A phenome-wide structural variant map from 467,152 UK Biobank genomes

Structural variants (SVs) are large (>50 base pairs) genomic rearrangements that can significantly influence human phenotypes, yet their contribution to health and disease remains undercharacterized. We conducted a phenome-wide association study (PheWAS) of 1.6 million SVs identified in whole-genome sequencing data from 467,152 UK Biobank participants, across 13,322 binary, 2,018 quantitative, and 2,923 plasma protein traits. Of these, 82.25% of SVs were outside the detectable range of prior copy-number variant studies. Protein quantitative trait loci analysis linked 3,467 SVs to 1,690 proteins, with effects dependent on SV type and location. In SV-PheWAS, we detected 28,184 associations with human health outcomes. Notably, we uncovered rare SVs with strong phenotypic effects. Furthermore, we show that at known genome-wide association study loci, 32.21% of associated SVs overlapped functional genomic regions. This study underscores the underestimated role of SVs in human genetics and their potential to advance understanding of human biology and drug discovery.