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Unified tests for fine-scale mapping and identifying sparse high-dimensional sequence associations.

ABSTRACT: In searching for genetic variants for complex diseases with deep sequencing data, genomic marker sets of high-dimensional genotypic data and sparse functional variants are quite common. Existing sequence association tests are incapable of identifying such marker sets or individual causal loci, although they appeared powerful to identify small marker sets with dense functional variants. In sequence association studies of admixed individuals, cryptic relatedness and population structure are known to confound the association analyses.We here propose a unified marker wise test (uFineMap) to accurately localize causal loci and a unified high-dimensional set based test (uHDSet) to identify high-dimensional sparse associations in deep sequencing genomic data of multi-ethnic individuals with random relatedness. These two novel tests are based on scaled sparse linear mixed regressions with Lp (0?

SUBMITTER: Cao S

PROVIDER: S-EPMC5006306 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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Unified tests for fine-scale mapping and identifying sparse high-dimensional sequence associations.

Cao Shaolong S Qin Huaizhen H Gossmann Alexej A Deng Hong-Wen HW Wang Yu-Ping YP

Bioinformatics (Oxford, England) 20151012 3

<h4>Motivation</h4>In searching for genetic variants for complex diseases with deep sequencing data, genomic marker sets of high-dimensional genotypic data and sparse functional variants are quite common. Existing sequence association tests are incapable of identifying such marker sets or individual causal loci, although they appeared powerful to identify small marker sets with dense functional variants. In sequence association studies of admixed individuals, cryptic relatedness and population s ...[more]

PMID: 26458888

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Project description:BackgroundWhole-genome sequence (WGS) data are increasingly available on large numbers of individuals in animal and plant breeding and in human genetics through second-generation resequencing technologies, 1000 genomes projects, and large-scale genotype imputation from lower marker densities. Here, we present a computationally fast implementation of a variable selection genomic prediction method, that could handle WGS data on more than 35,000 individuals, test its accuracy for across-breed predictions and assess its quantitative trait locus (QTL) mapping precision.MethodsThe Monte Carlo Markov chain (MCMC) variable selection model (Bayes GC) fits simultaneously a genomic best linear unbiased prediction (GBLUP) term, i.e. a polygenic effect whose correlations are described by a genomic relationship matrix (G), and a Bayes C term, i.e. a set of single nucleotide polymorphisms (SNPs) with large effects selected by the model. Computational speed is improved by a Metropolis-Hastings sampling that directs computations to the SNPs, which are, a priori, most likely to be included into the model. Speed is also improved by running many relatively short MCMC chains. Memory requirements are reduced by storing the genotype matrix in binary form. The model was tested on a WGS dataset containing Holstein, Jersey and Australian Red cattle. The data contained 4,809,520 genotypes on 35,549 individuals together with their milk, fat and protein yields, and fat and protein percentage traits.ResultsThe prediction accuracies of the Jersey individuals improved by 1.5% when using across-breed GBLUP compared to within-breed predictions. Using WGS instead of 600 k SNP-chip data yielded on average a 3% accuracy improvement for Australian Red cows. QTL were fine-mapped by locating the SNP with the highest posterior probability of being included in the model. Various QTL known from the literature were rediscovered, and a new SNP affecting milk production was discovered on chromosome 20 at 34.501126 Mb. Due to the high mapping precision, it was clear that many of the discovered QTL were the same across the five dairy traits.ConclusionsAcross-breed Bayes GC genomic prediction improved prediction accuracies compared to GBLUP. The combination of across-breed WGS data and Bayesian genomic prediction proved remarkably effective for the fine-mapping of QTL.

Dataset Information

Unified tests for fine-scale mapping and identifying sparse high-dimensional sequence associations.

Publications

Unified tests for fine-scale mapping and identifying sparse high-dimensional sequence associations.

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