Original Article

Neuropsychopharmacology (2009) 34, 2019–2027; doi:10.1038/npp.2009.19; published online 25 February 2009

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

Gabriella Juhasz1, Diana Chase1, Emma Pegg1, Darragh Downey1, Zoltan G Toth2, Kathryn Stones1, Hazel Platt3, Krisztina Mekli1,3,4, Antony Payton3, Rebecca Elliott1, Ian M Anderson1 and JF William Deakin1

  1. 1Neuroscience and Psychiatry Unit, School of Community Based Medicine, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK
  2. 2Faculty of Life Sciences, University of Manchester, Manchester, UK
  3. 3Centre for Integrated Genomic Medical Research, School of Translational Medicine, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK
  4. 4Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary

Correspondence: Dr G Juhasz, Neuroscience and Psychiatry Unit, School of Community Based Medicine, Faculty of Medical and Human Sciences, University of Manchester, Stopford Building, Oxford Road, Manchester M13 9PT, UK. E-mail: gabriella.juhasz@manchester.ac.uk

Received 25 November 2008; Revised 12 January 2009; Accepted 27 January 2009; Published online 25 February 2009.

Top

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 × 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.

Keywords:

CNR1, haplotype, personality, depression, epistasis, gene × environment interaction

Extra navigation

.
ADVERTISEMENT