Dataset Information

To identify associations with rare variants, just WHaIT: Weighted haplotype and imputation-based tests.

ABSTRACT: Empirical evidences suggest that both common and rare variants contribute to complex disease etiology. Although the effects of common variants have been thoroughly assessed in recent genome-wide association studies (GWAS), our knowledge of the impact of rare variants on complex diseases remains limited. A number of methods have been proposed to test for rare variant association in sequencing-based studies, a study design that is becoming popular but is still not economically feasible. On the contrary, few (if any) methods exist to detect rare variants in GWAS data, the data we have collected on thousands of individuals. Here we propose two methods, a weighted haplotype-based approach and an imputation-based approach, to test for the effect of rare variants with GWAS data. Both methods can incorporate external sequencing data when available. We evaluated our methods and compared them with methods proposed in the sequencing setting through extensive simulations. Our methods clearly show enhanced statistical power over existing methods for a wide range of population-attributable risk, percentage of disease-contributing rare variants, and proportion of rare alleles working in different directions. We also applied our methods to the IFIH1 region for the type 1 diabetes GWAS data collected by the Wellcome Trust Case-Control Consortium. Our methods yield p values in the order of 10?³, whereas the most significant p value from the existing methods is greater than 0.17. We thus demonstrate that the evaluation of rare variants with GWAS data is possible, particularly when public sequencing data are incorporated.

SUBMITTER: Li Y

PROVIDER: S-EPMC2978961 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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To identify associations with rare variants, just WHaIT: Weighted haplotype and imputation-based tests.

Li Yun Y Byrnes Andrea E AE Li Mingyao M

American journal of human genetics 20101104 5

Empirical evidences suggest that both common and rare variants contribute to complex disease etiology. Although the effects of common variants have been thoroughly assessed in recent genome-wide association studies (GWAS), our knowledge of the impact of rare variants on complex diseases remains limited. A number of methods have been proposed to test for rare variant association in sequencing-based studies, a study design that is becoming popular but is still not economically feasible. On the con ...[more]

PMID: 21055717

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Project description:BackgroundBoth common and rare genetic variants have been shown to contribute to the etiology of complex diseases. Recent genome-wide association studies (GWAS) have successfully investigated how common variants contribute to the genetic factors associated with common human diseases. However, understanding the impact of rare variants, which are abundant in the human population (one in every 17 bases), remains challenging. A number of statistical tests have been developed to analyze collapsed rare variants identified by association tests. Here, we propose a haplotype-based approach. This work inspired by an existing statistical framework of the pedigree disequilibrium test (PDT), which uses genetic data to assess the effects of variants in general pedigrees. We aim to compare the performance between the haplotype-based approach and the rare variant-based approach for detecting rare causal variants in pedigrees.ResultsExtensive simulations in the sequencing setting were carried out to evaluate and compare the haplotype-based approach with the rare variant methods that drew on a more conventional collapsing strategy. As assessed through a variety of scenarios, the haplotype-based pedigree tests had enhanced statistical power compared with the rare variants based pedigree tests when the disease of interest was mainly caused by rare haplotypes (with multiple rare alleles), and vice versa when disease was caused by rare variants acting independently. For most of other situations when disease was caused both by haplotypes with multiple rare alleles and by rare variants with similar effects, these two approaches provided similar power in testing for association.ConclusionsThe haplotype-based approach was designed to assess the role of rare and potentially causal haplotypes. The proposed rare variants-based pedigree tests were designed to assess the role of rare and potentially causal variants. This study clearly documented the situations under which either method performs better than the other. All tests have been implemented in a software, which was submitted to the Comprehensive R Archive Network (CRAN) for general use as a computer program named rvHPDT.

Project description:Genome-wide association (GWA) studies have been limited by the reliance on common variants present on microarrays or imputable from the HapMap Project data. More recently, the completion of the 1000 Genomes Project has provided variant and haplotype information for several million variants derived from sequencing over 1,000 individuals. To help understand the extent to which more variants (including low frequency (1% ? MAF <5%) and rare variants (<1%)) can enhance previously identified associations and identify novel loci, we selected 93 quantitative circulating factors where data was available from the InCHIANTI population study. These phenotypes included cytokines, binding proteins, hormones, vitamins and ions. We selected these phenotypes because many have known strong genetic associations and are potentially important to help understand disease processes. We performed a genome-wide scan for these 93 phenotypes in InCHIANTI. We identified 21 signals and 33 signals that reached P<5×10(-8) based on HapMap and 1000 Genomes imputation, respectively, and 9 and 11 that reached a stricter, likely conservative, threshold of P<5×10(-11) respectively. Imputation of 1000 Genomes genotype data modestly improved the strength of known associations. Of 20 associations detected at P<5×10(-8) in both analyses (17 of which represent well replicated signals in the NHGRI catalogue), six were captured by the same index SNP, five were nominally more strongly associated in 1000 Genomes imputed data and one was nominally more strongly associated in HapMap imputed data. We also detected an association between a low frequency variant and phenotype that was previously missed by HapMap based imputation approaches. An association between rs112635299 and alpha-1 globulin near the SERPINA gene represented the known association between rs28929474 (MAF?=?0.007) and alpha1-antitrypsin that predisposes to emphysema (P?=?2.5×10(-12)). Our data provide important proof of principle that 1000 Genomes imputation will detect novel, low frequency-large effect associations.

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.

Dataset Information

To identify associations with rare variants, just WHaIT: Weighted haplotype and imputation-based tests.

Publications

To identify associations with rare variants, just WHaIT: Weighted haplotype and imputation-based tests.

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