CNR1 variants are not only associated with neuroticism but also interact with recent life events to predict current depressive symptoms suggests the variants act on the core endophenotypic emotion regulation processes of neuroticism. CNR1 gene is implicated in determining a personality phenotype, may be a vulnerability factor for major depression. Effect of CNR1 on migraine headaches might be related to the alteration of peripheral trigeminovascular activation. Here, CNR1 is linked to major depressive disorder.