Parametric and Nonparametric Multipoint Linkage Analysis with Imprinting and Two-Locus–Trait Models: Application to Mite Sensitization

Strauch, Konstantin; Fimmers, Rolf; Kurz, Thorsten; Deichmann, Klaus A.; Wienker, Thomas F.; Baur, Max P.

doi:10.1086/302911

Cited by 164 publications

(191 citation statements)

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“…For illustration purposes, we choose the homozygote risk f d/d ¼ 0.1; the disease allele frequency p ¼ 0.01, 0.1, 0.5, and 0.8; and the sample size n ¼ 100, to evaluate the sizes of the TDT and the TDTI. For the completeness of this investigation, we choose the following 13 representative pairs of g 1p and g 1m , which are scattered uniformly in the diamond (Strauch et al 2000) composed of {(g 1p , g 1m ) j 1 # g 1p , g 1m # g 2 }: (g 1p , g 1m ) ¼ (g 2 , g 2 ), ((1 1 g 2 )/2, g 2 ), ((1 1 3g 2 )/4, (1 1 3g 2 )/4), (g 2 , (1 1 g 2 )/2), (1, g 2 ), ((3 1 g 2 )/4, (1 1 3g 2 )/4), ((1 1 g 2 )/2, (1 1 g 2 )/2), ((1 1 3g 2 )/4, (3 1 g 2 )/4), (g 2 , 1), (1, (1 1 g 2 )/2), ((3 1 g 2 )/4, (3 1 g 2 )/4), ((1 1 g 2 )/2, 1), (1, 1). It is noted that (g 1p , g 1m ) ¼ (g 2 , g 2 ) corresponds to the common dominant mode of inheritance, (g 1p , g 1m ) ¼ ((1 1 g 2 )/2, (1 1 g 2 )/2) corresponds to the additive mode of inheritance, (g 1p , g 1m ) ¼ (1, 1) corresponds to the common recessive mode of inheritance, (g 1p , g 1m ) ¼ (g 2 , 1) indicates complete maternal imprinting, and (g 1p , g 1m ) ¼ (1, g 2 ) indicates complete paternal imprinting.…”

Section: Simulation Resultsmentioning

confidence: 99%

“…For illustration, we choose b to be 1 4 , 1 2 , and 3 4 or equivalently g 1 to be (3 1 g 2 )/4, (1 1 g 2 )/2, and (1 1 3g 2 )/4, equally spaced in the range of 1 and g 2 . When g 1 (b) is given, we can derive the range of the degree of imprinting I from the diamond of inheritance (Strauch et al 2000) as follows:…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…Imprinting can happen when either the paternal or the maternal copy of a gene is inactivated. DNA methylation and the differential packing density of DNA by histone proteins are two mechanisms known to be involved in the process of imprinting, which is determined by chromosomal region of DNA or by differences in chromatin structure (Hall 1990;Ainscough and Surani 1996;Bartolomei and Tilghman 1997;Strauch et al 2000;Knapp and Strauch 2004 of genetic loci that show parent-of-origin effects in linkage analyses for alcoholism-related traits.According to a rule by Haldane (1922), it is more common to have crossovers in the homogametic sex (e.g., XX) than in the heterogametic sex (e.g., XY ) (Ott 1999, pp. 211-212).…”

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An Extension of the Transmission Disequilibrium Test Incorporating Imprinting

