title: Genetically reduced FAAH activity may be a risk for the development of anxiety and depression in persons with repetitive childhood trauma.
abstract: Fatty acid amide hydrolase (FAAH) inhibitors are addressed for promising anxiolytics, but human studies on genetically reduced FAAH activity, stress and affective phenotypes are scarce. We investigated the effect of a functional polymorphism of FAAH (FAAH C385A or rs324420; low FAAH activity and high anandamide concentration are associated with the A allele) together with childhood adversity on the anxious and depressive phenotypes in 858 subjects from the general population. Phenotypes were measured by the Zung Self-Rating Depression Scale (ZSDS), the depression and anxiety subscales of the Brief Symptom Inventory (BSI-DEP, BSI-ANX) and the State-Trait Anxiety scales (STAI-S, STAI-T). Childhood Adversity Questionnaire (CHA) was used to assess early life traumas. Frequency of the A allele was greater among subjects with high ZSDS scores compared to the CC genotype. Furthermore, FAAH C385A and the CHA have shown a robust gene-environment interaction, namely, significantly higher anxiety and depression scores were exhibited by individuals carrying the A allele if they had high CHA scores compared to CC carriers. These data provided preliminary evidence that genetically reduced FAAH activity and repetitive stress in the childhood are associated with increased vulnerability for anxiety and depression in later life. Our results together with earlier experimental data suggest that permanently elevated anandamide level together with early life stress may cause a lifelong damage on stress response probably via the downregulation of CB1R during the neurodevelopment in the brain. It may also point to pharmacogenomic consequences, namely ineffectiveness or adverse effects of FAAH inhibitors in this subpopulation.
authors.affiliation: Department of Psychiatry and Psychotherapy, Semmelweis University, Budapest, Hungary; MTA-SE Neuropsychopharmacology and Neurochemistry Research Group, Hungarian Academy of Sciences, Semmelweis University, Budapest, Hungary. Electronic address: lazaryjudit@gmail.com.
authors.forename: Judit
authors.initials: J
authors.lastname: Lazary
authors.affiliation: MTA-SE Neuropsychopharmacology and Neurochemistry Research Group, Hungarian Academy of Sciences, Semmelweis University, Budapest, Hungary; Department of Pharmacodynamics, Faculty of Pharmacy, Semmelweis University, Budapest, Hungary.
authors.forename: Nora
authors.initials: N
authors.lastname: Eszlari
authors.affiliation: MTA-SE Neuropsychopharmacology and Neurochemistry Research Group, Hungarian Academy of Sciences, Semmelweis University, Budapest, Hungary; Department of Pharmacodynamics, Faculty of Pharmacy, Semmelweis University, Budapest, Hungary; MTA-SE-NAP B Genetic Brain Imaging Migraine Research Group, Hungarian Academy of Sciences, Semmelweis University, Hungary.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Juhasz
authors.affiliation: MTA-SE Neuropsychopharmacology and Neurochemistry Research Group, Hungarian Academy of Sciences, Semmelweis University, Budapest, Hungary; Department of Pharmacodynamics, Faculty of Pharmacy, Semmelweis University, Budapest, Hungary.
authors.forename: Gyorgy
authors.initials: G
authors.lastname: Bagdy
mesh_terms: D000328:Adult; D000483:Alleles; D000581:Amidohydrolases / Q000096:biosynthesis / Q000235:genetics*; D001007:Anxiety / Q000235:genetics* / Q000523:psychology*; D002648:Child; D002649:Child Abuse / Q000523:psychology*; D003863:Depression / Q000235:genetics* / Q000523:psychology*; D003866:Depressive Disorder; D005260:Female; D059647:Gene-Environment Interaction; D056726:Genetic Association Studies; D006801:Humans; D008297:Male; D011110:Polymorphism, Genetic / Q000235:genetics; D011569:Psychiatric Status Rating Scales; D055815:Young Adult; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D000099252:Fatty Acid Amide Hydrolases
keywords: CB1 receptor; Endocannabinoids; Epigenetics; Neurodevelopment; Personalized medicine; Pharmacogenomics