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

• Published in: Nature communications 2022-07, Vol.13 (1), p.4073-4073, Article 4073
• Main Authors: Gilchrist, James J., Makino, Seiko, Naranbhai, Vivek, Sharma, Piyush K., Koturan, Surya, Tong, Orion, Taylor, Chelsea A., Watson, Robert A., de los Aires, Alba Verge, Cooper, Rosalin, Lau, Evelyn, Danielli, Sara, Hameiri-Bowen, Dan, Lee, Wanseon, Ng, Esther, Whalley, Justin, Knight, Julian C., Fairfax, Benjamin P.
• Format: Article
• Language: English
• Subjects: 631/208/200; 631/208/248/144; 631/208/480; 631/250/262; Antiviral agents; Autoimmune diseases; Autoimmunity; Disease; Gene expression; Gene mapping; Genes; Genetic diversity; Humanities and Social Sciences; Immune system; Immunosurveillance; Lymphocytes; multidisciplinary; Natural killer cells; Pathogenesis; Quantitative trait loci; Regulatory sequences; Science; Science (multidisciplinary); Transcriptomes; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-31626-4

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. Natural Killer cells are key mediators of anti-tumour immunosurveillance and anti-viral immunity. Here, the authors map regulatory genetic variation in primary Natural Killer cells, providing new insights into their role in human health and disease.