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 where apolipoprotein(a) (protein product of the LPA gene) is covalently attached to apolipoprotein B. Lp(a) is a highly heritable, causal risk factor for cardiovascular diseases and varies in concentrations across ancestries. To comprehensively delineate the inherited basis for plasma Lp(a), we performed deep-coverage whole genome sequencing in 8,392 individuals of European and African American ancestries. Through whole genome variant discovery and direct genotyping of all structural variants overlapping LPA, we quantified the 5.5kb kringle IV-2 copy number (KIV2-CN), a known LPA structural polymorphism, and developed a model for its imputation. Through common variant analysis, we discovered a novel locus (SORT1) associated with Lp(a)-cholesterol, and also genetic modifiers of KIV2-CN. Furthermore, in contrast to previous GWAS studies, we explain most of the heritability of Lp(a), observing Lp(a) to be 85% heritable among African Americans and 75% among Europeans, yet with notable inter-ethnic heterogeneity. Through analyses of aggregates of rare coding and non-coding variants with Lp(a)-cholesterol, we found the only genome-wide significant signal to be at a non-coding SLC22A3 intronic window also previously described to be associated with Lp(a); however, this association was mitigated by adjustment with KIV2-CN. Finally, using an additional imputation dataset (N=27,344), we performed Mendelian randomization of LPA variant classes, finding that genetically regulated Lp(a) is more strongly associated with incident cardiovascular diseases than directly measured Lp(a), and is significantly associated with measures of subclinical atherosclerosis in African Americans.

HEART UK consensus statement on Lipoprotein(a): A call to action

“…The rate of apo(a) synthesis and secretion is inversely related to its molecular mass, and consequently, individuals who produce the lower molecular mass apo(a) isoforms have higher serum Lp(a) levels than those who produce the higher molecular mass isoforms [21,23,24]. Indeed, this explains the results of early genetic studies which established that serum Lp(a) levels are predominantly genetically inherited in an autosomal co-dominant manner [20,21,25] and that allelic variation at the LPA locus is largely responsible for the wide, potentially as much as 1000-fold differences in serum Lp(a) levels [12,26,27].…”

Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program

“…The first set of 53,831 sequenced genomes from TOPMed is now available to the community. The samples are deeply phenotyped and enable discovery of important biology [72][73][74][75][76] for heart, lung, blood, and sleep disorders. In addition, they provide a rich resource for developing and testing methods for surveying human variation, for inference of human demography, and for exploring functional constraint in the genome.…”

Analyses of Biomarker Traits in Diverse UK Biobank Participants Identify Associations Missed by European-centric Analysis Strategies

“…We identified an association of an African ancestry specific PCSK9 stop variant already known to be associated with LDL and total cholesterol [14,25] with apolipoprotein B, an unsurprising extension of the existing literature. Our results also include identification of multiple novel signals at the LPA locus for lipoprotein A, adding to the already extensive evidence of multiple distinct cis pQTL signals at this locus [37][38][39]. We were not able to adjust for KIV2-CN (copy number) in the Lp(a) region with our imputed single nucleotide variant data, which makes these distinct signals somewhat difficult to interpret.…”