Genetic links to tuberculosis uncovered in Brazil

Tuberculosis remains a major global health challenge, and scientists have long suspected that a person’s genes influence their risk of developing the disease. Past genome-wide association studies (GWAS) have struggled to find clear causal variants that apply across different populations. In new work led by corresponding author Kimberly A. Dill‐McFarland, researchers turned to a careful, population-specific approach to look for genetic susceptibility to pulmonary tuberculosis (PTB). They combined low-pass whole genome sequencing (lpWGS) with imputation, thorough epidemiologic data, and single-cell analyses to get a richer view of risk. Their study used participants in the Regional Prospective Observational Research in TB (RePORT) study in Brazil, comparing 947 pulmonary tuberculosis (PTB) cases and 1807 close contact controls. Using these data they estimated PTB heritability at 47.7%, meaning nearly half of the variation in who got PTB in this sample could be attributed to genetic differences. By focusing on both genetic sequences and the people’s clinical and exposure histories, the team aimed to overcome limitations that have hampered earlier GWAS efforts.

To search for specific genetic signals the team used lpWGS with imputation and adjusted their analyses for major epidemiologic risk factors including HIV, diabetes, and smoking. They also paired the genetic study with single-cell expression quantitative loci (sceQTL) analysis, which links genetic variants to gene activity in individual immune cells. In this Brazilian sample the researchers identified 19 SNPs associated with PTB at genome-wide significance (P<5E-8) after accounting for the listed risk factors. Of those, seven SNPs were associated with peripheral blood cell-specific sceQTLs in the control group, indicating these variants influence baseline gene expression in particular immune cell types. Notably, some of the implicated SNPs are cis to the transcription factors ZNF717 and MAML3, and those SNPs were associated with PTB disease as well as gene expression changes in monocytes, T cells, or B cells. By combining lpWGS, in-depth epidemiology, and single-cell transcriptomics the study detected population-specific genetic risk factors for PTB in Brazil.

The findings suggest that genetic variation can shape a person’s baseline immune cell behavior in ways that influence tuberculosis risk. Because several of the PTB-associated SNPs affect expression of transcription factors such as ZNF717 and MAML3 in specific immune cell types, the study offers a biological link between inherited DNA differences and how immune cells are primed before infection. Importantly, the research shows that robust correction for known tuberculosis risk factors in GWAS — paired with single-cell transcriptomics — can reveal genetic signals that might be missed in broader, cross-population studies. While these results are specific to the Brazilian RePORT cohort, they provide a model for how lpWGS, imputation, and sceQTL analysis can be combined to uncover genetic contributors to infectious disease. Future work can build on these population-specific discoveries to deepen understanding of host-pathogen interactions and to guide more targeted research in other settings.