Category Genomics>Genetic Data Analysis/Tools

Abstract GENEHUNTER-MODSCORE is a further extension of GENEHUNTER-IMPRINTING (see below...).

The program is based on the original GENEHUNTER version 2.1 release 6 (Kruglyak et al. 1996; Kruglyak and Lander 1998; Markianos et al. 2001); it can handle Autosomal or pseudoautosomal loci.

GENEHUNTER-MODSCORE allows for a MOD-score analysis, in which parametric LOD scores (see below...) are maximized over the parameters of the trait model, i.e., the penetrances and disease allele frequency.

By this means, the disease-model parameter space is explored in an efficient way, and researchers do Not have to rely on a single trait model when performing a parametric linkage analysis.

This can be of great help in the context of genetically complex traits, for which the disease model parameters are usually unknown prior to the analysis.

LOD score - The LOD score (logarithm (base 10) of odds) is a statistical test often used for linkage analysis in human populations, and also in animal and plant populations. The test was developed by Newton E. Morton.

Computerized LOD score analysis is a simple way to analyze complex family pedigrees in order to determine the linkage between Mendelian traits (or between a trait and a marker, or two markers).

Please note that, because of the additional maximization, MOD scores are inflated when compared to LOD scores that were calculated under a single trait model. Therefore, in the context of a MOD-score analysis, significance criteria for LOD scores cannot be applied without correction.

In order to address this issue, a simulation routine has been introduced with version 3.0, in conjunction with a wider range of maximization options.

This allows users to calculate empirical P values for MOD scores and simple LOD scores. Hence, significance criteria can also be applied in a MOD-score analysis.

By performing simulations under various scenarios, it is shown that, under the null hypothesis of No linkage, the inflation of MOD scores with respect to simple LOD scores increases with the size of pedigrees in the sample.

The core of GENEHUNTER-MODSCORE is a highly optimized engine for the calculation of the disease-locus likelihood.

Here, the same techniques were used as for the optimization of the program GENEHUNTER-TWOLOCUS (see G6G Abstract Number 20396).

With GENEHUNTER-MODSCORE, the optimizations have led to a speed-up of a factor of almost 6. This is already of benefit in a standard LOD-score analysis, but it is absolutely essential for maximization over models, which is much more demanding.

As of version 2.0, GENEHUNTER-MODSCORE allows researchers to use sex-specific recombination frequencies.

In accordance with that, the program employs an intuitive and consistent method to choose the combinations of male and female genetic distances between the disease locus and its flanking markers at which the LOD, MOD, or NPL (nonparametric linkage) scores should be calculated.

The genetic positions of markers can be automatically read from a publicly available genetic map, such as deCODE, Duffy, Marshfield, Nievergelt-Schork, or the Rutgers map.

The option to use sex-specific recombination fractions also extends to the affected-sib-pair and Quantitative Trait Locus (QTL) analysis capabilities of GENEHUNTER.

A Perl script, GH_modview is provided with GENEHUNTER- MODSCORE.

It allows for the creation of a Gnuplot graph (Gnuplot is a portable command-line driven interactive data and function plotting utility) of the LOD or MOD score, displayed by the single family contributions.

This type of diagram is useful for both Mendelian and complex traits, since it identifies families with positive versus negative contribution to the linkage signal at a particular genetic position.

GENEHUNTER-MODSCORE can perform separate maximizations over penetrances of several liability classes, e.g. for males and females, individuals of different age, or different levels of risk due to environmental factors. By this means, it is also possible to study gene- environment interactions.

In case that a genome scan for a certain trait yields at least two linkage peaks, it is reasonable to perform a linkage analysis that explicitly models two trait loci.

Such an analysis can be done with the program GENEHUNTER- TWOLOCUS.

In the parametric context, the best-fitting trait models at the two loci obtained by a MOD-score analysis with GENEHUNTER-MODSCORE can be used to derive the underlying two-locus trait model.

GENEHUNTER-IMPRINTING -- is a modification of the GENEHUNTER software package (versions 1.3 and 2.1 release 3; Kruglyak et al. 1996; Kruglyak and Lander 1998; Markianos et al. 2001).

It allows for a parametric multi-marker linkage analysis of dichotomous traits caused by imprinted genes - that is, of traits showing a parent-of- origin effect.

By specification of two heterozygote penetrance parameters, paternal and maternal origin of the disease allele can be treated differently in terms of probability of expression of the trait.

Therefore, a disease model which accounts for imprinting includes four (4) penetrances instead of only three (3).

For an analysis, with a ‘four-penetrance’ imprinting model, the command “imprinting on” needs to be entered at the beginning of the GENEHUNTER-IMPRINTING session.

Otherwise, LOD scores are calculated under a standard three- penetrance model, in the same way as with the original GENEHUNTER.

The imprinting extension does Not affect NPL-score calculation or other types of analysis available with GENEHUNTER version 2 (affected sib pair, QTL, and TDT analyses).

Original GENEHUNTER references:

Kruglyak L, Daly MJ, Reeve-Daly MP, Lander ES (1996): Parametric and nonparametric linkage analysis: a unified multipoint approach. American Journal of Human Genetics 58:1347-1363.

Kruglyak L, Lander ES (1998): Faster multipoint linkage analysis using Fourier transforms. Journal of Computational Biology 5:1-7.

Markianos K, Daly MJ, Kruglyak L (2001): Efficient multipoint linkage analysis through reduction of inheritance space. American Journal of Human Genetics 68:963-977.

Reference publications for GENEHUNTER-TWOLOCUS:

Dietter J, Spiegel A, an Mey D, Pflug HJ, Al-Kateb H, Hoffmann K, Wienker TF, Strauch K (2004): Efficient two-trait-locus linkage analysis through program optimization and parallelization: application to hypercholesterolemia. European Journal of Human Genetics 12:542-550.

Strauch K, Fimmers R, Kurz T, Deichmann KA, Wienker TF, Baur MP (2000): Parametric and nonparametric multipoint linkage analysis with imprinting and two-locus-trait models: application to mite sensitization. American Journal of Human Genetics 66:1945-1957.

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G6G Abstract Number 20395

G6G Manufacturer Number 104029