Estimating gene-level false discovery probability improves eQTL statistical fine-mapping precision

Statistical fine-mapping prioritizes putative causal variants from a large number of candidate variants, and is widely used in expression quantitative loci (eQTLs) studies. In eQTL fine-mapping, the existence of causal variants for gene expression is not guaranteed, since the genetic heritability of gene expression explained by nearby (cis-) variants is limited. Here we introduce a refined fine-mapping algorithm, named Knockoff-Finemap combination (KFc). KFc estimates the probability that the causal variant(s) exist in the cis-window of a gene through construction of knockoff genotypes (i.e. a set of synthetic genotypes that resembles the original genotypes), and uses it to adjust the posterior inclusion probabilities (PIPs). Utilizing simulated gene expression data, we show that KFc results in calibrated PIP distribution with improved precision. When applied to gene expression data of 465 genotyped samples from the Japan COVID-19 Task Force (JCTF), KFc resulted in significant enrichment of a functional score as well as reporter assay hits in the top PIP bins. When combined with functional priors derived from an external fine-mapping study (GTEx), KFc resulted in a significantly higher proportion of hematopoietic trait putative causal variants in the top PIP bins. Our work presents improvements in the precision of a major fine-mapping algorithm.