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Direct Estimates of the Genomic Contributions to Blood Pressure Heritability within a Population-Based Cohort (ARIC).

Salfati E, Morrison AC, Boerwinkle E, Chakravarti A - PLoS ONE (2015)

Bottom Line: Second, common variants with allele frequency >10% recapitulate most of the BP heritability in these data.Fourth, the majority of this heritability arises from loci not harboring currently known cardiovascular and renal genes.Recent meta-analyses of large-scale genome-wide association studies (GWASs) and admixture mapping have identified ~50 loci associated with BP and hypertension (HTN), and yet they account for only a small fraction (~2%) of the heritability.

View Article: PubMed Central - PubMed

Affiliation: Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, United States of America; Université Paris Descartes, Sorbonne Paris Cite, 75005, Paris, France.

ABSTRACT
Blood pressure (BP) is a heritable trait with multiple environmental and genetic contributions, with current heritability estimates from twin and family studies being ~ 40%. Here, we use genome-wide polymorphism data from the Atherosclerosis Risk in Communities (ARIC) study to estimate BP heritability from genomic relatedness among cohort members. We utilized data on 6,365,596 and 9,578,528 genotyped and imputed common single nucleotide polymorphisms (SNPs), in 8,901 European ancestry (EA) and 2,860 African Ancestry (AA) ARIC participants, respectively, and a mixed linear model for analyses, to make four observations. First, for BP measurements, the heritability is ~20%/~50% and ~27%/~39% for systolic (SBP)/diastolic (DBP) blood pressure in European and African ancestry individuals, respectively, consistent with prior studies. Second, common variants with allele frequency >10% recapitulate most of the BP heritability in these data. Third, the vast majority of BP heritability varies by chromosome, depending on its length, and is largely concentrated in noncoding genomic regions annotated as DNaseI hypersensitive sites (DHSs). Fourth, the majority of this heritability arises from loci not harboring currently known cardiovascular and renal genes. Recent meta-analyses of large-scale genome-wide association studies (GWASs) and admixture mapping have identified ~50 loci associated with BP and hypertension (HTN), and yet they account for only a small fraction (~2%) of the heritability.

No MeSH data available.


Related in: MedlinePlus

(a) Estimates of the variance explained for SBP (red) and DBP (blue) by functional annotation class (promoter, UTR, DHS, exon, intron, intergenic) by joint analysis using genotyped and imputed SNPs for first-visit SBP and DBP respectively in 8,901 EA individuals, (b) Legend as in (a) but for 2,860 AA individuals.
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pone.0133031.g002: (a) Estimates of the variance explained for SBP (red) and DBP (blue) by functional annotation class (promoter, UTR, DHS, exon, intron, intergenic) by joint analysis using genotyped and imputed SNPs for first-visit SBP and DBP respectively in 8,901 EA individuals, (b) Legend as in (a) but for 2,860 AA individuals.

Mentions: We next investigated the likely locations of these common alleles modulating BP variation: were they preferentially located within genes or in non-coding genomic regions? To do so we classified all genotyped and imputed SNPs by their location within an annotated promoter, DNase I hypersensitive site (DHS), coding exon, intron or UTR (Fig 2). We performed analyses on both first visit and LTA BP values but only first visit measures are shown given the similarity of the results. Strikingly, in EA, irrespective of whether SBP or DBP is considered, almost the entire heritability contribution is from DHSs (Fig 2a). On the other hand, in AA, SBP and DBP give different results (Fig 2b). For SBP, the heritability is relatively equally contributed by DHSs and intronic sites with small contributions from coding and promoter SNPs. For DBP, however, almost the entire heritability contribution is from DHSs. These results suggest basic population-level EA versus AA differences in the genetic causes of BP heritability that need to be assessed in future studies since the modest sample sizes here may lead to sampling variation.


Direct Estimates of the Genomic Contributions to Blood Pressure Heritability within a Population-Based Cohort (ARIC).

Salfati E, Morrison AC, Boerwinkle E, Chakravarti A - PLoS ONE (2015)

(a) Estimates of the variance explained for SBP (red) and DBP (blue) by functional annotation class (promoter, UTR, DHS, exon, intron, intergenic) by joint analysis using genotyped and imputed SNPs for first-visit SBP and DBP respectively in 8,901 EA individuals, (b) Legend as in (a) but for 2,860 AA individuals.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4498745&req=5

pone.0133031.g002: (a) Estimates of the variance explained for SBP (red) and DBP (blue) by functional annotation class (promoter, UTR, DHS, exon, intron, intergenic) by joint analysis using genotyped and imputed SNPs for first-visit SBP and DBP respectively in 8,901 EA individuals, (b) Legend as in (a) but for 2,860 AA individuals.
Mentions: We next investigated the likely locations of these common alleles modulating BP variation: were they preferentially located within genes or in non-coding genomic regions? To do so we classified all genotyped and imputed SNPs by their location within an annotated promoter, DNase I hypersensitive site (DHS), coding exon, intron or UTR (Fig 2). We performed analyses on both first visit and LTA BP values but only first visit measures are shown given the similarity of the results. Strikingly, in EA, irrespective of whether SBP or DBP is considered, almost the entire heritability contribution is from DHSs (Fig 2a). On the other hand, in AA, SBP and DBP give different results (Fig 2b). For SBP, the heritability is relatively equally contributed by DHSs and intronic sites with small contributions from coding and promoter SNPs. For DBP, however, almost the entire heritability contribution is from DHSs. These results suggest basic population-level EA versus AA differences in the genetic causes of BP heritability that need to be assessed in future studies since the modest sample sizes here may lead to sampling variation.

Bottom Line: Second, common variants with allele frequency >10% recapitulate most of the BP heritability in these data.Fourth, the majority of this heritability arises from loci not harboring currently known cardiovascular and renal genes.Recent meta-analyses of large-scale genome-wide association studies (GWASs) and admixture mapping have identified ~50 loci associated with BP and hypertension (HTN), and yet they account for only a small fraction (~2%) of the heritability.

View Article: PubMed Central - PubMed

Affiliation: Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, United States of America; Université Paris Descartes, Sorbonne Paris Cite, 75005, Paris, France.

ABSTRACT
Blood pressure (BP) is a heritable trait with multiple environmental and genetic contributions, with current heritability estimates from twin and family studies being ~ 40%. Here, we use genome-wide polymorphism data from the Atherosclerosis Risk in Communities (ARIC) study to estimate BP heritability from genomic relatedness among cohort members. We utilized data on 6,365,596 and 9,578,528 genotyped and imputed common single nucleotide polymorphisms (SNPs), in 8,901 European ancestry (EA) and 2,860 African Ancestry (AA) ARIC participants, respectively, and a mixed linear model for analyses, to make four observations. First, for BP measurements, the heritability is ~20%/~50% and ~27%/~39% for systolic (SBP)/diastolic (DBP) blood pressure in European and African ancestry individuals, respectively, consistent with prior studies. Second, common variants with allele frequency >10% recapitulate most of the BP heritability in these data. Third, the vast majority of BP heritability varies by chromosome, depending on its length, and is largely concentrated in noncoding genomic regions annotated as DNaseI hypersensitive sites (DHSs). Fourth, the majority of this heritability arises from loci not harboring currently known cardiovascular and renal genes. Recent meta-analyses of large-scale genome-wide association studies (GWASs) and admixture mapping have identified ~50 loci associated with BP and hypertension (HTN), and yet they account for only a small fraction (~2%) of the heritability.

No MeSH data available.


Related in: MedlinePlus