Abstract
Large-scale deep-coverage whole-genome sequencing (WGS) is now feasible and offers potential advantages for locus discovery. We perform WGS in 16,324 participants from four ancestries at mean depth >29X and analyze genotypes with four quantitative traits—plasma total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol, and triglycerides. Common variant association yields known loci except for few variants previously poorly imputed. Rare coding variant association yields known Mendelian dyslipidemia genes but rare non-coding variant association detects no signals. A high 2M-SNP LDL-C polygenic score (top 5th percentile) confers similar effect size to a monogenic mutation (~30 mg/dl higher for each); however, among those with severe hypercholesterolemia, 23% have a high polygenic score and only 2% carry a monogenic mutation. At these sample sizes and for these phenotypes, the incremental value of WGS for discovery is limited but WGS permits simultaneous assessment of monogenic and polygenic models to severe hypercholesterolemia.
Highlights
Large-scale deep-coverage whole-genome sequencing (WGS) is feasible and offers potential advantages for locus discovery
WGS analysis of severe hypercholesterolemia shows a ten-fold enrichment of a high polygenic low-density lipoprotein cholesterol (LDL-C) score versus monogenic mutation for severe hypercholesterolemia
While the incremental value for WGS for locus discovery currently is limited largely due to relatively smaller sample sizes, WGS markedly improves the diagnostic yield of severe hypercholesterolemia through simultaneous assessment of monogenic and polygenic models
Summary
Large-scale deep-coverage whole-genome sequencing (WGS) is feasible and offers potential advantages for locus discovery. When performed at sufficient depth of coverage (>20-fold coverage per base), wholegenome sequencing (WGS) can detect single nucleotide polymorphisms (SNPs), insertions, and deletions across the allele frequency spectrum in both non-coding and coding regions These advances allow us to test the incremental value of WGS as a tool for locus discovery and develop a framework to understand why a specific individual might have an extreme lipid value. Toward these two goals, we studied the whole-genome sequences in 16,324 participants of European, African, East Asian, and Hispanic ancestries with available plasma lipids phenotypes. While the incremental value for WGS for locus discovery currently is limited largely due to relatively smaller sample sizes, WGS markedly improves the diagnostic yield of severe hypercholesterolemia through simultaneous assessment of monogenic and polygenic models
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