Genome scans with gene‐covariate interaction

Genetic models for gene‐covariate interactions are described. Methods of linkage analysis that utilize special features of these models and the corresponding score statistics are derived. Their power is compared with that of simple genome scans that ignore these special features, and substantial gains in power are observed when the gene‐covariate interaction is strong. Quantitative trait mapping in randomly ascertained sibships and affected sibpair mapping are discussed. For the latter case, a simpler statistic is proposed that has similar performance to the score statistic, but does not require the estimation of nuisance parameters. Since the nuisance parameters are not estimable solely from affected sib‐pair data, this statistic would be much easier to apply in practice. Similarities with linkage analysis of models for longitudinal data and multivariate phenotypes are also briefly discussed. Approximations for the P‐value and power are derived under the framework of local alternatives. Genet. Epidemiol. 2005. © 2005 Wiley‐Liss, Inc.

[1]  N. Risch Linkage strategies for genetically complex traits. I. Multilocus models. , 1990, American journal of human genetics.

[2]  E. Boerwinkle,et al.  Multivariate linkage analysis of blood pressure and body mass index , 2004, Genetic epidemiology.

[3]  Nancy J. Cox,et al.  Loci on chromosomes 2 (NIDDM1) and 15 interact to increase susceptibility to diabetes in Mexican Americans , 1999, Nature Genetics.

[4]  J. Olson A general conditional-logistic model for affected-relative-pair linkage studies. , 1999, American journal of human genetics.

[5]  L. Almasy,et al.  Multipoint oligogenic linkage analysis of quantitative traits , 1997, Genetic epidemiology.

[6]  M Farrall,et al.  Two-locus maximum lod score analysis of a multifactorial trait: joint consideration of IDDM2 and IDDM4 with IDDM1 in type 1 diabetes. , 1995, American journal of human genetics.

[7]  Mapping quantitative traits with random and with ascertained sibships. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[8]  D Siegmund,et al.  Mapping quantitative trait loci in oligogenic models. , 2001, Biostatistics.

[9]  D. Siegmund,et al.  Boundary crossing probabilities in linkage analysis , 2000 .

[10]  L. Almasy,et al.  Multipoint quantitative-trait linkage analysis in general pedigrees. , 1998, American journal of human genetics.

[11]  D. Siegmund Sequential Analysis: Tests and Confidence Intervals , 1985 .

[12]  J. James,et al.  Frequency in relatives for an all‐or‐none trait , 1971, Annals of human genetics.

[13]  S. Bull,et al.  Analysis of affected sib pairs, with covariates--with and without constraints. , 1999, American journal of human genetics.

[14]  Mapping Quantitative Trait Loci Using Multiple Phenotypes in General Pedigrees , 2003, Human Heredity.

[15]  E Feingold,et al.  Gaussian models for genetic linkage analysis using complete high-resolution maps of identity by descent. , 1993, American journal of human genetics.

[16]  J. Ware,et al.  Random-effects models for longitudinal data. , 1982, Biometrics.

[17]  David Siegmund,et al.  Mapping multiple genes for quantitative or complex traits , 2002, Genetic epidemiology.

[18]  J. Blangero,et al.  Effects of genotype‐by‐sex interaction on quantitative trait linkage analysis , 1997, Genetic epidemiology.

[19]  R. Elston,et al.  Regression Models for Linkage: Issues of Traits, Covariates, Heterogeneity, and Interaction , 2003, Human Heredity.

[20]  S. Shea,et al.  Random Effects Analysis of Children's Blood Pressure Data , 1997 .

[21]  J. Szatkiewicz,et al.  Recent advances in human quantitative-trait-locus mapping: comparison of methods for discordant sibling pairs. , 2003, American journal of human genetics.

[22]  D J Schaid,et al.  Regression models for linkage heterogeneity applied to familial prostate cancer. , 2001, American journal of human genetics.

[23]  K. Siegmund,et al.  Gene-Environment Interaction and Affected Sib Pair Linkage Analysis , 2001, Human Heredity.

[24]  R. Elston,et al.  Multilocus linkage tests based on affected relative pairs. , 2000, American journal of human genetics.