A Metabolome-Wide Mendelian Randomization Study Identifies Dysregulated Arachidonic Acid Synthesis as a Potential Causal Risk Factor for Bipolar Disorder

David Stacey; Beben Benyamin; S Hong Lee; Elina Hyppönen

doi:10.1016/j.biopsych.2024.02.1005

A Metabolome-Wide Mendelian Randomization Study Identifies Dysregulated Arachidonic Acid Synthesis as a Potential Causal Risk Factor for Bipolar Disorder

Biol Psychiatry. 2024 Feb 22:S0006-3223(24)01106-5. doi: 10.1016/j.biopsych.2024.02.1005. Online ahead of print.

Authors

David Stacey¹, Beben Benyamin², S Hong Lee², Elina Hyppönen³

Affiliations

¹ Australian Centre for Precision Health, University of South Australia, Adelaide, South Australia, Australia; University of South Australia Clinical and Health Sciences, Adelaide, South Australia, Australia; South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia. Electronic address: david.stacey@unisa.edu.au.
² Australian Centre for Precision Health, University of South Australia, Adelaide, South Australia, Australia; South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia; University of South Australia Allied Health and Human Performance, Adelaide, South Australia, Australia.
³ Australian Centre for Precision Health, University of South Australia, Adelaide, South Australia, Australia; University of South Australia Clinical and Health Sciences, Adelaide, South Australia, Australia; South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.

PMID: 38401803
DOI: 10.1016/j.biopsych.2024.02.1005

Abstract

Background: 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.

Methods: 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.

Results: We identified 33 metabolites associated with BPD (p_adjusted < 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.

Conclusions: Overall, our findings support the notion that arachidonic acid and other polyunsaturated fatty acids may represent potential targets for BPD.

Keywords: Arachidonic acid; Bipolar disorder; FADS1/2/3 gene cluster; Genetics; Mendelian randomization; Metabolomics.