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Sökning: WFRF:(Dominiczak Anna) > (2010-2014)

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1.
  • Ehret, Georg B., et al. (författare)
  • Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk
  • 2011
  • Ingår i: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 478:7367, s. 103-109
  • Tidskriftsartikel (refereegranskat)abstract
    • Blood pressure is a heritable trait(1) influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (>= 140 mm Hg systolic blood pressure or >= 90 mm Hg diastolic blood pressure)(2). Even small increments in blood pressure are associated with an increased risk of cardiovascular events(3). This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention.
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2.
  • Johnson, Toby, et al. (författare)
  • Blood Pressure Loci Identified with a Gene-Centric Array.
  • 2011
  • Ingår i: American Journal of Human Genetics. - : Cell Press. - 1537-6605 .- 0002-9297. ; 89:6
  • Tidskriftsartikel (refereegranskat)abstract
    • Raised blood pressure (BP) is a major risk factor for cardiovascular disease. Previous studies have identified 47 distinct genetic variants robustly associated with BP, but collectively these explain only a few percent of the heritability for BP phenotypes. To find additional BP loci, we used a bespoke gene-centric array to genotype an independent discovery sample of 25,118 individuals that combined hypertensive case-control and general population samples. We followed up four SNPs associated with BP at our p < 8.56 × 10(-7) study-specific significance threshold and six suggestively associated SNPs in a further 59,349 individuals. We identified and replicated a SNP at LSP1/TNNT3, a SNP at MTHFR-NPPB independent (r(2) = 0.33) of previous reports, and replicated SNPs at AGT and ATP2B1 reported previously. An analysis of combined discovery and follow-up data identified SNPs significantly associated with BP at p < 8.56 × 10(-7) at four further loci (NPR3, HFE, NOS3, and SOX6). The high number of discoveries made with modest genotyping effort can be attributed to using a large-scale yet targeted genotyping array and to the development of a weighting scheme that maximized power when meta-analyzing results from samples ascertained with extreme phenotypes, in combination with results from nonascertained or population samples. Chromatin immunoprecipitation and transcript expression data highlight potential gene regulatory mechanisms at the MTHFR and NOS3 loci. These results provide candidates for further study to help dissect mechanisms affecting BP and highlight the utility of studying SNPs and samples that are independent of those studied previously even when the sample size is smaller than that in previous studies.
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3.
  • Lango Allen, Hana, et al. (författare)
  • Hundreds of variants clustered in genomic loci and biological pathways affect human height.
  • 2010
  • Ingår i: Nature. - : Nature Publishing Group. - 1476-4687 .- 0028-0836. ; 467:7317, s. 832-8
  • Tidskriftsartikel (refereegranskat)abstract
    • Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.
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4.
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5.
  • Lindgren, Cecilia M., et al. (författare)
  • Genome-Wide Association Scan Meta-Analysis Identifies Three Loci Influencing Adiposity and Fat Distribution
  • 2010
  • Ingår i: PLoS Genetics. - : Public Library of Science. - 1553-7404. ; 5:6
  • Tidskriftsartikel (refereegranskat)abstract
    • To identify genetic loci influencing central obesity and fat distribution, we performed a meta-analysis of 16 genome-wide association studies (GWAS, N = 38,580) informative for adult waist circumference (WC) and waist-hip ratio (WHR). We selected 26 SNPs for follow-up, for which the evidence of association with measures of central adiposity (WC and/or WHR) was strong and disproportionate to that for overall adiposity or height. Follow-up studies in a maximum of 70,689 individuals identified two loci strongly associated with measures of central adiposity; these map near TFAP2B (WC, P = 1.9x10(-11)) and MSRA (WC, P=8.9x10(-9)). A third locus, near LYPLAL1, was associated with WHR in women only (P = 2.66x10(-8)). The variants near TFAP2B appear to influence central adiposity through an effect on overall obesity/fat-mass, whereas LYPLAL1 displays a strong female-only association with fat distribution. By focusing on anthropometric measures of central obesity and fat distribution, we have identified three loci implicated in the regulation of human adiposity.
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6.
  • Arking, D. E., et al. (författare)
  • Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization
  • 2014
  • Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 46:8, s. 826-836
  • Tidskriftsartikel (refereegranskat)abstract
    • The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼ 8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD. © 2014 Nature America, Inc.
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7.
