Natural Killer cells demonstrate distinct eQTL and transcriptome-wide disease associations, highlighting their role in autoimmunity

James J Gilchrist; Seiko Makino; Vivek Naranbhai; Piyush K Sharma; Surya Koturan; Orion Tong; Chelsea A Taylor; Robert A Watson; Alba Verge de Los Aires; Rosalin Cooper; Evelyn Lau; Sara Danielli; Dan Hameiri-Bowen; Wanseon Lee; Esther Ng; Justin Whalley; Julian C Knight; Benjamin P Fairfax

doi:10.1038/s41467-022-31626-4

Natural Killer cells demonstrate distinct eQTL and transcriptome-wide disease associations, highlighting their role in autoimmunity

Nat Commun. 2022 Jul 14;13(1):4073. doi: 10.1038/s41467-022-31626-4.

Authors

James J Gilchrist^#^{1

2

3}, Seiko Makino^#⁴, Vivek Naranbhai^#⁴, Piyush K Sharma^{5

6}, Surya Koturan^{5

6}, Orion Tong^{5

6}, Chelsea A Taylor^{5

6}, Robert A Watson^{5

6}, Alba Verge de Los Aires^{5

6}, Rosalin Cooper^{5

6}, Evelyn Lau⁴, Sara Danielli⁴, Dan Hameiri-Bowen⁴, Wanseon Lee⁴, Esther Ng⁴, Justin Whalley⁴, Julian C Knight^#^{7

8}, Benjamin P Fairfax^#^{9

10

11}

Affiliations

¹ Department of Paediatrics, University of Oxford, Oxford, UK. [email protected].
² MRC-Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK. [email protected].
³ Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK. [email protected].
⁴ Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
⁵ MRC-Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
⁶ Department of Oncology, University of Oxford, Oxford, UK.
⁷ Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK. [email protected].
⁸ Chinese Academy of Medical Science Oxford Institute, University of Oxford, Oxford, UK. [email protected].
⁹ MRC-Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK. [email protected].
¹⁰ Department of Oncology, University of Oxford, Oxford, UK. [email protected].
¹¹ NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK. [email protected].

^# Contributed equally.

Abstract

Natural Killer cells are innate lymphocytes with central roles in immunosurveillance and are implicated in autoimmune pathogenesis. The degree to which regulatory variants affect Natural Killer cell gene expression is poorly understood. Here we perform expression quantitative trait locus mapping of negatively selected Natural Killer cells from a population of healthy Europeans (n = 245). We find a significant subset of genes demonstrate expression quantitative trait loci specific to Natural Killer cells and these are highly informative of human disease, in particular autoimmunity. A Natural Killer cell transcriptome-wide association study across five common autoimmune diseases identifies further novel associations at 27 genes. In addition to these cis observations, we find novel master-regulatory regions impacting expression of trans gene networks at regions including 19q13.4, the Killer cell Immunoglobulin-like Receptor region, GNLY, MC1R and UVSSA. Our findings provide new insights into the unique biology of Natural Killer cells, demonstrating markedly different expression quantitative trait loci from other immune cells, with implications for disease mechanisms.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Autoimmune Diseases* / genetics
Autoimmunity / genetics
Carrier Proteins
Gene Expression Profiling
Genome-Wide Association Study
Humans
Killer Cells, Natural
Polymorphism, Single Nucleotide
Transcriptome*

Substances

Carrier Proteins
UVSSA protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding