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480
A new multipoint method for genome-wide association studies by imputation of genotypes. Nature genetics.
, 2007
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Population structure and eigenanalysis
- PLoS Genet 2(12): e190 DOI: 10.1371/journal.pgen.0020190
, 2006
"... Current methods for inferring population structure from genetic data do not provide formal significance tests for population differentiation. We discuss an approach to studying population structure (principal components analysis) that was first applied to genetic data by Cavalli-Sforza and colleague ..."
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Cited by 263 (9 self)
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Current methods for inferring population structure from genetic data do not provide formal significance tests for population differentiation. We discuss an approach to studying population structure (principal components analysis) that was first applied to genetic data by Cavalli-Sforza and colleagues. We place the method on a solid statistical footing, using results from modern statistics to develop formal significance tests. We also uncover a general ‘‘phase change’ ’ phenomenon about the ability to detect structure in genetic data, which emerges from the statistical theory we use, and has an important implication for the ability to discover structure in genetic data: for a fixed but large dataset size, divergence between two populations (as measured, for example, by a statistic like F ST) below a threshold is essentially undetectable, but a little above threshold, detection will be easy. This means that we can predict the dataset size needed to detect structure.
TRAF1–C5 as a Risk Locus for Rheumatoid Arthritis -- A Genomewide Study
"... Rheumatoid arthritis has a complex mode of inheritance. Although HLA-DRB1 and PTPN22 are well-established susceptibility loci, other genes that confer a modest level of risk have been identified recently. We carried out a genomewide association analysis to identify additional genetic loci associated ..."
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Cited by 83 (1 self)
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Rheumatoid arthritis has a complex mode of inheritance. Although HLA-DRB1 and PTPN22 are well-established susceptibility loci, other genes that confer a modest level of risk have been identified recently. We carried out a genomewide association analysis to identify additional genetic loci associated with an increased risk of rheumatoid arthritis. Methods We genotyped 317,503 single-nucleotide polymorphisms (SNPs) in a combined case– control study of 1522 case subjects with rheumatoid arthritis and 1850 matched control subjects. The patients were seropositive for autoantibodies against cyclic citrullinated peptide (CCP). We obtained samples from two data sets, the North American Rheumatoid Arthritis Consortium (NARAC) and the Swedish Epidemiological Investigation of Rheumatoid Arthritis (EIRA). Results from NARAC and EIRA for 297,086 SNPs that passed quality-control filters were combined with the use of Cochran– Mantel–Haenszel stratified analysis. SNPs showing a significant association with disease (P<1×10 −8) were genotyped in an independent set of case subjects with anti–
Assigning significance to peptides identified by tandem mass spectrometry using decoy databases
- J. Proteome Res
, 2008
"... Automated methods for assigning peptides to observed tandem mass spectra typically return a list of peptide-spectrum matches, ranked according to an arbitrary score. In this article, we describe methods for converting these arbitrary scores into more useful statistical significance measures. These m ..."
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Cited by 65 (13 self)
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Automated methods for assigning peptides to observed tandem mass spectra typically return a list of peptide-spectrum matches, ranked according to an arbitrary score. In this article, we describe methods for converting these arbitrary scores into more useful statistical significance measures. These methods employ a decoy sequence database as a model of the null hypothesis, and use false discovery rate (FDR) analysis to correct for multiple testing. We first describe a simple FDR inference method and then describe how estimating and taking into account the percentage of incorrectly identified spectra in the entire data set can lead to increased statistical power.
Genome-wide association scan shows genetic variants in the fto gene are associated with obesity-related traits. PLoS Genetics
, 2007
"... The obesity epidemic is responsible for a substantial economic burden in developed countries and is a major risk factor for type 2 diabetes and cardiovascular disease. The disease is the result not only of several environmental risk factors, but also of genetic predisposition. To take advantage of r ..."
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Cited by 60 (5 self)
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The obesity epidemic is responsible for a substantial economic burden in developed countries and is a major risk factor for type 2 diabetes and cardiovascular disease. The disease is the result not only of several environmental risk factors, but also of genetic predisposition. To take advantage of recent advances in gene-mapping technology, we executed a genome-wide association scan to identify genetic variants associated with obesity-related quantitative traits in the genetically isolated population of Sardinia. Initial analysis suggested that several SNPs in the FTO and PFKP genes were associated with increased BMI, hip circumference, and weight. Within the FTO gene, rs9930506 showed the strongest
Newly identified loci that influence lipid concentrations and risk of coronary artery disease.
- Nat. Genet.
, 2008
"... To identify genetic variants influencing plasma lipid concentrations, we first used genotype imputation and meta-analysis to combine three genome-wide scans totaling 8,816 individuals and comprising 6,068 individuals specific to our study (1,874 individuals from the FUSION study of type 2 diabetes ..."
