Using @genomicsengland.bsky.social imputation allowed us to test many more low-frequency variants in the UK Biobank than previous studies (95M total). As an example, in branched-chain amino acid GWAS, we detected hits for all five members of the BCKDH complex, two of which had MAF < 0.0005! - ThreadSky

kauralasoo.bsky.social • 40 days ago

Using @genomicsengland.bsky.social imputation allowed us to test many more low-frequency variants in the UK Biobank than previous studies (95M total). As an example, in branched-chain amino acid GWAS, we detected hits for all five members of the BCKDH complex, two of which had MAF < 0.0005!

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kauralasoo.bsky.social•40 days ago

This illustrates how difficult it is to saturate gene discovery in GWAS, even for realtively 'simple' traits.

kauralasoo.bsky.social•40 days ago

We also performed genome-wide Mendelian randomisation to explore links between metabolic traits and CAD/T2D. While this did recover known causal effects of LDL cholesterol on CAD and glucose on T2D, almost everything else appeared to be significant as well.

kauralasoo.bsky.social•40 days ago

While it might be tempting, I find it difficult convince myself that hundreds of metabolic traits have a direct causal effect on CAD and T2D, given the widespread pleiotropic effects many variants have on these traits.

kauralasoo.bsky.social•40 days ago

As an example, genome-wide MR suggested that branched-chain amino acids (BCAAs) are (weakly) associated with T2D. To explore this association further, we turned to cis-MR and focussed our attention to genes that have direct effect on BCAA catabolism (BCAT2/DBT/PPM1K).

kauralasoo.bsky.social•40 days ago

Here's the putative causal DAG. Instead of estimating the genome-wide average effect of BCAAs on T2D (which could be confounded by many factors), we are now asking if altered protein function of BCAT2/DBT/PPM1K might have a causal effect on T2D risk.

kauralasoo.bsky.social•40 days ago

In all three gene regions we are seeing a null effect on T2D (and CAD).

jeromeebb.bsky.social•39 days ago

@kauralasoo.bsky.social what I mean by biochemical properties would be saturated lipid/unsaturated lipid, fatty acids, cholesterol, lipid n-carbon etc. The pink dots segregate directionally and should track biochemical properties, reassuring rather than puzzling imo. Tag @ericfauman.bsky.social

jeromeebb.bsky.social•39 days ago

@kauralasoo.bsky.social the majority (90% or more) of 293 metabolites in nightingale are lipids and so this is just tagging lipid metabolism being causally linked to CAD/T2D. In this plot if you try to color the scatter by biochemical properties you’d probably see it more clearly.

kauralasoo.bsky.social•39 days ago

I agree! One of the reasons we included this plot was to illustrate you should not treat the 249 traits as independent when performing MR (as is often done). Leaving lipid traits aside, I would still be worried about intepreting genome-wide MR that includes a bunch of anonymous trans variants.

kauralasoo.bsky.social•39 days ago

This is why I think the BCAA example is informative - early genome-wide MR suggested a causal link (https://doi.org/10.1371/journal.pmed.1002179), but more recent studies (e.g. https://onlinelibrary.wiley.com/doi/10.1002/oby.23951) have attributed this to reverse causality and pleiotropy.

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