A great paper and a great thread! One point that I partcularly liked was this one: "In particular, [GWAS] variants can be trait specific in two ways: they can either affect a trait-specific gene or affect a pleiotropic gene in a context-specific manner." - ThreadSky

kauralasoo.bsky.social • 71 days ago

A great paper and a great thread! One point that I partcularly liked was this one:
"In particular, [GWAS] variants can be trait specific in two ways: they can either affect a trait-specific gene or affect a pleiotropic gene in a context-specific manner."

Reposted from Jeff Spence

What do GWAS and rare variant burden tests discover, and why?

Do these studies find the most IMPORTANT genes? If not, how DO they rank genes?

Here we present a surprising result: these studies actually test for SPECIFICITY! A 🧵on what this means... (🧪🧬)

www.biorxiv.org/content/10.1...

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kauralasoo.bsky.social•71 days ago

Since I usually like to understand biology through a collection of informative examples, I'd like to highlight one from our own recent work.

One of mine and @ericfauman.bsky.social's favourite GWAS hit is the HAL locus on chromosome 12 associated with vitamin D.

kauralasoo.bsky.social•71 days ago

The lead variant (rs3819817) is a non-coding variant near the HAL gene, which is also the obvious causal gene. HAL converts histidine to trans-urocanate which acts as natural sunscreen to block UV in the skin, thus also reducing vit D levels. More details in our pre-print: https://doi.org/10.1101/2024.10.21.24315891

kauralasoo.bsky.social•71 days ago

Surely this variant should have a much larger effect on histidine than on vitamin D, because histidine is the direct substrate for the HAL enzyme? Curiously, the rs3819817 was not even genome-wide significant for histidine in n = ~250k UK Biobank samples (beta = −0.014, p = 1.8×10−6).

kauralasoo.bsky.social•71 days ago

In our most recent meta-analysis of 600k+ samples the association did become signifcant, but the effect size was still tiny:
https://nmrmeta.gi.ut.ee/variant/12:95984993-C-T
https://www.medrxiv.org/content/10.1101/2024.10.15.24315557v2

kauralasoo.bsky.social•71 days ago

Why is that? Turns out that rs3819817 is a skin-specific eQTL for HAL, thus likely inreasing HAL protein abundance only in the skin!

kauralasoo.bsky.social•71 days ago

In GTEx, HAL is also highly expressed in the liver, spleen and whole blood, which are probably the more relevant tissues for determining plasma histidine levels.

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