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Multi-population GWA mapping via multi-task regularized regression.

ABSTRACT: Population heterogeneity through admixing of different founder populations can produce spurious associations in genome-wide association studies that are linked to the population structure rather than the phenotype. Since samples from the same population generally co-evolve, different populations may or may not share the same genetic underpinnings for the seemingly common phenotype. Our goal is to develop a unified framework for detecting causal genetic markers through a joint association analysis of multiple populations.Based on a multi-task regression principle, we present a multi-population group lasso algorithm using L(1)/L(2)-regularized regression for joint association analysis of multiple populations that are stratified either via population survey or computational estimation. Our algorithm combines information from genetic markers across populations, to identify causal markers. It also implicitly accounts for correlations between the genetic markers, thus enabling better control over false positive rates. Joint analysis across populations enables the detection of weak associations common to all populations with greater power than in a separate analysis of each population. At the same time, the regression-based framework allows causal alleles that are unique to a subset of the populations to be correctly identified. We demonstrate the effectiveness of our method on HapMap-simulated and lactase persistence datasets, where we significantly outperform state of the art methods, with greater power for detecting weak associations and reduced spurious associations.Software will be available at http://www.sailing.cs.cmu.edu/.

SUBMITTER: Puniyani K

PROVIDER: S-EPMC2881376 | biostudies-literature | 2010 Jun

REPOSITORIES: biostudies-literature

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Multi-population GWA mapping via multi-task regularized regression.

Puniyani Kriti K Kim Seyoung S Xing Eric P EP

Bioinformatics (Oxford, England) 20100601 12

<h4>Motivation</h4>Population heterogeneity through admixing of different founder populations can produce spurious associations in genome-wide association studies that are linked to the population structure rather than the phenotype. Since samples from the same population generally co-evolve, different populations may or may not share the same genetic underpinnings for the seemingly common phenotype. Our goal is to develop a unified framework for detecting causal genetic markers through a joint ...[more]

PMID: 20529908

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Project description:MotivationRecent advances in technology for brain imaging and high-throughput genotyping have motivated studies examining the influence of genetic variation on brain structure. Wang et al. have developed an approach for the analysis of imaging genomic studies using penalized multi-task regression with regularization based on a novel group l2,1-norm penalty which encourages structured sparsity at both the gene level and SNP level. While incorporating a number of useful features, the proposed method only furnishes a point estimate of the regression coefficients; techniques for conducting statistical inference are not provided. A new Bayesian method is proposed here to overcome this limitation.ResultsWe develop a Bayesian hierarchical modeling formulation where the posterior mode corresponds to the estimator proposed by Wang et al. and an approach that allows for full posterior inference including the construction of interval estimates for the regression parameters. We show that the proposed hierarchical model can be expressed as a three-level Gaussian scale mixture and this representation facilitates the use of a Gibbs sampling algorithm for posterior simulation. Simulation studies demonstrate that the interval estimates obtained using our approach achieve adequate coverage probabilities that outperform those obtained from the nonparametric bootstrap. Our proposed methodology is applied to the analysis of neuroimaging and genetic data collected as part of the Alzheimer's Disease Neuroimaging Initiative (ADNI), and this analysis of the ADNI cohort demonstrates clearly the value added of incorporating interval estimation beyond only point estimation when relating SNPs to brain imaging endophenotypes.Availability and implementationSoftware and sample data is available as an R package 'bgsmtr' that can be downloaded from The Comprehensive R Archive Network (CRAN).Contactnathoo@uvic.ca.Supplementary informationSupplementary data are available at Bioinformatics online.

Dataset Information

Multi-population GWA mapping via multi-task regularized regression.

Publications

Multi-population GWA mapping via multi-task regularized regression.

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