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Bayesian epistasis association mapping via SNP imputation.

ABSTRACT: Genetic mutations may interact to increase the risk of human complex diseases. Mapping of multiple interacting disease loci in the human genome has recently shown promise in detecting genes with little main effects. The power of interaction association mapping, however, can be greatly influenced by the set of single nucleotide polymorphism (SNP) genotyped in a case-control study. Previous imputation methods only focus on imputation of individual SNPs without considering their joint distribution of possible interactions. We present a new method that simultaneously detects multilocus interaction associations and imputes missing SNPs from a full Bayesian model. Our method treats both the case-control sample and the reference data as random observations. The output of our method is the posterior probabilities of SNPs for their marginal and interacting associations with the disease. Using simulations, we show that the method produces accurate and robust imputation with little overfitting problems. We further show that, with the type I error rate maintained at a common level, SNP imputation can consistently and sometimes substantially improve the power of detecting disease interaction associations. We use a data set of inflammatory bowel disease to demonstrate the application of our method.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC3062153 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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Bayesian epistasis association mapping via SNP imputation.

Zhang Yu Y

Biostatistics (Oxford, England) 20101005 2

Genetic mutations may interact to increase the risk of human complex diseases. Mapping of multiple interacting disease loci in the human genome has recently shown promise in detecting genes with little main effects. The power of interaction association mapping, however, can be greatly influenced by the set of single nucleotide polymorphism (SNP) genotyped in a case-control study. Previous imputation methods only focus on imputation of individual SNPs without considering their joint distribution ...[more]

PMID: 20923970

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Project description:Interactions among multiple genes across the genome may contribute to the risks of many complex human diseases. Whole-genome single nucleotide polymorphisms (SNPs) data collected for many thousands of SNP markers from thousands of individuals under the case-control design promise to shed light on our understanding of such interactions. However, nearby SNPs are highly correlated due to linkage disequilibrium (LD) and the number of possible interactions is too large for exhaustive evaluation. We propose a novel Bayesian method for simultaneously partitioning SNPs into LD-blocks and selecting SNPs within blocks that are associated with the disease, either individually or interactively with other SNPs. When applied to homogeneous population data, the method gives posterior probabilities for LD-block boundaries, which not only result in accurate block partitions of SNPs, but also provide measures of partition uncertainty. When applied to case-control data for association mapping, the method implicitly filters out SNP associations created merely by LD with disease loci within the same blocks. Simulation study showed that this approach is more powerful in detecting multi-locus associations than other methods we tested, including one of ours. When applied to the WTCCC type 1 diabetes data, the method identified many previously known T1D associated genes, including PTPN22, CTLA4, MHC, and IL2RA. The method also revealed some interesting two-way associations that are undetected by single SNP methods. Most of the significant associations are located within the MHC region. Our analysis showed that the MHC SNPs form long-distance joint associations over several known recombination hotspots. By controlling the haplotypes of the MHC class II region, we identified additional associations in both MHC class I (HLA-A, HLA-B) and class III regions (BAT1). We also observed significant interactions between genes PRSS16, ZNF184 in the extended MHC region and the MHC class II genes. The proposed method can be broadly applied to the classification problem with correlated discrete covariates.

Project description:BackgroundImputation of partially missing or unobserved genotypes is an indispensable tool for SNP data analyses. However, research and understanding of the impact of initial SNP-data quality control on imputation results is still limited. In this paper, we aim to evaluate the effect of different strategies of pre-imputation quality filtering on the performance of the widely used imputation algorithms MaCH and IMPUTE.ResultsWe considered three scenarios: imputation of partially missing genotypes with usage of an external reference panel, without usage of an external reference panel, as well as imputation of completely un-typed SNPs using an external reference panel. We first created various datasets applying different SNP quality filters and masking certain percentages of randomly selected high-quality SNPs. We imputed these SNPs and compared the results between the different filtering scenarios by using established and newly proposed measures of imputation quality. While the established measures assess certainty of imputation results, our newly proposed measures focus on the agreement with true genotypes. These measures showed that pre-imputation SNP-filtering might be detrimental regarding imputation quality. Moreover, the strongest drivers of imputation quality were in general the burden of missingness and the number of SNPs used for imputation. We also found that using a reference panel always improves imputation quality of partially missing genotypes. MaCH performed slightly better than IMPUTE2 in most of our scenarios. Again, these results were more pronounced when using our newly defined measures of imputation quality.ConclusionEven a moderate filtering has a detrimental effect on the imputation quality. Therefore little or no SNP filtering prior to imputation appears to be the best strategy for imputing small to moderately sized datasets. Our results also showed that for these datasets, MaCH performs slightly better than IMPUTE2 in most scenarios at the cost of increased computing time.

Dataset Information

Bayesian epistasis association mapping via SNP imputation.

Publications

Bayesian epistasis association mapping via SNP imputation.

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