Person:

Ulirsch, Jacob

Fine-mapping aims to identify causal variants impacting complex traits. We propose PolyFun, a computationally scalable framework to improve fine-mapping accuracy by leveraging functional annotations across the entire genome-not just genome-wide-significant loci-to specify prior probabilities for fine-mapping methods such as SuSiE or FINEMAP. In simulations, PolyFun + SuSiE and PolyFun + FINEMAP were well calibrated and identified >20% more variants with a posterior causal probability >0.95 than identified in their nonfunctionally informed counterparts. In analyses of 49 UK Biobank traits (average n = 318,000), PolyFun + SuSiE identified 3,025 fine-mapped variant-trait pairs with posterior causal probability >0.95, a >32% improvement versus SuSiE. We used posterior mean per-SNP heritabilities from PolyFun + SuSiE to perform polygenic localization, constructing minimal sets of common SNPs causally explaining 50% of common SNP heritability; these sets ranged in size from 28 (hair color) to 3,400 (height) to 2 million (number of children). In conclusion, PolyFun prioritizes variants for functional follow-up and provides insights into complex trait architectures.

Abstract: Effective interpretation of genome function and genetic variation requires a shift from epigenetic mapping of cis-regulatory elements (CREs) to characterization of endogenous function. We developed HCR-FlowFISH, a broadly applicable approach to characterize CRISPR-perturbed CREs via accurate quantification of native transcripts, alongside CASA (CRISPR Activity Screen Analysis), a hierarchical Bayesian model to quantify CRE activity. Across >325,000 perturbations, we provide evidence that CREs can regulate multiple genes, skip over the nearest gene, and can display activating and/or silencing effects. At the cholesterol-level associated FADS locus, we combine endogenous screens with reporter assays to exhaustively characterize multiple genome-wide association signals, functionally nominating causal variants and identifying their target genes.