title: Local True Discovery Rate Weighted Polygenic Scores Using GWAS Summary Data.
abstract: A polygenic score is commonly derived using genome-wide genotype data to summarize the genetic contribution to a particular disease at the individual level. Usually it is constructed as a linear combination of SNP genotype weighted by the SNP-wise regression coefficient of the SNP to the phenotype using SNPs with p values smaller than a particular threshold. Commonly a range of thresholds are used which can pose problems with multiple comparisons as well as over-fitting. Here, an alternative weighting scheme is proposed, making use of the local true discovery rate, estimated from summary statistics. Two methods of estimation are proposed-maximum likelihood and kernel density estimation. Simulation studies using real and artificial data suggest this new weighting scheme is highly comparable with standard polygenic scores using the best possible p value threshold in prediction, even though this threshold is not normally known in practice.
authors.affiliation: Centre for Genomic Sciences, University of Hong Kong, 5 Sassoon Road, Hong Kong, China.
authors.forename: Timothy Shin Heng
authors.initials: TS
authors.lastname: Mak
authors.affiliation: Department of Psychiatry, University of Hong Kong, Hong Kong, China.
authors.forename: Johnny Sheung Him
authors.initials: JS
authors.lastname: Kwan
authors.affiliation: Department of Psychiatry, University of Hong Kong, Hong Kong, China.
authors.forename: Desmond Dedalus
authors.initials: DD
authors.lastname: Campbell
authors.affiliation: Centre for Genomic Sciences, University of Hong Kong, 5 Sassoon Road, Hong Kong, China. pcsham@hku.hk.|Department of Psychiatry, University of Hong Kong, Hong Kong, China. pcsham@hku.hk.|State Key Laboratory of Brain and Cognitive Sciences, University of Hong Kong, Hong Kong, China. pcsham@hku.hk.
authors.forename: Pak Chung
authors.initials: PC
authors.lastname: Sham
mesh_terms: D019540:Area Under Curve; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D016013:Likelihood Functions; D020412:Multifactorial Inheritance / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics
keywords: Genome wide association studies; Local false discovery rate; Polygenic score; Risk prediction