GENEHUNTER-TWOLOCUS

GENEHUNTER-TWOLOCUS (GHT) is a modification of the GENEHUNTER software package version 1.3 (Kruglyak et al. 1996; Kruglyak and Lander 1998). The program performs parametric and nonparametric multi-marker linkage analysis of dichotomous traits with two autosomal diallelic disease loci. It uses two unlinked marker maps with one disease locus linked to each map. Like the single-disease-locus versions GENEHUNTER-IMPRINTING and GENEHUNTER-MODSCORE, GENEHUNTER-TWOLOCUS allows for a parametric (LOD-score) analysis with imprinting disease models. It can take into account parent-of-origin effects at both loci.

In the case of a parametric (LOD-score) analysis with two trait loci, the parameters of the two-locus model (i.e., two disease allele frequencies and 9 penetrances – or 16 penetrances if imprinting should be modeled) need to be specified prior to the analysis. It is possible to derive these parameters from the best-fitting trait models that were obtained by a single-trait-locus MOD-score analysis, e.g. with GENEHUNTER-MODSCORE, at the two loci. For details regarding this issue, please refer to the article by Strauch et al. (“How to model a complex trait. 2. Analysis with two disease loci", Human Heredity 56:200-211, 2003), in which the corresponding formulae are given. A spreadsheet for OpenOffice and MS-Excel as well as a C program, One-Two (written by Manuel Mattheisen), is provided (please see below) which implements these formulae. It allows researchers to easily derive the parameters of the two-locus trait model from the best-fitting single-locus parameters.

The optimized and parallelized version GENEHUNTER-TWOLOCUS PARALLEL, as described by Dietter et al. ("Efficient two-trait-locus linkage analysis through program optimization and parallelization: application to hypercholesterolemia", European Journal of Human Genetics 12:542-550, 2004), can analyze larger pedigrees than the previous version. In particular, the optimization of the serial program, before parallelization, has resulted in a speed-up of a factor of more than 10. Therefore, using the new GENEHUNTER-TWOLOCUS PARALLEL version is already of benefit in the context of a computer with a single processor. The parallelization further decreases the computation time by a factor of the number of processors (i.e., perfect or linear speed-up). In addition, with this new version, the genetic positions of both trait loci are varied on their respective marker maps, not just the position of the second trait locus with the first one fixed, as before. The two-locus LOD and NPL scores are conveniently prepared to be displayed in three-dimensional plots, e.g. using Gnuplot or any other graphics package. Here is an example of such a plot, showing a two-locus LOD score of 4.44 that has been obtained in a linkage study of high factor VIII levels in venous thromboembolism (Berger et al., "High factor VIII levels in venous thromboembolism show linkage to imprinted loci on chromosomes 5 and 11", Blood 105:638-644, 2005).

• 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

• 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