Causal relationship between circulating micronutrient levels and bipolar disorder: A Mendelian randomization study

Bipolar disorder (BD) is a significant mental health condition characterized by alternating episodes of mania and depression, impacting millions worldwide. Genetic factors are known to play a major role in BD, but the influence of circulating micronutrient levels remains unclear. Two-sample Mendelian randomization (MR) and multiple MR were used to assess the impact of 15 circulating micronutrients, including copper, selenium, zinc, calcium, iron, magnesium, potassium, carotene, folate, and vitamins A, B6, B12, C, D, and E on BD risk. Genetic data were sourced from Genome-Wide Association Studies, and BD case-control data were obtained from the FinnGen consortium. Inverse variance weighted was the main analysis method. The heterogeneity of the instrumental variables was assessed using inverse variance weighted and MR-Egger, simple mode, weighted median, and weighted mode, and the horizontal pleiotropy of the instrumental variables was assessed using MR-Egger and MR-PRESSO. Higher genetically predicted levels of vitamin B12 (odds ratio = 1.81, 95% confidence interval: 1.19-2.74, P = .005) and carotene (odds ratio = 1.49, 95% confidence interval: 1.07-2.08, P = .017) are associated with an increased risk of BD. No significant causal associations were found between BD and the levels of other circulating micronutrients. Sensitivity analyses confirmed the robustness of these findings, with no evidence of heterogeneity or horizontal pleiotropy detected. This study suggests that elevated levels of vitamin B12 and carotene may increase the risk of BD, pointing to potential nutritional targets for intervention. Further research is needed to elucidate these findings and understand their underlying mechanisms.