Dataset Information

Case-Control Genome-wide Joint Association Study Using Semiparametric Empirical Model and Approximate Bayes Factor.

ABSTRACT: We propose a semiparametric approach for the analysis of case-control genome-wide association study. Parametric components are used to model both the conditional distribution of the case status given the covariates and the distribution of genotype counts, whereas the distribution of the covariates are modeled nonparametrically. This yields a direct and joint modeling of the case status, covariates and genotype counts, and gives better understanding of the disease mechanism and results in more reliable conclusions. Side information, such as the disease prevalence, can be conveniently incorporated into the model by empirical likelihood approach and leads to more efficient estimates and powerful test in the detection of disease-associated SNPs. Profiling is used to eliminate a nuisance nonparametric component, and the resulting profile empirical likelihood estimates are shown to be consistent and asymptotically normal. For the hypothesis test on disease association, we apply the approximate Bayes factor (ABF) which is computationally simple and most desirable in genome-wide association studies where hundreds of thousands to a million genetic markers are tested. We treat the approximate Bayes factor as a hybrid Bayes factor which replaces the full data by the maximum likelihood estimates of the parameters of interest in the full model and derive it under a general setting. The deviation from Hardy-Weinberg Equilibrium (HWE) is also taken into account and the ABF for HWE using cases is shown to provide evidence of association between a disease and a genetic marker. Simulation studies and an application are further provided to illustrate the utility of the proposed methodology.

SUBMITTER: Xu J

PROVIDER: S-EPMC3921884 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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Case-Control Genome-wide Joint Association Study Using Semiparametric Empirical Model and Approximate Bayes Factor.

Xu Jinfeng J Zheng Gang G Yuan Ao A

Journal of statistical computation and simulation 20130101 7

We propose a semiparametric approach for the analysis of case-control genome-wide association study. Parametric components are used to model both the conditional distribution of the case status given the covariates and the distribution of genotype counts, whereas the distribution of the covariates are modeled nonparametrically. This yields a direct and joint modeling of the case status, covariates and genotype counts, and gives better understanding of the disease mechanism and results in more re ...[more]

PMID: 24532860

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Project description:Characterizing the distribution of effects from genome-wide genotyping data is crucial for understanding important aspects of the genetic architecture of complex traits, such as number or proportion of non-null loci, average proportion of phenotypic variance explained per non-null effect, power for discovery, and polygenic risk prediction. To this end, previous work has used effect-size models based on various distributions, including the normal and normal mixture distributions, among others. In this paper we propose a scale mixture of two normals model for effect size distributions of genome-wide association study (GWAS) test statistics. Test statistics corresponding to null associations are modeled as random draws from a normal distribution with zero mean; test statistics corresponding to non-null associations are also modeled as normal with zero mean, but with larger variance. The model is fit via minimizing discrepancies between the parametric mixture model and resampling-based nonparametric estimates of replication effect sizes and variances. We describe in detail the implications of this model for estimation of the non-null proportion, the probability of replication in de novo samples, the local false discovery rate, and power for discovery of a specified proportion of phenotypic variance explained from additive effects of loci surpassing a given significance threshold. We also examine the crucial issue of the impact of linkage disequilibrium (LD) on effect sizes and parameter estimates, both analytically and in simulations. We apply this approach to meta-analysis test statistics from two large GWAS, one for Crohn's disease (CD) and the other for schizophrenia (SZ). A scale mixture of two normals distribution provides an excellent fit to the SZ nonparametric replication effect size estimates. While capturing the general behavior of the data, this mixture model underestimates the tails of the CD effect size distribution. We discuss the implications of pervasive small but replicating effects in CD and SZ on genomic control and power. Finally, we conclude that, despite having very similar estimates of variance explained by genotyped SNPs, CD and SZ have a broadly dissimilar genetic architecture, due to differing mean effect size and proportion of non-null loci.

Dataset Information

Case-Control Genome-wide Joint Association Study Using Semiparametric Empirical Model and Approximate Bayes Factor.

Publications

Case-Control Genome-wide Joint Association Study Using Semiparametric Empirical Model and Approximate Bayes Factor.

Similar Datasets

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