Statistical Methods for Genetic Epidemiology

Environmental Health Sciences

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Abstract

Work has progressed in family-based statistical methods for studying genetic effects on qualitative and quantitative traits. We had previously developed methods for qualitative traits using genotypes for affected individuals and their parents. The loglinear approach we had proposed provides a likelihood ratio test and estimation of relative penetrances for variant alleles without requiring knowledge of the genetic model and is robust against bias due to population stratificatio. The method can incorporate parent-of-origin effects, and maternally-mediated genetic effects, and allows for the possibility that one or both parental genotypes may be missing. For early-onset conditions, grandparental genotypes can provide markedly improved statistical power. We have now extended the general approach to allow the identification of alleles related to a complex quantitative trait, and showed that our method provides improved power and robustness over analytic alternatives in widespread use. We are now extending the method to allow for multiple offspring from the same nuclear family, and we are studying potential power advantages of letting the sampling depend on the quantitative trait. For early onset disorders, or traits such as birth weight or adiposity, the prenatal environment can be particularly important and maternally-mediated genetic effects expressed during gestation can influence the phenotype of the offspring. We are extending our methods for quantitative trait analysis to allow for maternally-mediated effects, and also for gene-by-environmetn interaction. Work has also begun on methods based on genotyping of pooled DNA samples in epidemiologic studies, using case-parent designs for a qualitative trait.