Zhou

Fung

2007

Genetics

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The recombination rates in meioses of females and males are often different. Some genes that affect development and behavior in mammals are known to be imprinted, and .1% of all mammalian genes are believed to be imprinted. When the gene is imprinted and the recombination fractions are sex specific, the conventional transmission disequilibrium test (TDT) is shown to be still valid for testing for linkage. The power function of the TDT is derived, and the effect of the degree of imprinting on the power of the TDT is investigated. It is learned that imprinting has little effect on the power when the female and male recombination rates are equal. On the basis of case-parents trios, the transmissions from the heterozygous fathers/ mothers to their affected children are separated as paternal and maternal, and two TDT-like statistics, TDT p and TDT m , are consequently constructed. It is found that the TDT p possesses a higher power than the TDT for maternal imprinting genes, and the TDT m is more powerful than the TDT for paternal imprinting genes. On the basis of the parent-of-origin effects test statistic (POET), a novel statistic, TDT incorporating imprinting (TDTI) is proposed to test for linkage in the presence of linkage disequilibrium, which is shown to be more powerful than the TDT when parent-of-origin effects are significant but slightly less powerful than the TDT when parent-of-origin effects are negligible. The validity of the TDT and TDTI is assessed by simulation. The power approximation formulas for the TDT and TDTI are derived and the simulation results show that they are accurate. The simulation study on power comparison shows that the TDTI outperforms the TDT for imprinted genes. The improvement can be substantial in the case of complete paternal/maternal imprinting.T HE transmission disequilibrium test (TDT) is a powerful and major approach to search for genes underlying human complex/common diseases. It was introduced originally by Spielman et al. (1993) on the basis of the case-parents trios, to test directly for linkage between the marker locus and a disease susceptibility locus (DSL) when association due to linkage disequilibrium (LD) is present. The TDT essentially tests for the equality of the expected number of transmissions and that of nontransmissions of a marker allele from heterozygous parents to their affected offspring. When both parents' marker genotypes were unavailable, Spielman and Ewens (1998) extended the TDT to the sibship (S)-TDT for use in sibships with at least one affected individual and one unaffected individual. When only one of the parents was available, Sun et al. (1999) proposed a test, termed the 1-TDT, for use with marker genotypes of the affected individuals and the available parents. Sebastiani et al. (2004) proposed a robust TDT to handle incomplete genotypes on both parents and children, which does not rest on any assumption about a missing data mechanism.Genomic imprinting, also known as ''parent-of-origin effect,'' is an important epigenetic factor. More...

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Section: Simulation Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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confidence: 99%

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An Extension of the Transmission Disequilibrium Test Incorporating Imprinting

Zhou

Fung

2007

Genetics

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“…1 The methods can be roughly divided into parametric (LOD-score) and nonparametric (NPL) analysis. NPL analysis delivers results without relying on specific model assumptions, while with the LOD-score method a disease model has to be specified.…”

Section: Introductionmentioning

confidence: 99%

Efficient two-trait-locus linkage analysis through program optimization and parallelization: application to hypercholesterolemia

Dietter

Spiegel²,

Mey³

et al. 2004

Eur J Hum Genet

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We have optimized and parallelized the GENEHUNTER-TWOLOCUS program that allows to perform linkage analysis with two trait loci in the multimarker context. The optimization of the serial program, before parallelization, results in a speedup of a factor of more than 10. The parallelization affects the twolocus-score calculation, which is predominant in terms of computation time. We obtain perfect speedup, that is, the computation time decreases exactly by a factor of the number of processors. In addition, twolocus LOD and NPL scores are now calculated for varying genetic positions of both disease loci, not just one locus varied and the position of the other disease locus fixed, as before. This results in easily interpretable 3-D plots. We have reanalyzed a pedigree with hypercholesterolemia using our new version of GENEHUNTER-TWOLOCUS. Whereas originally, two individuals had to be discarded due to excessive computation-time demands, the entire 17-bit pedigree could now be analyzed as a whole. We obtain a two-trait-locus LOD score of 5.49 under a multiplicative model, compared to LOD scores of 3.08 and 2.87 under a heterogeneity and additive model, respectively. This further increases evidence for linkage to both 1p36.1 -p35 and 13q22 -q32 regions, and corroborates the hypothesis that the two genes act in a multiplicative way on LDL cholesterol level. Furthermore, we compare the computation times for two-traitlocus analysis needed by the programs GENEHUNTER-TWOLOCUS, TLINKAGE, and SUPERLINK. Altogether, our algorithmic improvements of GENEHUNTER-TWOLOCUS allow researchers to analyze complex diseases under realistic two-trait-locus models with pedigrees of reasonable size and using many markers.

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Gene mapping, imprinting, and epigenetics

Strauch

2005

Encyclopedia of Genetics, Genomics, Proteomics and Bioinformatics

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In this review, methods for linkage and association analysis are presented that take imprinting into account. This epigenetic factor is also known as the parent‐of‐origin effect. Here, it is described why it is important to adequately model imprinting in the context of gene mapping. Tests for linkage that account for imprinting are contrasted with tests for imprinting. Furthermore, the confounding between sex differences in recombination fractions and imprinting is mentioned, as well as how such confounding can be avoided in a mapping study.

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Parametric and Nonparametric Multipoint Linkage Analysis with Imprinting and Two-Locus–Trait Models: Application to Mite Sensitization

Cited by 164 publications

References 40 publications

An Extension of the Transmission Disequilibrium Test Incorporating Imprinting

An Extension of the Transmission Disequilibrium Test Incorporating Imprinting

Efficient two-trait-locus linkage analysis through program optimization and parallelization: application to hypercholesterolemia

Gene mapping, imprinting, and epigenetics

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