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
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.
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"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.
Full-text · Article · Mar 2011 · American Journal of Medical Genetics Part B Neuropsychiatric Genetics
"This is a strong assumption, and one that is unrealistic in the presence of population substructure. A series of papers (Kistner and Weinberg, 2004; Kistner et al., 2006; Umbach and Weinberg, 2000; Weinberg, 1999; Weinberg et al., 1998) describes an extension of the multinomial model to the Poisson that allows the incorporation of methods for testing for parental imprinting, gene–environment interaction , and quantitative phenotypes. Rather than score tests, these authors use likelihood ratio tests. "
[Show abstract][Hide abstract]ABSTRACT: Traditional epidemiological study concepts such as case-control or cohort designs can be used in the design of genetic association studies, giving them a prominent role in genetic association analysis. A different class of designs based on related individuals, typically families, uses the concept of Mendelian transmission to achieve design-independent randomization, which permits the testing of linkage and association. Family-based designs require specialized analytic methods but they have distinct advantages: They are robust to confounding and variance inflation, which can arise in standard designs in the presence of population substructure; they test for both linkage and association; and they offer a natural solution to the multiple comparison problem. This chapter focuses on family-based designs. We describe some basic study designs as well as general approaches to analysis for qualitative, quantitative, and complex traits. Finally, we review available software.
Preview · Article · Feb 2008 · Advances in genetics
"The QCEPG and QTDT M methods were implemented in Stata. For Kistner and Weinberg's approach [Kistner et al., 2006], the SAS macro provided at http://dir.niehs.nih.gov/dirbb/ weinbergfiles/qpl.htm was used. "
[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.
Full-text · Article · Dec 2007 · Genetic Epidemiology