Accuracy of predicting the genetic risk of disease using a genome-wide approach

Abstract

Background: The prediction of the genetic disease risk of an individual is a powerful public health tool. While predicting risk has been successful in diseases which follow simple Mendelian inheritance, it has proven challenging in complex diseases for which a large number of loci contribute to the genetic variance. The large numbers of single nucleotide polymorphisms now available provide new opportunities for predicting genetic risk of complex diseases with high accuracy.

Methodology/principal findings: We have derived simple deterministic formulae to predict the accuracy of predicted genetic risk from population or case control studies using a genome-wide approach and assuming a dichotomous disease phenotype with an underlying continuous liability. We show that the prediction equations are special cases of the more general problem of predicting the accuracy of estimates of genetic values of a continuous phenotype. Our predictive equations are responsive to all parameters that affect accuracy and they are independent of allele frequency and effect distributions. Deterministic prediction errors when tested by simulation were generally small. The common link among the expressions for accuracy is that they are best summarized as the product of the ratio of number of phenotypic records per number of risk loci and the observed heritability.

Conclusions/significance: This study advances the understanding of the relative power of case control and population studies of disease. The predictions represent an upper bound of accuracy which may be achievable with improved effect estimation methods. The formulae derived will help researchers determine an appropriate sample size to attain a certain accuracy when predicting genetic risk.

Figure 1. Predicted accuracy of estimated genetic values of a continuous phenotype.

Predicted accuracy of estimated additive genetic values of a continuous phenotype as a function of observed heritability and number of phenotypes per genotype tested, λ = 0.02, 0.1, 0.5, 1, 2, 5, 10 and 20 from minimum to maximum accuracy respectively.

Figure 2. Predicted accuracy of estimated genetic risk from population and case control designs of a dichotomous phenotype.

Contour plot of predicted accuracy for varied prevalence and additive heritability on the observed scale, in population studies (dashed vertical line) and case control studies (solid line) of dichotomous phenotypes. Each contour represents a line of constant accuracy, starting from the right 0.9, 0.8, 0.7, and 0.6. The narrowly dashed line is derived from Equation (5) with , so values below this line are not possible under the liability model.