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Extension of the generalized disequilibrium test to polytomous phenotypes and two-locus models.

Bureau A, Croteau J, Chagnon YC, Roy MA, Maziade M - Front Genet (2014)

Bottom Line: WE EXTEND THE USUAL LOGISTIC MODEL BETWEEN A DICHOTOMOUS PHENOTYPE AND AN ALLELE COUNT IN TWO WAYS: a polytomous phenotype with K > 2 levels, and modeling of allele counts at two unlinked marker loci.Simulations confirm that the tests have the expected statistical properties, and that their power exceeds that of the GDT under a favorable scenario.The score tests are illustrated with candidate genetic markers, a major psychosis phenotype and a cognitive endophenotype in large kindreds from Eastern Quebec.

View Article: PubMed Central - PubMed

Affiliation: Département de Médecine Sociale et Préventive, Université Laval Québec, QC, Canada ; Centre de Recherche de L'Institut Universitaire en Santé Mentale de Québec Québec, QC, Canada.

ABSTRACT
WE EXTEND THE USUAL LOGISTIC MODEL BETWEEN A DICHOTOMOUS PHENOTYPE AND AN ALLELE COUNT IN TWO WAYS: a polytomous phenotype with K > 2 levels, and modeling of allele counts at two unlinked marker loci. Inference is based on within-family information to guard against potential bias due to population genetic structure. Score tests of the model coefficients taking into account the correlation between relatives in entire pedigrees are derived as an extension of the Generalized Disequilibrium Test (GDT). Simulations confirm that the tests have the expected statistical properties, and that their power exceeds that of the GDT under a favorable scenario. The score tests are illustrated with candidate genetic markers, a major psychosis phenotype and a cognitive endophenotype in large kindreds from Eastern Quebec.

No MeSH data available.


Related in: MedlinePlus

Structure of simulated families with an example of phenotype realization.
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Figure 1: Structure of simulated families with an example of phenotype realization.

Mentions: The family structure used in the simulations is a 3-generation 16-member family depicted in Figure 1. The disease and endophenotype status of all family members was assumed to be observed. We generated genotype data for genetic variants with two alleles such as single nucleotide polymorphisms (SNPs) at two independent loci. The genotypes of pedigree founders were sampled under Hardy-Weinberg equilibrium using risk allele frequencies (RAFs) of 0.1 at locus 1 and 0.3 at locus 2. The transmission of alleles to their descendants was then simulated following the rules of Mendelian inheritance. Two dichotomous phenotypes Y1 and Y2 were generated in a two-step approach: we first simulated from the distribution of Yi1 for each subject i by summing over Yi2 in a polytomous model, then from the distribution of the vector Y2/Y1. In the model to simulate Yi2/Y1, Y1 is treated as a vector of fixed effect, with the effect of the endophenotype of subject h, Yh1, modulated by the kinship coefficient ϕih between i and h. An additive polygenic effect on the logit of Y2 was also included. The model can be written:


Extension of the generalized disequilibrium test to polytomous phenotypes and two-locus models.

Bureau A, Croteau J, Chagnon YC, Roy MA, Maziade M - Front Genet (2014)

Structure of simulated families with an example of phenotype realization.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4126369&req=5

Figure 1: Structure of simulated families with an example of phenotype realization.
Mentions: The family structure used in the simulations is a 3-generation 16-member family depicted in Figure 1. The disease and endophenotype status of all family members was assumed to be observed. We generated genotype data for genetic variants with two alleles such as single nucleotide polymorphisms (SNPs) at two independent loci. The genotypes of pedigree founders were sampled under Hardy-Weinberg equilibrium using risk allele frequencies (RAFs) of 0.1 at locus 1 and 0.3 at locus 2. The transmission of alleles to their descendants was then simulated following the rules of Mendelian inheritance. Two dichotomous phenotypes Y1 and Y2 were generated in a two-step approach: we first simulated from the distribution of Yi1 for each subject i by summing over Yi2 in a polytomous model, then from the distribution of the vector Y2/Y1. In the model to simulate Yi2/Y1, Y1 is treated as a vector of fixed effect, with the effect of the endophenotype of subject h, Yh1, modulated by the kinship coefficient ϕih between i and h. An additive polygenic effect on the logit of Y2 was also included. The model can be written:

Bottom Line: WE EXTEND THE USUAL LOGISTIC MODEL BETWEEN A DICHOTOMOUS PHENOTYPE AND AN ALLELE COUNT IN TWO WAYS: a polytomous phenotype with K > 2 levels, and modeling of allele counts at two unlinked marker loci.Simulations confirm that the tests have the expected statistical properties, and that their power exceeds that of the GDT under a favorable scenario.The score tests are illustrated with candidate genetic markers, a major psychosis phenotype and a cognitive endophenotype in large kindreds from Eastern Quebec.

View Article: PubMed Central - PubMed

Affiliation: Département de Médecine Sociale et Préventive, Université Laval Québec, QC, Canada ; Centre de Recherche de L'Institut Universitaire en Santé Mentale de Québec Québec, QC, Canada.

ABSTRACT
WE EXTEND THE USUAL LOGISTIC MODEL BETWEEN A DICHOTOMOUS PHENOTYPE AND AN ALLELE COUNT IN TWO WAYS: a polytomous phenotype with K > 2 levels, and modeling of allele counts at two unlinked marker loci. Inference is based on within-family information to guard against potential bias due to population genetic structure. Score tests of the model coefficients taking into account the correlation between relatives in entire pedigrees are derived as an extension of the Generalized Disequilibrium Test (GDT). Simulations confirm that the tests have the expected statistical properties, and that their power exceeds that of the GDT under a favorable scenario. The score tests are illustrated with candidate genetic markers, a major psychosis phenotype and a cognitive endophenotype in large kindreds from Eastern Quebec.

No MeSH data available.


Related in: MedlinePlus