Post

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...

GWAS and burden tests are conceptually similar, so we might expect them to prioritize genes similarly. We find that their prioritizations of genes are surprisingly discordant (even when trying to get them to match as much as possible!) 2/n

If GWAS and burden rank genes differently, then how exactly are they ranking genes? More fundamentally, if we could measure whatever we wanted about genes, how SHOULD we rank genes? We propose two possible criteria: trait importance and trait specificity. 3/n

Maybe instead, one might want to rank genes by their trait specificity – how important they are for the study trait relative to how important they are across all traits. A trait-specific gene might better capture how “core” it is to trait biology. 5/n

We developed theory to understand what determines burden test gene ranking: surprisingly, these rank by SPECIFICITY! We confirmed this in practice in UKB. This is surprising! Burden tests don’t rank genes by their importance! 6/n

The intuition is surprisingly simple! See our mini-thread here 7/n bsky.app/profile/jeff...

I don't think I understand what you mean by "core" here. More broadly, I think trying to define "core" vs" non-core" may be a mirage. It feels a bit like asking what contributes most to Usain Bolt's speed: left leg, right leg, heart or nervous system. 1/n

The specificity question you drill into here strikes me as being key when it comes to *interventions*. It answers the question, "is there anything I can do that will selectively modify just this one trait" 2/n