Causal Effects Of Fatty Acids On Depression: Mendelian Randomization Study

Objective:Observational studies have shown associations of plasma fatty acids level with depression.However,the relationship between plasma fatty acids level with depression were still unclear due to the influence of confounding factors and reverse causality in observational studies.In this study,we performed the two-sample Mendelian randomization（TSMR）approach to estimate the effect of plasma fatty acids level on depression.Methods:This study utilized summary data from publicly available large-scale genome-wide association studies（GWAS）to investigate the relationship between plasma fatty acids level and depression.A total of 16fatty acids（FA）were selected as exposure factors based on strict inclusion and exclusion criteria.These included 3 saturated fatty acids（SFA）:palmitic acid（PA）,arachidic acid,and stearic acid（SA）;2monounsaturated fatty acids（MUFA）:oleic acid（OA）and palmitoleic acid（POA）;and 11 polyunsaturated fatty acids（PUFA）:total n-3polyunsaturated fatty acids（total n-3 PUFAs）,eicosapentaenoic acid（EPA）,alpha-linolenic acid（ALA）,docosapentaenoic acid（DPA）,docosahexaenoic acid（DHA）,total n-6 polyunsaturated fatty acids（total n-6 PUFA）,arachidonic acid（AA）,adrenic acid（Ad A）,gamma-linolenic acid（GLA）,dihomo-gamma-linolenic acid（DGLA）,and linoleic acid（LA）.Single nucleotide polymorphism（SNP）were used as instrumental variables for exposure factors.Depression was selected as the outcome measure,and to avoid sample overlap,two different databases were chosen as summary data sources for depression.Two-sample Mendelian randomization（TSMR）was performed using the Wald ratio and inverse variance weighted（IVW）methods as the main analysis methods.MR-Egger was used for pleiotropy analysis,the Q test was used for heterogeneity test,and leave-one-out analysis was used for sensitivity analysis.Results:1.Based on strict selection criteria for instrumental variables,a total of 175 SNPs were included as instrumental variables for 16 types of fatty acids,as follows:SA（n=2）,arachidic acid（n=1）,PA（n=1）,OA（n=1）,POA（n=4）,total n-3 PUFAs（n=37）,ALA（n=1）,EPA（n=1）,DPA（n=3）,DHA（n=30）,total n-6 PUFAs（n=47）,AA（n=2）,Ad A（n=1）,GLA（n=2）,DGLA（n=2）,and LA（n=40）.2.This TSMR analysis revealed the causal effects for the levels of OA(OR=1.07,p=5.72×10^-4),Ad A(OR=0.74,p=1.01×10^-3),ALA(OR=2.52,p=1.01×10^-3),EPA(OR=0.84,p=3.11×10^-3)on depression risk,after Bonferroni correction.The sensitivity analyses indicated similar trends.Conclusion:This study utilized TSMR analysis to evaluate the causal relationship between 16 types of FAs and depression.This study provided evidence that ALA and OA levels increase the risk of depression,whereas EPA and Ad A levels decrease the risk of depression.Our study provides insight into the impact of different types of fatty acids on depression from a genetic perspective,offering evidence for further epidemiological and fundamental research exploring the causal relationship between fatty acids and the risk of depression.