#1

New Chinese paper: Fatty acids and colorectal cancer: Insights from Mendelian randomization 2025

Our analysis revealed that docosahexaenoic acid and omega-3 fatty acids were positively associated with CRC risk.
It is noteworthy that all 3 MR analysis methods yielded consistent conclusions: docosahexaenoic acid (DHA) and omega-3 fatty acid are risk factors for CRC.
We found that both DHA and omega-3 fatty acids were positively linked to CRC, whether in absolute levels or relative to total fatty acids. Omega-3 fatty acids are a class of PUFAs, primarily including alpha-linolenic acid, eicosapentaenoic acid (EPA), and DHA.[23] Due to our study’s exclusive focus on DHA and the absence of data on the other 2 omega-3 fatty acids, we cannot determine whether the relation between omega-3 fatty acids and CRC is primarily attributable to the effects of DHA alone or involves interactions among various omega-3 fatty acids. Numerous epidemiological studies[3–10] have indicated that a higher intake of omega-3 fatty acids, such as EPA and DHA, can reduce the risk of CRC. However, evidence from MR studies[11,12] suggested a positive correlation between omega-3 fatty acids and the risk of CRC. Our study utilized data different from previous MR studies to validate the conclusion that omega-3 fatty acids enhance the risk of CRC. Several studies[24–27] have found that CRC tissue contains significantly higher levels of omega-3 PUFAs compared to adjacent normal tissue. This further highlights the necessity for future research to clarify the relationship between omega-3 fatty acids and CRC.

@约瑟夫_拉维尔: a good example of the difference between association studies and causal relationships.
@DeStrider @Neo @DrFraser you might be interested.

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How much omega-3 do you need?
#2

I quickly discussed whether MR instruments for omega 3 are good with 4o, and this seems like a case where the instruments are not that good and hence MR may not be that valuable, for example outputs from 4o:

Several genome-wide association studies (GWAS), such as those from the UK Biobank and CHARGE consortium, have identified SNPs associated with plasma or red blood cell levels of EPA and DHA. However, these SNPs typically explain only a small proportion of variance in fatty acid levels (e.g., ~1-5%).

Pleiotropy Risk: Variants in FADS1/FADS2 influence both omega-3 and omega-6 pathways, complicating causal inference.

In cases where the instruments are great (clear, explain large portion of the variance) MR analysis can be the most amazing sets of evidence. Here it may bot be the case that instruments are reliable though.

And especially not for DHA

Instruments tend to be stronger for EPA than for DHA, likely due to more consistent GWAS associations.

Btw - I haven’t looked at the studies, but does seem like the inflammation benefits still is picked up:

Some MR studies show modest protective associations with inflammation markers (e.g., CRP), but these need replication.

Her is 4o’s conclusion

Mendelian randomization instruments for EPA and DHA are valid but modest in strength, especially compared to other traits like LDL or BMI. They’re useful for triangulating evidence, but limited power and pleiotropy must be carefully considered. For targeted questions (e.g., DHA and cognitive aging), stronger instruments or well-powered GWAS may still be needed.

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#3

You are on the mission… where do we buy the DHA sucks t-shirts ?

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#4

Thanks for sharing. So this paper is looking at SNPs associated with O3 handling and we’re making an assumption of SNPs → fatty acids → the persons actual fatty acid levels → CRC So it’s indicative, but not really conclusive, and it relies on the earlier GWAS studies correctly identifying the SNPs linked to omega 3 levels, and we also have no idea about the persons diet, supplements etc.

I also plugged the results section into some AI for some simple summarising:

  • Effect sizes (β) of 0.16–0.29 are moderate — not tiny, but not enormous either.
  • The consistency across all three methods strengthens confidence: even with different assumptions (e.g. pleiotropy), the effect holds.
  • The p-values are all < 0.01, often much smaller — indicating strong statistical evidence.

That said, these β values are not hazard ratios or risk percentages. They’re linear MR estimates — so while they show direction and significance, they don’t translate directly into “X% more risk” without extra modeling.

Is it intellectually lazy of me to simply say that it seems we have absolutely no idea how these things work? Do we think all the epidemiological and observational studies are simply due to healthy user bias and residual confounders? (Or essentially, a control population which is just incredibly unhealthy to begin with, so increasing omega-3 is likely because they’re decreasing ultra processed fats in microwaved pizzas etc?).

#5

@Neo it’s better to link to your other message rather than copy/pasting it.

Anyway here’s my answer: Predicting Alzheimers & Dementia (and minimizing risk) - #628 by adssx

Tl;dr: this result is very strong precisely because SNP only explain a small proportion of the DHA variance.

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#6

I’m definitely on a mission against DHA supplementation. Although I would love to be wrong. It would be amazing to have a “natural” supplement that is safe and prevents cancer, cardiovascular diseases and dementia. Unfortunately DHA does not seem to be such a supplement.

I started taking EPA + DHA years ago based on its purported benefits and some association studies. It’s only over the past few months that I decided to take time to look at the evidence, especially the recent MR studies and large RCTs. And it’s not good. When you dig, most studies other than association studies show no benefits or detrimental effects. With one exception: EPA seems good for mental health and cardiovascular health (and therefore, indirectly, for neuroprotection).

So I was sad and felt fooled by all these BS influencers. Omega 3 is so overrated. It’s touted everywhere as the cure-all supplement. So we need to have a proper debate on this: is DHA supplementation really beneficial? Is it backed by strong evidence? I don’t think so.

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#7

Above only addresses one of at least two big issues with MR instruments that I bought up

The instruments seem related to both Omega 3 and Omega 6 - and we know that Omega 6 might be bad for many aspects of health based on a lot of other types of studies. So can we rule out that it is the correlation of 3 to 6 and hence 6 that is driving the relationship and not 3?

See:

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#8

Answer here: Predicting Alzheimers & Dementia (and minimizing risk) - #632 by adssx