Functional Variation in the FAAH Gene Is Directly Associated with Subjective Well-Being and Indirectly Associated with Problematic Alcohol Use

Genes (Basel). 2023 Sep 21;14(9):1826. doi: 10.3390/genes14091826.

Abstract

Fatty acid amide hydrolase (FAAH) is an enzyme that degrades anandamide, an endocannabinoid that modulates mesolimbic dopamine release and, consequently, influences states of well-being. Despite these known interactions, the specific role of FAAH in subjective well-being remains underexplored. Since well-being is a dynamic trait that can fluctuate over time, we hypothesized that we could provide deeper insights into the link between FAAH and well-being using longitudinal data. To this end, we analyzed well-being data collected three years apart using the WHO (Ten) Well-Being Index and genotyped a functional polymorphism in the FAAH gene (rs324420, Pro129Thr) in a sample of 2822 individuals. We found that the A-allele of rs324420, which results in reduced FAAH activity and elevated anandamide levels, was associated with lower well-being scores at both time points (Wave I, B: -0.52, p = 0.007; Wave II, B: -0.41, p = 0.03, adjusted for age and sex). A subsequent phenome-wide association study (PheWAS) affirmed our well-being findings in the UK Biobank (N = 126,132, alternative C-allele associated with elevated happiness, p = 0.008) and revealed an additional association with alcohol dependence. In our cohort, using lagged longitudinal mediation analyses, we uncovered evidence of an indirect association between rs324420 and problematic alcohol use (AUDIT-P) through the pathway of lower well-being (indirect effect Boot: 0.015, 95% CI [0.003, 0.030], adjusted for AUDIT in Wave I). We propose that chronically elevated anandamide levels might influence disruptions in the endocannabinoid system-a biological contributor to well-being-which could, in turn, contribute to increased alcohol intake, though multiple factors may be at play. Further genetic studies and mediation analyses are needed to validate and extend these findings.

Keywords: Pro129Thr; alcoholism; anandamide; endocannabinoid system; fatty acid amide hydrolase; happiness; rs324420.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alcohol Drinking* / genetics
  • Alleles
  • Endocannabinoids* / genetics
  • Humans

Substances

  • anandamide
  • Endocannabinoids
  • fatty-acid amide hydrolase

Grants and funding

This work was supported by the Alcohol Research Council of the Swedish Alcohol Retailing Monopoly (2020-0080, 2020; P.A.M.), the Royal Physiographic Society in Lund (40581, 2019; P.A.M.), the Lars Hierta Memorial Foundation (FO2019-0331, 2019; P.A.M.), the Åke Wiberg Foundation (M20-0070, 2020; P.A.M.), the Magnus Bergvall Foundation (2020-03641, 2020; P.A.M.), the Sigurd and Elsa Golje Memorial Foundation (LA2020-0191, 2020; P.A.M.), the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institutet Stockholm County Council (RS2021-0855, SLL20190589; C.L.), and the Swedish Research Council (2014-10171; CL). The funding sources were not involved in the study design or the decision to submit the results for publication.