Human Heredity · 2000 · 190 citations · 9 references
Life SciencesBiostatisticsGeneticsGenetic EpidemiologyMedical GeneticsQuantitative GeneticsDisease ModelingDisease PhenotypingDisease Susceptibility LociGenotype-phenotype Association AnalysisQuantitative InheritanceQuantitative Trait AnalysisAdditive Effects ModelConditional Disease ModelsDisease ModellingDisease Susceptibility ModelingDominant Inheritance ModelsGenetic Disease ModelsHeterogeneityRecessive Inheritance Models
There are 512 fully penetrant two‑locus, two‑allele, two‑phenotype disease models, but permutations of alleles, loci, and case status collapse many into equivalent classes. This paper determines the number of nonredundant two‑locus models under various permutation schemes and exclusion criteria. The authors enumerate the nonredundant models, classify them by properties such as multiplicative, heterogeneity, threshold, and new categories (modifying‑effect, XOR, interference, etc.), and analyze marginal penetrance tables, expected joint IBD probabilities, and IBD correlation. The resulting classification and analyses aid linkage and correlation studies that use single‑locus models to infer two‑locus disease mechanisms.
There are 512 two-locus, two-allele, two-phenotype, fully penetrant disease models. Using the permutation between two alleles, between two loci, and between being affected and unaffected, one model can be considered to be equivalent to another model under the corresponding permutation. These permutations greatly reduce the number of two-locus models in the analysis of complex diseases. This paper determines the number of nonredundant two-locus models (which can be 102, 100, 96, 51, 50, or 58, depending on which permutations are used, and depending on whether zero-locus and single-locus models are excluded). Whenever possible, these nonredundant two-locus models are classified by their property. Besides the familiar features of multiplicative models (logical AND), heterogeneity models (logical OR), and threshold models, new classifications are added or expanded: modifying-effect models, logical XOR models, interference and negative interference models (neither dominant nor recessive), conditionally dominant/recessive models, missing lethal genotype models, and highly symmetric models. The following aspects of two-locus models are studied: the marginal penetrance tables at both loci, the expected joint identity-by-descent (IBD) probabilities, and the correlation between marginal IBD probabilities at the two loci. These studies are useful for linkage analyses using single-locus models while the underlying disease model is two-locus, and for correlation analyses using the linkage signals at different locations obtained by a single-locus model.
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Multi-Locus Nonparametric Linkage Analysis of Complex Trait Loci with Neural Networks
Paul R. Lucek, Jens Hanke, J. Reich et al. · Human Heredity · 1998 · 71 citations