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 theLPAgene) 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 overlappingLPA, we quantified the 5.5kb kringle IV-2 copy number (KIV2-CN), a knownLPAstructural 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-codingSLC22A3intronic 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 ofLPAvariant 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..
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Preprint| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
bioRxiv.org - (2022) vom: 08. Aug. Zur Gesamtaufnahme - year:2022 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Zekavat, Seyedeh M. [VerfasserIn] |
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| doi: |
10.1101/225169 |
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| PPN (Katalog-ID): |
XBI017902606 |
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| 520 | |a ABSTRACT Lipoprotein(a), Lp(a), is a modified low-density lipoprotein particle where apolipoprotein(a) (protein product of theLPAgene) 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 overlappingLPA, we quantified the 5.5kb kringle IV-2 copy number (KIV2-CN), a knownLPAstructural 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-codingSLC22A3intronic 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 ofLPAvariant 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. | ||
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| 700 | 1 | |a Handsaker, Robert E. |e verfasserin |4 aut | |
| 700 | 1 | |a Alver, Maris |e verfasserin |4 aut | |
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