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

Signal in association studies depends on effect size, γ, and variant frequency, p: signal ~ p(1-p) γ² But natural selection throws a wrench in this – variants with bigger effects will be under stronger selection, making them rarer. 2/6

But selection only cares about a variant because of how it impacts fitness-relevant traits. Under certain assumptions (see the paper!), we have that the strength of selection is the sum of effects across all fitness-relevant traits: s = Σₜ γₜ² www.biorxiv.org/content/10.1... 4/6

But this means that what matters for association study ranking is how specific a variant’s effects are to the trait you’re studying! signal ~ μ γ² / Σₜ γₜ² The most important variants don't end up with the largest z-scores! 5/6

See our main thread about the paper 👇 for what this means about how we should interpret GWAS and rare variant burden tests! 6/6 bsky.app/profile/jeff...