A proteome atlas of structural variation and VNTR effects on complex traits and diseases

Abstract

Structural variants (SVs), including variable number tandem repeats (VNTRs), are a major source of human genetic variation, but their impact on the proteome remains poorly characterized. Using a long-read assembly-based reference panel, we imputed 54,578 general SVs and 15,826 VNTRs in 54,306 UK Biobank participants to interrogate their effects on the abundances of 2,923 plasma proteins. SVs and VNTRs together explained [~]8.0% of variant-based heritability for protein abundance, with 123 proteins driven predominantly (>80%) by SVs. We identified 8,065 independent SV-protein and 4,101 VNTR-protein associations (with 601 highly unlikely to be driven by small genetic variants) that frequently perturb active regulatory elements, topologically associating domain boundaries, and post-transcriptional mechanisms. Integrative analyses with gene expression and complex trait SV association data identified 1,353 protein-trait association pairs, such as a highly pleiotropic insertion in MAN1A2 associated with 86 distinct phenotypes and a 3 UTR deletion in SULT2A1 linked to gallstone disease, illustrating plausible mechanisms whereby SV-induced regulatory perturbations mediate disease susceptibility. This SV-protein atlas bridges a critical gap between large-scale genomic alterations and proteomic variation, providing novel mechanistic insights into human disease biology and therapeutic discovery.