A metabolome-wide Mendelian randomization study identifies dysregulated arachidonic acid synthesis as a potential causal risk factor for bipolar disorder

BackgroundBipolar disorder (BPD) is a debilitating mood disorder with an unclear aetiology. A better understanding of the underlying pathophysiological mechanisms will help to identify novel targets for improved treatment options and prevention strategies. In this metabolome-wide Mendelian randomization study, we screened for metabolites that may have a causal role in BPD. MethodsWe tested a total of 913 circulating metabolite exposures assessed in 14,296 Europeans using a mass spectrometry-based platform. For the BPD outcome, we used summary data from the largest and most recent genome-wide association study (GWAS) to date, including 41,917 BPD cases. ResultsWe identified 33 metabolites associated with BPD (padj <5.48x10-5). Most of them were lipids, including arachidonic acid ({beta}=-0.154, se=0.023, p=3.30x10-11), a polyunsaturated omega-6 fatty acid, along with several complex lipids containing either an arachidonic or a linoleic fatty acid side chain. These associations did not extend to other closely related psychiatric disorders like schizophrenia or depression, though they may be involved in the regulation of lithium response. These lipid associations were driven by genetic variants within the FADS1/2/3 gene cluster, which is a robust BPD risk locus encoding a family of fatty acid desaturase enzymes responsible for catalysing the conversion of linoleic into arachidonic acid. Statistical colocalization analyses indicated that 27 of the 33 metabolites share the same genetic aetiology with BPD at the FADS1/2/3 cluster, demonstrating that our findings are not confounded by linkage disequilibrium. ConclusionsOverall, our findings support the notion that ARA and other polyunsaturated fatty acids may represent potential targets for BPD.