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Deep coverage whole genome sequences and plasma lipoprotein(a) in individuals of European and African ancestries. Nat Commun 2018 Jul 04;9(1):2606

Date

07/06/2018

Pubmed ID

29973585

Pubmed Central ID

PMC6031652

DOI

10.1038/s41467-018-04668-w

Scopus ID

2-s2.0-85049751193 (requires institutional sign-in at Scopus site)   83 Citations

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.

Author List

Zekavat SM, Ruotsalainen S, Handsaker RE, Alver M, Bloom J, Poterba T, Seed C, Ernst J, Chaffin M, Engreitz J, Peloso GM, Manichaikul A, Yang C, Ryan KA, Fu M, Johnson WC, Tsai M, Budoff M, Vasan RS, Cupples LA, Rotter JI, Rich SS, Post W, Mitchell BD, Correa A, Metspalu A, Wilson JG, Salomaa V, Kellis M, Daly MJ, Neale BM, McCarroll S, Surakka I, Esko T, Ganna A, Ripatti S, Kathiresan S, Natarajan P, NHLBI TOPMed Lipids Working Group

Author

Ulrich Broeckel MD Chief, Center Associate Director, Professor in the Pediatrics department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Adaptor Proteins, Vesicular Transport
Cardiovascular Diseases
Cholesterol, LDL
DNA Copy Number Variations
Gene Expression
Genome, Human
Genome-Wide Association Study
Humans
Lipoprotein(a)
Polymorphism, Single Nucleotide
Quantitative Trait Loci
Risk Factors
Whole Genome Sequencing