Genetic predisposition to higher levels of arachidonic acid may play a causal role in bipolar disorder (BPD), as suggested in a Mendelian randomization study.
In a cohort of 14,296 Europeans, 33 out of 913 circulating metabolites examined were associated with BPD (p<5.48 × 10−5). The relevant metabolites were mostly lipids, including the polyunsaturated omega-6 fatty acid arachidonic acid (β, −0.154; p=3.30 × 10−11), along with several complex lipids containing either an arachidonic or a linoleic fatty acid side chain. [Biol Psychiatry 2024;doi:10.1016/j.biopsych.2024.02.1005]
“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,” noted the investigators led by Dr David Stacey of Australian Centre for Precision Health, University of South Australia in Adelaide, Australia.
Notably, genetic variants within the FADS1/2/3 gene cluster, which encodes enzymes that are responsible for converting linoleic acid into arachidonic acid, mediated the association between the lipid metabolites and BPD.
Statistical colocalization analyses showed a strong genetic connection between 27 of the 33 metabolites and BPD at the FADS1/2/3 cluster, providing support that the observed associations were not just a coincidence due to “linkage disequilibrium,” as Stacey and colleagues pointed out in their paper.
“Intriguingly, we observed a pattern whereby a genetic propensity to higher levels of lipids containing an arachidonic acid fatty acid side chain was associated with a lower risk of BPD, while the inverse was true of lipids containing a linoleic acid side chain. Since arachidonic acid is synthesized from linoleic acid in the liver, this suggests arachidonic acid synthesizing pathways are important for BPD,” Stacey explained.
“To our knowledge, ours is the first study to highlight a potential causal role between arachidonic acid and BPD,” he said, adding that the observed data may have important clinical implications considering the lack of clinically useful biomarkers for different psychiatric disorders.
Stacey highlighted the need for conducting preclinical studies and randomized controlled trials to establish whether arachidonic acid supplements have preventive or therapeutic value in BPD, especially in people with a compromised arachidonic acid synthesizing pathway or with poor natural dietary sources.
“More broadly, our findings also support potential avenues for precision health interventions focused on early-life nutrition to ensure that infants and children are receiving enough arachidonic acid and other polyunsaturated fatty acids to support optimal brain development, which may also reduce the risk of BPD,” he continued.
The present study had several limitations, including the lack of data on how many patients from the BPD genome-wide association study used in the analysis had been prescribed lithium. As such, it is possible that the findings could be influenced by a subgroup of bipolar patients who respond well to lithium, even though Mendelian randomization studies are less susceptible to medication and lifestyle influences than observational studies, Stacey noted. Additionally, the current study involved European participants, which limit the generalizability of the findings to other populations.