in the brain; blocking CB1 can increase anxiety in baseline and post-stress scenarios and can increase HPA axis activity (Morena et al., 2016; Balsevich et al., 2017; Ibarra-Lecue et al., 2018; Hill et al., 2019). Moreover, another recent study found FAAH A carriers had higher anxiety (and depression) than CC individuals, but only if they were exposed to childhood adversity (Lazary et al., 2016); CRFR1 genotype, CB1, and cortisol were not assessed. These data suggest that the role of CB1 is likely important and may help to explain how gene by environment interactions impact anxiety. Future studies should determine if CRFR1 minor alleles play a role in the relationship between FAAH genotype, CB1 dynamics, and anxiety. It is important to note that despite the abundance of data on the role of CRFR1 SNPS in various stress and affective state outcomes, it is unclear what the functional significance of these SNPS are at the molecular/cellular level (Binder and Nemeroff, 2010). The gene encoding CRFR1 is located on chromosome 17 and contains 13 exons spanning 51 kB (Binder and Nemeroff, 2010). The three CRFR1 SNPS included here are located near the 5’ end and are in the first and second intron region (Chen et al., 1993; Vita et al., 1993). But it is unclear what these SNPs do to CRFR1 functionality; future studies addressing this would be beneficial for interpreting data. Additionally, several previous reports of CRFR1 minor alleles being protective are in situations that involved early life trauma (Tyrka et al., 2009; Bradley et al., 2008; Polanczyk et al., 2009). Specifically, in white, non-Hispanic individuals (n = 129), those with the common homozygous genotypes of GG (vs. AG or AA; rs110402) or GG (vs. GT or TT; rs242924) who experienced childhood trauma showed increased cortisol response to the Dex/CRF challenge test; but, there was no impact of genotype on cortisol in individuals without childhood trauma (Tyrka et al., 2009). Moreover, the presence of two copies of the minor allele for each of the three SNPs was found to be protective against adult depression in African American, non-Hispanic individuals (n = 422) who experienced severe early life stress/trauma (Bradley et al., 2008). Additionally, in an additive model, individuals (n = 368, Caucasians) homozygous for the minor allele at each SNP (TT, AA, or TT) showed decreased cortisol response to an acute stressor (Trier Social Stress Test; Mahon et al., 2013). And, higher baseline cortisol was associated with increased trait anxiety (Spielberger STAI-T) in individuals homozygous for the common allele of rs7209436 (CC) and rs110402 (GG); authors did not report main effects of genotype on anxiety measures (Mahon et al., 2013). Thus, it is therefore possible that a gene by environment interaction is important for interpreting the role of CRFR1 and FAAH genotype (see Lazary et al., 2016) in stress physiology and affect (Heim and Binder, 2012). In line with this, recent studies have shown that early life trauma can lead to differential DNA methylation (Roberts et al., 2018) and that this impact is directly related to stress-responsive genes (FKBP5) and affect, mainly depression (Binder, 2009; Binder et al., 2008; A. Zannas and Binder, 2014; Zannas et al., 2016). We do not have information on exposure to early life trauma in our study population, but this would be an interesting area for future study.