Principal component analysis of canine hip dysplasia phenotypes and their statistical power for genome-wide association mapping

The aims of this study were to undertake principal component analysis (PCA) of hip dysplasia (HD) and to examine the power of the principal components (PCs) in genome-wide association studies. A cohort of 278 dogs for PCA and that of 369 dogs for genotyping were used. The distraction index (DI), the dorsolateral subluxation (DLS) score, the Norberg angle (NA), and the extended-hip radiographic (EHR) score were used for the PCA. One thousand single-nucleotide polymorphisms (SNPs) (of 23,500) were used to simulate genetic locus sharing between the HD phenotypes and 1000 SNPs were used to calculate the genetic mapping power of the PCs. The DI and the DLS score (first group) reflected hip laxity and the NA and the EHR score (second group) reflected the congruency between the femoral head and acetabulum. The average hip measurements of the two groups reflected in the first PC captured 55% of total radiographic variation. The first four PCs captured 90% of the total variation. The PCs had higher statistical mapping power to detect pleiotropic quantitative trait loci (QTL) than the raw phenotypes. The PCA demonstrated for the first time that HD can be reduced mathematically into simpler components essential for its genetic dissection. Genes that contribute jointly to all four radiographic hip phenotypes can be detected by mapping their first four PCs, while those contributing to individual phenotypes can be mapped by association with the individual raw phenotype.     

A new interval mapping approach based on a general sib-pair regression model with a modified Wald test

Various regression models based on sib-pair data have been developed for mapping quantitative trait loci (QTL) in humans since the seminal paper published in 1972 by Haseman and Elston. Fulker and Cardon [D.W. Fulker, L.R. Cardon, A sib-pair approach to interval mapping of quantitative trait loci, Am. J. Hum. Genet. 54 (1994) 1092–1103] adapted the idea of interval mapping [E.S. Lander, D. Botstein, Mapping Mendelian factors underlying quantitative traits using RFLP linkage maps, Genetics 121 (1989) 185–199] to the Haseman–Elston regression model in order to increase the power of QTL mapping. However, in the interval mapping approach of Fulker and Cardon, the statistic for testing QTL effects does not obey the classical statistical theory and hence critical values of the test can not be appropriately determined. In this article, we consider a new interval mapping approach based on a general sib-pair regression model. A modified Wald test is proposed for the testing of QTL effects. The asymptotic distribution of the modified Wald test statistic is provided and hence the critical values or the $p$-values of the test can be well determined. Simulation studies are carried out to verify the validity of the modified Wald test and to demonstrate its desirable power.     

CAUSAL GRAPHICAL MODELS IN SYSTEMS GENETICS: A UNIFIED FRAMEWORK FOR JOINT INFERENCE OF CAUSAL NETWORK AND GENETIC ARCHITECTURE FOR CORRELATED PHENOTYPES

Causal inference approaches in systems genetics exploit quantitative trait loci (QTL) genotypes to infer causal relationships among phenotypes. The genetic architecture of each phenotype may be complex, and poorly estimated genetic architectures may compromise the inference of causal relationships among phenotypes. Existing methods assume QTLs are known or inferred without regard to the phenotype network structure. In this paper we develop a QTL-driven phenotype network method (QTLnet) to jointly infer a causal phenotype network and associated genetic architecture for sets of correlated phenotypes. Randomization of alleles during meiosis and the unidirectional influence of genotype on phenotype allow the inference of QTLs causal to phenotypes. Causal relationships among phenotypes can be inferred using these QTL nodes, enabling us to distinguish among phenotype networks that would otherwise be distribution equivalent. We jointly model phenotypes and QTLs using homogeneous conditional Gaussian regression models, and we derive a graphical criterion for distribution equivalence. We validate the QTLnet approach in a simulation study. Finally, we illustrate with simulated data and a real example how QTLnet can be used to infer both direct and indirect effects of QTLs and phenotypes that co-map to a genomic region.     

