Functional Variation in theFAAHGene is Directly Associated with Subjective Well-being and Indirectly Associated with Problematic Alcohol Use

Abstract

AbstractFatty 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, particularly with longitudinal data. In our study, we analyzed well-being data collected three years apart using the WHO (Ten) Well-Being Index and genotyped a functional polymorphism in theFAAHgene (rs324420, Pro129Thr) in a sample of 2,822 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. A subsequent phenome-wide association study (PheWAS) validated our well-being findings in the UK Biobank (N=126,132) 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. We propose that lifelong elevated anandamide levels can disrupt the endocannabinoid system – a biological contributor to well-being – potentially leading to increased alcohol intake. Further genetic studies and mediation analyses are needed to validate and extend these findings.