Predicting the causal relationship between polyunsaturated fatty acids and cerebral aneurysm risk from a Mendelian randomization study

Abstract Introduction No conclusive evidence for a link between polyunsaturated fatty acids (PUFA) and cerebral aneurysm has been found in observational research. The aim of our study was to determine the causal impact of PUFA on cerebral aneurysm. Methods Two sample Mendelian randomization (MR) was performed using genetic instruments derived from a recent genome wide association study (GWAS) of fatty acids from UK Biobank and outcome data obtained from the large-scale cerebral aneurysm GWASs in European ancestry which include IA, aneurysmal subarachnoid hemorrhage (aSAH) and unruptured intracranial aneurysm (uIA). Sensitivity analyses were implemented with MVMR, MR-Egger intercept test, MR-PRESSO, leave-one-out analysis and so on. Bayesian colocalization (COLOC) methods was conducted to focus on the association between the fatty acid gene expression and cerebral aneurysm. Results Genetically predicted assessed omega-3 fatty acids decreased the risk for IA (OR = 0.80, 95% CI: 0.69 - 0.91, P = 1.01ⅹ10 -3 ) and aSAH (OR = 0.71, 95% CI: 0.61 - 0.84, P = 3.73ⅹ10 -5 ). Furthermore, the Docosahexaenoic acid decreased the risk for IA (OR = 0.75, 95% CI: 0.63 - 0.87, P = 3.12ⅹ10 -4 ) and aSAH (OR = 0.67, 95% CI: 0.55 - 0.8, P = 2.32ⅹ10 -5 ). The same results were discovered from ratio of omega-3 fatty acids to total fatty acids. While the ratio of omega-6 fatty acids to omega-3 fatty acids increased the risk of IA (OR = 1.27, 95% CI: 1.12 – 1.44, P = 1.53ⅹ10 -4 ) and aSAH (OR = 1.35, 95% CI: 1.17 – 1.56, P = 5.78ⅹ10 -5 ). The result of the COLOC suggested that the above four kinds of fatty acids and IA, aSAH likely share causal variants in gene fatty acid desaturase 2, separately. Conclusion This study utilized integrative analysis of MR and colocalization to discover causal relationships between genetic variants, PUFA and cerebral aneurysm. Funding This study was funded by the Natural Science Foundation of China (82072777), the Natural Science Foundation of Xiamen (3502Z20227097), Fujian Provincial Health Commission, Provincial Health and Health Young and Middle-aged Backbone Talent Training Project (2022GGB010).