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

Abstract

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.

A New Strategy for Linkage Analysis under Epistasis Taking into Account Genetic Heterogeneity

“…Multipoint LOD scores not being usual LR statistics [42] , null distributions should always be determined by simulation, even under a fixed genetic model. The multipoint context also presents additional computational difficulties: programs designed for optimal multi-point computations (Genehunter Twolocus [43] ) impose severe limitations on pedigree size, while there is a trade-off between number of markers and pedigree size with Superlink.…”

Novel Pheochromocytoma Susceptibility Loci Identified by Integrative Genomics

“…To examine the potential interaction between these two loci, we employed a modified version of the GeneHunter Two-Locus software (kindly provided by Dr. J. Dietter, Institute for Medical Biometry, Informatics, and Epidemiology, University of Bonn, Bonn, Germany) as described (8,9). SNP array genotype data of all affected and two clinically unaffected siblings (individuals 13 and 15 from Fig.…”

“…In brief, the program was used to investigate whether the two loci identified by the single-locus analysis interacted. Three models were tested to examine the nature of the interaction between the two loci: a multiplicative or synergistic model, an additive or modulating model, or a heterogeneity model (8,9). Both parametric (recessive model, allele frequency of 0.01%) and nonparametric (NPL) results were obtained in these three models.…”

High factor VIII levels in venous thromboembolism show linkage to imprinted loci on chromosomes 5 and 11

“…Recently, GENEHUNTER-TWOLOCUS has been optimized and parallelized. 22 A 2-trait-locus model contains the allele frequencies for each disease locus and, in addition, the matrix of 3 ϫ 3 (in the case of imprinting of 4 ϫ 4) penetrances. In particular, a heterogeneity, multiplicative, and an additive 2-locus disease model were applied to each pair of chromosomes.…”