Genetic Epidemiology 17(Suppl 1): S169-S173 (1999)
An Empirical Test of the Significance of an
Observed Quantitative Trait Locus Effect
that Preserves Additive Genetic Variation
Stephen J. Iturria, Jeff T. Williams, Laura Almasy, Thomas D. Dyer, and John
Department of Genetics, Southwest Foundation for Biomedicai Research, San
We propose a constrained permutation test that assesses the significance of an observed
quantitative trait locus effect against a background of genetic and environmental vari
ation. Permutations of phenotypes are not selected at random, but rather are chosen
in a manner that attempts to maintain the additive genetic variability in phenotypes.
Such a constraint maintains the nonindependence among observations under the null
hypothesis of no linkage. The empirical distribution of the lod scores calculated using
permuted phenotypes is compared to that obtained using phenotypes simulated from
the assumed underlying multivariate normal model. We make comparisons of uni-
variate analyses for both a quantitative phenotype that appears consistent with a mul
tivariate normal model and a quantitative phenotype containing pronounced outliers.
An example of a bivariate analysis is also presented. ® 1999 Wiley-Liss, Inc.
Key words: permutation test, power, quantitative trait locus, statistical genetics
Consider the random effects model for phenotypic variation in which the quantitative
phenotype of an individual, y, is determined as
2/ = μ + 7 + 3 + ε,
where μ is the population mean phenotype, 7 is the effect due to a single quantitative trait
locus (QTL), g is a background polygenic effect, and e is a random environmental effect.
Address reprint requests to Dr. Stephen J. Iturria, Department of Genetics, Southwest Foundation for
Biomedicai Research, 7620 NW Loop 410, P.O. Box 760549, San Antonio, TX 78245-0549.
1999 Wiley-Liss, Inc.