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

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.

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.