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PubMed2001

Joint tests of linkage and association for quantitative traits.

In this paper we describe various study designs and analytic techniques for testing the joint hypothesis that a genetic marker is both linked to and associated with a quantitative phenotype. Issues of power and sampling are addressed. The distinction between methods that explicitly examine association and those that infer association by examining the distribution of allelic transmissions from a heterozygous parent is examined. Extensions to multivariate, multiallelic, and multilocus situations are addressed. Recent approaches that combine variance-components-based linkage analyses with joint tests of linkage in the presence of association for disentanglement of the linkage and association and the application of such methods to fine mapping are discussed. Finally, new classes of joint tests of linkage and association that do not require samples of related individuals are described.

Alleles↗
PubMed2001

Association between quantitative traits underlying asthma and the HLA-DRB1 locus in a family-based population sample.

The region of human chromosome 6 containing the MHC has been identified as influencing asthma and atopy (allergy) by several genome-wide searches. The MHC contains many genes with potential effects on innate and specific immunity. As a first step in dissecting MHC influences on asthma and its underlying quantitative phenotypes, we have examined the HLA-DRB1 locus in a population sample consisting of 1004 individuals from 230 families from the rural Australian town of Busselton. The locus was strongly associated with the (log(e)) total serum IgE concentration, accounting for 4.0% of the sigma(2) (variance) in that trait (multi-allelic test, P=0.00001). The locus also influenced specific IgE titres to common allergens (multi-allelic tests, 2.8% sigma(2) for the house dust mite allergen Der p I, P=0.0013; 3.0% of sigma(2) for Der p II, P=0.0007; and 2.1% of sigma(2) for the cat allergen Fel d I, P=0.014). No associations were found to the categorical phenotype of asthma, or to the quantitative traits of peripheral blood eosinophil counts and bronchial hyper-responsiveness. Transmission disequilibrium tests excluded genetic admixture as a cause of false-positive findings. The results indicate that HLA-DRB1 alleles modulate the total serum IgE concentration and IgE responses to allergens, but do not account for the previous observations of linkage of asthma to the MHC.

Adult↗
PubMed2000

Power of a score test for quantitative trait linkage analysis of relative pairs.

The score test of Dudoit and Speed [(2000) Biostatistics 1:1-26] to detect linkage between a trait locus and a marker locus, using identity by descent data on sib pairs, is extended to other types of relative pairs (grandparent/grandchild, avuncular, and half-sib relationships). The test is based on the likelihood of the recombination fraction theta between trait and marker loci, conditional on phenotypes of the relatives. We present results of simulation studies characterizing power and robustness properties of this linkage score test, and compare the power of the score test to that of the classical and modified Haseman-Elston tests. The score test has considerable power, particularly under sampling schemes where selection is on double probands. Use of a generic additive model [Goldstein et al., submitted] with allele frequency p = 0.2, heritability H = 0.3, and a moderate residual correlation of rho = 0.2 resulted in a very good overall performance across a wide range of trait-generating models.

Computer Simulation↗
PubMedDate not supplied

A generalized estimating equations approach to quantitative trait locus detection of non-normal traits.

To date, most statistical developments in QTL detection methodology have been directed at continuous traits with an underlying normal distribution. This paper presents a method for QTL analysis of non-normal traits using a generalized linear mixed model approach. Development of this method has been motivated by a backcross experiment involving two inbred lines of mice that was conducted in order to locate a QTL for litter size. A Poisson regression form is used to model litter size, with allowances made for under- as well as over-dispersion, as suggested by the experimental data. In addition to fixed parity effects, random animal effects have also been included in the model. However, the method is not fully parametric as the model is specified only in terms of means, variances and covariances, and not as a full probability model. Consequently, a generalized estimating equations (GEE) approach is used to fit the model. For statistical inferences, permutation tests and bootstrap procedures are used. This method is illustrated with simulated as well as experimental mouse data. Overall, the method is found to be quite reliable, and with modification, can be used for QTL detection for a range of other non-normally distributed traits.

