Post

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

17/12/24, 7:04 am0 reposts8 likes

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...

Jeff Spence@jeffspence.github.io

Why do association studies prioritize trait-specific variants??? A quick thread about the importance of thinking about all traits at once 👇 1/6 (🧪🧬)

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

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

Moreover, the two types of test answer that question for different audiences. Burden tests may be most medically relevant to pharma companies (i.e. drug development). They tell you which genes you can target with drugs or gene edits to have a specific effect on the trait of interest. 3/n