eQTLs identify regulatory networks and drivers of variation in the individual response to sepsis
Katie L. Burnham, Nikhil Milind, Wanseon Lee, Andrew Kwok, Kiki Cano-Gamez, Yuxin Mi, Cyndi G. Geoghegan, Ping Zhang, Jenni Addison, Helen F. Galley, Sally Hall, Siân Roughton, Jane R. Taylor, Heather Tennant, Nigel R. Webster, Achyut Guleri, Natalia Waddington, Dilshan Arawwawala, John Durcan, Christine Mitchell-Inwang, Alasdair Short, Susan Smolen, Karen Swan, Sarah Williams, Emily Errington, Tony Gordon, Maie Templeton, Marie McCauley, Pyda Venatesh, Geraldine Ward, Simon Baudouin, Sally Grier, Elaine Hall, Charley Higham, Jasmeet Soar, Stephen J. Brett, David H. Kitson, Juan C. Moreno, Laura Mountford, Robert B. Wilson, Peter S Hall, Jackie Hewlett, Stuart McKechnie, Roser Faras-Arraya, Christopher S. Garrard, Paula Hutton, Julian Millo, Penny Parsons, Alex Smiths, Duncan Young, Parizade Raymode, Jasmeet Soar, Prem Andreou, Sarah Bowrey, Dawn Hales, Sandra Kazembe, Natalie Rich, Emma A. Roberts, Jonathan P. Thompson, Simon P. Fletcher, Georgina Glister, Melissa Rosbergen, Jeronimo Cuesta, Julian Bion, Ronald Carrera, Sarah Lees, Joanne Millar, Natalie Mitchell, Annette Nilson, Elsa Jane Perry, Sebastian Ruel, Jude Wilde, Heather Willis, Jane C. Atkinson, Abby Brown, Nicola Jacques, Atul Kapila, Heather Prowse, Martin Bland, Lynne Bullock, Donna Harrison, Anton Krige, Gary Mills, John Humphreys, Kelsey Armitage, Shond Laha, Jacqueline Baldwin, Angela Walsh, Nicola Doherty, Stephen Drage, Laura Ortiz-Ruiz de Gordoa, Sarah Lowes, Charley Higham, Helen Walsh, Verity Calder, Catherine Swan, Heather Payne, David Higgins, Sarah F. Andrews, Sarah Mappleback
Abstract
Sepsis is a clinical syndrome of life-threatening organ dysfunction caused by a dysregulated response to infection, for which disease heterogeneity is a major obstacle to developing targeted treatments. We have previously identified gene-expression-based patient subgroups (sepsis response signatures [SRS]) informative for outcome and underlying pathophysiology. Here, we aimed to investigate the role of genetic variation in determining the host transcriptomic response and to delineate regulatory networks underlying SRS. Using genotyping and RNA-sequencing data on 638 adult sepsis patients, we report 16,049 independent expression (eQTLs) and 32 co-expression module (modQTLs) quantitative trait loci in this disease context. We identified significant interactions between SRS and genotype for 1,578 SNP-gene pairs and combined transcription factor (TF) binding site information (SNP2TFBS) and predicted regulon activity (DoRothEA) to identify candidate upstream regulators. Overall, these approaches identified putative mechanistic links between host genetic variation, cell subtypes, and the individual transcriptomic response to infection.