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Sökning: WFRF:(Peloso Gina M.)

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21.
  • Kathiresan, Sekar, et al. (författare)
  • Common variants at 30 loci contribute to polygenic dyslipidemia
  • 2009
  • Ingår i: Nature Genetics. - : Nature Publishing Group. - 1546-1718. ; 41:1, s. 56-65
  • Tidskriftsartikel (refereegranskat)abstract
    • Blood low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and triglyceride levels are risk factors for cardiovascular disease. To dissect the polygenic basis of these traits, we conducted genome-wide association screens in 19,840 individuals and replication in up to 20,623 individuals. We identified 30 distinct loci associated with lipoprotein concentrations (each with P < 5 x 10(-8)), including 11 loci that reached genome-wide significance for the first time. The 11 newly defined loci include common variants associated with LDL cholesterol near ABCG8, MAFB, HNF1A and TIMD4; with HDL cholesterol near ANGPTL4, FADS1-FADS2-FADS3, HNF4A, LCAT, PLTP and TTC39B; and with triglycerides near AMAC1L2, FADS1-FADS2-FADS3 and PLTP. The proportion of individuals exceeding clinical cut points for high LDL cholesterol, low HDL cholesterol and high triglycerides varied according to an allelic dosage score (P < 10(-15) for each trend). These results suggest that the cumulative effect of multiple common variants contributes to polygenic dyslipidemia.
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22.
  • Kathiresan, Sekar, et al. (författare)
  • A genome-wide association study for blood lipid phenotypes in the Framingham Heart Study
  • 2007
  • Ingår i: BMC Medical Genetics. - : BioMed Central (BMC). - 1471-2350. ; 8
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Blood lipid levels including low-density lipoprotein cholesterol ( LDL-C), high-density lipoprotein cholesterol ( HDL-C), and triglycerides ( TG) are highly heritable. Genome-wide association is a promising approach to map genetic loci related to these heritable phenotypes. Methods: In 1087 Framingham Heart Study Offspring cohort participants ( mean age 47 years, 52% women), we conducted genome-wide analyses ( Affymetrix 100K GeneChip) for fasting blood lipid traits. Total cholesterol, HDL-C, and TG were measured by standard enzymatic methods and LDL-C was calculated using the Friedewald formula. The long-term averages of up to seven measurements of LDL-C, HDL-C, and TG over a similar to 30 year span were the primary phenotypes. We used generalized estimating equations ( GEE), family-based association tests ( FBAT) and variance components linkage to investigate the relationships between SNPs ( on autosomes, with minor allele frequency >= 10%, genotypic call rate >= 80%, and Hardy-Weinberg equilibrium p >= 0.001) and multivariable-adjusted residuals. We pursued a three-stage replication strategy of the GEE association results with 287 SNPs ( P < 0.001 in Stage I) tested in Stage II ( n similar to 1450 individuals) and 40 SNPs ( P < 0.001 in joint analysis of Stages I and II) tested in Stage III ( n similar to 6650 individuals). Results: Long-term averages of LDL-C, HDL-C, and TG were highly heritable ( h(2) = 0.66, 0.69, 0.58, respectively; each P < 0.0001). Of 70,987 tests for each of the phenotypes, two SNPs had p < 10(-5) in GEE results for LDL-C, four for HDL-C, and one for TG. For each multivariable-adjusted phenotype, the number of SNPs with association p < 10(-4) ranged from 13 to 18 and with p < 10(-3), from 94 to 149. Some results confirmed previously reported associations with candidate genes including variation in the lipoprotein lipase gene ( LPL) and HDL-C and TG ( rs7007797; P = 0.0005 for HDL-C and 0.002 for TG). The full set of GEE, FBAT and linkage results are posted at the database of Genotype and Phenotype (dbGaP). After three stages of replication, there was no convincing statistical evidence for association ( i.e., combined P < 10(-5) across all three stages) between any of the tested SNPs and lipid phenotypes. Conclusion: Using a 100K genome-wide scan, we have generated a set of putative associations for common sequence variants and lipid phenotypes. Validation of selected hypotheses in additional samples did not identify any new loci underlying variability in blood lipids. Lack of replication may be due to inadequate statistical power to detect modest quantitative trait locus effects ( i.e., < 1% of trait variance explained) or reduced genomic coverage of the 100K array. GWAS in FHS using a denser genome-wide genotyping platform and a better-powered replication strategy may identify novel loci underlying blood lipids.
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23.
