Genetic variation in FAAH is associated with cannabis use disorders in a young adult sample of Mexican Americans

Melroy-Greif, Whitney E.; Wilhelmsen, Kirk C.; Ehlers, Cindy L.

doi:10.1016/j.drugalcdep.2016.06.021

Cited by 25 publications

(25 citation statements)

References 49 publications

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“…The underlying mechanisms that dictate why only a fraction of those individuals experimenting with cannabis become dependent remain unknown. Substantial evidence implicates genetic factors mediating the risk for drug dependence, including cannabis use disorder, in susceptible individuals (1,11,13,32). In addition, adolescence, particularly in female mice, represents a highly vulnerable developmental period in which cannabis use predicts a higher risk of dependence compared to adulthood (24,25).…”

Section: Discussionmentioning

confidence: 99%

Endocannabinoid genetic variation enhances vulnerability to THC reward in adolescent female mice

et al. 2020

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Adolescence represents a developmental period with the highest risk for initiating cannabis use. Little is known about whether genetic variation in the endocannabinoid system alters mesolimbic reward circuitry to produce vulnerability to the rewarding properties of the exogenous cannabinoid Δ9-tetrahydrocannabinol (THC). Using a genetic knock-in mouse model (FAAHC/A) that biologically recapitulates the human polymorphism associated with problematic drug use, we find that in adolescent female mice, but not male mice, this FAAH polymorphism enhances the mesolimbic dopamine circuitry projecting from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) and alters cannabinoid receptor 1 (CB1R) levels at inhibitory and excitatory terminals in the VTA. These developmental changes collectively increase vulnerability of adolescent female FAAHC/A mice to THC preference that persists into adulthood. Together, these findings suggest that this endocannabinoid genetic variant is a contributing factor for increased susceptibility to cannabis dependence in adolescent females.

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Section: Discussionmentioning

confidence: 99%

Endocannabinoid genetic variation enhances vulnerability to THC reward in adolescent female mice

et al. 2020

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“…This indicated that FAAH 385C/A polymorphism might play an important role in the pathophysiological process of tolerance, and addiction of METH dependence, and could be used to identify high‐risk individuals. Previous studies revealed that the allele A or carried A genotypes of the FAAH 385C/A polymorphism played a risk role in alcohol dependence and illicit drug abuse, including cannabis, amphetamine, METH, and cocaine (Dlugos et al., ; Filbey et al., ; Melroy‐Greif et al., ; Sim et al., ; Sloan et al., ; Tyndale et al., ).…”

Section: Discussionmentioning

confidence: 99%

“…The endocannabinoid system (ECS) was one of the most important neural signaling pathways implicated in substance abuse and dependence, such as modulated brain reward effect, related behaviors, and influenced addiction vulnerability (Morita et al., ; Parsons & Hurd, ). The fatty acid amide hydrolase (FAAH) gene is a membrane‐bound serine hydrolase of the ECS, and may be involved in the pathophysiological process of METH dependence, such as oxidative stress, excitotoxicity, and inflammation (Melroy‐Greif et al., , Moratalla et al., ).…”

Section: Introductionmentioning

confidence: 99%

FAAH levels and its genetic polymorphism association with susceptibility to methamphetamine dependence

Zhang

Liu

Deng

et al. 2019

Annals of Human Genetics

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The fatty acid amide hydrolase (FAAH) gene was involved in the modulation of reward and addiction pathophysiology of illicit drugs abuse, and its polymorphisms might be associated with risk of methamphetamine (METH) dependence. This study aimed to investigate the FAAH mRNA levels in peripheral blood mononuclear cells and plasma protein levels and to analyze the 385C/A polymorphism (rs324420) between METH‐dependent patients and controls. The levels of FAAH mRNA in METH dependence were significantly lower than in controls (P < 0.001), however, its plasma protein underwent a significant ∼2‐fold increase (P < 0.001). The A allele of the 385C/A polymorphism significantly increased the METH dependence risk (P < 0.001, odds ratio [OR] = 1.646, 95% confidence interval [CI] = 1.332–2.034). The carried A genotypes (AA, AC, and AA/AC) of 385C/A polymorphism also increased METH‐dependence risks under a different genetic model (AA vs. CC: P = 0.017, OR = 2.454, 95%CI = 1.171–2.143; AC vs. CC: P < 0.001, OR = 1.818, 95%CI = 1.404–2.353; AC/AA vs. CC: P < 0.001, OR = 1.858, 95%CI = 1.444–2.319). The similar results were obtained after adjusting for age and sex. Unfortunately, we failed to find that any genotype of 385C/A polymorphism affected the mRNA or plasma protein levels in controls, respectively (P > 0.05). These data indicate that the FAAH may play an important role in the pathophysiological process of METH dependence, and the 385C/A polymorphism may be associated with METH dependence susceptibility in a Chinese Han population.

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“…Common single nucleotide polymorphisms in or near CNR1 , CNR2 , FAAH and MGLL have been reported to be associated with a variety of clinical phenotypes in candidate gene association studies (substance abuse disorders, cardiovascular disease risk factors, irritable bowel syndrome, migraine, chronic pain and mood disorders) [ 21 – 30 ]. The effect sizes are generally small, however, and replication studies in larger independent cohorts have been met with mixed results [ 31 – 35 ]. In contrast, the impact of rare genetic variation in genes associated with the endocannabinoid system has not been studied systematically.…”

Section: Introductionmentioning

confidence: 99%

Rare genetic variants in the endocannabinoid system genes CNR1 and DAGLA are associated with neurological phenotypes in humans

Smith¹,

Stanley²,

Foss³

et al. 2017

PLoS ONE

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Rare genetic variants in the core endocannabinoid system genes CNR1, CNR2, DAGLA, MGLL and FAAH were identified in molecular testing data from 6,032 patients with a broad spectrum of neurological disorders. The variants were evaluated for association with phenotypes similar to those observed in the orthologous gene knockouts in mice. Heterozygous rare coding variants in CNR1, which encodes the type 1 cannabinoid receptor (CB1), were found to be significantly associated with pain sensitivity (especially migraine), sleep and memory disorders—alone or in combination with anxiety—compared to a set of controls without such CNR1 variants. Similarly, heterozygous rare variants in DAGLA, which encodes diacylglycerol lipase alpha, were found to be significantly associated with seizures and neurodevelopmental disorders, including autism and abnormalities of brain morphology, compared to controls. Rare variants in MGLL, FAAH and CNR2 were not associated with any neurological phenotypes in the patients tested. Diacylglycerol lipase alpha synthesizes the endocannabinoid 2-AG in the brain, which interacts with CB1 receptors. The phenotypes associated with rare CNR1 variants are reminiscent of those implicated in the theory of clinical endocannabinoid deficiency syndrome. The severe phenotypes associated with rare DAGLA variants underscore the critical role of rapid 2-AG synthesis and the endocannabinoid system in regulating neurological function and development. Mapping of the variants to the 3D structure of the type 1 cannabinoid receptor, or primary structure of diacylglycerol lipase alpha, reveals clustering of variants in certain structural regions and is consistent with impacts to function.

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Genetic variation in FAAH is associated with cannabis use disorders in a young adult sample of Mexican Americans

Cited by 25 publications

References 49 publications

Endocannabinoid genetic variation enhances vulnerability to THC reward in adolescent female mice

Endocannabinoid genetic variation enhances vulnerability to THC reward in adolescent female mice

FAAH levels and its genetic polymorphism association with susceptibility to methamphetamine dependence

Rare genetic variants in the endocannabinoid system genes CNR1 and DAGLA are associated with neurological phenotypes in humans

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