Fine-mapping cellular QTLs with RASQUAL and ATAC-seq

Nat Genet. 2016 Feb;48(2):206-13. doi: 10.1038/ng.3467. Epub 2015 Dec 14.

Abstract

When cellular traits are measured using high-throughput DNA sequencing, quantitative trait loci (QTLs) manifest as fragment count differences between individuals and allelic differences within individuals. We present RASQUAL (Robust Allele-Specific Quantitation and Quality Control), a new statistical approach for association mapping that models genetic effects and accounts for biases in sequencing data using a single, probabilistic framework. RASQUAL substantially improves fine-mapping accuracy and sensitivity relative to existing methods in RNA-seq, DNase-seq and ChIP-seq data. We illustrate how RASQUAL can be used to maximize association detection by generating the first map of chromatin accessibility QTLs (caQTLs) in a European population using ATAC-seq. Despite a modest sample size, we identified 2,707 independent caQTLs (at a false discovery rate of 10%) and demonstrated how RASQUAL and ATAC-seq can provide powerful information for fine-mapping gene-regulatory variants and for linking distal regulatory elements with gene promoters. Our results highlight how combining between-individual and allele-specific genetic signals improves the functional interpretation of noncoding variation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • European Continental Ancestry Group / genetics
  • Genetics, Population
  • Genomic Imprinting
  • Genotype
  • High-Throughput Nucleotide Sequencing*
  • Humans
  • Polymorphism, Single Nucleotide
  • Quantitative Trait Loci*