5,156 research outputs found
Bayesian methods to overcome the winner's curse in genetic studies
Parameter estimates for associated genetic variants, report ed in the initial
discovery samples, are often grossly inflated compared to the values observed
in the follow-up replication samples. This type of bias is a consequence of the
sequential procedure in which the estimated effect of an associated genetic
marker must first pass a stringent significance threshold. We propose a
hierarchical Bayes method in which a spike-and-slab prior is used to account
for the possibility that the significant test result may be due to chance. We
examine the robustness of the method using different priors corresponding to
different degrees of confidence in the testing results and propose a Bayesian
model averaging procedure to combine estimates produced by different models.
The Bayesian estimators yield smaller variance compared to the conditional
likelihood estimator and outperform the latter in studies with low power. We
investigate the performance of the method with simulations and applications to
four real data examples.Comment: Published in at http://dx.doi.org/10.1214/10-AOAS373 the Annals of
Applied Statistics (http://www.imstat.org/aoas/) by the Institute of
Mathematical Statistics (http://www.imstat.org
A statistical framework for joint eQTL analysis in multiple tissues
Mapping expression Quantitative Trait Loci (eQTLs) represents a powerful and
widely-adopted approach to identifying putative regulatory variants and linking
them to specific genes. Up to now eQTL studies have been conducted in a
relatively narrow range of tissues or cell types. However, understanding the
biology of organismal phenotypes will involve understanding regulation in
multiple tissues, and ongoing studies are collecting eQTL data in dozens of
cell types. Here we present a statistical framework for powerfully detecting
eQTLs in multiple tissues or cell types (or, more generally, multiple
subgroups). The framework explicitly models the potential for each eQTL to be
active in some tissues and inactive in others. By modeling the sharing of
active eQTLs among tissues this framework increases power to detect eQTLs that
are present in more than one tissue compared with "tissue-by-tissue" analyses
that examine each tissue separately. Conversely, by modeling the inactivity of
eQTLs in some tissues, the framework allows the proportion of eQTLs shared
across different tissues to be formally estimated as parameters of a model,
addressing the difficulties of accounting for incomplete power when comparing
overlaps of eQTLs identified by tissue-by-tissue analyses. Applying our
framework to re-analyze data from transformed B cells, T cells and fibroblasts
we find that it substantially increases power compared with tissue-by-tissue
analysis, identifying 63% more genes with eQTLs (at FDR=0.05). Further the
results suggest that, in contrast to previous analyses of the same data, the
majority of eQTLs detectable in these data are shared among all three tissues.Comment: Summitted to PLoS Genetic
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Accounting for genetic interactions improves modeling of individual quantitative trait phenotypes in yeast.
Experiments in model organisms report abundant genetic interactions underlying biologically important traits, whereas quantitative genetics theory predicts, and data support, the notion that most genetic variance in populations is additive. Here we describe networks of capacitating genetic interactions that contribute to quantitative trait variation in a large yeast intercross population. The additive variance explained by individual loci in a network is highly dependent on the allele frequencies of the interacting loci. Modeling of phenotypes for multilocus genotype classes in the epistatic networks is often improved by accounting for the interactions. We discuss the implications of these results for attempts to dissect genetic architectures and to predict individual phenotypes and long-term responses to selection
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Cell-type-specific resolution epigenetics without the need for cell sorting or single-cell biology.
High costs and technical limitations of cell sorting and single-cell techniques currently restrict the collection of large-scale, cell-type-specific DNA methylation data. This, in turn, impedes our ability to tackle key biological questions that pertain to variation within a population, such as identification of disease-associated genes at a cell-type-specific resolution. Here, we show mathematically and empirically that cell-type-specific methylation levels of an individual can be learned from its tissue-level bulk data, conceptually emulating the case where the individual has been profiled with a single-cell resolution and then signals were aggregated in each cell population separately. Provided with this unprecedented way to perform powerful large-scale epigenetic studies with cell-type-specific resolution, we revisit previous studies with tissue-level bulk methylation and reveal novel associations with leukocyte composition in blood and with rheumatoid arthritis. For the latter, we further show consistency with validation data collected from sorted leukocyte sub-types
The Population Genetic Signature of Polygenic Local Adaptation
Adaptation in response to selection on polygenic phenotypes may occur via
subtle allele frequencies shifts at many loci. Current population genomic
techniques are not well posed to identify such signals. In the past decade,
detailed knowledge about the specific loci underlying polygenic traits has
begun to emerge from genome-wide association studies (GWAS). Here we combine
this knowledge from GWAS with robust population genetic modeling to identify
traits that may have been influenced by local adaptation. We exploit the fact
that GWAS provide an estimate of the additive effect size of many loci to
estimate the mean additive genetic value for a given phenotype across many
populations as simple weighted sums of allele frequencies. We first describe a
general model of neutral genetic value drift for an arbitrary number of
populations with an arbitrary relatedness structure. Based on this model we
develop methods for detecting unusually strong correlations between genetic
values and specific environmental variables, as well as a generalization of
comparisons to test for over-dispersion of genetic values among
populations. Finally we lay out a framework to identify the individual
populations or groups of populations that contribute to the signal of
overdispersion. These tests have considerably greater power than their single
locus equivalents due to the fact that they look for positive covariance
between like effect alleles, and also significantly outperform methods that do
not account for population structure. We apply our tests to the Human Genome
Diversity Panel (HGDP) dataset using GWAS data for height, skin pigmentation,
type 2 diabetes, body mass index, and two inflammatory bowel disease datasets.
This analysis uncovers a number of putative signals of local adaptation, and we
discuss the biological interpretation and caveats of these results.Comment: 42 pages including 8 figures and 3 tables; supplementary figures and
tables not included on this upload, but are mostly unchanged from v
Bayesian Model Selection in Complex Linear Systems, as Illustrated in Genetic Association Studies
Motivated by examples from genetic association studies, this paper considers
the model selection problem in a general complex linear model system and in a
Bayesian framework. We discuss formulating model selection problems and
incorporating context-dependent {\it a priori} information through different
levels of prior specifications. We also derive analytic Bayes factors and their
approximations to facilitate model selection and discuss their theoretical and
computational properties. We demonstrate our Bayesian approach based on an
implemented Markov Chain Monte Carlo (MCMC) algorithm in simulations and a real
data application of mapping tissue-specific eQTLs. Our novel results on Bayes
factors provide a general framework to perform efficient model comparisons in
complex linear model systems
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