  • Peloso, Gina M., et al. (författare)
  • Association of Exome Sequences with Cardiovascular Traits among Blacks in the Jackson Heart Study
  • Ingår i: Circulation: Cardiovascular Genetics. - : American Heart Association. - 1942-325X. ; 9:4, s. 368-374
  • Tidskriftsartikel (refereegranskat)abstract
    • Background-The correlation of null alleles with human phenotypes can provide insight into gene function in humans. In individuals of African ancestry, we set out to identify null and damaging missense variants, and test these variants for association with a range of cardiovascular phenotypes. Methods and Results-We performed whole-exome sequencing in 3223 black individuals from the Jackson Heart Study and found a total of 729 666 variant sites with minor allele frequency <5%, including 17 263 null variants and 49 929 missense variants predicted to be damaging by in silico algorithms. We tested null and damaging missense variants within each gene for association with 36 cardiovascular traits. We found 3 associations that met our prespecified level of significance (α=1.1×10-7). Null and damaging missense variants in PCSK9 were associated with 36 mg/dL lower low-density lipoprotein cholesterol (P=3×10-21). Three individuals in their 50s with complete PCSK9 deficiency (each compound heterozygote for PCSK9 p.Y142X and p.C679X) were identified, with one having a coronary artery calcification score in the 83rd percentile despite a low-density lipoprotein cholesterol of 32 mg/dL. A damaging missense variant in HBQ1 (p.G52A) was associated with a 2 pg/cell lower mean corpuscular hemoglobin (P=9×10-13) and rare damaging missense variants in VPS13A with higher red blood cell distribution width (P=9.9×10-8). Conclusions-A limited number of null/damaging alleles with a large effect on cardiovascular traits were detectable in ≈3000 black individuals.
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24.
  • Thanassoulis, George, et al. (författare)
  • Genetic Associations with Valvular Calcification and Aortic Stenosis
  • 2013
  • Ingår i: New England Journal of Medicine. - : Massachusetts Medical Society. - 0028-4793. ; 368:6, s. 503-512
  • Tidskriftsartikel (refereegranskat)abstract
    • Background Limited information is available regarding genetic contributions to valvular calcification, which is an important precursor of clinical valve disease. Methods We determined genomewide associations with the presence of aortic-valve calcification (among 6942 participants) and mitral annular calcification (among 3795 participants), as detected by computed tomographic (CT) scanning; the study population for this analysis included persons of white European ancestry from three cohorts participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (discovery population). Findings were replicated in independent cohorts of persons with either CT-detected valvular calcification or clinical aortic stenosis. Results One SNP in the lipoprotein(a) (LPA) locus (rs10455872) reached genomewide significance for the presence of aortic-valve calcification (odds ratio per allele, 2.05; P = 9.0x10(-10)), a finding that was replicated in additional white European, African-American, and Hispanic-American cohorts (P<0.05 for all comparisons). Genetically determined Lp(a) levels, as predicted by LPA genotype, were also associated with aortic-valve calcification, supporting a causal role for Lp(a). In prospective analyses, LPA genotype was associated with incident aortic stenosis (hazard ratio per allele, 1.68; 95% confidence interval [CI], 1.32 to 2.15) and aortic-valve replacement (hazard ratio, 1.54; 95% CI, 1.05 to 2.27) in a large Swedish cohort; the association with incident aortic stenosis was also replicated in an independent Danish cohort. Two SNPs (rs17659543 and rs13415097) near the proinflammatory gene IL1F9 achieved genomewide significance for mitral annular calcification (P = 1.5x10(-8) and P = 1.8x10(-8), respectively), but the findings were not replicated consistently. Conclusions Genetic variation in the LPA locus, mediated by Lp(a) levels, is associated with aortic-valve calcification across multiple ethnic groups and with incident clinical aortic stenosis. (Funded by the National Heart, Lung, and Blood Institute and others.)
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25.
  • Liu, Dajiang J, et al. (författare)
  • Meta-analysis of gene-level tests for rare variant association.
  • 2014
  • Ingår i: Nature Genetics. - : Nature Publishing Group. - 1546-1718. ; 46:2, s. 200-200
  • Tidskriftsartikel (refereegranskat)abstract
    • The majority of reported complex disease associations for common genetic variants have been identified through meta-analysis, a powerful approach that enables the use of large sample sizes while protecting against common artifacts due to population structure and repeated small-sample analyses sharing individual-level data. As the focus of genetic association studies shifts to rare variants, genes and other functional units are becoming the focus of analysis. Here we propose and evaluate new approaches for performing meta-analysis of rare variant association tests, including burden tests, weighted burden tests, variable-threshold tests and tests that allow variants with opposite effects to be grouped together. We show that our approach retains useful features from single-variant meta-analysis approaches and demonstrate its use in a study of blood lipid levels in ∼18,500 individuals genotyped with exome arrays.
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26.
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  • Resultat 21-26 av 26
  • Föregående 12[3]
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Peloso, Gina M. (26)
Kathiresan, Sekar (23)
Loos, Ruth J F (19)
Rotter, Jerome I. (17)
Boerwinkle, Eric (17)
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