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The interrelationship between mental health and autoimmunity gains more and more attention in recent years. However, the causality between personality traits and autoimmune diseases remained largely unknown. We first conducted two-sample mendelian randomization (MR) analysis on the relationships between mood instability, which is a common personality trait in the general population, and 10 autoimmune diseases. The results were further validated in secondary analyses of sensitivity where different MR methods, ethnicities, genders, and ascertainment methods were compared. In the primary analyses, three autoimmune diseases showed genetical predisposition to mood instability: asthma (OR [95%CI] = 3.45 [2.48, 4.78], P = 1.33E- 13), hypothyroidism (OR [95%CI] = 1.02 [1.00, 1.03], P = 1.71E-02), and systemic lupus erythematosus (OR [95%CI] = 5.25 [1.21, 22.76], P = 2.67E-02). The results were consistent in subsequent secondary analyses. Three diseases remained significantly correlated with mood instability by different MR methods with asthma remaining significant in Finnish and mixed populations, and in females from the UK biobank, while hypothyroidism remained significant in both genders from the UK biobank. Mood instability is a modifiable risk factor for three autoimmune diseases including asthma, hypothyroidism and systemic lupus erythematosus. [ABSTRACT FROM AUTHOR]