Multipoint Quantitative-Trait Linkage Analysis in General Pedigrees

Department of Genetics, Southwest Foundation for Biomedical Research, San Antonio, TX 78245-0549, USA.
The American Journal of Human Genetics (Impact Factor: 10.93). 05/1998; 62(5):1198-211. DOI: 10.1086/301844
Source: PubMed


Multipoint linkage analysis of quantitative-trait loci (QTLs) has previously been restricted to sibships and small pedigrees. In this article, we show how variance-component linkage methods can be used in pedigrees of arbitrary size and complexity, and we develop a general framework for multipoint identity-by-descent (IBD) probability calculations. We extend the sib-pair multipoint mapping approach of Fulker et al. to general relative pairs. This multipoint IBD method uses the proportion of alleles shared identical by descent at genotyped loci to estimate IBD sharing at arbitrary points along a chromosome for each relative pair. We have derived correlations in IBD sharing as a function of chromosomal distance for relative pairs in general pedigrees and provide a simple framework whereby these correlations can be easily obtained for any relative pair related by a single line of descent or by multiple independent lines of descent. Once calculated, the multipoint relative-pair IBDs can be utilized in variance-component linkage analysis, which considers the likelihood of the entire pedigree jointly. Examples are given that use simulated data, demonstrating both the accuracy of QTL localization and the increase in power provided by multipoint analysis with 5-, 10-, and 20-cM marker maps. The general pedigree variance component and IBD estimation methods have been implemented in the SOLAR (Sequential Oligogenic Linkage Analysis Routines) computer package.

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    • "Familiality was estimated using a maximum likelihood method in the Sequential Oligogenic Linkage Analysis Routines (SOLAR) software (v4.3.1; (Almasy and Blangero, 1998)) using an ascertainment bias correction since families were recruited through the identification of a psychotic proband rather than as a representative community sample (Beaty and Liang, 1987). Familiality was determined using a maximum likelihood ratio test of a model in which phenotypic variation explained by family membership was compared to one in which it was not. "
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    • "In the absence of population substructure, dominance or any environmental effect shared by family members, the phenotypic covariances can be expressed as a function of the kinship coefficient between family members in family-based samples. Under this parameterization, the additive polygenic variance is obtained from the covariances between family members using variance component models [2] [3] [4] [5]. Alternatively, since the advent of large-scale genome data, which reveals similarity in genotypic background, the genetic relationships between individuals have become estimable from genome-wide data and this has also been used to identify population substructure. "
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    • "Finite size of the 36 genome (i.e., there are no infinite unlinked loci) causes that true " realized " IBD relationships deviate 37 from expected IBD relationships (Hill and Weir, 2011). Thus, more accurate measures of relationships 38 can be obtained using identity by descent measured with markers (Fernando and Grossmann, 1989, 39 Almasy and Blangero, 1998, Visscher et al., 2006). Other estimators of relationships based on 40 markers that do not use pedigree are based on identity by state (IBS) at markers, sometimes 41 corrected to be on an IBD scale (Ritland, 1996; Toro et al., 2002; VanRaden, 2008). "
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