Functional dissection of complex trait variants at single-nucleotide resolution

Nature

by Layla Siraj

February 26, 2026

AI-Generated Deep Dive Summary

Genome-wide association studies (GWAS) have identified thousands of loci linked to complex traits and diseases, but pinpointing the causal variants within these loci remains a significant challenge. This study addresses this issue by leveraging a massively parallel reporter assay (MPRA), which evaluates the regulatory activity of over 220,000 fine-mapped trait-associated variants across five diverse cell types. By testing variants in both promoters and distal regulatory elements, researchers identified 13,121 regulatory variants with high precision. These findings demonstrate that MPRA effectively distinguishes causal variants from non-causal controls, providing a scalable solution to resolve genetic correlations and pinpoint functional variants. The study reveals that while many of these regulatory variants disrupt transcription factor (TF) binding motifs, only 69% can be explained by known mechanisms. Through saturation mutagenesis and functional testing, the researchers assigned affected TFs to 91% of variants without clear canonical explanations. This highlights the diversity of regulatory mechanisms at play and underscores the importance of exploring less understood pathways in genetic regulation. Additionally, the study identifies regulatory epistasis—non-additive interactions between variants—at 11% of tested loci. These findings suggest that multiple functional variants on the same haplotype can influence trait-associated loci, adding a layer of complexity to our understanding of how genetic variations contribute to disease risk. Overall, this systematic characterization of causal variants provides new insights into the regulatory grammar underlying complex traits and diseases, offering valuable tools for advancing precision medicine and improving therapeutic targeting.

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Originally published on Nature on 2/26/2026