Predicting the causal relationship between polyunsaturated fatty acids and cerebral aneurysm risk from a Mendelian randomization study
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Yu and colleagues used two-sample MR to test the effect of PUFA on cerebral aneurysms. They found that genetically predicted omega-3 and DHA decreased the risk for Intracranial Aneurysm and Subarachnoid Haemorrhage. This work is useful, although the evidence is incomplete as it lacks a robust set of analyses to provide credibility to the findings.
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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).
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eLife assessment
Yu and colleagues used two-sample MR to test the effect of PUFA on cerebral aneurysms. They found that genetically predicted omega-3 and DHA decreased the risk for Intracranial Aneurysm and Subarachnoid Haemorrhage. This work is useful, although the evidence is incomplete as it lacks a robust set of analyses to provide credibility to the findings.
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Reviewer #1 (Public Review):
Summary:
The authors performed two-sample MR combined with sensitivity analyses and colocalization to test the effect of PUFA on cerebral aneurysms. They found that genetically predicted omega-3 and DHA decreased the risk for intracranial aneurysm (IA) and subarachnoid haemorrhage (SAH) but not for unruptured IA (uIA).
Strengths:
PUFA on the risk of cerebral aneurysms is of clinical importance; the authors performed multiple sensitivity analyses to ensure MR fulfills its assumptions.
Weakness:
In my opinion, the major weakness is the selection of IVs, the same IVs should be used for each exposure, especially when the outcomes (IA, SAH, and uIA) are closely related. The removal of IVs was inconsistent, for example, why was LPA rs10455872 removed for SAH but not for uIA? (significantly more IVs were used for …
Reviewer #1 (Public Review):
Summary:
The authors performed two-sample MR combined with sensitivity analyses and colocalization to test the effect of PUFA on cerebral aneurysms. They found that genetically predicted omega-3 and DHA decreased the risk for intracranial aneurysm (IA) and subarachnoid haemorrhage (SAH) but not for unruptured IA (uIA).
Strengths:
PUFA on the risk of cerebral aneurysms is of clinical importance; the authors performed multiple sensitivity analyses to ensure MR fulfills its assumptions.
Weakness:
In my opinion, the major weakness is the selection of IVs, the same IVs should be used for each exposure, especially when the outcomes (IA, SAH, and uIA) are closely related. The removal of IVs was inconsistent, for example, why was LPA rs10455872 removed for SAH but not for uIA? (significantly more IVs were used for uIA). The authors should provide more details for the justification of the removal of IVs other than only indicating "confounder" in supplementary tables. The authors should also perform additional analyses including all IVs and IVs from other PUFA GWAS.
In addition, it seems that the SNPs in the FADS locus were driving the MR association, while FADS is a very pleiotropic locus associated with many lipid traits, removing FADS could attenuate the MR effect. The authors should perform a sensitivity analysis to remove this locus.
Instead of removing multiple "confounder" IVs which I think may bias the MR results due to very closely related lipid traits, the authors should perform multivariable MR to identify independent effects of PUFAs to IA, conditioning on other PUFAs and/or other lipids.
Colocalization was not well described, the authors should include the colocalization results for each locus in a supplementary table. They also mentioned "a large PP for H4 (PP.H4 above 0.75) strongly supports shared causal variants affecting both gene expression and phenotype". The authors should make sure that the colocalization was performed using the expression data of each gene or using the GWAS summary of each PUFA locus.
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Reviewer #2 (Public Review):
Summary:
In the manuscript, Yu et al reported a two-sample Mendelian randomization study to evaluate the causation between polyunsaturated fatty acids (PUFA) and cerebral aneurysm, based on summary statistics from published genome-wide association studies. The authors identified that omega-3 fatty acids and Docosahexaenoic acid decreased the risk for intracranial aneurysm (IA) and aneurysmal subarachnoid hemorrhage (aSAH). COLOC analysis suggested that the acids and IA, aSAH likely share causal variants in gene fatty acid desaturase 2.
Strengths:
The methodology is sound, with appropriate sensitivity analysis.
Weaknesses:
The results did not provide significant novel findings. The interpretation of the results is not sound.
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