Population Based Linkage Disequilibrium Mapping of QTL: An Application to Simulated Data in an Isolated Population

Zhao, Jinying; Li, Wuju; Xiong, Momiao

doi:10.1002/gepi.2001.21.s1.s655

Cited by 8 publications

(5 citation statements)

References 7 publications

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“…However, there is not sufficient statistical analysis regarding the high resolution mapping by linkage disequilibrium mapping method. Using population data, Zhao et al 10 applied an approach of linkage disequilibrium mapping based on regression to map QTL in humans. Abecasis et al, 7 Allison et al, 26 Fulker et al, 3 Göring and Terwillinger, 27 and Sham et al 9 have explored linkage and association studies of quantitative traits by variance -component procedures allowing a simultaneous test of allelic association for family data.…”

Section: Discussionmentioning

confidence: 99%

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High resolution mapping of quantitative trait loci by linkage disequilibrium analysis

Fan

Xiong²

2002

Eur J Hum Genet

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Two methods, linkage analysis and linkage disequilibrium (LD) mapping or association study, are usually utilised for mapping quantitative trait loci (QTL). Linkage mapping is appropriate for low resolution mapping to localise trait loci to broad chromosome regions within a few cM (510 cM), and is based on family data. Linkage disequilibrium mapping, on the other hand, is useful in high resolution or fine mapping, and is based on both population and family data. Using only one marker, one may carry out single-point linkage analysis and linkage disequilibrium mapping. Using two or more markers, it is possible to flank the QTL by multipoint analysis. The development and thus availability of dense marker maps, such as single nucleotide polymorphisms (SNP) in human genome, presents a tremendous opportunity for multipoint fine mapping. In this article, we propose a regression approach of mapping QTL by linkage disequilibrium mapping based on population data. Assuming that two marker loci flank one quantitative trait locus, a two-point linear regression is proposed to analyse population data. We derive analytical formulas of parameter estimations, and non-centrality parameters of appropriate tests of genetic effects and linkage disequilibrium coefficients. The merit of the method is shown by the power calculation and comparison. The two-point regression model can capture much more linkage and linkage disequilibrium information than that derived when only one marker is used. For a complex disease with heritability h 2 50.15, a study with sample size of 250 can provide high power for QTL detection under moderate linkage disequilibria. European Journal of Human Genetics (2002Genetics ( ) 10, 607 -615. doi:10.1038 Keywords: high resolution mapping; linkage mapping; linkage disequilibrium mapping; QTL IntroductionMuch research has been done on linkage mapping of qualitative or quantitative trait loci (QTL). Schork investigated multipoint identity-by-descent analysis of human quantitative traits. 1 Fulker and Cardon worked out a sib-pair approach of a two-point interval mapping for QTL. 2 Researchers have been extending the available methods toward several directions: (1) Fulker et al. 3 extended the method of Fulker and Cardon 2 for usage in multipoint interval mapping; (2) Almasy and Blangero worked on multipoint mapping for general pedigrees; 4 (3) Liang et al. proposed a unified sampling method for both qualitative and quantitative traits; 5 (4) Pratt et al. used an exact multipoint algorithm to analyse family data by variance component models. 6 The focus of the above studies was on linkage mapping, which is based on family data. Linkage analysis is appropriate for low resolution genetic mapping to localise trait loci to broad chromosome regions within a few cM (510 cM).Linkage disequilibrium (LD) mapping or association study, on the other hand, is based on both family and population data, and is useful in high resolution of genetic mapping, ie, fine disease gene mapping. The reason for the These exciting developments a...

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Section: Discussionmentioning

confidence: 99%

“…Zhao et al 10 applied a regression approach of linkage disequilibrium mapping to localise QTL in humans. In these studies the investigators used only one marker in their analysis.…”

Section: Introductionmentioning

confidence: 99%

High resolution mapping of quantitative trait loci by linkage disequilibrium analysis

Fan

Xiong²

2002

Eur J Hum Genet

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“…Population‐based quantitative trait loci (QTL) regression association was performed as described previously (Zhao et al ., 2001). Briefly, each locus tested is assumed to have two alleles, A (wild‐type) and a (mutant), with frequencies P A and P a respectively.…”

