Genetic Control of the Transcriptional Response to Active Tuberculosis Disease and Treatment

Abstract

Understanding the functional impact of genomic sequence variants is critical for evaluating the role of genetic variation in the host response during tuberculosis (TB) disease and anti-TB treatment (ATT). Hitherto, there have been no genome-wide in vivo response expression quantitative trait loci (reQTL) studies conducted for active TB and ATT. Here, using longitudinal peripheral blood RNA-seq data from n = 48 patients with active TB who underwent ATT, we call sequence variants directly from these transcriptomes and impute them with a multi-ancestry reference panel. Associating our variants with the expression of nearby genes, we characterise thousands of cis-eQTL and hundreds of reQTL. We further show significant changes in cell type proportions during ATT through deconvolution of the bulk RNA-seq data and identify the putative cell type specific nature of cis-eQTL. Our work sheds light on the immunogenetics of TB disease and treatment, while providing a framework for studies using only RNA-seq data.

Note:
Funding Information: J.F.O’G was supported by Research Ireland through the Research Ireland Centre for Research 1291 Training in Genomics Data Science (grant no. 18/CRT/6214). This study was also supported by 1292 Science Foundation Ireland (SFI) Investigator Programme Awards to D.E.M. and S.V.G. (grant nos. 1293 SFI/08/IN.1/B2038 and SFI/15/IA/3154), and University College Dublin (UCD) College of Health 1294 and Agricultural Sciences seed funding awarded to J.F.O’G. Note: Since the 1st of August 2024, 1295 Science Foundation Ireland (SFI) has been part of Taighde Éireann – Research Ireland 1296 (www.researchireland.ie).

Declaration of Interests: The authors declare no competing interests.

Keywords: tuberculosis, Mycobacterium tuberculosis, RNA-Seq, Deconvolution, cis-eQTL, response-eQTL, interaction-eQTL, Transcriptomics, treatment