CNR1 Gene is Associated with High Neuroticism and Low Agreeableness and Interacts with Recent Negative Life Events to Predict Current Depressive Symptoms

Neuroscience and Psychiatry Unit, School of Community Based Medicine, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology (Impact Factor: 7.05). 03/2009; 34(8):2019-27. DOI: 10.1038/npp.2009.19
Source: PubMed


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.

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Available from: Darragh Downey, Mar 26, 2014
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    • "have been associated with heavy cannabis use in humans. For example, the endocannabinoid system has been proposed to play a role in the pathogenesis of schizophrenia (although, as noted earlier, the evidence to support this hypothesis has been mixed; Ferretjans et al., 2012), while two recent studies have provided evidence that variation in the CNRI gene moderates the effect of stressful life events on depressive symptoms (Juhasz et al., 2009; Agrawal et al., 2012). While a detailed discussion of the interaction between multiple risk factors is beyond the scope of this review, these studies provide insight into how processes associated with the development of the endocannabinoid system may impact variability in risk within adolescent populations, as well as making the developing brain vulnerable to the effects of cannabis more generally. "
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    • "Genome-wide association studies (GWAS) have generally failed to support an association between depression and specific genes (Hek et al., 2013; Major Depressive Disorder Working Group of the Psychiatric GWAS Consortium, 2013), perhaps reflecting a situation in which genes predispose to increased responsiveness to stress, rather than to depression per se. Nevertheless, several genes have been identified that are associated with both predisposition to depression and antidepressant treatment resistance – for example, polymorphisms of genes coding for the CB1 receptor (Domschke et al., 2008; Juhasz et al., 2009) and the 5HT1A receptor (Kato and Serretti, 2010). The genetic variant that has been most studied AQ7 is a functional polymorphism in the promoter region of the serotonin transporter gene, 5HTTLPR, which has been reported to moderate the effects of stressful life events on depression . "
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