A Long-read based Haplotype Panel Enhances Imputation and Discovery of Functional Small and Structural Variants

Haplotype reference panels are commonly used for genotype imputation in genome-wide association studies (GWAS). Although structural variations (SVs) are recognized as major contributors to human phenotypes, they are often excluded from GWAS analyses. Here, we integrate long-read-based and statistical methods to provide a comprehensive haplotype reference panel (Han-SV panel) incorporating 32,603,300 single nucleotide variants (SNPs), 3,180,227 small deletions and insertions and 172,569 SVs derived from 943 Han Chinese individuals. Our hybrid phasing approach had a 12.7-fold reduction in phasing error for small variants and 3.6-fold for SVs compared to conventional statistical phasing. This Han-SV panel enabled a more than two-fold in amount and four-fold in accuracy improvement of SV imputation compared to the expanded 1000 Genomes Project panel. Two GWASs using our panel-imputed variants identified 69 associated SVs and 101 previously unreported regions associated with skin-related and fingerprint phenotypes—substantially outperforming both short-read and SNP-array-based GWAS. This Han-SV panel offers a valuable resource for variant imputation and SV-included association studies to further uncover the novel phenotype associations and address critical gaps in missing heritability. An imputation server was provided for the use of the Han-SV panel (https://www.biosino.org/svrp).