Multifactorial Models for Familial Diseases in Man

Curnow, R. N.; Smith, Charles

doi:10.2307/2984646

Cited by 84 publications

(47 citation statements)

References 61 publications

(67 reference statements)

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“…One approach advocates that a fixed threshold exists in the liability that divides individuals with or without the phenotype (Pearson, 1900;Wright, 1934;Dempster and Lerner, 1950;Risch et al, 1993). Another approach is to say that each individual has its own liability threshold, which follows a Gaussian distribution in the population (Curnow, 1972;Curnow and Smith, 1975). One can also use logistic regression models, which approximate the Gaussian liability distribution by the (standard) Logistic distribution (Baxter, 2001).…”

Section: Independent Action Models (Iams)mentioning

confidence: 99%

Allelic penetrance approach as a tool to model two-locus interaction in complex binary traits

et al. 2007

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Many binary phenotypes do not follow a classical Mendelian inheritance pattern. Interaction between genetic and environmental factors is thought to contribute to the incomplete penetrance phenomena often observed in these complex binary traits. Several two-locus models for penetrance have been proposed to aid the genetic dissection of binary traits. Such models assume linear genetic effects of both loci in different mathematical scales of penetrance, resembling the analytical framework of quantitative traits. However, changes in phenotypic scale are difficult to envisage in binary traits and limited genetic interpretation is extractable from current modeling of penetrance. To overcome this limitation, we derived an allelic penetrance approach that attributes incomplete penetrance to the stochastic expression of the alleles controlling the phenotype, the genetic background and environmental factors. We applied this approach to formulate dominance and recessiveness in a single diallelic locus and to model different genetic mechanisms for the joint action of two diallelic loci. We fit the models to data on the genetic susceptibility of mice following infections with Listeria monocytogenes and Plasmodium berghei. These models gain in genetic interpretation, because they specify the alleles that are responsible for the genetic (inter)action and their genetic nature (dominant or recessive), and predict genotypic combinations determining the phenotype. Further, we show via computer simulations that the proposed models produce penetrance patterns not captured by traditional two-locus models. This approach provides a new analysis framework for dissecting mechanisms of interlocus joint action in binary traits using genetic crosses.

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Section: Independent Action Models (Iams)mentioning

confidence: 99%

Allelic penetrance approach as a tool to model two-locus interaction in complex binary traits

et al. 2007

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“…Both these models have been extensively analyzed (Smith 1971) and for some purposes they represent extremes of the range of possible quantitative genetic models (Curnow and Smith 1975). Neither model depends on the number of loci, on the frequencies of alleles at each locus, or on explicit assumptions about interactions within and between loci.…”

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confidence: 99%

Exchangeable Models of Complex Inherited Diseases

Slatkin

2008

Genetics

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A model of unlinked diallelic loci affecting the risk of a complex inherited disease is explored. The loci are equivalent in their effect on disease risk and are in Hardy-Weinberg and linkage equilibrium. The goal is to determine what assumptions about dependence of disease risk on genotype are consistent with data for diseases such as schizophrenia, bipolar disorder, autism, and multiple sclerosis that are relatively common (0.1-2% prevalence) and that have high concordance rates for monozygotic twins (30-50%) and high risks to first-degree relatives of affected individuals (risk ratios exceeding 4). These observations are consistent with a variety of models, including generalized additive, multiplicative, and threshold models, provided that disease risk increases rapidly for a narrow range of numbers of causative alleles. If causative alleles are in relatively high frequency, then the combined effects of numerous causative loci are necessary to substantially elevate disease risk. C OMPLEX inherited diseases are, by definition, affected by more than one genetic locus. Although many alleles associated with higher risks of complex diseases have been identified, almost nothing is known about interactions among them or whether there is any commonality to the genetic architecture of different diseases. In this article, I examine a class of models of complex inherited diseases in which all loci increasing disease risk are equivalent in their effects. The goal is to find general properties of such models in randomly mating populations.I am particularly concerned with diseases that have prevalences in the range 0.1-2% and that are highly heritable, meaning that the concordance probability for monozygotic (MZ) twins is in the range 30-50% and the risk ratio for first-degree relatives [Risch's (1990) l 1 ] is in the range 4-10. Such diseases are regarded as common because their prevalence is much higher than monogenic diseases and because they constitute a major burden on health care systems in developed countries. Several diseases, including autism (Szatmari et al. I show that evidence of high heritability requires that there be a large variance in risk among individuals.Consequently, risk considered as a function of the number of causative alleles has to be steeply increasing in the narrow range of genotypes found in appreciable frequency in a population.Most recent analyses of complex diseases have been based on a model of multiplicative interactions across loci. The use of the multiplicative model is traceable to Risch (1990), who showed it provides a better fit to estimates of recurrence risk in first-, second-, and thirddegree relatives than do models of additive and heterogeneous interactions. Specifically, Risch (1990) showed that, under the multiplicative model, estimated recurrence risks for schizophrenia (and by implication other complex diseases) decreased more rapidly with the degree of relationship than is predicted by an additive model. He also showed that a model of genetic heterogeneity (Morton ...

