Allele-Specific QTL Fine-Mapping with PLASMA

Abstract Although quantitative trait locus (QTL) associations have been identified for many molecular traits such as gene expression, it remains challenging to distinguish the causal nucleotide from nearby variants. In addition to traditional QTLs by association, allele-specific (AS) QTLs are a powerful measure of cis-regulation that are largely concordant with traditional QTLs, and can be less susceptible to technical/environmental noise. However, existing asQTL analysis methods do not produce probabilities of causality for each marker, and do not take into account correlations among markers at a locus in linkage disequilibrium (LD). We introduce PLASMA (PopuLation Allele-Specific MApping), a novel, LD-aware method that integrates QTL and asQTL information to fine-map causal regulatory variants while drawing power from both the number of individuals and the number of allelic reads per individual. We demonstrate through simulations that PLASMA successfully detects causal variants over a wide range of genetic architectures. We apply PLASMA to RNA-Seq data from 524 kidney tumor samples and show that over 17 percent of loci can be fine-mapped to within 5 causal variants, compared less than 2 percent of loci using existing QTL-based fine-mapping. PLASMA furthermore achieves a greater power at 50 samples than conventional QTL fine-mapping does at over 500 samples. Overall, PLASMA achieves a 6.9-fold reduction in median 95% credible set size compared to existing QTL-based fine-mapping. We additionally apply PLASMA to H3K27AC ChIP-Seq from 28 prostate tumor/normal samples and demonstrate that PLASMA is able to prioritize markers even at small samples, with PLASMA achieving a 1.3-fold reduction in median 95% credible set sizes over existing QTL-based fine-mapping. Variants in the PLASMA credible sets for RNA-Seq and ChIP-Seq were enriched for open chromatin and chromatin looping (respectively) at a comparable or greater degree than credible variants from existing methods, while containing far fewer markers. Our results demonstrate how integrating AS activity can substantially improve the detection of causal variants from existing molecular data and at low sample size.