Genetic architecture of tuberculosis susceptibility: A comprehensive research synopsis, meta-analyses, and epidemiological evidence.

To date, many studies have been conducted to investigate associations between variants and tuberculosis risk; however, the results have been inconclusive. Here, we systematically provide a summary of the understanding of the genetic architecture of tuberculosis susceptibility. We searched PubMed, Embase and Web of Science to identify genetic association studies of tuberculosis published through October 31, 2021. We conducted meta-analyses for the genetic association with tuberculosis risk. We graded levels of cumulative epidemiological evidence of significant associations with risk of tuberculosis and false-positive report probability tests. We performed functional annotations for these variants using data from the Encyclopedia of DNA Elements (ENCODE) Project and other databases. We identified 703 eligible articles comprising 298,074 cases and 879,593 controls through screening a total of 24,398 citations. Meta-analyses were conducted for 614 genetic variants in 469 genes or loci. We found 39 variants that were nominally significantly associated with tuberculosis risk. Cumulative epidemiological evidence for a significant association was graded strong for 9 variants in or near 9 genes. Among them, 5 variants were associated with tuberculosis risk in at least three main ethnicity (African, Asian and White) which together explained approximately 9.59% of the familial relative risk of tuberculosis. Data from ENCODE and other databases suggested that 8 of these 9 genetic variants with strong evidence might fall within putative functional regions. Our study summarizes the current literature on the genetic architecture of tuberculosis susceptibility and provides useful data for designing future studies to investigate the genetic association with tuberculosis risk.