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Comparison of gene-based rare variant association mapping methods for quantitative traits in a bovine population with complex familial relationships.

ABSTRACT: There is growing interest in the role of rare variants in the variation of complex traits due to increasing evidence that rare variants are associated with quantitative traits. However, association methods that are commonly used for mapping common variants are not effective to map rare variants. Besides, livestock populations have large half-sib families and the occurrence of rare variants may be confounded with family structure, which makes it difficult to disentangle their effects from family mean effects. We compared the power of methods that are commonly applied in human genetics to map rare variants in cattle using whole-genome sequence data and simulated phenotypes. We also studied the power of mapping rare variants using linear mixed models (LMM), which are the method of choice to account for both family relationships and population structure in cattle.We observed that the power of the LMM approach was low for mapping a rare variant (defined as those that have frequencies lower than 0.01) with a moderate effect (5 to 8 % of phenotypic variance explained by multiple rare variants that vary from 5 to 21 in number) contributing to a QTL with a sample size of 1000. In contrast, across the scenarios studied, statistical methods that are specialized for mapping rare variants increased power regardless of whether multiple rare variants or a single rare variant underlie a QTL. Different methods for combining rare variants in the test single nucleotide polymorphism set resulted in similar power irrespective of the proportion of total genetic variance explained by the QTL. However, when the QTL variance is very small (only 0.1 % of the total genetic variance), these specialized methods for mapping rare variants and LMM generally had no power to map the variants within a gene with sample sizes of 1000 or 5000.We observed that the methods that combine multiple rare variants within a gene into a meta-variant generally had greater power to map rare variants compared to LMM. Therefore, it is recommended to use rare variant association mapping methods to map rare genetic variants that affect quantitative traits in livestock, such as bovine populations.

SUBMITTER: Zhang Q

PROVIDER: S-EPMC4989328 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Comparison of gene-based rare variant association mapping methods for quantitative traits in a bovine population with complex familial relationships.

Zhang Qianqian Q Guldbrandtsen Bernt B Calus Mario P L MP Lund Mogens Sandø MS Sahana Goutam G

Genetics, selection, evolution : GSE 20160817 1

<h4>Background</h4>There is growing interest in the role of rare variants in the variation of complex traits due to increasing evidence that rare variants are associated with quantitative traits. However, association methods that are commonly used for mapping common variants are not effective to map rare variants. Besides, livestock populations have large half-sib families and the occurrence of rare variants may be confounded with family structure, which makes it difficult to disentangle their e ...[more]

PMID: 27534618

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Project description:Quantitative Susceptibility Mapping (QSM) is an MRI tool with the potential to reveal pathological changes from magnetic susceptibility measurements. Before phase data can be used to recover susceptibility (Δχ), the QSM process begins with two steps: data acquisition and phase estimation. We assess the performance of these steps, when applied without user intervention, on several variations of a phantom imaging task. We used a rotating-tube phantom with five tubes ranging from Δχ=0.05 ppm to Δχ=0.336 ppm. MRI data was acquired at nine angles of rotation for four different pulse sequences. The images were processed by 10 phase estimation algorithms including Laplacian, region-growing, branch-cut, temporal unwrapping, and maximum-likelihood methods, resulting in approximately 90 different combinations of data acquisition and phase estimation methods. We analyzed errors between measured and expected phases using the probability mass function and Cumulative Distribution Function. Repeatable acquisition and estimation methods were identified based on the probability of relative phase errors. For single-echo GRE and segmented EPI sequences, a region-growing method was most reliable with Pr (relative error <0.1) = 0.95 and 0.90, respectively. For multiecho sequences, a maximum-likelihood method was most reliable with Pr (relative error <0.1) = 0.97. The most repeatable multiecho methods outperformed the most repeatable single-echo methods. We found a wide range of repeatability and reproducibility for off-the-shelf MRI acquisition and phase estimation approaches, and this variability may prevent the techniques from being widely integrated in clinical workflows. The error was dominated in many cases by spatially discontinuous phase unwrapping errors. Any postprocessing applied on erroneous phase estimates, such as QSM's background field removal and dipole inversion, would suffer from error propagation. Our paradigm identifies methods that yield consistent and accurate phase estimates that would ultimately yield consistent and accurate Δχ estimates.

Dataset Information

Comparison of gene-based rare variant association mapping methods for quantitative traits in a bovine population with complex familial relationships.

Publications

Comparison of gene-based rare variant association mapping methods for quantitative traits in a bovine population with complex familial relationships.

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