GENEHUNTER-MODSCORE 4.0

GENEHUNTER-MODSCORE (GHM) 4.0 is a further extension of GENEHUNTER-MODSCORE 3.1.1. 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 4.0 allows for a joint linkage and association (JLA) MOD score analysis, in which parametric LOD scores are maximized over the parameters of the trait model, i.e., the penetrances and disease allele frequency, as well as over parameters of the linkage disequilibrium (LD) between alleles at the trait and marker loci. JLA analysis hence combines two disease gene mapping strategies: linkage information contained in families and association information contained in populations. Such a JLA analysis can increase mapping power, especially when the evidence for both linkage and association is low to moderate. Similarly, an association analysis based on haplotypes instead of single markers can increase mapping power when the association pattern is complex. The JLA analysis method implemented in GHM 4.0 is based on haplotypes and uses information from arbitrary pedigree types and unrelated individuals. LD is modelled between alleles at a single diallelic disease locus and up to three diallelic test markers forming the marker-trait locus haplotypes. Linkage information is contributed by additional multi-allelic flanking markers. Optimization of trait-model and LD parameters for the JLA MOD score is achieved utilizing the derivative-free optimization algorithm COBYLA (Powell MJD. A direct search optimization method that models the objective and constraint functions by linear interpolation. In: Gomez S, Hennart JP, editors. Advances in Optimization and Numerical Analysis. Dordrecht: Kluwer Academic; 1994. p. 51-67; Powell MJD. Direct search algorithms for optimization calculations. Acta Numerica 1998;7:287-336) as implemented in the free library NLopt (Johnson SG. The NLopt nonlinear-optimization package. 2020. github.com/stevengj/nlopt). Because the null distribution of the JLA MOD score is unknown, we also implemented a corresponding simulation routine allowing for parallel computing to obtain an empiric p value for the JLA test.

Reference publications for GENEHUNTER-MODSCORE 4.0:

• Brugger M, Lutz M, Müller-Nurasyid M, Lichtner P, Slater EP, Matthäi E, Bartsch DK, and Strauch K (2023): Joint linkage and association analysis using GENEHUNTER-MODSCORE with an application to familial pancreatic cancer. Submitted to Human Heredity
• Brugger M, Strauch K (2014): Fast linkage analysis with MOD scores using algebraic calculation. Human Heredity 78(3-4):179-194
• Mattheisen M, Dietter J, Knapp M, Baur MP, Strauch K (2008): Inferential testing for linkage with GENEHUNTER-MODSCORE: the impact of the pedigree structure on the null distribution of multipoint MOD scores. Genetic Epidemiology 32:73-83
• Dietter J, Mattheisen M, Fürst R, Rüschendorf F, Wienker TF, Strauch K (2007): Linkage analysis using sex-specific recombination fractions with GENEHUNTER-MODSCORE. Bioinformatics 23:64-70
• Strauch K, Fürst R, Rüschendorf F, Windemuth C, Dietter J, Flaquer A, Baur MP, Wienker TF (2005): Linkage analysis of alcohol dependence using MOD scores. BMC Genetics 6(Suppl1):S162
• Strauch K (2003): Parametric linkage analysis with automatic optimization of the disease model parameters. American Journal of Human Genetics 73 (Suppl1):A2624

Reference publication for the imprinting analysis option:

• 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

Reference publication for the permutation procedure to obtain empiric p values for the MOBIT imprinting test:

• Brugger M, Knapp M, Strauch K (2019): Properties and evaluation of the MOBIT – a novel linkage-based test statistic and quantification method for imprinting. Statistical Applications in Genetics and Molecular Biology 18(4):20180025

Original GENEHUNTER references:

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