Of the 1.8 billion people worldwide infected with Mycobacterium tuberculosis, 5-15% will develop active tuberculosis (TB). Approximately half will progress to active TB within the first 18 months after infection, presumably because they fail to mount an effective initial immune response. Here, in a genome-wide genetic study of early TB progression, we genotype 4,002 active TB cases and their household contacts in Peru. We quantify genetic heritability (h_g^2) of early TB progression to be 21.2% (standard error 0.08). This suggests TB progression has a strong genetic basis, and is comparable to traits with well¬ established genetic bases. We identify a novel association between early TB progression and variants located in a putative enhancer region on chromosome 3q23 (rs73226617, OR=1.19; P=3.93×10-8). With in silico and in vitro analyses we identify rs73226617 or rs148722713 as the likely functional variant and ATP1B3 as a potential causal target gene with monocyte specific function.
Manuscript can be found here https://www.nature.com/articles/s41467-019-11664-1
Summary statistics is available through the NHGRI-EBI GWAS Catalog https://www.ebi.ac.uk/gwas/downloads/summary-statistics
Raw and processed RNA-sequencing data from the edited THP1 clones have been deposited in the GEO accession GSE134419 [https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE134419].
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