Deep coverage whole genome sequences and plasma lipoprotein(a) in individuals of European and African ancestries

Abstract

Lipoprotein(a), Lp(a), is a modified low-density lipoprotein particle that contains apolipoprotein(a), encoded by LPA, and is a highly heritable, causal risk factor for cardiovascular diseases that varies in concentrations across ancestries. Here, we use deep-coverage whole genome sequencing in 8392 individuals of European and African ancestry to discover and interpret both single-nucleotide variants and copy number (CN) variation associated with Lp(a). We observe that genetic determinants between Europeans and Africans have several unique determinants. The common variant rs12740374 associated with Lp(a) cholesterol is an eQTL for SORT1 and independent of LDL cholesterol. Observed associations of aggregates of rare non-coding variants are largely explained by LPA structural variation, namely the LPA kringle IV 2 (KIV2)-CN. Finally, we find that LPA risk genotypes confer greater relative risk for incident atherosclerotic cardiovascular diseases compared to directly measured Lp(a), and are significantly associated with measures of subclinical atherosclerosis in African Americans.

Clinical Utility of Lipoprotein(a) and LPA Genetic Risk Score in Risk Prediction of Incident Atherosclerotic Cardiovascular Disease

“…Previous studies suggest that small apolipoprotein(a) isoforms, which are also associated with higher lipoprotein(a) levels, may increase an individual’s risk of ASCVD more than expected by changes in lipoprotein(a) concentration alone. However, in this study we did not find that the LPA GRS, which contains several genetic variants associated with small apolipoprotein(a) size, explained additional ASCVD risk beyond measured levels of lipoprotein(a). Unlike isoform-independent lipoprotein(a) molar concentration, the associations of apolipoprotein(a), and by extension isoform-dependent measurements, with ASCVD may be confounded by pleiotropic effects on high-density lipoprotein cholesterol and triglycerides.…”

A simple and accurate method to determine genomewide significance for association tests in sequencing studies

“…Third, SKAT‐O is computationally demanding, especially for WGS studies. Indeed, only the burden and SKAT tests have been used in recent publications on WGS studies (e.g., Natarajan et al, ; Zekavat et al, ).…”

The Brazilian Initiative on Precision Medicine (BIPMed): fostering genomic data-sharing of underrepresented populations

“…To investigate the presence of pathogenic variants in WES, we compared WES data with Clinvar version 20190211 42 . Additionally, we compared the distribution of rare and common pathogenic/likely pathogenic variants within WES data with distributions determined using the 1000 Genome Project, gnomAD, and TOPMed databases 4 , 14 , 43 , 44 . These data analyses were performed using VariantAnnotation 45 , vcfR 46 , and ggplot2 47 packages from Bioconductor, and in-house scripts in R software.…”