Bayesian hierarchical regression models for detecting QTLs in plant experiments

Quantitative trait loci (QTL) mapping is a growing field in statistical genetics. In plants, QTL detection experiments often feature replicates or clones within a specific genetic line. In this work, a Bayesian hierarchical regression model is applied to simulated QTL data and to a dataset from the Arabidopsis thaliana plants for locating the QTL mapping associated with cotyledon opening. A conditional model search strategy based on Bayesian model averaging is utilized to reduce the computational burden.     

Power and robustness of sib-pair linkage tests and extension to larger sibships

We investigate the power and robustness of Haseman and Elstonfs sib-pair test for genetic linkage between a marker locus and a locus affecting a quantitative trait, and compare the test to that of Penrose. The Haseman-Elston test is more powerful than Penrrose's test; its power is acceptable for cases of tight linkage and high heritability due to the hypothesized quantitative trait locus, but is quite low in other situations. Computer simulations indicate that both tests are valid for normally distributed trait values, and that the Haseman-Elston test is robust for a variety of continuous distributions of the trait values. Several linkage tests are developed for sib trios that are much more powerful , for the same total number of sibs, than the test on independent sib pairs. The Haseman-Elston test on all possible sib pairs is suggested for sibships of size larger than three and for samples including sibships of various sizes.     

Asymptotic test of mixture model and its applications to QTL interval mapping

Quantitative trait loci (QTL) mapping has been a standard means in identifying genetic regions harboring potential genes underlying complex traits. Likelihood ratio test (LRT) has been commonly applied to assess the significance of a genetic locus in a mixture model content. Given the time constraint in commonly used permutation tests to assess the significance of LRT in QTL mapping, we study the behavior of the LRT statistic in mixture model when the proportions of the distributions are unknown. We found that the asymptotic null distribution is stationary Gaussian process after suitable transformation. The result can be applied to one-parameter exponential family mixture model. Under certain condition, such as in a backcross mapping model, the tail probability of the supremum of the process is calculated and the threshold values can be determined by solving the distribution function. Simulation studies were performed to evaluate the asymptotic results.     

A robust QTL mapping procedure

In quantitative trait linkage studies using experimental crosses, the conventional normal location-shift model or other parameterizations may be unnecessarily restrictive. We generalize the mapping problem to a genuine nonparametric setup and provide a robust estimation procedure for the situation where the underlying phenotype distributions are completely unspecified. Classical Wilcoxon–Mann–Whitney statistics are employed for point and interval estimation of QTL positions and effects.     

On stochastic processes for quantitative trait locus mapping under selective genotyping

We consider the likelihood ratio test (LRT) process related to the test of the absence of QTL (a QTL denotes a quantitative trait locus, i.e. a gene with quantitative effect on a trait) on the interval [0, T] representing a chromosome. The originality of this study is that we are under selective genotyping: only the individuals with extreme phenotypes are genotyped. We give the asymptotic distribution of this LRT process under the null hypothesis that there is no QTL on [0, T] and under local alternatives with a QTL at t^☆ on [0, T]. We show that the LRT process is asymptotically the square of a ‘non-linear interpolated and normalized Gaussian process’. We have an easy formula in order to compute the supremum of the square of this interpolated process. We prove that we have to genotype symmetrically and that the threshold is exactly the same as in the situation where all the individuals are genotyped.     

Hypothesis testing for quantitative trait locus effects in both location and scale in genetic backcross studies

Testing the existence of a quantitative trait locus (QTL) effect is an important task in QTL mapping studies. Most studies concentrate on the case where the phenotype distributions of different QTL groups follow normal distributions with the same unknown variance. In this paper we make a more general assumption that the phenotype distributions come from a location-scale distribution family. We derive the limiting distribution of the likelihood ratio test (LRT) for the existence of the QTL effect in both location and scale in genetic backcross studies. We further identify an explicit representation for this limiting distribution. As a complement, we study the limiting distribution of the LRT and its explicit representation for the existence of the QTL effect in the location only. The asymptotic properties of the LRTs under a local alternative are also investigated. Simulation studies are used to evaluate the asymptotic results, and a real-data example is included for illustration.     

