rs324420 The FAAH gene contains a
single nucleotide polymorphism (SNP) called rs324420. The variant allele, C385A, is associated with a higher sensitivity of FAAH to
proteolytic degradation and a shorter
half-life compared to the standard C variant. As a result, carriers of the A variant has increased
N-acylethanolamine (NAE) levels and
anandamide (AEA) signaling at the
cannabinoid receptors. The A variant may be responsible for lower levels of the FAAH protein seen in high-performing athletes, providing increased physical and mental fitness. However, among elite
Polish athletes, the A variant is under-represented regardless of metabolic characteristics of their sport disciplines; this seems to suggest an opposite role for the A variant. A 2017 study found a strong correlation between national percentage of very happy people (as measured by the
World Values Survey) and the presence of the rs324420 C385A allele in citizens' genetic make-up. The C385A allele was initially provisionally linked to drug abuse and dependence but this was not borne out in subsequent studies. According to later studies, carriers of the A allele are more likely to try cannabis, but less likely to become dependent.
microdeletion FAAH-OUT is a
pseudogene downstream of the
FAAH coding region. It expresses a
long non-coding RNA (lncRNA) that increases the expression of FAAH. In 2019, a Scottish woman named
Jo Cameron was found to have both a previously unreported
microdeletion mutation in
FAAH-OUT and a rs324420 C385A mutation. The result is extreme disruption of FAAH function leading to elevated anandamide levels. She was immune to anxiety, unable to experience fear, and insensitive to pain. The frequent burns and cuts suffered due to her hypoalgesia healed quicker than average with little or no scarring. Her son, who shares the
FAAH-OUT deletion but has no C385A mutation, has a lesser degree of pain insensitivity. A 2023 study looks further into the functions of
FAAH-OUT using transcriptomic analyses of cell models, some created anew using CRISPR-Cas9, others obtained from the 2019 patient. The study confirms that
FAAH-OUT increases the expression of FAAH, both via its lncRNA product and through an
intronic enhancer called FAAH-AMP. Loss of
FAAH-OUT also changes the expression of a wide network of genes beyond FAAH itself. For example, although the pain insensitivity is mostly due to loss of FAAH function (via increased
endocannabinoid levels and reduced
ACKR3 expression), lack of depression and anxiety is instead due to a non-canonical
Wnt pathway upregulating
BDNF. The increased wound healing is due to both pathways: loss of FAAH function increases
N-acyltaurine levels; the non-canonical Wnt pathway is also beneficial to healing. ==Assays==