Testing rare variants for association with diseases: a Bayesian marker selection approach.
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ABSTRACT:
SUBMITTER: Zhang L
PROVIDER: S-EPMC3242831 | biostudies-literature | 2012 Jan
REPOSITORIES: biostudies-literature
Publications
Testing rare variants for association with diseases: a Bayesian marker selection approach.
Zhang Lei L Pei Yu-Fang YF Hai Rong R Lin Yong Y Deng Hong-Wen HW
Annals of human genetics 20111031 1
It has been a research focus to uncover the genetic determination of complex diseases caused by rare variants. As the vast majority of genomic variants represent background variation, highlighting potentially causal mutations through a weighting scheme is critical to the success of association studies aimed at identifying rare variants. In this study, we propose a novel Bayesian marker selection approach to perform a weighting-based association test. In this approach, an individual association s ...[more]
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Project description:BackgroundWith the advent of next-generation sequencing (NGS) technologies, researchers are now generating a deluge of data on high dimensional genomic variations, whose analysis is likely to reveal rare variants involved in the complex etiology of disease. Standing in the way of such discoveries, however, is the fact that statistics for rare variants are currently designed for use with population-based data. In this paper, we introduce a pedigree-based statistic specifically designed to test for rare variants in family-based data. The additional power of pedigree-based statistics stems from the fact that while rare variants related to diseases or traits of interest occur only infrequently in populations, in families with multiple affected individuals, such variants are enriched. Note that while the proposed statistic can be applied with and without statistical weighting, our simulations show that its power increases when weighting (WSS and VT) are applied.ResultsOur working hypothesis was that, since rare variants are concentrated in families with multiple affected individuals, pedigree-based statistics should detect rare variants more powerfully than population-based statistics. To evaluate how well our new pedigree-based statistics perform in association studies, we develop a general framework for sequence-based association studies capable of handling data from pedigrees of various types and also from unrelated individuals. In short, we developed a procedure for transforming population-based statistics into tests for family-based associations. Furthermore, we modify two existing tests, the weighted sum-square test and the variable-threshold test, and apply both to our family-based collapsing methods. We demonstrate that the new family-based tests are more powerful than corresponding population-based test and they generate a reasonable type I error rate.To demonstrate feasibility, we apply the newly developed tests to a pedigree-based GWAS data set from the Framingham Heart Study (FHS). FHS-GWAS data contain approximately 5000 uncommon variants with frequencies less than 0.05. Potential association findings in these data demonstrate the feasibility of the software PB-STAR (note, PB-STAR is now freely available to the public).ConclusionOur tests show that when analyzing for rare variants, a pedigree-based design is more powerful than a population-based case-control design. We further demonstrate that a pedigree-based statistic's power to detect rare variants increases in direct relation to the proportion of affected individuals within the pedigree.
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Project description:New sequencing technologies provide an opportunity for assessing the impact of rare and common variants on complex diseases. Several methods have been developed for evaluating rare variants, many of which use weighted collapsing to combine rare variants. Some approaches require arbitrary frequency thresholds below which to collapse alleles, and most assume that effect sizes for each collapsed variant are either the same or a function of minor allele frequency. Some methods also further assume that all rare variants are deleterious rather than protective. We expect that such assumptions will not hold in general, and as a result performance of these tests will be adversely affected. We propose a hierarchical model, implemented in the new program CHARM, to detect the joint signal from rare and common variants within a genomic region while properly accounting for linkage disequilibrium between variants. Our model explores the scale, rather than the center of the odds ratio distribution, allowing for both causative and protective effects. We use cross-validation to assess the evidence for association in a region. We use model averaging to widen the range of disease models under which we will have good power. To assess this approach, we simulate data under a range of disease models with effects at common and/or rare variants. Overall, our method had more power than other well-known rare variant approaches; it performed well when either only rare, or only common variants were causal, and better than other approaches when both common and rare variants contributed to disease.
| S-EPMC4339046 | biostudies-literature