GWAS studies have identified thousands of genetic variants associated with human disease. However, as the majority of the identified loci are found in non-coding regions, a long-standing problem in human genetics has been how to identify the genes driving these associations. - ThreadSky

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adamauton.bsky.social • 269 days ago

GWAS studies have identified thousands of genetic variants associated with human disease. However, as the majority of the identified loci are found in non-coding regions, a long-standing problem in human genetics has been how to identify the genes driving these associations.

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adamauton.bsky.social•269 days ago

Multiple methods have been developed to identify the causal gene in GWAS studies. These methods often integrate additional functional information, or make use of colocalization with expression or proteomics QTL datasets.

adamauton.bsky.social•269 days ago

As good as these methods are, I have often seen research scientists relying on biological knowledge or literature when reviewing GWAS loci, and they can often identify very plausible causal genes, even in the absence of a link from functional data.

adamauton.bsky.social•269 days ago

However, humans bring their own biases to this problem; they tend to over-focus on genes they know about and are able to construct narratives as to why those genes *must be* the causal ones!

adamauton.bsky.social•269 days ago

As I once heard David Altshuler say "There is always a gene at the top of the list, and there is always a postdoc who can tell you why that gene must be important!" (It may be a mis-quote; it was a long time ago!)

adamauton.bsky.social•269 days ago

However, LLMs have been trained on virtually all biological literature on the internet. We wondered, could they help us address the causal gene problem?

adamauton.bsky.social•269 days ago

The answer appears to be yes! In fact, using a *really simple* approach, LLMs appear to outperform state-of-the-art methods at identifying the causal gene in a variety of 'gold standard' truth datasets!

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