title: Effective genetic-risk prediction using mixed models.
abstract: For predicting genetic risk, we propose a statistical approach that is specifically adapted to dealing with the challenges imposed by disease phenotypes and case-control sampling. Our approach (termed Genetic Risk Scores Inference [GeRSI]), combines the power of fixed-effects models (which estimate and aggregate the effects of single SNPs) and random-effects models (which rely primarily on whole-genome similarities between individuals) within the framework of the widely used liability-threshold model. We demonstrate in extensive simulation that GeRSI produces predictions that are consistently superior to current state-of-the-art approaches. When applying GeRSI to seven phenotypes from the Wellcome Trust Case Control Consortium (WTCCC) study, we confirm that the use of random effects is most beneficial for diseases that are known to be highly polygenic: hypertension (HT) and bipolar disorder (BD). For HT, there are no significant associations in the WTCCC data. The fixed-effects model yields an area under the ROC curve (AUC) of 54%, whereas GeRSI improves it to 59%. For BD, using GeRSI improves the AUC from 55% to 62%. For individuals ranked at the top 10% of BD risk predictions, using GeRSI substantially increases the BD relative risk from 1.4 to 2.5.
authors.affiliation: Department of Statistics, Tel Aviv University, Tel Aviv 69978, Israel. Electronic address: golandavid@gmail.com.
authors.forename: David
authors.initials: D
authors.lastname: Golan
authors.affiliation: Department of Statistics, Tel Aviv University, Tel Aviv 69978, Israel. Electronic address: saharon@post.tau.ac.il.
authors.forename: Saharon
authors.initials: S
authors.lastname: Rosset
mesh_terms: D016022:Case-Control Studies; D019295:Computational Biology; D004194:Disease / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D015233:Models, Statistical; D020412:Multifactorial Inheritance / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D018570:Risk Assessment