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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

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

What about GWAS? GWAS prioritize genes near trait-specific VARIANTS. This is profoundly different from prioritizing trait-specific GENES. Variants can be specific because they act on trait-specific genes, or because they act on pleiotropic genes in a context-specific way. 8/n

We find that both of these ways of being specific contribute to variants being ranked highly in GWAS: 1) Coding variants in specifically-expressed genes are more highly ranked 2) Non-coding variants in tissue-specific ATAC peaks are more highly ranked 9/n

To recap so far: burden tests prioritize trait-specific genes; GWAS prioritize genes near trait-specific variants. Height GWAS and burden tests give a couple of really nice examples: NPR2 and HHIP. 10/n