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Seed, C.

Publications and source records attributed to Seed, C..

2 recordsLinked to original sources
bioRxiv2017

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

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.

genomics↗
bioRxiv2017

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

Deep-coverage whole genome sequencing at the population level is now feasible and offers potential advantages for locus discovery, particularly in the analysis rare mutations in non-coding regions. Here, we performed whole genome sequencing in 16,324 participants from four ancestries at mean depth >29X and analyzed correlations of genotypes with four quantitative traits - plasma levels of total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol, and triglycerides. We conducted a discovery analysis including common or rare variants in coding as well as non-coding regions and developed a framework to interpret genome sequence for dyslipidemia risk. Common variant association yielded loci previously described with the exception of a few variants not captured earlier by arrays or imputation. In coding sequence, rare variant association yielded known Mendelian dyslipidemia genes and, in non-coding sequence, we detected no rare variant association signals after application of four approaches to aggregate variants in non-coding regions. We developed a new, genome-wide polygenic score for LDL-C and observed that a high polygenic score conferred similar effect size to a monogenic mutation (~30 mg/dl higher LDL-C for each); however, among those with extremely high LDL-C, a high polygenic score was considerably more prevalent than a monogenic mutation (23% versus 2% of participants, respectively).

genomics↗