Section: Methodsmentioning

confidence: 99%

Multiple transporters associated with malaria parasite responses to chloroquine and quinine

Ferdig

Feng

et al. 2003

Molecular Microbiology

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269

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SummaryMutations and/or overexpression of various transporters are known to confer drug resistance in a variety of organisms. In the malaria parasite Plasmodium falciparum , a homologue of P-glycoprotein, PfMDR1, has been implicated in responses to chloroquine (CQ), quinine (QN) and other drugs, and a putative transporter, PfCRT, was recently demonstrated to be the key molecule in CQ resistance. However, other unknown molecules are probably involved, as different parasite clones carrying the same pfcrt and pfmdr1 alleles show a wide range of quantitative responses to CQ and QN. Such molecules may contribute to increasing incidences of QN treatment failure, the molecular basis of which is not understood. To identify additional genes involved in parasite CQ and QN responses, we assayed the in vitro susceptibilities of 97 culture-adapted cloned isolates to CQ and QN and searched for single nucleotide polymorphisms (SNPs) in DNA encoding 49 putative transporters (total 113 kb) and in 39 housekeeping genes that acted as negative controls. SNPs in 11 of the putative transporter genes, including pfcrt and pfmdr1 , showed significant associations with decreased sensitivity to CQ and/or QN in P. falciparum . Significant linkage disequilibria within and between these genes were also detected, suggesting interactions among the transporter genes. This study provides specific leads for better understanding of complex drug resistances in malaria parasites.

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“…Zhang and Zhao [2001] propose a quantitative similarity-based test to identify association between a bi-allelic marker and a quantitative trait. Zhao et al [2001] apply a regression approach of LD mapping to localize QTL in humans. In these studies, most investigators use only one bi-allelic marker in their analysis.…”

Section: Discussionmentioning

confidence: 99%

High-Resolution Joint Linkage Disequilibrium and Linkage Mapping of Quantitative Trait Loci Based on Sibship Data

Fan

Jung²

2003

Hum Hered

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This paper proposes variance component models for high resolution joint linkage disequilibrium (LD) and linkage mapping of quantitative trait loci (QTL) based on sibship data; this can include population data if independent individuals are treated as single sibships. One application of these models is late onset complex disease gene mapping, when parental data are not available. The models simultaneously incorporate both LD and linkage information. The LD information is contained in mean coefficients of sibship data. The linkage information is contained in the variance-covariance matrices of trait values for sibships with at least two siblings. We derive formulas for calculating the probability of sharing two trait alleles identical by descent (IBD) for sibpairs in interval mapping of QTL; this is the coefficient of dominant variance of the trait covariance of sibpairs on major QTL. To investigate the performance of the formulas, we calculate the numerical values via the formulas and get satisfactory approximations. We compare the power and sample sizes for both LD and linkage mapping. By simulation and theoretical analysis, we compare the results with those of Fulker and Abecasis ‘AbAw’ approach. It is well known that the resolution of linkage analysis can be low for complex disease gene mapping. LD mapping, on the other hand, can increase mapping precision and is useful in high resolution mapping. Linkage analysis is less sensitive to population subdivisions and admixtures. The level of LD is sensitive to population stratification which may easily lead to spurious association. Performing a joint analysis of LD and linkage mapping can help to overcome the limits of both approaches. Moreover, the advantages of the two complementary strategies can be utilized maximally. In practice, linkage analysis may be performed using pedigree data to identify suggestive linkage between markers and trait loci based on a sparse marker map. In the presence of linkage, joint LD and linkage mapping can be carried out to do fine gene mapping based on a dense genetic map using both pedigree and population data. Population and pedigree data of any type can be combined to perform a joint analysis of high resolution LD and linkage mapping of QTL by generalizing the method.

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Population Based Linkage Disequilibrium Mapping of QTL: An Application to Simulated Data in an Isolated Population

Cited by 8 publications

References 7 publications

High resolution mapping of quantitative trait loci by linkage disequilibrium analysis

High resolution mapping of quantitative trait loci by linkage disequilibrium analysis

Multiple transporters associated with malaria parasite responses to chloroquine and quinine

High-Resolution Joint Linkage Disequilibrium and Linkage Mapping of Quantitative Trait Loci Based on Sibship Data

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