Deep-coverage whole genome sequences and blood lipids among 16,324 individuals

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.

Fig. 1

Schematic of genomic variant discovery and analyses. Variants were jointly discovered in three distinct sets: (1) FHS, JHS, and OOA; (2) MESA; and (3) EST and FIN. Cohorts included in analyses are denoted by color-coded icons. Allele frequency spaces assessed are indicated for analyses. EST Estonia, FHS Framingham Heart Study, FIN Finland, JHS Jackson Heart Study, MESA Multi-Ethnic Study of Atherosclerosis, OOA Old Order Amish

Fig. 2

Deep-coverage WGS identifies genomic variation across the allelic spectrum. Variant counts by allele count/frequency bin within each of the cohorts. Singletons (“AC 1”) and doubletons (“AC 2”) are separately distinguished from allele frequency bins within each cohort. Variants were jointly discovered in three distinct sets: (1) FHS, JHS, and OOA; (2) MESA; and (3) EST and FIN. AC allele count, EST Estonia, FHS Framingham Heart Study, FIN Finland, JHS Jackson Heart Study, MAF minor allele frequency, MESA Multi-Ethnic Study of Atherosclerosis, OOA Old Order Amish

Fig. 3

Schematic of non-coding rare variant analyses. Four grouping schematics of rare non-coding variants (MAF <1%). (1) The sliding window approach tiles across the genome at fixed widths, only including variants overlying annotations consistent with enhancers, promoters, and DHS in non-exonic regions. All other approaches attempt to map non-coding putative functional genomic regions with discrete genes as the analytical unit. Overall, they are based on: (2) promoter, enhancer, and DHS annotations near a gene’s transcription start site, (3) co-occurrence of enhancer and DHS annotations with HepG2 gene expression, and (4) H3K27ac marks within Hi-C contact regions mapped to genes. DHS DNase hypersensitivity site, MAF minor allele frequency