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<p>Structural variants (SVs) are a major type of genetic variation, yet their role in human traits remains largely uncharacterized, primarily due to challenges in genotyping them on a genome-wide scale in large cohorts. Here we identified 171,233 high-quality, genome-wide SVs from 482 haplotype-resolved genome assemblies derived from PacBio HiFi long-read sequencing of 241 individuals. We developed a reference panel and a web application (ImputeSV) to impute these SVs from single-nucleotide polymorphism (SNP) data and demonstrated high imputation accuracy at both the individual and cohort levels. Using this tool, we imputed 54,578 common SVs (minor allele frequencies (MAFs) ≥1%) in 456,643 UK Biobank (UKB) participants of European ancestry. Through analysis of UKB data and simulations, we estimated that SVs contributed to at least 4.7% of the common genetic variation for complex traits. Genome-wide association analyses of SVs for 2,624 UKB traits identified 17,335 SV–trait associations, including 958 unlikely to be driven by small genetic variants. Our study demonstrates the power of using long-read assemblies for imputing SVs from SNPs, unveils the role of SVs in complex trait variation and provides a catalog of SV associations in the UKB.</p>

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Genome-wide associations of structural variants with human traits through imputation from long-read assemblies

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月20日

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  • Wei-Yang Bai,
  • Shuli Liu,
  • Zhongqu Duan,
  • Ji-Jian Yang,
  • Jie Chen,
  • Junren Hou,
  • Lianfeng Wu,
  • Nan Li,
  • Ting Qi,
  • Jian Yang

摘要

Structural variants (SVs) are a major type of genetic variation, yet their role in human traits remains largely uncharacterized, primarily due to challenges in genotyping them on a genome-wide scale in large cohorts. Here we identified 171,233 high-quality, genome-wide SVs from 482 haplotype-resolved genome assemblies derived from PacBio HiFi long-read sequencing of 241 individuals. We developed a reference panel and a web application (ImputeSV) to impute these SVs from single-nucleotide polymorphism (SNP) data and demonstrated high imputation accuracy at both the individual and cohort levels. Using this tool, we imputed 54,578 common SVs (minor allele frequencies (MAFs) ≥1%) in 456,643 UK Biobank (UKB) participants of European ancestry. Through analysis of UKB data and simulations, we estimated that SVs contributed to at least 4.7% of the common genetic variation for complex traits. Genome-wide association analyses of SVs for 2,624 UKB traits identified 17,335 SV–trait associations, including 958 unlikely to be driven by small genetic variants. Our study demonstrates the power of using long-read assemblies for imputing SVs from SNPs, unveils the role of SVs in complex trait variation and provides a catalog of SV associations in the UKB.