孟德尔随机化
代谢组
全基因组关联研究
亚油酸
连锁不平衡
花生四烯酸
双相情感障碍
遗传关联
多不饱和脂肪酸
生物信息学
医学
脂肪酸
生物
精神科
遗传学
单倍型
代谢组学
内科学
心情
基因
等位基因
生物化学
基因型
单核苷酸多态性
遗传变异
酶
作者
David Stacey,Beben Benyamin,Sang Lee,Elina Hyppönen
标识
DOI:10.1016/j.biopsych.2024.02.1005
摘要
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 (padjusted < 5.48 × 10-5). Most of them were lipids, including arachidonic acid (β = -0.154, SE = 0.023, p = 3.30 × 10-11), 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, although 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 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 FADS1/2/3 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.
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