Post

Jeff Spence
@jeffspence.github.io

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

Jeff Spence
@jeffspence.github.io

If a variant experiences strong selection, with selection coefficient s then p(1-p) ~ μ/s , where μ is the mutation rate (thanks JBS Haldane!!!). We see this in the UKB! This means: signal ~ μγ²/s 3/6

Jeff Spence
@jeffspence.github.io

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

1 repost3 likes

Jeff Spence
@jeffspence.github.io

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...

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...
Jeff Spence
@jeffspence.github.io

Thinking about selection on lots of traits in the context of GWAS was pioneered by @yuvalsim.bsky.social, Guy Sella, and coauthors in a couple of really beautiful papers that laid the foundation for our work: journals.plos.org/plosbiology/... www.biorxiv.org/content/10.1...

journals.plos.orgA population genetic interpretation of GWAS findings for human quantitative traitsAuthor summary One of the central goals of evolutionary genetics is to understand the processes that give rise to phenotypic variation in humans and other taxa. Genome-wide association studies (GWASs)...