Fig. 1: Identification of functional genetic elements housing fine-mapped complex and molecular traits.

a, Fine-mapped complex trait variants from UKBB and BBJ, as well as fine-mapped eQTL variants from GTEx v.8, were included in this study. b, We tested 304,278 unique variants using MPRAs, including 86,064 unique control variants. Nearly 25% of high-PIP (>0.5) eQTLs were associated with gene expression in multiple tissue systems (black), whereas high-PIP complex trait variants were more domain specific. Annot, annotated; Loc, location; Ref, reference; Alt, alternative. c, Experimental overview of the MPRA experiment. All variants were tested in K562, HepG2 and SK-N-SH cells, with complex trait variants also tested in A549 cells, and eQTL variants also tested in HCT116 cells. d, Correlation (Pearson r and generalized additive model) of element MPRA activity with chromatin accessibility at promoters (orange) and distal CREs (blue). Shaded areas represent 95% confidence intervals. e, Results from a linear regression of MPRA activity on normalized motif counts from 120,336 CREs in K562 and HepG2 cells. Specific motif families are shown in different colours. f, Element activity and allelic activity results for variants. Each point represents one variant measurement, with significant emVars shown in orange and non-significant variants in purple. Active elements were defined as |log₂FC | > 1 and Bonferroni-adjusted P < 0.01 (two-sided Wald test). Variants in active elements were classified as emVars if they showed a significant difference in activity between alleles (FDR < 0.1, two-sided Wald test with Benjamini–Hochberg correction). The maximum activity of each variant (reference or alternative allele) is shown on the x axis with a bimodal activity distribution around 0. Variants with fewer than 20 normalized RNA counts are omitted. Experimental schematic in c is adapted from figure 1a in ref. ⁶⁴, Springer Nature Limited.