Accurate Haplotype Inference for Multiple Linked Single-Nucleotide Polymorphisms Using Sibship Data

Liu, Pengyuan; Lü, Yan; Deng, Hong−Wen

doi:10.1534/genetics.105.054213

Cited by 9 publications

(7 citation statements)

References 29 publications

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“…Means with different superscripts within one row differ significantly at the a , 0.01 significance level. Liu et al(2006) proposed another EM-based approach for haplotype inference from sibship data, which was not included in the comparison in our study. Liu et al(2006) report that their approach performs slightly better than FAMHAP and that the variability of discrepancy of their performance is small with the sample size.…”

Section: Resultsmentioning

confidence: 99%

“…However, only sibships with two children were taken into account in their study. The approach proposed by Liu et al(2006) is similar to our approach by considering different parental mating designs; however, the calculation of posterior parental combinations is different. On the other hand, Liu et al(2006) do not make effective use of the joint information of full sibs given the parental configuration; therefore we expect our approach to be more efficient with increasing family sizes.…”

Section: Resultsmentioning

confidence: 99%

“…Several methods have been suggested for haplotype inference using sibship data (Becker and Knapp 2004;Horvath et al 2004;Liu et al 2006), which have their own strengths and weaknesses. In this article, we propose a new maximum-likelihood-based method for haplotype reconstruction and estimation of haplotype frequencies using full-sib families, which allows genetic markers to be in linkage disequilibrium and assumes that no recombination occurs between the markers.…”

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A New Method for Haplotype Inference Including Full-Sib Information

2007

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Recent literature has suggested that haplotype inference through close relatives, especially from nuclear families, can be an alternative strategy in determining linkage phase and estimating haplotype frequencies. In the case of no possibility to obtain genotypes for parents, and only full-sib information being used, a new approach is suggested to infer phase and to reconstruct haplotypes. We present a maximum-likelihood method via an expectation-maximization algorithm, called FSHAP, using only full-sib information when parent information is not available. FSHAP can deal with families with an arbitrary number of children, and missing parents or missing genotypes can be handled as well. In a simulation study we compare FSHAP with another existing expectation-maximization (EM)-based approach (FAMHAP), the conditioning approach implemented in FBAT and GENEHUNTER, which is only pedigree based and assumes linkage equilibrium. In most situations, FSHAP has the smallest discrepancy of haplotype frequency estimation and the lowest error rate in haplotype reconstruction, only in some cases FAMHAP yields comparable results. GENEHUNTER produces the largest discrepancy, and FBAT produces the highest error rate in offspring in most situations. Among the methods compared, FSHAP has the highest accuracy in reconstructing the diplotypes of the unavailable parents. Potential limitations of the method, e.g., in analyzing very large haplotypes, are indicated and possible solutions are discussed.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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confidence: 99%

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A New Method for Haplotype Inference Including Full-Sib Information

2007

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“…The program MACH1 Willer and Sanna, 2008] also imputes missing genotypes in samples of unrelated individuals, despite its requirement of a pedigree file. Liu and Lu [2006] proposed a new statistical method tailored for sibships to estimate population haplotype frequencies but does not address the aforementioned issue of correlated errors when statistically inferring haplotypes from genotype data. As far as we can tell, methods for dealing with the correlation between genotypes within sibships when resolving haplotypes are yet to be incorporated into existing algorithms and although it may not be computationally feasible it certainly warrants further investigation.…”

Section: Discussionmentioning

confidence: 99%

Sibship analysis of associations between SNP haplotypes and a continuous trait with application to mammographic density

Stone

Gurrin

Hayes

et al. 2009

Genetic Epidemiology

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Haplotype-based association studies have been proposed as a powerful comprehensive approach to identify causal genetic variation underlying complex diseases. Data comparisons within families offer the additional advantage of dealing naturally with complex sources of noise, confounding and population stratification. Two problems encountered when investigating associations between haplotypes and a continuous trait using data from sibships are (i) the need to define within-sibship comparisons for sibships of size greater than two and (ii) the difficulty of resolving the joint distribution of haplotype pairs within sibships in the absence of parental genotypes. We therefore propose first a method of orthogonal transformation of both outcomes and exposures that allow the decomposition of between- and within-sibship regression effects when sibship size is greater than two. We conducted a simulation study, which confirmed analysis using all members of a sibship is statistically more powerful than methods based on cross-sectional analysis or using subsets of sib-pairs. Second, we propose a simple permutation approach to avoid errors of inference due to the within-sibship correlation of any errors in haplotype assignment. These methods were applied to investigate the association between mammographic density (MD), a continuously distributed and heritable risk factor for breast cancer, and single nucleotide polymorphisms (SNPs) and haplotypes from the VDR gene using data from a study of 430 twins and sisters. We found evidence of association between MD and a 4-SNP VDR haplotype. In conclusion, our proposed method retains the benefits of the between- and within-pair analysis for pairs of siblings and can be implemented in standard software.

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“…We carry out a simulation can work well and is robust against population stratification, but it is difficult to extend the approach to general nuclear families or haplotypes [3] . On the other hand, because complex traits are often associated with multiple (interacting) markers [4][5][6][7][8][9] , haplotype-based analysis has gained increasing attention as it could potentially be more efficient than a single-marker-based analysis. As such, Becker et al [3] proposed an extension of PAT, the HAP-PAT, to test for parent-of-origin effects using multiple tightly linked markers in the case of nuclear families with two genotyped parents and multiple affected children.…”

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Detection of Parent-of-Origin Effects in Complete and Incomplete Nuclear Families with Multiple Affected Children Using Multiple Tightly Linked Markers

et al. 2008

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For a diallelic marker locus, the parental-asymmetry test (PAT) based on case-parents trios and its extensions to accommodate incomplete unclear families (1-PAT and C-PAT) are simple and powerful approaches to test for parent-of-origin effects. However, haplotype analysis is generally regarded as advantageous over single-marker analysis in genetic study of common complex diseases. This is mainly due to the fact that complex diseases are often associated with multiple markers. As such, HAP-PAT was constructed to test for parent-of-origin effects in the framework of haplotype analysis. However, its applicability is limited due to the need for complete parental information. In this paper, for nuclear families with only one parent and multiple affected children, we develop HAP-1-PAT to test for parent-of-origin effects using multiple tightly linked markers. We further propose HAP-C-PAT to combine data from families with both parents and those with only one parent. We carry out a simulation study to evaluate the validity and power of the test statistics in various settings, including incomplete family rates, marker/disease-locus linkage disequilibrium patterns, and population models. We perform analysis for all possible combinations of the markers being considered. A permutation-based Monte Carlo procedure is devised to determine the significance of the tests; the corrected global p values taking into account of multiple testing are used for inferences. The results show that HAP-1-PAT and HAP-C-PAT would work well even under the population stratification demographic model and assortative mating demographic model. Furthermore, for the disease models considered, there are significant gains in power from haplotype analysis compared to single-marker analysis, and from combined analysis using HAP-C-PAT compared to analysis using HAP-PAT for the complete family data only.

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Accurate Haplotype Inference for Multiple Linked Single-Nucleotide Polymorphisms Using Sibship Data

Cited by 9 publications

References 29 publications

A New Method for Haplotype Inference Including Full-Sib Information

A New Method for Haplotype Inference Including Full-Sib Information

Sibship analysis of associations between SNP haplotypes and a continuous trait with application to mammographic density

Detection of Parent-of-Origin Effects in Complete and Incomplete Nuclear Families with Multiple Affected Children Using Multiple Tightly Linked Markers

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