Early progression to active tuberculosis is a highly heritable trait driven by 3q23 in Peruvians

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 4002 active TB cases and their household contacts in Peru. We quantify genetic heritability ( $${\it{h}}_{\it{g}}^2$$ ) 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 = 1.18; 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. Between 5 and 15% of latent Mycobacterium tuberculosis infections develop into active tuberculosis (TB). Here, Luo et al. report a genome-wide association study for early TB progression in a total of 4002 active TB cases and their household contacts in Peru and they identify a locus on 3q23 in which ATP1B3 is mapped as the likely causal gene.