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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    • "Genome wide significance was defined by p-values <5x10 −8 , and suggestive significance was defined by p-values <1x10 −5 . The association analysis was adjusted for F2 G20210A mutation as known genetic determinant of thrombin generation, if needed.All statistical analyses were performed employing the computer package Sequential Oligogenic Linkage Analysis Routines (SOLAR, version 8, official)[28]. SOLAR employs the maximum likelihood approach for variance component models with the standard likelihood ratio tests (LRT) to evaluate the statistical significance of the model parameters[32]. "
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    ABSTRACT: Background: Venous thromboembolism (VTE) is a common disease where known genetic risk factors explain only a small portion of the genetic variance. Then, the analysis of intermediate phenotypes, such as thrombin generation assay, can be used to identify novel genetic risk factors that contribute to VTE. Objectives: To investigate the genetic basis of distinct quantitative phenotypes of thrombin generation and its relationship to the risk of VTE. Patients/methods: Lag time, thrombin peak and endogenous thrombin potential (ETP) were measured in the families of the Genetic Analysis of Idiopathic Thrombophilia 2 (GAIT-2) Project. This sample consisted of 935 individuals in 35 extended families selected through a proband with idiopathic thrombophilia. We performed also genome wide association studies (GWAS) with thrombin generation phenotypes. Results: The results showed that 67% of the variation in the risk of VTE is attributable to genetic factors. The heritabilities of lag time, thrombin peak and ETP were 49%, 54% and 52%, respectively. More importantly, we demonstrated also the existence of positive genetic correlations between thrombin peak or ETP and the risk of VTE. Moreover, the major genetic determinant of thrombin generation was the F2 gene. However, other suggestive signals were observed. Conclusions: The thrombin generation phenotypes are strongly genetically determined. The thrombin peak and ETP are significantly genetically correlated with the risk of VTE. In addition, F2 was identified as a major determinant of thrombin generation. We reported suggestive signals that might increase our knowledge to explain the variability of this important phenotype. Validation and functional studies are required to confirm GWAS results.
    Full-text · Article · Jan 2016 · PLoS ONE
    • "Briefly, heritability estimates, genetic correlations, and two-point log of the odds ratio (LOD) scores were calculated for each candidate endophenotype using the variance components method in SOLAR v.4.3.1 (Almasy and Blangero, 1998; Almasy et al., 1997). Multipoint LOD scores were computed using both variance components and pedigree-wide regression methods in SOLAR and MERLIN, as each has favorable properties (Almasy and Blangero, 1998; Schork and Greenwood, 2004; Sham et al., 2002). Empirical p values were estimated from 10,000 replicates (Blangero et al., 2000). "
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    ABSTRACT: The Consortium on the Genetics of Schizophrenia Family Study (COGS-1) has previously reported our efforts to characterize the genetic architecture of 12 primary endophenotypes for schizophrenia. We now report the characterization of 13 additional measures derived from the same endophenotype test paradigms in the COGS-1 families. Nine of the measures were found to discriminate between schizophrenia patients and controls, were significantly heritable (31 to 62%), and were sufficiently independent of previously assessed endophenotypes, demonstrating utility as additional endophenotypes. Genotyping via a custom array of 1536 SNPs from 94 candidate genes identified associations for CTNNA2, ERBB4, GRID1, GRID2, GRIK3, GRIK4, GRIN2B, NOS1AP, NRG1, and RELN across multiple endophenotypes. An experiment-wide p value of 0.003 suggested that the associations across all SNPs and endophenotypes collectively exceeded chance. Linkage analyses performed using a genome-wide SNP array further identified significant or suggestive linkage for six of the candidate endophenotypes, with several genes of interest located beneath the linkage peaks (e.g., CSMD1, DISC1, DLGAP2, GRIK2, GRIN3A, and SLC6A3). While the partial convergence of the association and linkage likely reflects differences in density of gene coverage provided by the distinct genotyping platforms, it is also likely an indication of the differential contribution of rare and common variants for some genes and methodological differences in detection ability. Still, many of the genes implicated by COGS through endophenotypes have been identified by independent studies of common, rare, and de novo variation in schizophrenia, all converging on a functional genetic network related to glutamatergic neurotransmission that warrants further investigation.
    No preview · Article · Nov 2015 · Schizophrenia Research
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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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    Full-text · Article · Oct 2015 · Schizophrenia Research
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