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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

17/12/24, 7:04 am1 repost6 likes

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

Trait importance is how much of an effect a gene has on the study trait. Genes with big effects should be ranked highly. But what if a gene has huge effects across a ton of traits? Should a gene that affects everything still be ranked highly? 4/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

Peter Ellis

@pjie2.bsky.social