Depression is a common and debilitating mental disorder that seriously affects psychosocial functioning and reduces the quality of life (1). Current evidence suggests that the disability-adjusted life-years (DALYs) due to depressive disorders have steadily increased over the past 30 years in the 10–24 and 25–49 age groups, impeding social and economic development and overwhelming the public health sector (2). Notwithstanding that the past decade has witnessed significant scientific advances, the mechanism and etiology of depression remain unclear, impeding the development of effective preventive treatment regimens and prognostic assessment (3–5). Diet represents a potentially modifiable factor that could be the focus of such preventative measures (6). The emergence of new area of research, “Nutritional Psychiatry” holds the promise of identifying which dietary components are indeed critical for mental health, including psychiatric disease. Moreover, it is essential to identify the populations, conditions, and dosages required for these nutritional interventions to exert preventative and therapeutic effects (7). The relationship between food and depression has received increasing attention (8).

Given that dietary factors may contribute to the onset of depression, a better understanding of this relationship can be harnessed to develop preventive measures for depression. Fatty acids (FA), which make up the bulk of fat in our bodies and food, are crucial for various physiological and pathological processes (9, 10). Common dietary FAs can be grouped as saturated fatty acids (SFA), mono-unsaturated fatty acids (MUFA), and polyunsaturated fatty acids (PUFA) based on the number of double bonds, type of double bonds, and chain length (11). SFAs have been linked to depressive symptoms, such as palmitic acid (PA) was positively associated with depressive symptoms, and arachidonic acid proportions showed negative association with depressive symptoms (12). MUFA fats were reported to have a negative effect on depressive symptoms (13). PUFAs, including long-chain omega-3 (mainly from fish), α-linolenic acid (ALA, a plant-based omega-3), and omega-6 (mainly from vegetable oils), participate in the synthesis, release, reuptake, and binding of neurotransmitters, as well as in the structure and function of the brain (9, 10, 12). Increased consumption of unsaturated FA, particularly PUFA, and decreased consumption of SFA have been found to lessen the risk of depression (14–17). These above findings demonstrate the importance of dietary fat content in research on the pathogenesis and treatment of depression. However, some studies have yielded inconsistent findings (18, 19). A previous randomized controlled trial (RCT) indicated an overall beneficial effect of omega-3 PUFAs on depression symptoms (20). Nevertheless, another large-scale RCT provides no support for the use of omega-3 PUFAs to prevent depression (21). Although it has been suggested that FA might contribute to the pathologic of depression risk, the potential causal relationship between FA and depression remains unclear.

Previous observational studies and meta-analyses have investigated the association between FA and depression risk (18, 20–22). However, observational studies cannot comprehensively evaluate causal links and exclude unreliable and biased factors. RCTs are the gold standard for studying causal links between exposure and outcome, which can be costly, impractical, or unethical (23). Furthermore, conventional observational studies can alter exposure-outcome relationships by confounding variables and reverse causal connections, restricting causal inference (24). Fortunately, in recent years, much emphasis has been placed on delineating the causal genetic variants and biological mechanisms based on genome-wide association studies (GWAS) methodology, generating a wide range of robust associations for various traits and disorders (25, 26). By utilizing genetic variations as a natural experiment, Mendelian randomization (MR) is a novel method to assess the apparent causal relationships between a potential exposure factor and the outcome (27). In addition, MR methods can overcome confounding and reverse causality association problems on causal inference (28–31). Moreover, the Two-sample MR method refers to the application of MR approach to summary-level GWAS results estimated in non-overlapping sets of individuals, but from the same ethnicity. In recent years, MR analysis has been used to examine the causative role of FA on ischemic stroke (32), frailty (33), Alzheimer’s disease (34), and schizophrenia (35). Nonetheless, little MR evidence is available on the relationship between FA and depression. To further analyze the influence of different types of FAs on depression, the causal link between FA and depression was assessed using MR. To conduct a comprehensive MR analysis between FA and depression, we selected 16 types of FAs, including SFAs [palmitic acid (PA), arachidic acid, and stearic acid (SA)], MUFAs [oleic acid (OA), and palmitoleic acid (POA)], omega-3 PUFAs [eicosapentaenoic acid (EPA), α-linolenic acid (ALA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA)], omega-6 PUFAs [arachidonic acid (AA), adrenic acid, gamma–linolenic acid (GLA), Dihomo-gamma–linolenic acid (DGLA), and linoleic acid (LA)], total omega-3 PUFA and total omega-6 PUFA.

In this work, the MR approach was used to obtain accurate findings regarding the influence of FA on depression. We found that higher levels of adrenic acid and EPA were associated with a decreased risk of depression. In contrast, our MR results suggested that higher levels of OA and ALA could increase the risk of depression. Most importantly, the present investigation found no causal relationship between other omega-3 PUFAs (DHA and DPA), omega-6 PUFAs (AA, GLA, DGLA, and LA), MUFA (POA), and SFA (arachidic acid, PA, and SA) and depression risk. Our study was based on GWAS summary data and provided novel insights into the potential roles of specific FAs on depression risk for follow-up studies.

