Genetic variation in endocannabinoid signaling is associated with differential network‐level functional connectivity in youth

Abstract

The endocannabinoid system is an important regulator of emotional responses such as fear, and a number of studies have implicated endocannabinoid signaling in anxiety. The fatty acid amide hydrolase (FAAH) C385A polymorphism, which is associated with enhanced endocannabinoid signaling in the brain, has been identified across species as a potential protective factor from anxiety. In particular, adults with the variant FAAH 385A allele have greater fronto‐amygdala connectivity and lower anxiety symptoms. Whether broader network‐level differences in connectivity exist, and when during development this neural phenotype emerges, remains unknown and represents an important next step in understanding how the FAAH C385A polymorphism impacts neurodevelopment and risk for anxiety disorders. Here, we leveraged data from 3,109 participants in the nationwide Adolescent Brain Cognitive Development Study℠ (10.04 ± 0.62 years old; 44.23% female, 55.77% male) and a cross‐validated, data‐driven approach to examine associations between genetic variation and large‐scale resting‐state brain networks. Our findings revealed a distributed brain network, comprising functional connections that were both significantly greater (95% CI for p values = [<0.001, <0.001]) and lesser (95% CI for p values = [0.006, <0.001]) in A‐allele carriers relative to non‐carriers. Furthermore, there was a significant interaction between genotype and the summarized connectivity of functional connections that were greater in A‐allele carriers, such that non‐carriers with connectivity more similar to A‐allele carriers (i.e., greater connectivity) had lower anxiety symptoms (β = −0.041, p = 0.030). These findings provide novel evidence of network‐level changes in neural connectivity associated with genetic variation in endocannabinoid signaling and suggest that genotype‐associated neural differences may emerge at a younger age than genotype‐associated differences in anxiety.

Lipid-Based Molecules on Signaling Pathways in Autism Spectrum Disorder

“…With respect to genetic factors of eCB signaling, a recent study reported that the fatty acid amide hydrolase (FAAH) C385A polymorphism was associated with this signaling in the brain [ 73 ]. Epigenetic modifications of the eCB may be related to DNA methylation or histone acetylation/deacetylation [ 73 ].…”

“…With respect to genetic factors of eCB signaling, a recent study reported that the fatty acid amide hydrolase (FAAH) C385A polymorphism was associated with this signaling in the brain [ 73 ]. Epigenetic modifications of the eCB may be related to DNA methylation or histone acetylation/deacetylation [ 73 ]. Epigenetic modifications of the eCB may be related to DNA methylation and histone acetylation/deacetylation, and FAAH genes encoding the CB1 receptor and FAAH hydrolyzing enzyme play a relevant role in neurological disease pathogenesis and progression [ 73 ].…”

“…Epigenetic modifications of the eCB may be related to DNA methylation or histone acetylation/deacetylation [ 73 ]. Epigenetic modifications of the eCB may be related to DNA methylation and histone acetylation/deacetylation, and FAAH genes encoding the CB1 receptor and FAAH hydrolyzing enzyme play a relevant role in neurological disease pathogenesis and progression [ 73 ]. Moreover, FAAH genes may be involved in ASD via network-level changes in neural connectivity associated with genetic variations in endocannabinoid signaling and genotype-associated neural differences [ 74 ].…”

Endocannabinoid Hydrolase Inhibitors: Potential Novel Anxiolytic Drugs

“… 131 Healthy male adults carrying AC heterozygotes have higher levels of AEA and lower anxiety scores than CC homozygotes, 132 and carriers of the A allele have been found to have more robust neural network connectivity and lower anxiety levels in adolescents. 133 Similarly, knock-in of the FAAH C385A gene in mice significantly ameliorated anxiety-like behavior, which was associated with reduced FAAH expression, elevated AEA levels, and enhanced eCB signaling. 134 However, additional studies have shown that the FAAH C385A genetic variant in children increased the risk of anxiety.…”

The endocannabinoid system as a putative target for the development of novel drugs for the treatment of psychiatric illnesses

“…As such, humans who possess the rare variant of the C385A FAAH SNP represent a population who have elevations in AEA signaling. Consistent with what has been found in the rodent literature, humans bearing the C385A FAAH SNP exhibit lower levels of trait anxiety, blunted reactivity of the amygdala in response to threat, increased functional and structural connectivity between the ventromedial prefrontal cortex and the amygdala and enhanced fear extinction (Demers, Drabant Conley, Bogdan, & Hariri, 2016 ; Dincheva et al, 2015 ; Gärtner et al, 2019 ; Gee et al, 2016 ; Green et al, 2021 ; Gunduz-Cinar et al, 2013 ; Hariri et al, 2009 ; Sisk et al, 2022 ; Zabik et al, 2022 ). Individuals with PTSD who possess this FAAH SNP also exhibit reduced symptoms of arousal and blunted stress-induced anxiety (Spagnolo et al, 2016 ), as well as enhanced treatment responses to virtual reality-assisted psychotherapy with D-cycloserine augmentation, particularly in those who have comorbid major depression and PTSD (Difede et al, 2022 ).…”