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Jeff Spence
@jeffspence.github.io

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...

biorxiv.orgSpecificity, length, and luck: How genes are prioritized by rare and common variant association studiesStandard genome-wide association studies (GWAS) and rare variant burden tests are essential tools for identifying trait-relevant genes. Although these methods are conceptually similar, we show by anal...

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Jeff Spence
@jeffspence.github.io

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

Jeff Spence
@jeffspence.github.io

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

Jeff Spence
@jeffspence.github.io

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

Jeff Spence
@jeffspence.github.io

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