title: CNR1 gene is associated with high neuroticism and low agreeableness and interacts with recent negative life events to predict current depressive symptoms.
abstract: Cannabinoid receptor 1 (CB1) gene (CNR1) knockout mice are prone to develop anhedonic and helpless behavior after chronic mild stress. In humans, the CB1 antagonist rimonabant increases the risk of depressed mood disorders and anxiety. These studies suggest the hypothesis that genetic variation in CB1 receptor function influences the risk of depression in humans in response to stressful life events. In a population sample (n=1269), we obtained questionnaire measures of personality (Big Five Inventory), depression and anxiety (Brief Symptom Inventory), and life events. The CNR1 gene was covered by 10 SNPs located throughout the gene to determine haplotypic association. Variations in the CNR1 gene were significantly associated with a high neuroticism and low agreeableness phenotype (explained variance 1.5 and 2.5%, respectively). Epistasis analysis of the SNPs showed that the previously reported functional 5' end of the CNR1 gene significantly interacts with the 3' end in these phenotypes. Furthermore, current depression scores significantly associated with CNR1 haplotypes but this effect diminished after covariation for recent life events, suggesting a gene x environment interaction. Indeed, rs7766029 showed highly significant interaction between recent negative life events and depression scores. The results represent the first evidence in humans that the CNR1 gene is a risk factor for depression--and probably also for co-morbid psychiatric conditions such as substance use disorders--through a high neuroticism and low agreeableness phenotype. This study also suggests that the CNR1 gene influences vulnerability to recent psychosocial adversity to produce current symptoms of depression.
authors.affiliation: Neuroscience and Psychiatry Unit, School of Community Based Medicine, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK. gabriella.juhasz@manchester.ac.uk
authors.forename: Gabriella
authors.initials: G
authors.lastname: Juhasz
authors.forename: Diana
authors.initials: D
authors.lastname: Chase
authors.forename: Emma
authors.initials: E
authors.lastname: Pegg
authors.forename: Darragh
authors.initials: D
authors.lastname: Downey
authors.forename: Zoltan G
authors.initials: ZG
authors.lastname: Toth
authors.forename: Kathryn
authors.initials: K
authors.lastname: Stones
authors.forename: Hazel
authors.initials: H
authors.lastname: Platt
authors.forename: Krisztina
authors.initials: K
authors.lastname: Mekli
authors.forename: Antony
authors.initials: A
authors.lastname: Payton
authors.forename: Rebecca
authors.initials: R
authors.lastname: Elliott
authors.forename: Ian M
authors.initials: IM
authors.lastname: Anderson
authors.forename: J F William
authors.initials: JF
authors.lastname: Deakin
mesh_terms: D000223:Adaptation, Psychological / Q000502:physiology; D000293:Adolescent; D000328:Adult; D001008:Anxiety Disorders / Q000235:genetics / Q000378:metabolism / Q000523:psychology; D001923:Brain Chemistry / Q000235:genetics*; D004252:DNA Mutational Analysis; D003866:Depressive Disorder / Q000235:genetics* / Q000378:metabolism / Q000523:psychology; D004777:Environment; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009497:Neurotic Disorders / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D010551:Personality / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics*; D011795:Surveys and Questionnaires; D055815:Young Adult
chemical_list: D043884:Receptor, Cannabinoid, CB1