POLARIS: Polygenic LD ‐adjusted risk score approach for set‐based analysis of GWAS data

ABSTRACT
Polygenic risk scores (PRSs) are a method to summarize the additive trait variance captured by a set of SNPs, and can increase the power of set‐based analyses by leveraging public genome‐wide association study (GWAS) datasets. PRS aims to assess the genetic liability to some phenotype on the basis of polygenic risk for the same or different phenotype estimated from independent data. We propose the application of PRSs as a set‐based method with an additional component of adjustment for linkage disequilibrium (LD), with potential extension of the PRS approach to analyze biologically meaningful SNP sets. We call this method POLARIS: POlygenic Ld‐Adjusted RIsk Score. POLARIS identifies the LD structure of SNPs using spectral decomposition of the SNP correlation matrix and replaces the individuals' SNP allele counts with LD‐adjusted dosages. Using a raw genotype dataset together with SNP effect sizes from a second independent dataset, POLARIS can be used for set‐based analysis. MAGMA is an alternative set‐based approach employing principal component analysis to account for LD between markers in a raw genotype dataset. We used simulations, both with simple constructed and real LD‐structure, to compare the power of these methods. POLARIS shows more power than MAGMA applied to the raw genotype dataset only, but less or comparable power to combined analysis of both datasets. POLARIS has the advantages that it produces a risk score per person per set using all ...

Source: Genetic Epidemiology - March 1, 2018 Category: Epidemiology Authors: Emily Baker, Karl Michael Schmidt, Rebecca Sims, Michael C. O'Donovan, Julie Williams, Peter Holmans, Valentina Escott ‐Price, with the GERAD Consortium Tags: RESEARCH ARTICLE Source Type: research