A new study published in Biological Psychiatry01106-5/fulltext) reveals a potential link between higher levels of arachidonic acid, an omega-6 polyunsaturated fatty acid, and a reduced risk of bipolar disorder. The findings suggest that dietary or lifestyle interventions targeting arachidonic acid levels might help mitigate the risk of developing this debilitating mood disorder.
Bipolar disorder is characterized by recurrent episodes of mania and depression, severely impacting the lives of those affected. The exact causes of bipolar disorder remain unclear, but it is known to have a strong genetic component. Previous studies have highlighted the potential role of metabolites—small molecules involved in metabolism—in psychiatric disorders. The researchers aimed to identify specific metabolites that could causally influence the risk of bipolar disorder, potentially opening new avenues for prevention and treatment.
The researchers employed a method called Mendelian randomization, which uses genetic variants as tools to infer causal relationships between exposures (in this case, metabolite levels) and outcomes (bipolar disorder). They analyzed genetic data from large genome-wide association studies (GWAS) covering 913 metabolites in over 14,000 European individuals and bipolar disorder data from over 413,000 participants, including 41,917 diagnosed with bipolar disorder.
By focusing on genetic variants associated with lipid metabolism, the researchers identified a cluster of genes (FADS1/2/3) that encode enzymes involved in the synthesis of arachidonic acid from linoleic acid, another omega-6 fatty acid. They examined the levels of various metabolites in the blood and their genetic associations with bipolar disorder risk.
The study uncovered 33 metabolites associated with bipolar disorder, most of which were lipids. A key finding was that a genetic predisposition to higher levels of lipids containing arachidonic acid was linked to a lower risk of bipolar disorder. Conversely, higher levels of lipids containing linoleic acid were associated with a higher risk. This pattern suggests that the pathway converting linoleic acid to arachidonic acid is crucial in modulating bipolar disorder risk.
Arachidonic acid, widely present in the body and brain, contributes to the health of cell membranes and is essential for infant brain development. It can be obtained directly from foods such as meat and seafood or synthesized from linoleic acid found in nuts, seeds, and oils.
The researchers also noted that the FADS1/2/3 gene cluster mediates the relationship between bipolar disorder and lipid levels. This cluster is crucial for lipid metabolism, highlighting a genetic mechanism through which arachidonic acid levels might influence bipolar disorder risk.
“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 bipolar disorder, 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 bipolar disorder,” said study author David Stacey of the University of South Australia and South Australian Health and Medical Research Institute.
“To our knowledge, ours is the first study to highlight a potential causal role between arachidonic acid and bipolar disorder. Preclinical studies and randomized controlled trials will be necessary to determine the preventive or therapeutic value of arachidonic acid supplements, perhaps with a particular focus on people with a compromised arachidonic acid synthesizing pathway or with poor natural dietary sources.”
“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 bipolar disorder.”
While the findings are promising, the study has several limitations. First, the results are based on genetic data from individuals of European descent, so the applicability to other populations is uncertain. Second, the study relies on genetic associations, which, while robust, do not account for all potential environmental and lifestyle factors influencing bipolar disorder.
Future research should focus on replication in diverse populations and further exploration of the mechanisms through which arachidonic acid influences bipolar disorder. Preclinical studies and randomized controlled trials are necessary to determine the potential preventive or therapeutic value of arachidonic acid supplements, particularly for individuals with genetic variations affecting their ability to synthesize arachidonic acid.
Additionally, research into the impact of early-life nutrition on brain development could provide insights into how ensuring adequate intake of arachidonic acid and other polyunsaturated fatty acids in infants and children might reduce the risk of bipolar disorder. This could lead to precision health interventions tailored to individual genetic profiles, enhancing mental health outcomes from an early age.
Despite the limitations, the study marks a significant step forward in understanding the complex interplay between genetics, metabolism, and mental health.
“Arachidonic acid is typically a widely present omega-6 fatty acid in the body and brain that contributes to the health of cell membranes. This study provides a fascinating step forward in the effort to develop blood biomarkers of bipolar disorder risk, particularly in those patients with bipolar disorder and risk gene variations in the FADS1/2/3 gene cluster,” said John Krystal, the editor of Biological Psychiatry.
The study, “A Metabolome-Wide Mendelian Randomization Study Identifies Dysregulated Arachidonic Acid Synthesis as a Potential Causal Risk Factor for Bipolar Disorder,” was authored by David Stacey, Beben Benyamin, S. Hong Lee, and Elina Hyppönen.
