Department of Public Health Sciences, Stockholm University, 10691 Stockholm, Sweden.
Department of Global Public Health, Karolinska Institutet, 17177 Stockholm, Sweden.
Genes (Basel). 2023 Sep 21;14(9):1826. doi: 10.3390/genes14091826.
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 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, = 0.007; Wave II, B: -0.41, = 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, = 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.
脂肪酸酰胺水解酶（FAAH）是一种能够降解花生四烯酸乙醇酰胺（anandamide）的酶，后者是一种内源性大麻素，能够调节中脑边缘多巴胺的释放，从而影响幸福感状态。尽管存在这些已知的相互作用，但 FAAH 对主观幸福感的具体作用仍未得到充分探索。由于幸福感是一种动态特征，会随时间波动，因此我们假设，使用纵向数据，我们可以更深入地了解 FAAH 与幸福感之间的联系。为此，我们使用世界卫生组织（WHO）的十项幸福感指数（Ten Well-Being Index）分析了相隔三年收集的幸福感数据，并对 2822 名个体的 FAAH 基因中的一个功能性多态性（rs324420，Pro129Thr）进行了基因分型。我们发现，rs324420 的 A 等位基因（导致 FAAH 活性降低和花生四烯酸乙醇酰胺水平升高）与两个时间点的幸福感评分较低相关（波 I，B：-0.52， = 0.007；波 II，B：-0.41， = 0.03，调整年龄和性别）。随后进行的表型全基因组关联研究（PheWAS）在英国生物样本库中证实了我们的幸福感发现（N = 126132，C 等位基因与幸福感升高相关， = 0.008），并发现与酒精依赖的额外关联。在我们的队列中，使用滞后的纵向中介分析，我们发现了 rs324420 与问题性饮酒（AUDIT-P）之间存在间接关联的证据，这种关联是通过幸福感降低的途径产生的（间接效应 Boot：0.015，95%CI[0.003，0.030]，在波 I 中调整 AUDIT）。我们提出，慢性升高的花生四烯酸乙醇酰胺水平可能会影响内源性大麻素系统的紊乱，而内源性大麻素系统是幸福感的一个生物学贡献因素，进而可能导致饮酒量增加，但可能有多种因素在起作用。需要进一步的遗传研究和中介分析来验证和扩展这些发现。