  • Alvarez-Madrazo, S., et al. (författare)
  • Common Polymorphisms in the CYP11B1 and CYP11B2 Genes: Evidence for a Digenic Influence on Hypertension
  • 2013
  • Ingår i: Hypertension. - : Lippincott Williams & Wilkins. - 0194-911X .- 1524-4563. ; 61:1, s. 232-239
  • Tidskriftsartikel (refereegranskat)abstract
    • The locus encompassing the corticosteroidogenic genes CYP11B2 and CYP11B1 is of potential importance in essential hypertension. We analyzed the association of polymorphisms at this locus with risk of essential hypertension, using 2 white case-control collections for discovery (n = 3340) and confirmation (n = 2929). Single-marker and haplotype analyses were performed, with the CYP11B2 Intron 2 Conversion polymorphism showing strongest association with hypertension in both cohorts and in combined analysis (odds ratio = 1.16, P = 8.54x10(-5)). The CYP11B1 ACA haplotype associated with increased risk of hypertension relative to the alternative, GTC (odds ratio = 1.11; P = 7.4x10(-3)), whereas the CYP11B2 TWtC haplotype seemed protective relative to the contrasting CConvT (odds ratio = 0.88, P = 2.2x10(-3)). Analysis spanning the whole CYP11B1/CYP11B2 locus showed that haplotypes associated with raised risk of hypertension tend to coexist. Functional analysis of heterozygous human adrenal tissue demonstrated decreased CYP11B2 expression and increased CYP11B1 expression for those alleles associating with reduced risk of hypertension. These results confirm the hypertensive influence of this locus, with data suggesting a complex digenic mechanism whereby altered relative CYP11B1 and CYP11B2 gene expression could have a chronic effect on enzyme activity and corticosteroid synthesis.
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8.
  • Chambers, John C., et al. (författare)
  • Genetic loci influencing kidney function and chronic kidney disease
  • 2010
  • Ingår i: Nature Genetics. - : Nature Publishing Group. - 1546-1718. ; 42:5, s. 373-375
  • Tidskriftsartikel (refereegranskat)abstract
    • Using genome-wide association, we identify common variants at 2p12-p13, 6q26, 17q23 and 19q13 associated with serum creatinine, a marker of kidney function (P = 10(-10) to 10(-15)). Of these, rs10206899 (near NAT8, 2p12-p13) and rs4805834 (near SLC7A9, 19q13) were also associated with chronic kidney disease (P = 5.0 x 10(-5) and P = 3.6 x 10(-4), respectively). Our findings provide insight into metabolic, solute and drug-transport pathways underlying susceptibility to chronic kidney disease.
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9.
  • Craddock, Nick, et al. (författare)
  • Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls
  • 2010
  • Ingår i: Nature. - 0028-0836 .- 1476-4687. ; 464:7289, s. 713-720
  • Tidskriftsartikel (refereegranskat)abstract
    • Copy number variants (CNVs) account for a major proportion of human genetic polymorphism and have been predicted to have an important role in genetic susceptibility to common disease. To address this we undertook a large, direct genome-wide study of association between CNVs and eight common human diseases. Using a purpose-designed array we typed,19,000 individuals into distinct copy-number classes at 3,432 polymorphic CNVs, including an estimated similar to 50% of all common CNVs larger than 500 base pairs. We identified several biological artefacts that lead to false-positive associations, including systematic CNV differences between DNAs derived from blood and cell lines. Association testing and follow-up replication analyses confirmed three loci where CNVs were associated with disease-IRGM for Crohn's disease, HLA for Crohn's disease, rheumatoid arthritis and type 1 diabetes, and TSPAN8 for type 2 diabetes-although in each case the locus had previously been identified in single nucleotide polymorphism (SNP)-based studies, reflecting our observation that most common CNVs that are well-typed on our array are well tagged by SNPs and so have been indirectly explored through SNP studies. We conclude that common CNVs that can be typed on existing platforms are unlikely to contribute greatly to the genetic basis of common human diseases.
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10.
  • Lanktree, Matthew B., et al. (författare)
  • Meta-analysis of Dense Genecentric Association Studies Reveals Common and Uncommon Variants Associated with Height
  • 2011
  • Ingår i: American Journal of Human Genetics. - : Cell Press. - 0002-9297 .- 1537-6605. ; 88:1, s. 41443-41443
  • Tidskriftsartikel (refereegranskat)abstract
    • Height is a classic complex trait with common variants in a growing list of genes known to contribute to the phenotype. Using a genecentric genotyping array targeted toward cardiovascular-related loci, comprising 49,320 SNPs across approximately 2000 loci, we evaluated the association of common and uncommon SNPs with adult height in 114,223 individuals from 47 studies and six ethnicities. A total of 64 loci contained a SNP associated with height at array-wide significance (p < 2.4 x 10(-6)), with 42 loci surpassing the conventional genome-wide significance threshold (p < 5 x 10(-8)). Common variants with minor allele frequencies greater than 5% were observed to be associated with height in 37 previously reported loci. In individuals of European ancestry, uncommon SNPs in IL11 and SMAD3, which would not be genotyped with the use of standard genome-wide genotyping arrays, were strongly associated with height (p < 3 x 10(-11)). Conditional analysis within associated regions revealed five additional variants associated with height independent of lead SNPs within the locus, suggesting allelic heterogeneity. Although underpowered to replicate findings from individuals of European ancestry, the direction of effect of associated variants was largely consistent in African American, South Asian, and Hispanic populations. Overall, we show that dense coverage of genes for uncommon SNPs, coupled with large-scale meta-analysis, can successfully identify additional variants associated with a common complex trait.
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