44,052 research outputs found
Replication in Genome-Wide Association Studies
Replication helps ensure that a genotype-phenotype association observed in a
genome-wide association (GWA) study represents a credible association and is
not a chance finding or an artifact due to uncontrolled biases. We discuss
prerequisites for exact replication, issues of heterogeneity, advantages and
disadvantages of different methods of data synthesis across multiple studies,
frequentist vs. Bayesian inferences for replication, and challenges that arise
from multi-team collaborations. While consistent replication can greatly
improve the credibility of a genotype-phenotype association, it may not
eliminate spurious associations due to biases shared by many studies.
Conversely, lack of replication in well-powered follow-up studies usually
invalidates the initially proposed association, although occasionally it may
point to differences in linkage disequilibrium or effect modifiers across
studies.Comment: Published in at http://dx.doi.org/10.1214/09-STS290 the Statistical
Science (http://www.imstat.org/sts/) by the Institute of Mathematical
Statistics (http://www.imstat.org
A Quadratically Regularized Functional Canonical Correlation Analysis for Identifying the Global Structure of Pleiotropy with NGS Data
Investigating the pleiotropic effects of genetic variants can increase
statistical power, provide important information to achieve deep understanding
of the complex genetic structures of disease, and offer powerful tools for
designing effective treatments with fewer side effects. However, the current
multiple phenotype association analysis paradigm lacks breadth (number of
phenotypes and genetic variants jointly analyzed at the same time) and depth
(hierarchical structure of phenotype and genotypes). A key issue for high
dimensional pleiotropic analysis is to effectively extract informative internal
representation and features from high dimensional genotype and phenotype data.
To explore multiple levels of representations of genetic variants, learn their
internal patterns involved in the disease development, and overcome critical
barriers in advancing the development of novel statistical methods and
computational algorithms for genetic pleiotropic analysis, we proposed a new
framework referred to as a quadratically regularized functional CCA (QRFCCA)
for association analysis which combines three approaches: (1) quadratically
regularized matrix factorization, (2) functional data analysis and (3)
canonical correlation analysis (CCA). Large-scale simulations show that the
QRFCCA has a much higher power than that of the nine competing statistics while
retaining the appropriate type 1 errors. To further evaluate performance, the
QRFCCA and nine other statistics are applied to the whole genome sequencing
dataset from the TwinsUK study. We identify a total of 79 genes with rare
variants and 67 genes with common variants significantly associated with the 46
traits using QRFCCA. The results show that the QRFCCA substantially outperforms
the nine other statistics.Comment: 64 pages including 12 figure
Gene expression in large pedigrees: analytic approaches.
BackgroundWe currently have the ability to quantify transcript abundance of messenger RNA (mRNA), genome-wide, using microarray technologies. Analyzing genotype, phenotype and expression data from 20 pedigrees, the members of our Genetic Analysis Workshop (GAW) 19 gene expression group published 9 papers, tackling some timely and important problems and questions. To study the complexity and interrelationships of genetics and gene expression, we used established statistical tools, developed newer statistical tools, and developed and applied extensions to these tools.MethodsTo study gene expression correlations in the pedigree members (without incorporating genotype or trait data into the analysis), 2 papers used principal components analysis, weighted gene coexpression network analysis, meta-analyses, gene enrichment analyses, and linear mixed models. To explore the relationship between genetics and gene expression, 2 papers studied expression quantitative trait locus allelic heterogeneity through conditional association analyses, and epistasis through interaction analyses. A third paper assessed the feasibility of applying allele-specific binding to filter potential regulatory single-nucleotide polymorphisms (SNPs). Analytic approaches included linear mixed models based on measured genotypes in pedigrees, permutation tests, and covariance kernels. To incorporate both genotype and phenotype data with gene expression, 4 groups employed linear mixed models, nonparametric weighted U statistics, structural equation modeling, Bayesian unified frameworks, and multiple regression.Results and discussionRegarding the analysis of pedigree data, we found that gene expression is familial, indicating that at least 1 factor for pedigree membership or multiple factors for the degree of relationship should be included in analyses, and we developed a method to adjust for familiality prior to conducting weighted co-expression gene network analysis. For SNP association and conditional analyses, we found FaST-LMM (Factored Spectrally Transformed Linear Mixed Model) and SOLAR-MGA (Sequential Oligogenic Linkage Analysis Routines -Major Gene Analysis) have similar type 1 and type 2 errors and can be used almost interchangeably. To improve the power and precision of association tests, prior knowledge of DNase-I hypersensitivity sites or other relevant biological annotations can be incorporated into the analyses. On a biological level, eQTL (expression quantitative trait loci) are genetically complex, exhibiting both allelic heterogeneity and epistasis. Including both genotype and phenotype data together with measurements of gene expression was found to be generally advantageous in terms of generating improved levels of significance and in providing more interpretable biological models.ConclusionsPedigrees can be used to conduct analyses of and enhance gene expression studies
Whole-genome sequencing to understand the genetic architecture of common gene expression and biomarker phenotypes.
Initial results from sequencing studies suggest that there are relatively few low-frequency (<5%) variants associated with large effects on common phenotypes. We performed low-pass whole-genome sequencing in 680 individuals from the InCHIANTI study to test two primary hypotheses: (i) that sequencing would detect single low-frequency-large effect variants that explained similar amounts of phenotypic variance as single common variants, and (ii) that some common variant associations could be explained by low-frequency variants. We tested two sets of disease-related common phenotypes for which we had statistical power to detect large numbers of common variant-common phenotype associations-11 132 cis-gene expression traits in 450 individuals and 93 circulating biomarkers in all 680 individuals. From a total of 11 657 229 high-quality variants of which 6 129 221 and 5 528 008 were common and low frequency (<5%), respectively, low frequency-large effect associations comprised 7% of detectable cis-gene expression traits [89 of 1314 cis-eQTLs at P < 1 × 10(-06) (false discovery rate ∼5%)] and one of eight biomarker associations at P < 8 × 10(-10). Very few (30 of 1232; 2%) common variant associations were fully explained by low-frequency variants. Our data show that whole-genome sequencing can identify low-frequency variants undetected by genotyping based approaches when sample sizes are sufficiently large to detect substantial numbers of common variant associations, and that common variant associations are rarely explained by single low-frequency variants of large effect
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