Animals↗
PubMed1993

Effects of multiple retrovirus insertions on quantitative traits of mice.

To assess the potential to generate quantitative genetic variation by insertional mutagenesis in a vertebrate, lines of mice in which many provirus vector inserts segregated at a low initial frequency on an inbred background (insert lines) were subjected to divergent artificial selection on body weight at 6 weeks and responses and heritability estimates compared to control lines lacking inserts. Heritability estimates were more than 1.5 times greater in the insert lines than in the controls, but because the phenotypic variance was substantially higher in the insert lines the genetic variance was about 3 times greater. Realized heritability estimates tended to be lower than heritabilities estimated by an animal model which utilizes information in covariances between all relatives in the data set. A surprisingly large response to selection occurred in the inbred control line. Insert lines were about 20% less fertile than controls. Division of the selection lines into inbred sublines in the later generations of the experiment revealed substantially greater variation among sublines of the insert lines than among the controls. Heritabilities were similar to typical estimates for the trait in outbred populations. In conclusion, there was clear evidence of extra variation deriving from inserts, which has yet to be attributed to individual genes.

Animals↗
PubMed2004

Simultaneous estimation of haplotype frequencies and quantitative trait parameters: applications to the test of association between phenotype and diplotype configuration.

The analysis of the haplotype-phenotype relationship has become more and more important. We have developed an algorithm, using individual genotypes at linked loci as well as their quantitative phenotypes, to estimate the parameters of the distribution of the phenotypes for subjects with and without a particular haplotype by an expectation-maximization (EM) algorithm. We assumed that the phenotype for a diplotype configuration follows a normal distribution. The algorithm simultaneously calculates the maximum likelihood (L0max) under the null hypothesis (i.e., nonassociation between the haplotype and phenotype), and the maximum likelihood (Lmax) under the alternative hypothesis (i.e., association between the haplotype and phenotype). Then we tested the association between the haplotype and the phenotype using a test statistic, -2 log(L0max/Lmax). The above algorithm along with some extensions for different modes of inheritance was implemented as a computer program, QTLHAPLO. Simulation studies using single-nucleotide polymorphism (SNP) genotypes have clarified that the estimation was very accurate when the linkage disequilibrium between linked loci was rather high. Empirical power using the simulated data was high enough. We applied QTLHAPLO for the analysis of the real data of the genotypes at the calpain 10 gene obtained from diabetic and control subjects in various laboratories.

Algorithms↗
PubMed1987

[Linkage between quantitative and marker loci. V. Joint analysis of various marker and quantitative traits].

New versions are suggested to analyse marker and quantitative characters combinations. Possible modes of application of the algorithms developed for recombination analysis are discussed, including: 1) the estimation of crossing-over frequency between markers with incomplete penetrance, 2) the quantitative character variability account to analyse genetic interference, 3) search for genetic factors affecting a set of quantitative characters, 4) the evaluation of differences between male and female meiosis at the crossingover level etc.

Algorithms↗
PubMed2003

Multitrait fine mapping of quantitative trait loci using combined linkage disequilibria and linkage analysis.

A novel multitrait fine-mapping method is presented. The method is implemented by a model that treats QTL effects as random variables. The covariance matrix of allelic effects is proportional to the IBD matrix, where each element is the probability that a pair of alleles is identical by descent, given marker information and QTL position. These probabilities are calculated on the basis of similarities of marker haplotypes of individuals of the first generation of genotyped individuals, using "gene dropping" (linkage disequilibrium) and transmission of markers from genotyped parents to genotyped offspring (linkage). A small simulation study based on a granddaughter design was carried out to illustrate that the method provides accurate estimates of QTL position. Results from the simulation also indicate that it is possible to distinguish between a model postulating one pleiotropic QTL affecting two traits vs. one postulating two closely linked loci, each affecting one of the traits.

Chromosome Mapping↗