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

Seyedeh Maryam ZekavatSanni RuotsalainenRobert E HandsakerMaris AlverJonathan M BloomTimothy PoterbaCotton SeedJason ErnstMark ChaffinJesse M EngreitzGina M PelosoAni ManichaikulChaojie YangKathleen A RyanMao FuW Craig JohnsonMichael TsaiMatthew BudoffRamachandran S VasanL Adrienne CupplesJerome I RotterStephen S RichWendy PostBraxton D MitchellAdolfo CorreaAndres MetspaluJames G WilsonVeikko SalomaaManolis KellisMark J DalyBenjamin M NealeSteven McCarrollIda SurakkaTõnu EskoAndrea GannaSamuli RipattiSekar KathiresanPradeep Natarajannull null
Published in: Nature communications (2018)
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.
Keyphrases
  • low density lipoprotein
  • copy number
  • cardiovascular disease
  • mitochondrial dna
  • genome wide
  • dna methylation
  • lymph node metastasis
  • healthcare
  • type diabetes
  • squamous cell carcinoma
  • cardiovascular risk factors