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Fine-mapping cellular QTLs with RASQUAL and ATAC-seq

A Corrigendum to this article was published on 29 March 2016

This article has been updated


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.

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Figure 1: Schematic of the RASQUAL approach.
Figure 2: Comparing between-individual only, allele-specific only and combined models.
Figure 3: Comparison of RASQUAL with CHT, TReCASE and simple linear regression of log-transformed, principal component–corrected FPKM values.
Figure 4: ATAC-QTL mapping with RASQUAL.
Figure 5: Enrichment of caQTLs and multi-peak caQTLs for SNPs associated with other cellular and organismal traits from GWAS.

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European Nucleotide Archive

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European Nucleotide Archive

Gene Expression Omnibus

Change history

  • 08 February 2016

    In the version of this article initially published, the accession code for the ATAC-seq data was omitted. These data have been deposited in the European Nucleotide Archive under accession ERP011141. The error has been corrected in the HTML and PDF versions of the article.


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We thank O. Stegle, M. Hemberg, G. Trynka and the three anonymous reviewers for their helpful comments. N.K., A.J.K. and D.J.G. were funded by Wellcome Trust grant 098051.

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Authors and Affiliations



D.J.G. and N.K. conceived and designed the experiments. N.K. and A.J.K. performed the experiments. N.K. performed statistical analysis and analyzed the data. N.K. and A.J.K. contributed reagents, materials and analysis tools. D.J.G., N.K. and A.J.K. wrote the manuscript.

Corresponding authors

Correspondence to Natsuhiko Kumasaka or Daniel J Gaffney.

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The authors declare no competing financial interests.

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Supplementary Figures 1–30, Supplementary Tables 1–4 and Supplementary Note. (PDF 9239 kb)

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Kumasaka, N., Knights, A. & Gaffney, D. Fine-mapping cellular QTLs with RASQUAL and ATAC-seq. Nat Genet 48, 206–213 (2016).

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