Multiple Interval Mapping for Quantitative Trait Loci via EM Algorithm in the Presence of Crossover Interference

The rapid advance in molecular biology has made feasible systematic studies of mapping quantitative trait loci (QTL) in experiment organisms. The method of multiple interval mapping provides an appropriate way for mapping QTL using genetic makers. However, crossover interference has not been considered sufficiently in the current QTL mapping in which no crossover interference is assumed, and the length of maker interval is always kept fixed. In this article, we consider the issue of statistical inference in multiple interval mapping for QTL when crossover interference is present. The marker interval can be chosen appropriately in our method without keeping the maker interval lengths fixed in advance, and the asymptotic variance–covariance matrix of the MLEs is also derived. Two simulations are performed to evaluate the proposed method and show the impact of crossover interference to QTL mapping.     

Flexible semiparametric analysis of longitudinal genetic studies by reduced rank smoothing

In family-based longitudinal genetic studies, investigators collect repeated measurements on a trait that changes with time along with genetic markers. Since repeated measurements are nested within subjects and subjects are nested within families, both the subject-level and measurement-level correlations must be taken into account in the statistical analysis to achieve more accurate estimation. In such studies, the primary interests include to test for quantitative trait locus (QTL) effect, and to estimate age-specific QTL effect and residual polygenic heritability function. We propose flexible semiparametric models along with their statistical estimation and hypothesis testing procedures for longitudinal genetic designs. We employ penalized splines to estimate nonparametric functions in the models. We find that misspecifying the baseline function or the genetic effect function in a parametric analysis may lead to substantially inflated or highly conservative type I error rate on testing and large mean squared error on estimation. We apply the proposed approaches to examine age-specific effects of genetic variants reported in a recent genome-wide association study of blood pressure collected in the Framingham Heart Study.     

Test for homogeneity in Hardy–Weinberg normal mixture model

The phenotype of a quantitative trait locus (QTL) is often modeled by a finite mixture of normal distributions. If the QTL effect depends on the number of copies of a specific allele one carries, then the mixture model has three components. In this case, the mixing proportions have a binomial structure according to the Hardy–Weinberg equilibrium. In the search for QTL, a significance test of homogeneity against the Hardy–Weinberg normal mixture model alternative is an important first step. The LOD score method, a likelihood ratio test used in genetics, is a favored choice. However, there is not yet a general theory for the limiting distribution of the likelihood ratio statistic in the presence of unknown variance. This paper derives the limiting distribution of the likelihood ratio statistic, which can be described by the supremum of a quadratic form of a Gaussian process. Further, the result implies that the distribution of the modified likelihood ratio statistic is well approximated by a chi-squared distribution. Simulation results show that the approximation has satisfactory precision for the cases considered. We also give a real-data example.     

BLOCK-BASED BAYESIAN EPISTASIS ASSOCIATION MAPPING WITH APPLICATION TO WTCCC TYPE 1 DIABETES DATA

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.     

Mixture cure model with an application to interval mapping of quantitative trait loci

When censored time-to-event data are used to map quantitative trait loci (QTL), the existence of nonsusceptible subjects entails extra challenges. If the heterogeneous susceptibility is ignored or inappropriately handled, we may either fail to detect the responsible genetic factors or find spuriously significant locations. In this article, an interval mapping method based on parametric mixture cure models is proposed, which takes into consideration of nonsusceptible subjects. The proposed model can be used to detect the QTL that are responsible for differential susceptibility and/or time-to-event trait distribution. In particular, we propose a likelihood-based testing procedure with genome-wide significance levels calculated using a resampling method. The performance of the proposed method and the importance of considering the heterogeneous susceptibility are demonstrated by simulation studies and an application to survival data from an experiment on mice infected with Listeria monocytogenes.     

