A Fast Method that Uses Polygenic Scores to Estimate the Variance Explained by Genome-wide Marker Panels and the Proportion of Variants Affecting a Trait.

Palla, L. Dudbridge, F. 
Am J Hum Genet, 2015, Aug 6;97(2):250-9.

Several methods have been proposed to estimate the variance in disease liability explained by large sets of genetic markers. However, current methods do not scale up well to large sample sizes. Linear mixed models require solving high-dimensional matrix equations, and methods that use polygenic scores are very computationally intensive. Here we propose a fast analytic method that uses polygenic scores, based on the formula for the non-centrality parameter of the association test of the score. We estimate model parameters from the results of multiple polygenic score tests based on markers with p values in different intervals. We estimate parameters by maximum likelihood and use profile likelihood to compute confidence intervals. We compare various options for constructing polygenic scores, based on nested or disjoint intervals of p values, weighted or unweighted effect sizes, and different numbers of intervals, in estimating the variance explained by a set of markers, the proportion of markers with effects, and the genetic covariance between a pair of traits. Our method provides nearly unbiased estimates and confidence intervals with good coverage, although estimation of the variance is less reliable when jointly estimated with the covariance. We find that disjoint p value intervals perform better than nested intervals, but the weighting did not affect our results. A particular advantage of our method is that it can be applied to summary statistics from single markers, and so can be quickly applied to large consortium datasets. Our method, named AVENGEME (Additive Variance Explained and Number of Genetic Effects Method of Estimation), is implemented in R software.