Bipolar disorder (BPD) is a debilitating mood disorder with an unclear etiology. 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. We 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 reported to date, including 41,917 BPD cases. We identified 33 metabolites associated with BPD ( < 5.48 × 10). Most of them were lipids, including arachidonic acid (β = −0.154, SE = 0.023, = 3.30 × 10), 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, although they may be involved in the regulation of lithium response. These lipid associations were driven by genetic variants within the gene cluster, which is a robust BPD risk locus encoding a family of fatty acid desaturase enzymes that are responsible for catalyzing the conversion of linoleic acid into arachidonic acid. Statistical colocalization analyses indicated that 27 of the 33 metabolites shared the same genetic etiology with BPD at the cluster, demonstrating that our findings are not confounded by linkage disequilibrium. Overall, our findings support the notion that arachidonic acid and other polyunsaturated fatty acids may represent potential targets for BPD.

中文翻译：

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代谢组范围孟德尔随机化研究确定花生四烯酸合成失调是双相情感障碍的潜在因果危险因素

双相情感障碍（BPD）是一种令人衰弱的情绪障碍，病因尚不清楚。更好地了解潜在的病理生理机制将有助于确定改进治疗方案和预防策略的新靶标。在这项全代谢组孟德尔随机化研究中，我们筛选了可能与 BPD 具有因果关系的代谢物。我们使用基于质谱的平台对 14,296 名欧洲人进行了总共 913 种循环代谢物暴露测试。对于 BPD 结果，我们使用了迄今为止报告的最大且最新的全基因组关联研究的汇总数据，其中包括 41,917 个 BPD 病例。我们鉴定出 33 种与 BPD 相关的代谢物 (< 5.48 × 10)。其中大部分是脂质，包括花生四烯酸（β = -0.154，SE = 0.023，= 3.30 × 10），一种多不饱和 omega-6 脂肪酸，以及几种含有花生四烯酸或亚油酸脂肪酸侧链的复杂脂质。这些关联并没有扩展到其他密切相关的精神疾病，如精神分裂症或抑郁症，尽管它们可能参与锂反应的调节。这些脂质关联是由基因簇内的遗传变异驱动的，该基因簇是一个强大的 BPD 风险位点，编码脂肪酸去饱和酶家族，负责催化亚油酸转化为花生四烯酸。统计共定位分析表明，33 种代谢物中有 27 种与簇中的 BPD 具有相同的遗传病因，这表明我们的研究结果并未因连锁不平衡而混淆。总体而言，我们的研究结果支持花生四烯酸和其他多不饱和脂肪酸可能代表 BPD 的潜在目标的观点。