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“…This, however, is explained by the fact that most male pedigrees, being imported, had to be excluded from analysis because of insufficient or unrecorded bleeder data; a good proportion of imported fillies never raced or were from unraced dams, or had raced overseas where bleeder data were not available. The most reliable estimate is probably that from 2nd-degree relatives because 1st-degree relatives may have some environmental correlation through maternal effects 5 while 2nd-and 3rd-degree relatives could be very useful in discriminating between different models of inheritance 3 , but because of the lower degrees of relationship, larger numbers of such relatives will be required, for example to get heritability estimates with low standard errors, and the information on these relatives is often less reliable than on 1st-degree relatives.…”

Section: Discussionmentioning

confidence: 99%

The inheritance of liability to epistaxis in the southern African Thoroughbred

Weideman¹,

Schoeman²,

Jordaan³

2004

J. S. Afr. Vet. Assoc.

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This study was carried out to estimate the heritability of liability to epistaxis in the southern African Thoroughbred population. Data of all horses that suffered epistaxis while racing in southern Africa and Mauritius from 1986 to 2002 and involving 1252 bleeders were analysed. Pedigree data covering the period 1960-1986 was used as required to calculate the incidence of bleeding amongst ancestors of the post-1986 era. Only pedigrees of horses that raced were included in this study as it was not possible to predict whether non-runners would have bled had they raced. Consequently all non-runners and also those that raced overseas in countries where bleeding occurrence was not recorded, were excluded. The heritability of liability method as described by Falconer (1989) was used to estimate the relative importance of heredity and environment. For the period investigated, the population incidence for epistaxis in southern African horses was 2.1 %. The estimation of heritability of liability showed that 1st-degree relatives had a figure of 55.4 %. Second-degree relatives had a heritability of 41.3 % and 3rd-degree relatives came in at 30.4 %. The heritability of liability shown in this study could be regarded as being at the lower end of the range but could be appreciably higher. The data depict horses that bled almost exclusively on race days, as only a small percentage (~5 %) was reported as having bled during exercise. Accordingly, the full extent of epistaxis amongst racing Thoroughbreds in southern Africa is difficult to gauge. It is clear that epistaxis in the racing Thoroughbred has a strong genetic basis. It is suggested that horses showing frank bleeding from the nostrils after racing or exercise be suspended, and not used for breeding purposes. This should result in relatively fast progress being made towards eradicating this costly scourge of the modern Thoroughbred racehorse

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Multifactorial Models for Familial Diseases in Man

Cited by 84 publications

References 61 publications

Allelic penetrance approach as a tool to model two-locus interaction in complex binary traits

Allelic penetrance approach as a tool to model two-locus interaction in complex binary traits

Exchangeable Models of Complex Inherited Diseases

The inheritance of liability to epistaxis in the southern African Thoroughbred

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