Multipoint Quantitative-Trait Linkage Analysis in General Pedigrees
TL;DR: It is shown how variance-component linkage methods can be used in pedigrees of arbitrary size and complexity, and a general framework for multipoint identity-by-descent (IBD) probability calculations is developed.
Abstract: 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.
Citations
More filters
TL;DR: A unified mixed-model approach to account for multiple levels of relatedness simultaneously as detected by random genetic markers is developed and provides a powerful complement to currently available methods for association mapping.
Abstract: As population structure can result in spurious associations, it has constrained the use of association studies in human and plant genetics. Association mapping, however, holds great promise if true signals of functional association can be separated from the vast number of false signals generated by population structure. We have developed a unified mixed-model approach to account for multiple levels of relatedness simultaneously as detected by random genetic markers. We applied this new approach to two samples: a family-based sample of 14 human families, for quantitative gene expression dissection, and a sample of 277 diverse maize inbred lines with complex familial relationships and population structure, for quantitative trait dissection. Our method demonstrates improved control of both type I and type II error rates over other methods. As this new method crosses the boundary between family-based and structured association samples, it provides a powerful complement to currently available methods for association mapping.
3,467 citations
Cites background from "Multipoint Quantitative-Trait Linka..."
...The fixed SNP effect can be replaced with either a fixed or a random haplotype effec...
[...]
TL;DR: These findings are consistent with the hypothesized role of visceral fat as a unique, pathogenic fat depot and Measurement of VAT may provide a more complete understanding of metabolic risk associated with variation in fat distribution.
Abstract: Background— Visceral adipose tissue (VAT) compartments may confer increased metabolic risk. The incremental utility of measuring both visceral and subcutaneous abdominal adipose tissue (SAT) in association with metabolic risk factors and underlying heritability has not been well described in a population-based setting. Methods and Results— Participants (n=3001) were drawn from the Framingham Heart Study (48% women; mean age, 50 years), were free of clinical cardiovascular disease, and underwent multidetector computed tomography assessment of SAT and VAT volumes between 2002 and 2005. Metabolic risk factors were examined in relation to increments of SAT and VAT after multivariable adjustment. Heritability was calculated using variance-components analysis. Among both women and men, SAT and VAT were significantly associated with blood pressure, fasting plasma glucose, triglycerides, and high-density lipoprotein cholesterol and with increased odds of hypertension, impaired fasting glucose, diabetes mellitus, ...
2,501 citations
TL;DR: A website for performing power calculations for the design of linkage and association genetic mapping studies of complex traits and the package is made available atstatgen.iop.ac.uk/gpc.
Abstract: Summary: Aw ebsite for performing power calculations for the design of linkage and association genetic mapping studies of complex traits. Availibility: The package is made available at http://
2,108 citations
Cites background from "Multipoint Quantitative-Trait Linka..."
...Variance components models provide a powerful framework for both linkage and association mapping (Almasy and Blangero, 1998; Fulker and Cherny, 1996; Pratt et al., 2000; Fulker et al., 1999)....
[...]
TL;DR: It is suggested that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations.
Abstract: African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5×10(-8)). SNP rs7560163 (P = 7.0×10(-9), OR (95% CI) = 0.75 (0.67-0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5×10(-5)) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations.
1,957 citations
TL;DR: It is proposed that basic emotion theories no longer explain adequately the vast number of empirical observations from studies in affective neuroscience, and it is suggested that a conceptual shift is needed in the empirical approaches taken to the study of emotion and affective psychopathologies.
Abstract: The circumplex model of affect proposes that all affective states arise from cognitive interpretations of core neural sensations that are the product of two independent neurophysiological systems. This model stands in contrast to theories of basic emotions, which posit that a discrete and independent neural system subserves every emotion. We propose that basic emotion theories no longer explain adequately the vast number of empirical observations from studies in affective neuroscience, and we suggest that a conceptual shift is needed in the empirical approaches taken to the study of emotion and affective psychopathologies. The circumplex model of affect is more consistent with many recent findings from behavioral, cognitive neuroscience, neuroimaging, and developmental studies of affect. Moreover, the model offers new theoretical and empirical approaches to studying the development of affective disorders as well as the genetic and cognitive underpinnings of affective processing within the central nervous system.
1,910 citations
Cites methods from "Multipoint Quantitative-Trait Linka..."
...Use of dimensional measures has been shown to be more powerful statistically than the use of categorical variables in identifying of loci of genetic susceptibility for complex disorders ~Almasy & Blangero, 1998; Amos, 1994!....
[...]
References
More filters
TL;DR: Specific standards designed to maintain rigor while also promoting communication are proposed for the interpretation of linkage results in genetic studies under way for many complex traits.
Abstract: Genetic studies are under way for many complex traits, spurred by the recent feasibility of whole genome scans. Clear guidelines for the interpretation of linkage results are needed to avoid a flood of false positive claims. At the same time, an overly cautious approach runs the risk of causing true hints of linkage to be missed. We address this problem by proposing specific standards designed to maintain rigor while also promoting communication.
5,317 citations
"Multipoint Quantitative-Trait Linka..." refers background in this paper
...These authors and Lander and Kruglyak (1995) were primarily interested in the p-autocorrelations in order to assess the importance of correlated test statistics in genome scanning....
[...]
...These authors and Lander and Kruglyak (1995) were primarily interested in the p-autocorrelations in order to assess the importance of correlated test statistics in genome scanning....
[...]
Journal Article•
TL;DR: It is shown that NPL is robust to uncertainty about mode of inheritance, is much more powerful than commonly used nonparametric methods, and loses little power relative to parametric linkage analysis, and appears to be the method of choice for pedigree studies of complex traits.
