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A metabolome-wide mendelian randomization study identifies dysregulated arachidonic acid synthesis as a potential causal risk factor for bipolar disorder
The cause of bipolar disorder (BPD), a crippling mental disease, remains unknown. A deeper comprehension of its underlying physiological mechanisms is crucial for identifying new avenues for treatment enhancement and preventative measures. This study by Stacey et al. (2024) employs metabolome-wide Mendelian randomization to explore metabolites potentially linked to BPD causality. The authors examined 913 circulating metabolites in 14,296 Europeans using mass spectrometry. Data on BPD were sourced from the largest genome-wide association study to date, encompassing 41,917 BPD cases. The authors identified 33 metabolites associated with BPD, predominantly lipids. Notably, arachidonic acid, an omega-6 polyunsaturated fatty acid, and several complex lipids containing arachidonic or linoleic acid side chains showed strong associations. These links were specific to BPD and not observed in related disorders like schizophrenia or depression, although they might influence lithium response. Genetic variants within the FADS1/2/3 gene cluster, known BPD risk loci, were found to be responsible for these lipid associations. Fatty acid desaturase enzymes, which convert linoleic acid into arachidonic acid, are encoded by this gene cluster. The authors’ findings were further supported by colocalization analysis, which showed that 27 of the 33 metabolites shared genetic origins with BPD in the FADS1/2/3 cluster. The authors conclude that their results show how arachidonic acid and other polyunsaturated fatty acids could be potential targets for BPD intervention. [NPID: Arachidonic acid, bipolar disorder, FADS1/2/3 gene cluster, genetics, mendelian randomization, metabolomics]
Year: 2024
