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 ¼ 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 0 end of the CNR1 gene significantly interacts with the 3 0 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  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.

Variants in the CNR1 gene predispose to headache with nausea in the presence of life stress

“…In the present research, we included participants who were European white origin, completed the questionnaires and consented to DNA. Details of the recruitment strategies and response rate were published earlier (Juhasz et al 2009a; Lazary et al 2009). …”

“…Genomic DNA was extracted from buccal mucosa cells (Juhasz et al 2009a). After extraction of DNA all samples were normalized and genotyped using the Sequenom ® MassARRAY Technology (Sequenom ® , San Diego, CA, USA, www.sequenom.com).…”

“…In addition, CNR1 genetic variants in interaction with recent negative life events (RLE) increased the risk of depression (Juhasz et al 2009a), and in interaction with the serotonin transporter functional polymorphism ( 5HTTLPR) exerted anxiogenic effects (Lazary et al 2009, 2011). Regarding migraine, we demonstrated that a CNR1 haplotype increased the risk of migraine headaches (Juhasz et al 2009b).…”

Risk-Taking Behavior in a Gambling Task Associated with Variations in the Tryptophan Hydroxylase 2 Gene: Relevance to Psychiatric Disorders

“…The 53-item Brief Symptom Inventory (BSI) (Derogatis, 1993) was used to measure anxiety symptoms (using the anxiety subscale) and depressive symptoms (using the depression subscale plus additional items); a continuous weighted dimension score was calculated for Depression and Anxiety. Validation data of neuroticism and symptom scores were published previously (Juhasz et al, 2009).…”

“…We recruited participants aged 18-60 years from Greater Manchester, United Kingdom, through general practices, and a website (http://www.newmood.co.uk); details of our recruitment strategy and responses were published previously (Juhasz et al, 2009). The included participants were of Caucasian European origin and could have a selfreported history of depression or anxiety disorders; we excluded those reporting manic or hypomanic episodes, psychotic symptoms, or obsessive-compulsive disorder (all information based on background self-report questionnaire data).…”