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Cited by 55 (3 self)
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To identify genetic variants influencing plasma lipid concentrations, we first used genotype imputation and meta-analysis to combine three genome-wide scans totaling 8,816 individuals and comprising 6,068 individuals specific to our study (1,874 individuals from the FUSION study of type 2 diabetes and 4,184 individuals from the SardiNIA study of aging-associated variables) and 2,758 individuals from the Diabetes Genetics Initiative, reported in a companion study in this issue. We subsequently examined promising signals in 11,569 additional individuals. Overall, we identify strongly associated variants in eleven loci previously implicated in lipid metabolism (ABCA1, the APOA5-APOA4-APOC3-APOA1 and APOE-APOC clusters, APOB, CETP, GCKR, LDLR, LPL, LIPC, LIPG and PCSK9) and also in several newly identified loci (near MVK-MMAB and GALNT2, with variants primarily associated with high-density lipoprotein (HDL) cholesterol; near SORT1, with variants primarily associated with low-density lipoprotein (LDL) cholesterol; near TRIB1, MLXIPL and ANGPTL3, with variants primarily associated with triglycerides; and a locus encompassing several genes near NCAN, with variants strongly associated with both triglycerides and LDL cholesterol). Notably, the 11 independent variants associated with increased LDL cholesterol concentrations in our study also showed increased frequency in a sample of coronary artery disease cases versus controls. Coronary artery disease (CAD) and stroke are the leading causes of morbidity, mortality and disability in industrialized countries, and the prevalence of these diseases is increasing rapidly in developing countries 1 . A main underlying pathology is atherosclerosis, a process of cumulative deposition of LDL cholesterol in the arteries supplying blood to the heart and brain that eventually leads to impaired or absent blood supply and myocardial infarction or stroke 1 . Consistent and compelling evidence has demonstrated association between lipoprotein-associated lipid concentrations and cardiovascular disease incidence worldwide 2-4 . Whereas high concentrations of LDL
Estimating Local Ancestry in Admixed Populations
, 2008
"... Large-scale genotyping of SNPs has shown a great promise in identifying markers that could be linked to diseases. One of the major obstacles involved in performing these studies is that the underlying population substructure could produce spurious associations. Population substructure can be caused ..."
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Cited by 52 (6 self)
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Large-scale genotyping of SNPs has shown a great promise in identifying markers that could be linked to diseases. One of the major obstacles involved in performing these studies is that the underlying population substructure could produce spurious associations. Population substructure can be caused by the presence of two distinct subpopulations or a single pool of admixed individuals. In this work, we focus on the latter, which is significantly harder to detect in practice. New advances in this research direction are expected to play a key role in identifying loci that are different among different populations and are still associated with a disease. We evaluated current methods for inference of population substructure in such cases and show that they might be quite inaccurate even in relatively simple scenarios. We therefore introduce a new method, LAMP (Local Ancestry in adMixed Populations), which infers the ancestry of each individual at every single-nucleotide polymorphism (SNP). LAMP computes the ancestry structure for overlapping windows of contiguous SNPs and combines the results with a majority vote. Our empirical results show that LAMP is significantly more accurate and more efficient than existing methods for inferrring locus-specific ancestries, enabling it to handle large-scale datasets. We further show that LAMP can be used to estimate the individual admixture of each individual. Our experimental evaluation indicates that this extension yields a considerably more accurate estimate of individual admixture than state-of-the-art methods such as STRUCTURE or EIGENSTRAT, which are frequently used for the correction of population stratification in association studies.
Practical aspects of imputation-drivenmeta-analysis of genome-wide association studies.
- Hum. Mol. Genet.
, 2008
"... Motivated by the overwhelming success of genome-wide association studies, droves of researchers are working vigorously to exchange and to combine genetic data to expediently discover genetic risk factors for common human traits. The primary tools that fuel these new efforts are imputation, allowing ..."
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Cited by 45 (4 self)
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Motivated by the overwhelming success of genome-wide association studies, droves of researchers are working vigorously to exchange and to combine genetic data to expediently discover genetic risk factors for common human traits. The primary tools that fuel these new efforts are imputation, allowing researchers who have collected data on a diversity of genotype platforms to share data in a uniformly exchangeable format, and meta-analysis for pooling statistical support for a genotype -phenotype association. As many groups are forming collaborations to engage in these efforts, this review collects a series of guidelines, practical detail and learned experiences from a variety of individuals who have contributed to the subject.
Assessing the impact of population stratification on genetic association studies,”
- Nature Genetics,
, 2004
"... Population stratification refers to differences in allele frequencies between cases and controls due to systematic differences in ancestry rather than association of genes with disease. It has been proposed that false positive associations due to stratification can be controlled by genotyping a few ..."
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Cited by 40 (1 self)
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Population stratification refers to differences in allele frequencies between cases and controls due to systematic differences in ancestry rather than association of genes with disease. It has been proposed that false positive associations due to stratification can be controlled by genotyping a few dozen unlinked genetic markers. To assess stratification empirically, we analyzed data from 11 case-control and casecohort association studies. We did not detect statistically significant evidence for stratification but did observe that assessments based on a few dozen markers lack power to rule out moderate levels of stratification that could cause false positive associations in studies designed to detect modest genetic risk factors. After increasing the number of markers and samples in a case-cohort study (the design most immune to stratification), we found that stratification was in fact present. Our results suggest that modest amounts of stratification can exist even in well designed studies.
Nanoparticles – a review
- Trop J Pharm Res
"... Apoptotic cell: linkage of inflammation and wound healing ..."
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Cited by 39 (1 self)
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Apoptotic cell: linkage of inflammation and wound healing