Allele-Specific QTL Fine Mapping with PLASMA

Am J Hum Genet. 2020 Feb 6;106(2):170-187. doi: 10.1016/j.ajhg.2019.12.011. Epub 2020 Jan 30.


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 concordant with traditional QTLs but typically less susceptible to technical/environmental noise. However, existing methods for estimating causal variant probabilities (i.e., fine mapping) cannot produce valid estimates from asQTL signals due to complexities in linkage disequilibrium (LD). We introduce PLASMA (Population Allele-Specific Mapping), a fine-mapping method that integrates QTL and asQTL information to improve accuracy. In simulations, PLASMA accurately prioritizes causal variants over a wide range of genetic architectures. Applied to RNA-seq data from 524 kidney tumor samples, PLASMA achieves a greater power at 50 samples than conventional QTL-based fine mapping at 500 samples, with more than 17% of loci fine mapped to within five causal variants, compared to 2% by QTL-based fine mapping, and a 6.9-fold overall reduction in median credible set size compared to QTL-based fine mapping when applied to H3K27AC ChIP-seq from just 28 prostate tumor/normal samples. 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.

Keywords: ChIP-seq; QTL; RNA-seq; allele-specific; causal variant; cis-regulation; fine-mapping; gene regulation; regulatory variant.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms*
  • Allelic Imbalance*
  • Biomarkers, Tumor / genetics*
  • Chromosome Mapping / methods*
  • Computer Simulation
  • Data Interpretation, Statistical
  • Humans
  • Kidney Neoplasms / genetics*
  • Kidney Neoplasms / pathology
  • Linkage Disequilibrium
  • Male
  • Phenotype
  • Polymorphism, Single Nucleotide
  • Prostatic Neoplasms / genetics*
  • Prostatic Neoplasms / pathology
  • Quantitative Trait Loci*


  • Biomarkers, Tumor