A model selection approach for the identification of quantitative trait loci in experimental crosses

Summary. We consider the problem of identifying the genetic loci (called quantitative trait loci (QTLs)) contributing to variation in a quantitative trait, with data on an experimental cross. A large number of different statistical approaches to this problem have been described; most make use of multiple tests of hypotheses, and many consider models allowing only a single QTL. We feel that the problem is best viewed as one of model selection. We discuss the use of model selection ideas to identify QTLs in experimental crosses. We focus on a back-cross experiment, with strictly additive QTLs, and concentrate on identifying QTLs, considering the estimation of their effects and precise locations of secondary importance. We present the results of a simulation study to compare the performances of the more prominent methods.     

General strong convergence for negatively associated random variables

For negatively associated (NA) random variables, we obtain two general strong laws of large numbers (SLLN) in which the coefficient of sum and the weight are both general functions. As corollaries, we obtain Marcinkiewicz-type SLLN, the logarithmic SLLN and Marcinkiewicz SLLN for NA random variables.     

Locating genes involved in human diseases

The increasing amount of information that is becoming available about the structure and composition of the DNA constituting the human chromosomes has provided new opportunities to locate genes that affect susceptibilities to a range of diseases. The accurate location of these genes is important in genetic counselling and in understanding the effects of genes that may result in disease. Various methods of analysing the data when DNA information is available at a single marker locus for an affected child and his or her parents are reviewed and applied to data on insulin-dependent diabetes mellitus . The importance of distinguishing between the association of alleles at a marker locus and at a disease locus resulting from chromosomal linkage from that resulting from other causes is emphasized.     

SNP selection for predicting a quantitative trait

Molecular markers combined with powerful statistical tools have made it possible to detect and analyze multiple loci on the genome that are responsible for the phenotypic variation in quantitative traits. The objectives of the study presented in this paper are to identify a subset of single nucleotide polymorphism (SNP) markers that are associated with a particular trait and to construct a model that can best predict the value of the trait given the genotypic information of the SNPs using a three-step strategy. In the first step, a genome-wide association test is performed to screen SNPs that are associated with the quantitative trait of interest. SNPs with p-values of less than 5% are then analyzed in the second step. In the second step, a large number of randomly selected models, each consisting of a fixed number of randomly selected SNPs, are analyzed using the least angle regression method. This step will further remove redundant SNPs due to the complicated association among SNPs. A subset of SNPs that are shown to have a significant effect on the response trait more often than by chance are considered for the third step. In the third step, two alternative methods are considered: the least angle shrinkage and selection operation and sparse partial least squares regression. For both methods, the predictive ability of the fitted model is evaluated by an independent test set. The performance of the proposed method is illustrated by the analysis of a real data set on Canadian Holstein cattle.     

An Additive Genetic Gamma Frailty Model for Linkage Analysis of Diseases with Variable Age of Onset Using Nuclear Families

Many late-onset complex diseases exhibit variable age of onset. Efficiently incorporating age of onset information into linkage analysis can potentially increase the power of dissecting complex diseases. In this paper, we treat age of onset as a genetic trait with censored observations. We use multiple markers to infer the inheritance vector at the disease susceptibility (DS) locus in order to extract information about the inheritance pattern of the disease allele in a pedigree. Given the inheritance distribution at the DS locus, we define the genetic frailty for each individual within a nuclear family as the sum of frailties due to a putative major disease gene and a polygenic effect due to any remaining DS loci. Conditioning on these frailties we use the proportional hazards model for the risk of developing disease. We show that a test of linkage can be formulated as a test of zero variance due to a specific locus of the additive gamma frailties. Maximum likelihood estimation, using the EM algorithm, and likelihood ratio tests are employed for parameter estimation and tests of linkage. A simulation study presented indicates that the proposed method is well behaved and can be more powerful than the currently available allele-sharing based linkage methods. A breast cancer data example is used for illustration.