Kistner, E. O., Infante-Rivard, C. & Weinberg, C. R. A method for using incomplete triads to test maternally mediated genetic effects and parent-of-origin effects in relation to a quantitative trait. Am. J. Epidemiol. 163, 255-261

Biostatistics Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
American Journal of Epidemiology (Impact Factor: 5.23). 03/2006; 163(3):255-61. DOI: 10.1093/aje/kwj030
Source: PubMed


The authors recently developed a semiparametric family-based test for linkage and association between markers and quantitative traits. This quantitative polytomous logistic regression test allows for analysis of families with incomplete information on parental genotype. In addition, it is not necessary to assume normality of the quantitative trait. Previous simulations have shown that the new test is as powerful as the other widely used tests for linkage disequilibrium in relation to a quantitative trait. Here the authors propose an extension to quantitative polytomous logistic regression that allows testing for maternally mediated effects and parent-of-origin effects in the same framework. Missing data on parental genotype are accommodated through an expectation-maximization algorithm approach. Simulations show robustness of the new tests and good power for detecting effects in the presence or absence of offspring effects. Methods are illustrated with birth weight and gestational length, two quantitative outcomes for which data were collected in a Montreal, Canada, study of intrauterine growth restriction between May 1998 and June 2000.

10 Reads
  • Source
    • "For each population and subpopulation, specifically, the original sample, the European ancestry sample, the Non-European ancestry sample, the male sample, and the female sample, tests of offspring genotype, maternal genotype, and parent-of-origin were conducted for both the autism and overall language level phenotype. All tests were conducted with freeware developed using SAS V9.1 (Weinberg CR, Wilcox AJ, Lie RT, 1998; Weinberg 1999; Kistner et al., 2006). "
    [Show abstract] [Hide abstract]
    ABSTRACT: A promoter-linked insertion/deletion polymorphism of the serotonin transporter gene (SLC6A4) has been implicated in autism spectrum disorders (ASDs) in numerous family based association studies. However, the results of these investigations have been inconsistent in that both the long and short alleles have been shown to be over-transmitted to affected offspring. In order to further elucidate the relationship between the 5-HTTLPR variant and autism risk, we undertook a thorough study of parent-of-origin effects, maternal genotype effects, and offspring genotype effects in a sample of affected offspring from the Autism Genetic Resource Exchange (AGRE). Both the overall autism phenotype and measures of autism behaviors from the Autism Diagnostic Interview-Revised [Lord et al. (1994); J Autism Dev Disord 24(5): 659–685] were considered. We found evidence of over-transmission (risk allele short, P = 0.012), maternal effects (risk allele long, P = 0.035), and parent-of-origin effects (risk allele short from mother, P = 0.018) of the 5-HTTLPR variant in the AGRE sample. Population- and gender-specific effects were also explored as associations may be heterogeneous across populations and sexes. Parent-of-origin effects of the variant were associated with maternally inherited copies of the short allele that resulted in more impaired overall level of language (P = 0.04). Our study was conducted to further investigate the 5-HTTLPR risk variants by identifying allelic associations that may be population-specific, phenotype-specific, or conferred by maternal or parent-of-origin effects. In light of conflicting observations from previous studies, these are just a few of the possible explanations that deserve attention.
    American Journal of Medical Genetics Part B Neuropsychiatric Genetics 03/2011; 156(2):139-44. DOI:10.1002/ajmg.b.31146 · 3.42 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Both population-based and family-based designs are commonly used in genetic association studies to locate genes that underlie complex diseases. The simplest version of the family-based design--the transmission disequilibrium test--is well known, but the numerous extensions that broaden its scope and power are less widely appreciated. Family-based designs have unique advantages over population-based designs, as they are robust against population admixture and stratification, allow both linkage and association to be tested for and offer a solution to the problem of model building. Furthermore, the fact that family-based designs contain both within- and between-family information has substantial benefits in terms of multiple-hypothesis testing, especially in the context of whole-genome association studies.
    Nature Reviews Genetics 06/2006; 7(5):385-94. DOI:10.1038/nrg1839 · 36.98 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The case/pseudocontrol method provides a convenient framework for family-based association analysis of case-parent trios, incorporating several previously proposed methods such as the transmission/disequilibrium test and log-linear modelling of parent-of-origin effects. The method allows genotype and haplotype analysis at an arbitrary number of linked and unlinked multiallelic loci, as well as modelling of more complex effects such as epistasis, parent-of-origin effects, maternal genotype and mother-child interaction effects, and gene-environment interactions. Here we extend the method for analysis of quantitative as opposed to dichotomous (e.g. disease) traits. The resulting method can be thought of as a retrospective approach, modelling genotype given trait value, in contrast to prospective approaches that model trait given genotype. Through simulations and analytical derivations, we examine the power and properties of our proposed approach, and compare it to several previously proposed single-locus methods for quantitative trait association analysis. We investigate the performance of the different methods when extended to allow analysis of haplotype, maternal genotype and parent-of-origin effects. With randomly ascertained families, with or without population stratification, the prospective approach (modeling trait value given genotype) is found to be generally most effective, although the retrospective approach has some advantages with regard to estimation and interpretability of parameter estimates when applied to selected samples.
    Genetic Epidemiology 12/2007; 31(8):813-33. DOI:10.1002/gepi.20243 · 2.60 Impact Factor
Show more


10 Reads