title: Variants in the CNR1 gene predispose to headache with nausea in the presence of life stress.
abstract: 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.
authors.affiliation: 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.
authors.forename: G
authors.initials: G
authors.lastname: Juhasz
authors.affiliation: MTA-SE-NAP B Genetic Brain Imaging Migraine Research Group, Hungarian Academy of Sciences, Budapest, Hungary.|Department of Neurology, Faculty of Medicine, Semmelweis University, Budapest, Hungary.
authors.forename: E
authors.initials: E
authors.lastname: Csepany
authors.affiliation: MTA-SE-NAP B Genetic Brain Imaging Migraine Research Group, Hungarian Academy of Sciences, Budapest, Hungary.|Department of Neurology, Faculty of Medicine, Semmelweis University, Budapest, Hungary.
authors.forename: M
authors.initials: M
authors.lastname: Magyar
authors.affiliation: MTA-SE-NAP B Genetic Brain Imaging Migraine Research Group, Hungarian Academy of Sciences, Budapest, Hungary.|MTA-SE Neuropsychopharmacology and Neurochemistry Research Group, Hungarian Academy of Sciences.
authors.forename: A E
authors.initials: AE
authors.lastname: Edes
authors.affiliation: MTA-SE-NAP B Genetic Brain Imaging Migraine Research Group, Hungarian Academy of Sciences, Budapest, Hungary.|MTA-SE Neuropsychopharmacology and Neurochemistry Research Group, Hungarian Academy of Sciences.|NAP-A-SE Research Group, Semmelweis University, Budapest, Hungary.
authors.forename: N
authors.initials: N
authors.lastname: Eszlari
authors.affiliation: MTA-SE Neuropsychopharmacology and Neurochemistry Research Group, Hungarian Academy of Sciences.|Department of Measurement and Information Systems, Budapest University of Technology and Economics, Budapest, Hungary.|NAP-A-SE Research Group, Semmelweis University, Budapest, Hungary.
authors.forename: G
authors.initials: G
authors.lastname: Hullam
authors.affiliation: Neuroscience and Psychiatry Unit, The University of Manchester and Manchester Academic Health Sciences Centre, Manchester, United Kingdom.|Department of Measurement and Information Systems, Budapest University of Technology and Economics, Budapest, Hungary.|NAP-A-SE Research Group, Semmelweis University, Budapest, Hungary.
authors.forename: P
authors.initials: P
authors.lastname: Antal
authors.affiliation: MTA-SE-NAP B Genetic Brain Imaging Migraine Research Group, Hungarian Academy of Sciences, Budapest, Hungary.|Institute of Psychology, Eötvös Loránd University, Budapest, Hungary.
authors.forename: G
authors.initials: G
authors.lastname: Kokonyei
authors.affiliation: Neuroscience and Psychiatry Unit, The University of Manchester and Manchester Academic Health Sciences Centre, Manchester, United Kingdom.
authors.forename: I M
authors.initials: IM
authors.lastname: Anderson
authors.affiliation: Neuroscience and Psychiatry Unit, The University of Manchester and Manchester Academic Health Sciences Centre, Manchester, United Kingdom.
authors.forename: J F W
authors.initials: JF
authors.lastname: Deakin
authors.affiliation: 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.|MTA-SE Neuropsychopharmacology and Neurochemistry Research Group, Hungarian Academy of Sciences.|NAP-A-SE Research Group, Semmelweis University, Budapest, Hungary.
authors.forename: G
authors.initials: G
authors.lastname: Bagdy
mesh_terms: D000328:Adult; D003430:Cross-Sectional Studies; D063388:Endocannabinoids / Q000235:genetics / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006261:Headache / Q000235:genetics* / Q000523:psychology; D006801:Humans; D008297:Male; D008881:Migraine Disorders / Q000235:genetics / Q000378:metabolism / Q000523:psychology; D009325:Nausea / Q000235:genetics* / Q000523:psychology; D020641:Polymorphism, Single Nucleotide; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics* / Q000378:metabolism; D013315:Stress, Psychological / Q000235:genetics* / Q000378:metabolism / Q000523:psychology*; D011795:Surveys and Questionnaires; D044465:White People / Q000235:genetics
chemical_list: C571130:CNR1 protein, human; D063388:Endocannabinoids; D043884:Receptor, Cannabinoid, CB1
keywords: Bayesian relevance analysis; endocannabinoid system; gene-environment interaction; migraine; nausea; stress