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Genetics of gene expression in primary immune cells identifies cell type–specific master regulators and roles of HLA alleles

Nature Genetics volume 44, pages 502–510 (2012)Cite this article

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Abstract

Trans-acting genetic variants have a substantial, albeit poorly characterized, role in the heritable determination of gene expression. Using paired purified primary monocytes and B cells, we identify new predominantly cell type–specific cis and trans expression quantitative trait loci (eQTLs), including multi-locus trans associations to LYZ and KLF4 in monocytes and B cells, respectively. Additionally, we observe a B cell–specific trans association of rs11171739 at 12q13.2, a known autoimmune disease locus, with IP6K2 (P = 5.8 × 10−15), PRIC285 (P = 3.0 × 10−10) and an upstream region of CDKN1A (P = 2 × 10−52), suggesting roles for cell cycle regulation and peroxisome proliferator-activated receptor γ (PPARγ) signaling in autoimmune pathogenesis. We also find that specific human leukocyte antigen (HLA) alleles form trans associations with the expression of AOAH and ARHGAP24 in monocytes but not in B cells. In summary, we show that mapping gene expression in defined primary cell populations identifies new cell type–specific trans-regulated networks and provides insights into the genetic basis of disease susceptibility.

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Figure 1: Shared and cell type–specific cis and trans associations in B cells and monocytes.
Figure 2: eSNPs shared between cell types may lead to opposing directional effects on gene expression or associate with expression of different genes in a cell type–specific manner.
Figure 3: rs10784774 marks a monocyte-specific cis eSNP to LYZ and constitutes a monocyte-specific master regulator of multiple genes, including CREB1.
Figure 4: rs11171739, a SNP at 12q13.2 with strong autoimmune association, is a B cell–specific trans eQTL to three genes.
Figure 5: Imputation of HLA status resolves cell type–specific trans-associated gene expression to the carriage of specific HLA alleles.
Figure 6: Cell type–specific cis eQTLs involve disease-associated SNP markers.

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  • 11 April 2012

    In the version of this article initially published online, the legend to Figure 6 included an incorrect reference to celiac disease. The correct reference should be to Crohn's disease. The error has been corrected for the print, PDF and HTML versions of this article.

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Acknowledgements

We are very grateful to all the volunteers who participated in this study, together with members of the Knight laboratory and A. Hill for their support. We thank A. Auton for his assistance in the identification of probes containing SNPs with European MAF of >0.01% using the 1000 Genomes Project data set and to J. Broxholme for bioinformatic support and mapping of all probes to the reference sequence. We thank G. Gibson, A. Hill and colleagues for critical reading of the manuscript and helpful suggestions. This work was supported by the Wellcome Trust (074318 to J.C.K., 088891 to B.P.F. and 075491/Z/04 to the core facilities at the Wellcome Trust Centre for Human Genetics), the European Research Council under the European Union's Seventh Framework Programme (FP7/2007-2013) (281824 to J.C.K.) and the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre.

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Authors and Affiliations

  1. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK

    Benjamin P Fairfax, Seiko Makino, Jayachandran Radhakrishnan, Katharine Plant, Fredrik O Vannberg & Julian C Knight

  2. Department of Oncology, University of Oxford, Oxford, UK

    Stephen Leslie

  3. Department of Statistics, University of Oxford, Oxford, UK

    Alexander Dilthey

  4. Wellcome Trust Sanger Institute, University of Cambridge, Cambridge, UK

    Peter Ellis & Cordelia Langford

  5. School of Biology, Georgia Institute of Technology, Atlanta, Georgia, USA

    Fredrik O Vannberg

Authors
  1. Benjamin P Fairfax
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Contributions

B.P.F. and J.C.K. conceived, designed and initiated the study. B.P.F., J.C.K., K.P. and S.M. established the volunteer cohort and sample collection. B.P.F., K.P., P.E. and S.M. performed the experimental work. B.P.F., J.C.K., J.R. and S.M. analyzed the data. C.L., F.O.V. and S.L. contributed reagents and expertise. A.D. and S.L. performed the HLA imputation. B.P.F. and J.C.K. wrote the paper, with contributions to manuscript editing from other authors. All authors read and approved the manuscript before submission.

Corresponding authors

Correspondence to Benjamin P Fairfax or Julian C Knight.

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Supplementary information

Supplementary Text and Figures

Supplementary Note and Supplementary Figures 1–15 (PDF 12223 kb)

Supplementary Table 1

Cis-eQTL listed by eSNP and cell type (XLS 43358 kb)

Supplementary Table 2

Trans-eQTL listed by eSNP and cell type (XLS 474 kb)

Supplementary Table 3

Summary of cis-eQTL at different significance thresholds (XLS 31 kb)

Supplementary Table 4

Directional eQTL (XLS 49 kb)

Supplementary Table 5

Correlation analysis of gene expression for genes involved in LYZ trans-eQTL (XLS 10363 kb)

Supplementary Table 6

Relationship between GWAS marker SNPs and observed eQTL in B cells and monocytes (XLS 2110 kb)

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Fairfax, B., Makino, S., Radhakrishnan, J. et al. Genetics of gene expression in primary immune cells identifies cell type–specific master regulators and roles of HLA alleles. Nat Genet 44, 502–510 (2012). https://doi.org/10.1038/ng.2205

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