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Genes Brain Behav. 2017 Mar;16(3):384-393. doi: 10.1111/gbb.12352. Epub 2016 Nov 23.

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

Juhasz G1,2,3,4,5, Csepany E1,6, Magyar M1,6, Edes AE1,4, Eszlari N1,4,5, Hullam G4,7,5, Antal P3,7,5, Kokonyei G1,8, Anderson IM3, Deakin JF3, Bagdy G1,2,4,5.

Author information

MTA-SE-NAP B Genetic Brain Imaging Migraine Research Group, Hungarian Academy of Sciences, Budapest, Hungary.
Department of Pharmacodynamics, Faculty of Pharmacy, Semmelweis University, Budapest, Hungary.
Neuroscience and Psychiatry Unit, The University of Manchester and Manchester Academic Health Sciences Centre, Manchester, United Kingdom.
MTA-SE Neuropsychopharmacology and Neurochemistry Research Group, Hungarian Academy of Sciences.
NAP-A-SE Research Group, Semmelweis University, Budapest, Hungary.
Department of Neurology, Faculty of Medicine, Semmelweis University, Budapest, Hungary.
Department of Measurement and Information Systems, Budapest University of Technology and Economics, Budapest, Hungary.
Institute of Psychology, Eötvös Loránd University, Budapest, Hungary.


One of the main effects of the endocannabinoid system in the brain is stress adaptation with presynaptic endocannabinoid receptor 1 (CB1 receptors) playing a major role. In the present study, we investigated whether the effect of the CB1 receptor coding CNR1 gene on migraine and its symptoms is conditional on life stress. In a cross-sectional European population (n = 2426), recruited from Manchester and Budapest, we used the ID-Migraine questionnaire for migraine screening, the Life Threatening Experiences questionnaire to measure recent negative life events (RLE), and covered the CNR1 gene with 11 SNPs. The main genetic effects and the CNR1 × RLE interaction with age and sex as covariates were tested. None of the SNPs showed main genetic effects on possible migraine or its symptoms, but 5 SNPs showed nominally significant interaction with RLE on headache with nausea using logistic regression models. The effect of rs806366 remained significant after correction for multiple testing and replicated in the subpopulations. This effect was independent from depression- and anxiety-related phenotypes. In addition, a Bayesian systems-based analysis demonstrated that in the development of headache with nausea all SNPs were more relevant with higher a posteriori probability in those who experienced recent life stress. In summary, the CNR1 gene in interaction with life stress increased the risk of headache with nausea suggesting a specific pathological mechanism to develop migraine, and indicating that a subgroup of migraine patients, who suffer from life stress triggered migraine with frequent nausea, may benefit from therapies that increase the endocannabinoid tone.


Bayesian relevance analysis; endocannabinoid system; gene-environment interaction; migraine; nausea; stress

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