Abstract: In complex disease studies, it is crucial to perform multipoint linkage analysis with many markers and to use robust nonparametric methods that take account of all pedigree information. Currently available methods fall short in both regards. In this paper, we describe how to extract complete multipoint inheritance information from general pedigrees of moderate size. This information is captured in the multipoint inheritance distribution, which provides a framework for a unified approach to both parametric and nonparametric methods of linkage analysis. Specifically, the approach includes the following: (1) Rapid exact computation of multipoint LOD scores involving dozens of highly polymorphic markers, even in the presence of loops and missing data. (2) Non-parametric linkage (NPL) analysis, a powerful new approach to pedigree analysis. We show that NPL is robust to uncertainty about mode of inheritance, is much more powerful than commonly used nonparametric methods, and loses little power relative to parametric linkage analysis. NPL thus appears to be the method of choice for pedigree studies of complex traits. (3) Information-content mapping, which measures the fraction of the total inheritance information extracted by the available marker data and points out the regions in which typing additional markers is most useful. (4) Maximum-likelihood reconstruction of many-marker haplotypes, even in pedigrees with missing data. We have implemented NPL analysis, LOD-score computation, information-content mapping, and haplotype reconstruction in a new computer package, GENEHUNTER. The package allows efficient multipoint analysis of pedigree data to be performed rapidly in a single user-friendly environment.
2,997 citations
"Multipoint Quantitative-Trait Linka..." refers background or methods in this paper
...To date, practical application of multipoint IBD methods has been confined to sibships or small pedigrees (Fulker et al. 1995; Kruglyak and Lander 1995; Kruglyak et al. 1996; Todorov et al. 1997), although there have been some recent promising developments utilizing computer-intensive Monte Carlo– based techniques (Sobel and Lange 1996; Heath 1997; Heath et al....
[...]
...…practical application of multipoint IBD methods has been confined to sibships or small pedigrees (Fulker et al. 1995; Kruglyak and Lander 1995; Kruglyak et al. 1996; Todorov et al. 1997), although there have been some recent promising developments utilizing computer-intensive Monte Carlo–…...
[...]
...In contrast to the Elston-Stewart algorithm (1971), in which computation increases exponentially with the number of markers, or the Lander-Green Hidden Markov Model (Lander and Green 1987; Kruglyak et al. 1996), in which computation increases exponentially with the number of nonfounders in a pedigree, because the suggested multipoint algorithms are linear functions of previously computed IBDs, processing time increases only linearly for additional individuals or additional loci....
[...]
...…(1971), in which computation increases exponentially with the number of markers, or the Lander-Green Hidden Markov Model (Lander and Green 1987; Kruglyak et al. 1996), in which computation increases exponentially with the number of nonfounders in a pedigree, because the suggested multipoint…...
[...]
TL;DR: In this article, the authors derived the asymptotic distribution of maximum likelihood estimators and likelihood ratio statistics, which is the same as the distribution of the projection of the Gaussian random variable.
Abstract: Large sample properties of the likelihood function when the true parameter value may be on the boundary of the parameter space are described. Specifically, the asymptotic distribution of maximum likelihood estimators and likelihood ratio statistics are derived. These results generalize the work of Moran (1971), Chant (1974), and Chernoff (1954). Some of Chant's results are shown to be incorrect. The approach used in deriving these results follows from comments made by Moran and Chant. The problem is shown to be asymptotically equivalent to the problem of estimating the restricted mean of a multivariate Gaussian distribution from a sample of size 1. In this representation the Gaussian random variable corresponds to the limit of the normalized score statistic and the estimate of the mean corresponds to the limit of the normalized maximum likelihood estimator. Thus the limiting distribution of the maximum likelihood estimator is the same as the distribution of the projection of the Gaussian random v...
2,564 citations
TL;DR: Assuming random mating and random sampling of pedigrees, the likelihood of a set of pedigree data is developed in terms of the population distribution of the different genotypes.
Abstract: Assuming random mating and random sampling of pedigrees, the likelihood of a set of pedigree data is developed in terms of: (1) the population distribution of the different genotypes; (2) the phenotyp
1,480 citations
TL;DR: Several alternative algorithms for constructing human linkage maps given a specified gene order are described, one of which allows maximum-likelihood multilocus linkage maps for dozens of DNA markers in such three-generation pedigrees to be constructed in minutes.
Abstract: Human genetic linkage maps are most accurately constructed by using information from many loci simultaneously. Traditional methods for such multilocus linkage analysis are computationally prohibitive in general, even with supercomputers. The problem has acquired practical importance because of the current international collaboration aimed at constructing a complete human linkage map of DNA markers through the study of three-generation pedigrees. We describe here several alternative algorithms for constructing human linkage maps given a specified gene order. One method allows maximum-likelihood multilocus linkage maps for dozens of DNA markers in such three-generation pedigrees to be constructed in minutes.
1,401 citations
"Multipoint Quantitative-Trait Linka..." refers methods in this paper
...…Elston-Stewart algorithm (1971), in which computation increases exponentially with the number of markers, or the Lander-Green Hidden Markov Model (Lander and Green 1987; Kruglyak et al. 1996), in which computation increases exponentially with the number of nonfounders in a pedigree, because the…...
[...]
...In contrast to the Elston-Stewart algorithm (1971), in which computation increases exponentially with the number of markers, or the Lander-Green Hidden Markov Model (Lander and Green 1987; Kruglyak et al. 1996), in which computation increases exponentially with the number of nonfounders in a pedigree, because the suggested multipoint algorithms are linear functions of previously computed IBDs, processing time increases only linearly for additional individuals or additional loci....
[...]