Our results indicated that elevated ALA levels were associated with increased depression risk, whereas higher EPA levels were associated with decreased depression risk. ALA is the precursor for long-chain PUFAs, including EPA and DHA (50), which are essential components of neuronal membrane phospholipids and regulate the physical and physiological features of neuronal membranes (51). Although the conversion efficiency is reportedly moderate, enough ALA consumption from flaxseed oil can dramatically increase the amounts of neuronal long-chain omega-3 PUFAs in rats (52). It has been established that neurotransmitter signaling in the GABAergic, serotonergic, or dopaminergic systems might be related to the neurobehavioral effects of ALA on depression risk (53). Our result for the causal relationship between EPA and depression is consistent with the earlier MR study (54). Growing evidence implicated that EPA plays a crucial role in the development and nervous system repair of synapse and nerve growth cones which are the basis of the neurodevelopmental hypothesis in depression (55–60). However, previous observational and clinical trial data on the association of omega-3 PUFA with depression have yielded conflicting results. A meta-analysis of observational studies suggested that marine omega-3 PUFA may reduce the risk of depression and promote a favorable mood (18). A cross-sectional observational study found no evidence for associations between DHA and omega-3 index and depression (19). The discrepancy among these observational studies may be explained by residual confounding. Additionally, the effect of supplementation with omega-3 PUFA on the risk of depression has been extensively studied over the years (20–22). For example, a meta-analysis of double-blind randomized placebo-controlled trials showed an overall beneficial effect of omega-3 PUFAs with EPA ≥ 60% at a dosage of ≤1 g/d on depression symptoms, whereas DHA-pure and DHA-major formulations did not yield such benefits (20). However, a large-scale randomized clinical trial involving 18,353 adults aged 50 years or older found no evidence supporting the use of omega-3 supplements in adults to prevent depression (21). Therefore, we hypothesized that omega-3 PUFA supplementation might not be beneficial for the prevention of depression but might be beneficial (specifically EPA) for the treatment of MDD. The confounding factors may be responsible for the inconsistent outcomes. Given that MR techniques might overcome confounding variables and offer the causal effects of FA on depression, we hypothesized that increasing levels of ALA might increase the risk of depression.

Our MR study found no association between total omega-6 PUFA and depression, showing consistent results compared with previous observational studies (61, 62). In a previous cross-sectional observational study, no association was found between omega-6 PUFA levels and depression (61). Meanwhile, observational research revealed that circulating omega-6 PUFA levels were not associated with depression relapse risk (62). As for the specific type of omega-6 PUFAs, the current investigation revealed that the higher level of adrenic acid was associated with a reduced risk of depression. Adrenic acid, the immediate precursor derived from arachidonic acid, is necessary for neuronal development and enrichment of myelinic lipids (63, 64). Adrenic acid is metabolized by cytochrome P450s to a group of epoxy fatty acids and epoxyeicosatrienoic acids, which are the vital lipid mediators playing key role in exerting analgesia and reducing endoplasmic reticulum stress (65). Furthermore, functional studies showed that adrenic acid potently inhibited the formation of the chemoattractant leukotriene B4 (LTB4), which has been proposed as a contributor for chronic neuroinflammatory effects (66–68). Given that, we could pay more attention to the role of the specific type of omega-6 PUFAs in depression, such as adrenic acid. Our findings might provide novel insights into the link between omega-6 PUFA and depression, given the paucity of existing research on the associations between omega-6 PUFA levels and depression.

Our MR analysis found a significant causal effect between specific types of MUFAs and the risk of depression. Little evidence is available on the association between MUFA and the risk of depression. The consumption of OA was positively related to depressive symptoms, according to a cross-sectional study involving 2,793 perimenopausal women (69). Mechanically, neural differentiation depends on OA production (70). Moreover, it has been shown that the composition of FA in the hippocampus and brain of rats with cognitive impairment is altered by OA (71). Hamilton and Fernandes (72) found that co-infusion with OA reduced the abundance of proliferating neural stem cells (NSCs) and suppressed the activation of NSCs in mice models. Therefore, OA might be involved in depression by affecting neural functions. However, the relationships between OA and depression remain largely unclear, warranting further experiments.

Importantly, in the present study, we adopted MR analyses which can avoid reverse causality induced by intrinsic confounders in conventional observational research. Moreover, due to the relatively large sample size, our MR study had more statistical power, which made the findings more accurate. However, some limitations must be considered when interpreting our findings. Our current MR investigation used GWAS summary data, and the study populations were predominantly European. The applicability of the study’s findings to other populations remains unclear, emphasizing the need for more studies. Besides, the original GWAS data of depression and characteristics of subjects could not be retrieved directly. Consequently, no subgroup analysis according to characteristics of subjects (sex, geography, and so on) was conducted. Moreover, the MR approach could only provide a preliminary indication of the causative link between FA and depression. The biological mechanism between FA and depression would be comprehensively investigated the further experiments.

Overall, our MR analyses provide evidence that ALA and OA levels increase the risk of depression, whereas EPA and adrenic acid levels decrease the risk of depression. Nonetheless, more in-depth work is still needed to elucidate the underlying mechanisms that mediate the relationship between ALA, OA, EPA, and adrenic acid levels and depression.

The original contributions presented in this study are included in the article/Supplementary material, further inquiries can be directed to the corresponding authors.

HL, LZ, and HY designed the study, contributed to analysis and interpretation of data, and wrote the first draft of the manuscript. HL, LZ, XW, XL, RX, CZ, and HY did the statistical analyses and prepared the tables and figures. HY provided further data interpretation. All authors contributed to drafting the work or revising it critically for important intellectual content and made substantial contributions to the concept and design of the study and acquisition, analysis, and interpretation of data.