Common centromeric variation associates with molecular and complex traits in humans

Human centromeres harbor extensive structural variation that has remained largely inaccessible to human genetics because their repetitive -satellite arrays are absent from standard reference and imputation panels. Here we catalog 188,589 centromeric structural variants (SVs) from haplotype-resolved long-read assemblies of 196 Human Pangenome Reference Consortium individuals aligned to the telomere-to-telomere CHM13 reference. Resolving recurrent SVs into monophyletic components along centromeric haplotype phylogenies makes them imputable from pericentromeric ([Formula] = 0.407 vs. 0.065 unresolved). In 124 individuals with haplotype-resolved nanopore methylation, we identify 418 same-chromosome SV-CpG associations that form local hypomethylation-enriched domains in the centromeric region, most strongly for deletions. We also show that a truncated 113-bp monomer on chromosome 8 is associated with the position of the CENP-A-associated centromere dip region (CDR) in 151 individuals, independent of array length. Imputed into 630 individuals with expression and splicing data, centromeric SVs are associated with 141 genes, 14 of them new relative to the SNP-based cis-QTL analysis, including the H3K9 methyltransferase SUV39H1. In 315,204 All of Us participants, we identify 170 associations between 61 SV predictors and 27 clinical phenotypes, including substance-related disorders and breast cancer. Our study brings a previously inaccessible class of variation into population-scale genetics and links centromeric SVs to centromere organization, gene expression, splicing and complex traits.